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Hepatopulmonary Fascioliasis Presenting with Lung Abscess: A Case Report and Literature Review
Abstract Introduction: Fascioliasis is a rare food-borne parasitic infection primarily of the hepatobiliary system caused by Fasciola hepatica. The liver is the principal site of infection, and involvement of other organs is infrequent. This report presents a rare case of fascioliasis associated with a lung abscess. Case presentation: A 37-year-old female presented with abdominal pain and hematochezia. General examination was normal. Computed tomography (CT) scan showed multiple hypodense liver lesions with peripheral enhancement, with moderate left pleural effusion and a left lower lobe cavitary lesion. Ultrasonography (US) showed cystic liver lesions with curvilinear tracts. She underwent VATS (Video-assisted thoracic surgery) wedge resection of the left lower lobe cavitary lesion. She then received triclabendazole (TCBZ). Follow-up US showed new liver lesions, so a second course of TCBZ was given. Subsequently, the patient improved and was asymptomatic at the last follow-up. Literature review: A review of seven reported cases of fascioliasis between 2013 and 2024 was performed, of which only two cases had pulmonary involvement. Five patients were females (71.43%), with a mean age of approximately 45 years (range: late 20s-58 years). The most prevalent presentation was fever in five cases (71.43%). Eosinophilia was present in six cases (85.71%). On clinical examination, abdominal tenderness was noted in three patients (42.86%). Management was exclusively conservative in six cases (85.71%). Conclusion: This report highlights the diagnostic challenges of fascioliasis with extrahepatic involvement. Pulmonary findings require careful evaluation, and clinicians should maintain a high index of suspicion for ectopic fascioliasis, even without definitive parasitological confirmation. Introduction Fascioliasis is a rare food-borne parasitic infection affecting primarily the hepatobiliary system, caused by the digenean flatworms, Fasciola hepatica (F. hepatica) or Fasciola gigantica (F. gigantica), commonly known as liver flukes [1,2]. Fasciola gigantica is predominantly found in tropical regions, whereas F. hepatica thrives in temperate climates. Both species parasitize a wide range of herbivorous animals, with their larval stages residing on aquatic plants. Human infection most frequently occurs through the consumption of vegetation, such as watercress, that has been contaminated with metacercariae [1]. Cattle and sheep serve as the primary definitive hosts, placing individuals in livestock farming communities and those consuming raw aquatic vegetation at the greatest risk [1,2]. The main risk factors for human infection include ingestion of contaminated plants or water and consumption of undercooked infected animal liver [3]. Ectopic fascioliasis is an infection occurring outside the hepatobiliary system [1]. Although F. hepatica predominantly affects the liver, involvement of other organs has been documented in rare instances [4]. Pulmonary involvement, including lung abscess formation, represents a rare ectopic manifestation [5]. This report presents a rare case of fascioliasis with pulmonary manifestation. The report was prepared in accordance with the CaReL guidelines, and all referenced sources were critically assessed for reliability [6,7] Case presentation Patient information A 37-year-old female presented with abdominal pain for three months, mainly postprandial epigastric pain, associated with weight loss. She also had occasional hematochezia and night sweats, along with a one-week history of hemoptysis. There was no travel history. There was a history of heavy consumption of watercress (Nasturtium officinale). Past medical history included a possible thrombotic event during pregnancy. Clinical findings General examination was unremarkable. During the course of illness, she developed urticaria and an anaphylactic reaction characterized by shortness of breath, along with mild abdominal discomfort. Diagnostic assessments Laboratory investigations revealed leukocytosis 11.7 × 10^9/L (normal range: 3.4–9.6 ×10^9/L) and eosinophilia 13% (normal range: 1% to 6%), suggesting an active inflammatory or parasitic process. Thrombocytosis was also noted 494 x10^9/L (normal range: 157–371 ×10^9/L). Inflammatory and biochemical markers were elevated, including C-reactive protein (CRP) 16.9 mg/L (normal range: below 3.0 mg/L). Additionally, the CA-125 level was 55.0 U/mL (normal range: 0–35 U/mL). Renal function remained normal (Table 1). Computed Tomography (CT) scan of chest, abdomen, and pelvis showed multiple hypodense liver lesions with peripheral enhancement, suggestive of infection, mostly fascioliasis, with moderate left pleural effusion and a left lower lobe cavitary lesion suggestive of a lung abscess with possible rupture into the pleural space (Figure 1). Ultrasonography (US) showed cystic liver lesions with curvilinear tracts in keeping with fascioliasis. Fasciola hepatica serology was positive, while hydatid serology, pleural fluid culture, and the acid-fast bacilli tests were negative. Table 1. Summary of the findings of the laboratory tests performed for the patient. Test category Result Normal range WBC count 11.7 × 10^9/L 3.4–9.6 ×10^9/L Eosinophil 13.00% 1% to 6% Platelet 494 × 10^9/L 157–371 ×10^9/L Creatinine 0.625 mg/dL 0.6-1.1 mg/dL CRP 16.9 mg/L below 3.0 mg/L LDH 257 IU/L 105–233 IU/L CA-125 55.0 U/mL 0–35 U/mL WBC: White blood cell, CRP: C-reactive protein, LDH: Lactate dehydrogenase, CA: Cancer antigen <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-96096880511782042527513.jpg" alt="Figure 1. A) Chest CT scan with IV (intravenous) contrast axial section cavity with air bubble “green arrow” inside collapsed basal segments of left lower lobe, associated with marked left pleural effusion, suggesting lung abscess with possible rupture to pleural cavity B) Abdominal CT with IV contrast axial section, showing intrahepatic loculated collection “white arrow”, tortuous linear hypodensities “yellow arrow” which is migrating fasciola inside liver parenchyma known as furrow sign. " width="2322" height="1239" /> Therapeutic intervention Medical therapy was considered; however, due to the thick-walled nature of the lesion and the uncertainty regarding the underlying diagnosis, and the possibility of the condition not responding adequately to conservative treatment, surgical management was preferred. She underwent VATS (Video-assisted thoracic surgery) wedge resection of the left lower lobe cavitary lesion. Postoperatively, she was treated with triclabendazole (TCBZ). Histopathological examination of the lung wedge specimen demonstrated pyogenic necrotizing inflammation with abscess formation, no malignancy, and no identifiable Fasciola eggs, larvae, or parasites. Follow-up and outcomes Follow-up US showed new liver lesions consistent with ongoing fascioliasis, for which a second course of TCBZ was administered. At the two-week postoperative follow-up, the patient had improved and was asymptomatic. Discussion Fascioliasis presents with variable manifestations depending on the disease phase, with the chronic stage often being asymptomatic. It is frequently misdiagnosed as other hepatobiliary conditions, particularly metastatic liver disease [2]. Delayed or misdiagnosis is still frequent because the disease is rarely encountered in nonendemic areas and its clinical presentation is non-specific. The history of recent travel to endemic zones should be considered when consistent radiological findings are suggestive of infection [2]. Fascioliasis involves two distinct phases: an acute stage characterized by larval migration through the liver parenchyma, and a chronic phase where mature flukes reside in the bile ducts. These flukes can survive in the biliary ducts for many years and may cause biliary inflammation and/or obstruction [8]. In rare cases, the parasites may migrate beyond the hepatobiliary system and involve other organs, including the lungs, with F. hepatica more commonly associated with ectopic infection [5,9]. A review of the literature on Google Scholar was conducted. Seven reported cases from 2013 to 2024 were reviewed, of which only two cases had pulmonary involvement. Five patients were females (71.43%), and two were males (28.57%), with a mean age of approximately 45 years (range: late 20s-58 years). The most prevalent presentations were fever in five cases (71.43%) and abdominal pain in four cases (57.14%). Eosinophilia was present in six cases (85.71%). On clinical examination, abdominal tenderness was noted in three patients (42.86%). Imaging findings included US in three cases (42.86%), chest X-ray in two cases (28.57%), CT scan in five cases (71.43%), and MRI (magnetic resonance imaging) in four cases (57.14%). Management was exclusively conservative in six cases (85.71%), with one case combining conservative and surgical approaches (14.29%). Follow-up showed clinical improvement in five cases (71.43%), complete cure in one case (14.29%), and no available data in one case (14.29%) (Table 2) [2,3,5,8,10–12]. Table 2. Summary of fascioliasis reported cases. Author/Reference Year No. of Patients Sex Age Presentation Clinical findings Diagnostic Technique Management & Treatment Follow-up & Outcome Salahshour & Tajmalzai [2] 2021 1 F 35 RUQ pain, fever, fatigue, and anorexia. RUQ tenderness, eosinophilia, slightly raised CRP CT scan, MRI, and ELISA. TCBZ Clinical improvement Matin et al. [10] 2022 1 F 38 Fever, RUQ pain, chills, non-productive coughs, anorexia, and nausea Tenderness in the RUQ, eosinophilia US, CT scan, ELISA, biopsy TCBZ Complete resolution of symptoms Rinaldi et al. [3] 2020 1 M 58 Abdominal pain, nausea, anorexia, and jaundice. cold night sweats, weight loss, weakness Eosinophilia US, MRI, x-ray, colonoscopy, EGD, ELISA, and ERCP TCBZ and sphincterotomy Reduction in mass size; clinical improvement. Pinarlik et al. [11] 2023 1 F 57 Fever, nausea, vomiting, and weight loss Fever, RUQ tenderness, and eosinophilia. MRI, Biopsy, and ELISA TCBZ Regression of abscess at 12-month follow-ups Girma et al. [8] 2024 1 M 20s Chronic bilateral upper quadrant pain, nausea, loss of appetite, fatigue, intermittent fever, and weight loss Mildly elevated transaminases; no identified risk factors. US, CT, MRI , MRCP, and ELISA TCBZ N/A Musa et al. [5] 2013 1 F 56 Chest pain, Fever, chills, cough, and weight loss. Eosinophilia X-Ray, CT, and bronchoscopy TCBZ Clinically well at present. Serology was repeated after 2 months and was still positive Castillo et al. [12] 2020 1 F 25 diarrhea and bloating, fatigue, nighttime urticaria, and a nonproductive cough Eosinophilia CT, EGD, MRI, biopsy TCBZ clinical and radiographic resolution of liver lesions, improvement of eosinophilia M: Male, F: Female, RUQ: Right upper quadrant, CRP: C-reactive protein, CT: Computed tomography, MRI: Magnetic resonance imaging, ELISA: Enzyme-linked immunosorbent assay, TCBZ: Triclabendazole, US: Ultrasonography, ERCP: Endoscopic retrograde cholangiopancreatography, MRCP: Magnetic resonance cholangiopancreatography, EGD: Esophagogastroduodenoscopy Presentations of fascioliasis usually include eosinophilia, right hypochondrial pain, intermittent fever, cold night sweats, nausea, vomiting, loss of appetite, weight loss, and urticarial itching [2,8,11]. Eosinophilia is considered a hallmark feature of fascioliasis [5]. Eosinophilia might still be absent because it subsides after the immunologic response; instead, it is replaced with mild inflammation, which explains persisting fever, loss of appetite, and weight loss [11]. Lung abscess typically presents with fever, cough, dyspnea, and may be associated with hemoptysis [9]. Pulmonary changes such as infiltrates may arise indirectly due to a strong immunological response triggered during the early phases of Fasciola hepatica invasion and migration. Respiratory manifestations have been documented, but they are rare in fascioliasis [12]. In the present case, the patient presented with abdominal pain and eosinophilia, typical of fascioliasis. She also had occasional bright per-rectal bleeding and night sweats. Hemoptysis was also noted, potentially a sign of the associated lung abscess. Diagnosis of fascioliasis can be done through direct parasitological and indirect immunological tests, as well as imaging modalities. Stool examination for eggs has traditionally been used but has limited sensitivity [3]. Imaging plays a key role in diagnosis. Characteristic findings include “tunnels and caves” reflecting fluke migration tracts [5]. Liver flukes produce microabscesses, resulting in hypoechoic nodules and cystic lesions on US, and nodular or linear hypodensities on CT, which enhance homogeneously with dye. While nodular lesions are non-specific, the linear tracks are diagnostic of fascioliasis [5,8]. Computed tomography scan may also demonstrate areas of necrosis, fibrosis, and subcapsular lesions [11]. Chest imaging, particularly CT, is essential for identifying pulmonary complications such as lung abscess [9,13]. In the current case, the diagnosis of fascioliasis was based on clinical features, positive serology, and characteristic imaging findings in the absence of direct parasitological confirmation. This highlights a diagnostic limitation in ectopic fascioliasis, where definitive identification of the parasite may not be feasible. Ectopic involvement of Fasciola in the pleura or lungs has also been difficult to confirm in a previous report [14]. A direct causal relationship with F. hepatica often cannot be definitively established, and the association may remain presumptive. Given the lack of direct parasitic visualization, alternative etiologies for the lung abscess were considered. A primary alternative is a standalone pyogenic bacterial lung abscess co-occurring with an unrelated hepatic process. However, the patient's pleural fluid cultures were negative, and the liver lesions demonstrated pathognomonic 'furrow signs' rather than the standard spherical appearance of typical pyogenic or amebic liver abscesses. Other regional pulmonary pathogens, such as Mycobacterium tuberculosis and Echinococcus granulosus, were explicitly ruled out via negative acid-fast bacilli testing and negative hydatid serology, respectively. Additionally, histopathological evaluation of the resected lung tissue ruled out underlying malignancy. Triclabendazole is the treatment of choice for fascioliasis [12]. It is effective against both immature and adult parasites, making it suitable for both acute and chronic phases [9]. Treatment typically consists of one to two oral doses, achieving high cure rates, although repeat dosing may be required in refractory cases [1,5,9]. F. hepatica is resistant to praziquantel [3], and alternative agents such as bithionol and nitazoxanide may be considered in selected cases [1,3,9]. Empiric antibiotic therapy should be considered when a lung abscess is suspected. Larger lung abscesses are less likely to respond to antibiotics alone and may necessitate surgical management, such as lobectomy [9]. In the reported case, the patient underwent VATS wedge resection of the left lower lobe cavitary lesion. Follow-up US demonstrated persistent hepatic lesions, for which a second course of TCBZ was administered. During follow-up, several parameters should be assessed, including resolution of eosinophilia, absence of eggs in stool samples, decreasing serologic titers, and overall clinical improvement. In addition, normalization of biliary tract abnormalities on US can offer important information [3]. Prognosis is excellent once the diagnosis of fascioliasis is made [1]. In most cases, empiric antibiotic therapy successfully treats primary lung abscesses [9]. In this case, follow-up US showed new liver lesions consistent with ongoing fascioliasis, for which a second course of TCBZ was administered. Subsequently, the patient improved and was asymptomatic at the last follow-up. Our report has several limitations. Definitive parasitological confirmation was not achieved, and no causative organism for the lung abscess was identified. In addition, a short follow-up limited assessment of long-term outcomes. Conclusion This report highlights the diagnostic challenges of fascioliasis with extrahepatic involvement. Pulmonary findings require careful evaluation, and clinicians should maintain a high index of suspicion for ectopic fascioliasis, even without definitive parasitological confirmation. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Informed consent was obtained from the patient for the publication of the present and any accompanying images. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: SHS, DTG, and HRA: designed the study and managed the case. HKA, KAN, and AKH: contributed to the literature review, revision and table preparation. SHT: reviewed the imaging techniques used. RAY: contributed to the preparation of the manuscript. FHK and BAA: critically revised the manuscript. All authors approved the final version of the manuscript. Use of AI: AI was not employed in drafting the manuscript, creating graphical elements, or gathering and analyzing data. Data availability statement: The data generated by this study are fully included in the figures and/or tables of this article.
Copyright (c) 2026 The Author(s) https://creativecommons.org/licenses/by/4.0/
Anaplastic Thyroid Carcinoma and Toxic Multinodular Goiter: A Case Report and Literature Review
Abstract Introduction: Anaplastic thyroid carcinoma (ATC) is a rare thyroid malignancy, comprising approximately 2% of all thyroid cancers, yet accounting for the majority of thyroid cancer-related deaths. ATC is characterized by aggressive behavior and rapid local invasion, leading to life-threatening complications such as airway compromise, dysphagia, and vascular encasement. Longstanding thyroid conditions such as multinodular goiter (MNG) may predispose to malignant transformation into ATC. We report a case of ATC arising in a patient with a decade-long history of toxic MNG, underscoring the potential for severe complications even in seemingly stable thyroid disease. Case presentation: A 68-year-old female with a 10-year history of toxic MNG presented with neck swelling, dyspnea, and dysphagia. Laboratory findings showed suppressed thyroid-stimulating hormone and elevated free T4. Ultrasonography revealed nodules with macrocalcifications. A total thyroidectomy was performed, and histopathological examination revealed ATC originating from one of the MNG nodules. Postoperatively, she received adjuvant chemoradiotherapy with carboplatin and doxorubicin. Initial imaging showed no metastasis, but after 10 months, a supraclavicular lymph node and posterior lung nodules indicated disease progression. She developed pneumonia during treatment, leading to its discontinuation. Despite restarting therapy, her condition worsened, and she passed away eight months later. Literature review: A literature review identified six reported cases of ATC arising from MNG published between 2001 and 2020. The duration of MNG before malignant transformation varied from years to decades. Conclusion: Longstanding MNG may progress to malignancy over time. Early diagnosis and appropriate management of MNGs are critical to minimizing the risk of malignant transformation. Introduction Thyroid malignancy is the most common endocrine cancer, representing 2.1% of cases. Papillary thyroid carcinoma accounts for the majority at 80%, followed by follicular thyroid carcinoma (10%), medullary thyroid carcinoma (4%), oncocytic cell carcinoma (3%), and anaplastic thyroid carcinoma (ATC) (2%) [1]. Anaplastic thyroid carcinoma is among the most aggressive and deadly solid tumors in humans, with an incidence rate of 1–2 cases per million [2]. It has the worst prognosis among thyroid cancers, with an average survival period of 3–9 months and a 3-year overall survival rate of just 10% [3]. Clinically, ATC presents with rapid onset of compressive symptoms, including dyspnea, dysphagia, and hoarseness, and frequently progresses to local invasion and distant metastasis, posing significant life-threatening complications [4]. Pre-existing thyroid conditions, such as longstanding multinodular goiter (MNG) or well-differentiated thyroid malignancies, may act as risk factors for anaplastic transformation [5]. Multinodular goiter, currently classified in the WHO 2022 classification as thyroid follicular nodular disease, is an enlargement of the thyroid gland distinguished by the presence of discrete palpable nodules. It is more prevalent in mountainous areas, including Southeast Asia, Latin America, and Central Africa. Among thyroid cancers, papillary thyroid carcinoma is most frequently associated with MNG, followed by follicular carcinoma and anaplastic carcinoma [3]. The prevalence of thyroid malignancy in thyrotoxic conditions, particularly toxic MNG, remains a subject of debate. Reported rates of thyroid cancer in MNG range from 3% to 35%, whereas cases of ATC arising from long-standing toxic MNG are exceedingly rare [3,4,6,7]. Here, we present a case of ATC occurring in a patient with a 10-year history of toxic MNG. The report was prepared in accordance with the CaReL guidelines, and all references were assessed for eligibility and relevance [8,9]. Case presentation Patient information A 68-year-old female patient presented with anterior neck swelling for 10 years. She reported symptoms of dyspnea and dysphagia. She had a medical history of diabetes mellitus, hypertension, and anemia, but no history of prior surgeries. Clinical findings During the physical examination, the patient’s vital signs were stable. A large anterior neck swelling was observed on physical examination, with a firm consistency upon palpation. Diagnostic approach Routine thyroid function tests revealed a thyroid-stimulating hormone level of <0.005 mIU/mL (reference range: 0.4 to 4.0 mIU/mL), free T4 of 27.04 pmol/L (reference range: 9.0 to 23.0 pmol/L), and a serum calcium level of 9.04 mg/dL (reference range: 8.5 to 10.5 mg/dL). A neck ultrasound showed a significantly enlarged thyroid gland with heterogeneous echotexture containing multiple well-defined nodules of varying sizes. The largest nodule in the right lobe measured 37 × 31 × 30 mm and was categorized as TI-RADS 3 (TR3), while the largest nodule in the left lobe measured 59 × 40 × 38 mm (TR3). Macrocalcifications were noted within some nodules. These findings were consistent with MNG and mild retrosternal extension on the left side. Therapeutic intervention The patient underwent a total thyroidectomy under general anesthesia, with the procedure lasting 90 minutes. A drain was placed, and the excised tissue was sent for histopathological examination. The surgery was completed without complications. The surgical specimen was fixed in 10% neutral-buffered formalin at room temperature for 24 hours, embedded in paraffin, and sectioned at 5 μm thickness. Histological examination was performed using hematoxylin and eosin (H&E) staining (Bio Optica Co.), applied for 1–2 minutes at room temperature, and evaluated under a light microscope (Leica Microsystems GmbH). Microscopic examination demonstrated a heterogeneous tumor arising within an MNG. Low-power evaluation revealed residual benign thyroid follicles adjacent to extensive malignant epithelial proliferation arranged in nests, accompanied by areas of necrosis. Higher-magnification examination showed malignant squamous cells with prominent intercellular bridges and extracellular keratin formation, intermixed with malignant spindle-cell proliferation. Additional sections demonstrated a clear transition between benign thyroid tissue and the malignant component, with numerous mitotic figures indicating a highly proliferative neoplasm. Collectively, these histopathological findings were consistent with ATC arising from one of the nodules within the longstanding MNG (Fig. 1). <img id="image_2" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-77251446321781933724073.jpg" alt="Figure 1. Histopathological analysis images: A) Low-magnification view (4x) showing benign thyroid follicles (dark arrow) in the upper left corner, with numerous nests of malignant squamous cells (blue arrows) and an area of necrosis (red star) in the lower right corner. Hematoxylin and eosin stain. B) High-magnification view (40x) of another tumor area, displaying nests of malignant squamous cells (dark arrows) with clear intercellular bridges and extracellular keratin formation, intermixed with malignant spindle cell proliferation (blue arrows). Hematoxylin and eosin stain. C) Another area of the tumor, showing the interface between benign thyroid tissue on the left (blue star) and malignant spindle cell proliferation on the right (dark star), with numerous mitotic figures present (black arrows). Hematoxylin and eosin stain." width="12072" height="4152" /> Follow-up The patient’s vital signs remained stable following surgery, and levothyroxine 100 µg daily was initiated as replacement therapy. At the six-week follow-up, neck ultrasonography demonstrated a complex cystic nodule in the right thyroid lobe operative bed, along with small solid hypoechoic, hypovascular nodules in the left operative bed. The bilateral lateral cervical lymph nodes were largely unremarkable, except for two nodes in the right level III region; one exhibited features suggestive of malignancy and was subsequently confirmed on histopathological examination as an ATC-positive lymph node. The patient subsequently initiated weekly chemoradiotherapy with carboplatin (40 mg) and doxorubicin (60 mg). At the three-month follow-up, neck ultrasound demonstrated a well-defined hypoechoic, mildly vascular nodule measuring 22 × 19 × 18 mm in the right thyroid bed. At eight months, the patient developed pneumonia during chemotherapy, likely secondary to treatment-related immunosuppression, necessitating temporary interruption of therapy. Contrast-enhanced computed tomography (CT) of the chest and abdomen showed no evidence of distant metastasis at that time. However, subsequent CT imaging revealed an enlarged right supraclavicular lymph node or recurrent mass compared with prior studies, suggesting possible disease progression. In addition, two suspicious nodules were identified in the posterior segments of both lower lobes of the lungs. During this period, the patient’s clinical condition deteriorated significantly, with evidence of rapid disease progression. Chemotherapy was later resumed in an attempt to control the advancing disease; however, despite reinitiation of treatment, the patient died eight months later. Discussion Anaplastic thyroid carcinoma is most commonly diagnosed between the ages of 55 and 65, with peak incidence occurring in the sixth and seventh decades of life. Anaplastic thyroid carcinoma is more common in women, although the degree of female predominance varies among studies, with reported female-to-male ratios ranging from approximately 1.2:1 to 3.1:1 [5]. ATC carries one of the highest mortality rates among solid malignancies, with a median survival of approximately 3–5 months after diagnosis. One-year and 10-year survival rates are estimated at 10–20% and less than 5%, respectively, although the validity of some long-term survival reports has been questioned. ATC accounts for up to 14–50% of annual thyroid cancer–related mortality. Recent advances in understanding its genetic and molecular pathogenesis have opened new avenues for the development of targeted therapies [2]. A notable feature of the present case is the prolonged 10-year history of MNG before the diagnosis of ATC. This clinical course differs from the typical presentation of ATC, which is characterized by the rapid enlargement of a neck mass over weeks to months, often accompanied by compressive symptoms such as dysphagia, dyspnea, and hoarseness. McIver et al. reported that rapidly progressive neck swelling is the predominant presenting feature in the vast majority of patients with ATC, reflecting the highly aggressive nature of the disease [10]. However, accumulating evidence suggests that ATC may arise through dedifferentiation of pre-existing benign thyroid lesions or well-differentiated thyroid carcinomas, a process that can occur over many years before the onset of the aggressive anaplastic phase [5]. Consistent with this hypothesis, several case reports have documented the development of ATC in patients with longstanding MNG, with disease durations ranging from several years to decades before malignant transformation became clinically evident (Table 1) [3,4,7,11-13]. The relatively indolent course observed in the present patient likely reflects the prolonged presence of MNG, with subsequent anaplastic transformation occurring within one of the pre-existing nodules rather than the de novo development of ATC. This observation highlights an important diagnostic consideration: although most MNGs follow a benign course and ultrasound risk stratification may suggest a low risk of malignancy, longstanding nodular thyroid disease may rarely harbor or develop highly aggressive malignancies. Therefore, new or worsening compressive symptoms, accelerated growth, or other concerning clinical changes in patients with chronic MNG should prompt careful reassessment, even when previous imaging findings appear relatively reassuring. Table 1. Review of the anaplastic thyroid carcinoma cases associated with MNG Authors, year [Reference] Age/Sex History Clinical Presentation TSH Imaging Met Diagnostic method Treatment Follow-up Shahi et al., 2020 [3] 54y/M Anterior neck swelling for 20 years Pain, gradual swelling, dysphagia, shortness of breath, fever, loss of appetite N/A Multinodular goiter, multilocular cystic and solid mass, trachea shift No FNA, Cytology, US, CECT, Histo Total thyroidectomy with neck dissection, IMRT radiation therapy No progression for 12 weeks Marcelino et al., 2014 [4] 70y/M A recent growth of a toxic MNG Initial complaints of the growth of a goiter; later, dyspnea, hoarseness, and dysphagia <0.001 mU/l Showed two nodules (51 mm and 38 mm in diameter) No US, CT, TS, FNAB, Bronchoscopy Methimazole, β-blockers, radiotherapy (70 Gy in 30 sessions). Tracheostomy, PEG tube No symptom relief; refused surgery; the patient died from tracheal compression Villa et al., 2004 [7] 76y/F Large, euthyroid multinodular goiter, Wegener’s Granulomatosis Weight loss, hoarseness, shortness of breath, and rapid goiter growth <0.005 mU/L Showed a large thyroid mass with coarse calcification extending into the mediastinum. The iodine-131 scan showed low uptake in the thyroid lobes No CT, FNA Propranolol for thyrotoxic symptoms, high-dose oral dexamethasone, and urgent radiotherapy (30 Gy over 10 fractions) Died after four weeks Maatouk et al., 2009 [11] 90y/M Over 45 years of multinodular goiter (MNG) with thyrotoxicosis, multiple radioiodine (I-131) treatments Dyspnea, dysphagia, neck swelling, unintentional weight loss N/A Showed large MNG with retrosternal extension and calcifications No CT, FNA, Histo The patient refused management and was discharged Died 2 days later; no autopsy was performed Camargo et al., 2001[12] 53y/F Congenital deafness and a large multinodular goiter (150 g) present since childhood Weight loss, hoarseness of voice, shortness of breath, rapid enlargement of goiter, noticed over 6 months. 2.8 mU/mL Showed a large thyroid mass with retrosternal extension Lung Histo, genetic analysis Total thyroidectomy, Radioiodine therapy Died after one week due to severe hemoptysis Yoon et al., 2020 [13] 46y/F LT4 therapy since age 14 Compressive symptoms 0.205 µIU/mL 6 cm hypoechoic nodule with calcification (right lobe) and 0.9 cm calcification (left lobe) Lung, bone FNA, CT, US, Histo, Molecular genetics Total thyroidectomy, Lenvatinib 20 mg/day Died in 14 months post-surgery Abbreviations. M: male, F: female, y: year, LT4: levothyroxine, RT: radiotherapy, MNG: multinodular goiter, N/A: not available, FNA: fine-needle aspiration, CT: computed tomography, US: ultrasound, CECT: contrast-enhanced computed tomography, Histo: histopathology, FNAB: fine-needle aspiration biopsy, PEG: percutaneous endoscopic gastrostomy, IMRT: Intensity-Modulated Radiation Therapy, Met: Metastasis Thyroid carcinogenesis models have demonstrated that the progression from well-differentiated thyroid cancer to ATC is often linked to the loss of the p53 tumor suppressor gene. Additionally, many ATCs occur in elderly individuals with long-standing goiter or a history of thyroid malignancy, supporting the idea of anaplastic transformation. It is also well-established that the incidence of ATC is higher in regions endemic for goiter and among patients with inadequately treated papillary or follicular thyroid cancer [5]. Around 15–50% of patients presenting with ATC have extensive local invasion and distant metastasis at the time of diagnosis, with the lungs and pleura being the most common metastatic sites (up to 90% of metastatic cases) [11]. In the present case, although ATC developed from a longstanding MNG, no metastasis was observed either at the time of diagnosis or during the initial follow-up. The time frame for MNG to progress to ATC can vary greatly. Villa et al. described a case with a goiter persisting for 50 years, marking the most prolonged reported duration. In contrast, Capraru et al. noted the onset of ATC after only six years of goiter [7,14]. The patient in this report had been diagnosed with MNG for 10 years. The progression of a decade-long MNG into ATC emphasizes the need for careful monitoring and timely intervention of MNGs. The diagnosis of ATC is typically established through clinical examination and fine-needle aspiration biopsy (FNAB). The FNAB plays a crucial role in confirming the diagnosis, demonstrating an accuracy rate of 90% [5]. The FNAB is widely recognized as a key component in the assessment of thyroid nodules, particularly in MNGs with suspicious imaging features. Maatouk et al. and Marcelino et al. have shown that FNAB is instrumental in identifying cytological abnormalities indicative of malignancy, allowing for timely intervention [4,11]. By contrast, in this case, the diagnosis of ATC was made only after total thyroidectomy. Moreover, no molecular or genetic analyses were conducted, limiting our understanding of the mechanisms underlying the progression from MNG to ATC. Molecular studies, such as the detection of p53 mutations or thyroglobulin gene alterations, have been shown to play a pivotal role in identifying the malignant potential of thyroid lesions [3,13]. The role of surgery in managing ATC remains controversial and is largely determined by the extent of the disease at diagnosis. Unfortunately, most patients present with a disease that has progressed beyond the scope of effective surgical resection. It is widely recognized that surgery alone is unlikely to significantly influence the disease's progression [5]. In the case reported by Camargo et al., the patient underwent a total thyroidectomy followed by postoperative radioiodine therapy [12]. In the present case, total thyroidectomy was initially performed because of the patient's longstanding toxic multinodular goiter, substantial thyroid enlargement, and compressive symptoms, including dyspnea and dysphagia. The diagnosis of ATC was established postoperatively through histopathological examination. Following surgery, the patient underwent adjuvant weekly chemoradiotherapy with carboplatin (40 mg) and doxorubicin (60 mg). Therefore, surgical resection not only provided definitive treatment for the symptomatic goiter but also facilitated subsequent oncologic management by reducing local tumor burden and enabling adjuvant therapy. While surgery alone is unlikely to significantly alter the overall prognosis of ATC, it may improve local disease control and form an essential component of multidisciplinary care in appropriately selected patients. The development of pneumonia during treatment represented a significant clinical event in this case. Although the exact etiology could not be definitively established, several factors may have contributed. Chemotherapy with carboplatin and doxorubicin is associated with immunosuppression, which can increase susceptibility to respiratory infections [15]. Furthermore, the patient presented with dysphagia at diagnosis, raising the possibility of aspiration-related pneumonia [16]. The resulting interruption of chemoradiotherapy may have adversely affected disease control, as ATC is characterized by rapid progression and limited therapeutic windows. The interval without treatment may have contributed to tumor progression. This case highlights the importance of promptly identifying and managing treatment-related complications to minimize interruptions and maintain therapeutic continuity whenever possible. This report has several limitations. First, fine-needle aspiration cytology was not performed preoperatively despite the presence of thyroid nodules, limiting the opportunity for preoperative cytological assessment. Second, preoperative cross-sectional imaging, including computed tomography, and laryngoscopic evaluation were not obtained despite the presence of compressive symptoms, which restricted the assessment of possible tracheal, esophageal, or laryngeal involvement before surgery. Third, no molecular or genetic analyses, such as evaluation of TP53 or other thyroid cancer–related mutations, were conducted, limiting insights into the mechanisms underlying the transformation from MNG to anaplastic thyroid carcinoma. Finally, as a single case report, the findings have limited generalizability and do not allow conclusions regarding causality or the incidence of malignant transformation in patients with longstanding MNG. Conclusion Longstanding MNG may progress to malignancy over time. Early diagnosis and appropriate management are critical to minimizing the risk of malignant transformation. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Ethical approval was not required for this case report, in accordance with our institution's policies. Consent for participation: Not applicable. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and the accompanying images following the initial diagnosis. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: AMS, ReMA: Major contributors to the conception of the study, as well as the literature search for related studies, and critical revision. RaMA, HAN, AHA, SHH, SAN, AAQ, HAA: Literature review, drafting the first and last versions of the manuscript, and processing of the tables and figures. All authors have read and approved the final version of the manuscript. Use of AI: During the preparation of this work, the authors used ChatGPT (version 4.0) to enhance the clarity, coherence, and overall linguistic quality of the manuscript. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article. Data availability statement: Not applicable.
Video-Assisted Thoracoscopic Surgery for Bilateral Giant Pulmonary Hydatid Cysts: A Case Report and Literature Review
Abstract Introduction: Bilateral giant pulmonary hydatid cysts (HCs) are rare but can lead to serious respiratory complications. Despite growing interest in minimally invasive surgery, the role of Video-Assisted Thoracoscopic Surgery (VATS) in their management remains controversial. This report describes a case of giant bilateral pulmonary HCs managed using a VATS approach. Case presentation: A 34-year-old male presented with chest discomfort, productive cough, and exertional dyspnea. Imaging revealed bilateral giant pulmonary HCs, including an uncomplicated cyst in the right upper lobe and a ruptured, infected cyst in the left lower lobe. The patient underwent single-session bi-port VATS with cyst evacuation, hypertonic saline irrigation, and closure of bronchopleural fistulae. Intraoperative culture grew Pseudomonas aeruginosa, and the patient received albendazole and culture-directed antibiotics, resulting in an uneventful recovery. Literature review: Among 12 reviewed cases of pulmonary HCs, patients’ ages ranged from 3 to 42 years, with a predominance of males (7/12). Cough was present in all cases, while dyspnea and fever were reported in 50% of the cases. Bilateral cysts were documented in 6 cases. Management included VATS alone in 5 cases, thoracotomy-based surgery in 4, hybrid approaches in 2, and conservative treatment in 1. Complications occurred in 2 cases. Albendazole therapy was administered postoperatively in 7 cases, and overall outcomes were positive, with 11 patients experiencing uneventful recovery. Conclusion: Bilateral VATS in a single session may be a feasible therapeutic approach for giant pulmonary HCs, even when complicated cysts are present. Introduction Echinococcosis is a widely recognized zoonotic disease caused by the larval form of the tapeworm Echinococcus granulosus [1]. Although the disease can occur globally, it is considered endemic in several regions, including the Middle East, the Mediterranean basin, parts of South America, South Africa, and Australia [1]. Humans serve as accidental intermediate hosts for the parasite, acquiring the infection through direct contact with definitive hosts (such as dogs) or via ingestion of food or water contaminated with feces that contain parasitic eggs, often originating from livestock environments involving sheep, goats, or cattle [2]. Major risk factors include close contact with dogs, involvement in livestock activities, and living in endemic areas [2]. The prevalence of hydatid cysts in children differs by region, with a reported incidence of 2-6 cases per 100,000 children affecting individuals as young as six months old. Human infections typically occur incidentally through the ingestion of parasite eggs in contaminated food or water or by direct contact with infected hosts [3,4]. Hydatid cysts (HCs) are typically found in the liver and lungs, while the adrenal gland is a rare and unusual site of involvement [5]. This report presents a case of a primary adrenal HC (AHC) that was incidentally diagnosed in a child. The references cited in this report have been reviewed to ensure the exclusion of any non-peer-reviewed data, and the study has been structured following the CaReL guidelines [6,7]. Case presentation Patient information A 34-year-old non-smoking male from an urban area presented with a 15-day history of chest discomfort and productive cough, accompanied by dyspnea on exertion. He denied fever, rigors, or hemoptysis. There was no history of contact with dogs or cattle, and no family history of hydatid disease. His past medical and surgical history was unremarkable. Clinical findings On physical examination, the patient was afebrile and hemodynamically stable. Chest auscultation revealed decreased air entry bilaterally. Diagnostic approach Hematological analysis showed leukocytosis with a white blood cell count of 14.3 × 10⁹/L (Normal range: 4.5–11.0 × 10⁹/L). Inflammatory markers were markedly elevated, with an ESR (erythrocyte sedimentation rate) of 100 mm/hr (Normal range: 0–15 mm/hr) and CRP of 237 mg/dL (Normal range: <1.0 mg/dL). Chest radiography revealed a well-defined opacity in the right upper zone and a cavitary lesion in the left lower zone (Figure 1). Contrast-enhanced computed tomography (CT) confirmed the presence of bilateral giant cysts suggestive of HCs. The right upper lobe contained a large, uncomplicated HC measuring 14 × 12 × 11 cm, associated with mild adjacent atelectasis. In addition, a complicated (ruptured and infected) HC was identified in the left lower lobe, measuring 12 × 12 × 11 cm, characterized by a thick, irregularly enhancing wall and a prominent air–fluid level with undulating internal membranes, consistent with the water-lily sign (Figure 2). <img id="image_6" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-98922016761781768325709.jpg" alt="Figure 2. Contrast-enhanced CT chest (axial view). (A) Right upper lobe giant uncomplicated hydatid cyst causing compression of adjacent lung parenchyma. (B) Left lower lobe ruptured cyst showing air-fluid level and detached floating membranes ("water-lily sign")." width="1221" height="405" /> Therapeutic intervention Under general anesthesia, the patient was placed in the left lateral decubitus position. Single-lumen endotracheal intubation was used with intermittent apnea as the patient did not tolerate single-lung ventilation. A bi-port VATS approach was employed. Controlled cyst drainage was performed, the germinal membrane was removed (Figure 3), and the cavity was irrigated with hypertonic saline (20% NaCl), followed by pericystectomy, closure of the bronchopleural fistulae, and capitonnage. Intercostal nerve cryoablation was performed from levels 3 to 11. <img id="image_8" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-50622313281781768389648.jpg" alt="Figure 3. Intra-operative images. (A) View of the right hemithorax showing the bi-port access sites and the large, intact germinal membrane extracted from the uncomplicated giant cyst. (B) View of the left hemithorax showing the trocar placement and the extracted, fragmented, thickened membranes from the ruptured, infected cyst." width="1221" height="531" /> A chest tube was inserted, and the patient was repositioned to the right lateral decubitus position. The same procedure was repeated; however, dense pleural adhesions with pleural thickening and a foul odor were encountered. Therefore, extensive irrigation with hypertonic saline (20% NaCl) was performed, and bronchopleural fistulae were closed without capitonnage. Intraoperative pleural fluid culture revealed growth of Pseudomonas aeruginosa. Follow-up Postoperatively, the patient was empirically started on oral Amoxicillin–clavulanate (1 g twice daily for 3 days) and albendazole (400 mg twice daily). Albendazole therapy was continued (400 mg twice daily for 3 months). The postoperative course was uneventful, and she has remained well during 6 months of follow-up. She continues to be followed up on regularly. Discussion Uncomplicated pulmonary HCs are often asymptomatic and are frequently discovered incidentally on imaging. Their slow growth may contribute to delayed clinical presentation. When symptoms occur, pulmonary hydatid disease most commonly presents with cough, chest pain, fever, and hemoptysis [8]. For the present report, twelve cases of pulmonary hydatid cysts were reviewed as part of a brief literature review (Table 1). Cough was the most frequently reported symptom, occurring in all cases, followed by dyspnea and fever, both in 6 cases [1,2,9-15]. In the present case, the patient presented with chest discomfort, a productive cough, and dyspnea on exertion. Pulmonary HCs can develop in any lobe; however, they most frequently affect the right lung, particularly the lower lobes. Approximately 60% of cases are reported in the right lower lobe [4]. Table 1. Review of Pulmonary hydatid cyst cases Author, year [citation] Age/Sex Residence/ Contacts with dogs or cattle Presentation Location/Size (cm) Management Complications Postoperative Management Outcome Anari et al., 2023 [1] 14/M NR/NR Abdominal pain, cough, nausea, and vomiting Bilateral/ Gigantic (unspecified) Bilateral anterolateral mini-thoracotomy None Albendazole Uneventful recovery Mayyaleh et al., 2025 [9] 5/F Urban/No contact Left-sided flank pain, anorexia, hypoactivity, dyspnea on exertion, productive cough & fever Left lower lobe/ 9x8.5x11 Lateral thoracotomy and VATS None Albendazole (130 mg) for 30 days Uneventful recovery Aghajanzadeh et al., 2012 [10] 20/F NR/NR Right upper quadrant pain, right-sided chest pain, persistent cough, and a low-grade fever Bilateral/Giant (unspecified) Bilateral antero-lateral thoracotomies and phrenotomy None Albendazole for 90 days Uneventful recovery Alpay et al., 2012 [11] 16/M NR/NR Fever, shortness of breath, and recurrent attacks of cough. Left lower lobe/ 5x4.5 VATS None None Uneventful recovery 40/F NR/NR Recurrent attacks of cough Left lower lobe/5x5 VATS None None Uneventful recovery 30/M NR/NR Recurrent attacks of cough Left lower lobe/4x4 VATS None None Uneventful recovery 28/M NR/NR Recurrent attacks of cough and shortness of breath Left lower lobe/4x4 VATS None None Uneventful recovery Abubaker et al., 2026 [8] 19/F Rural/None Persistent dry cough, shortness of breath, and left flank pain Bilateral L:15x11 R:10x6.8 Bronchoscopy and uVATS Right pneumothorax Albendazole for 6 months and a pigtail catheter for pneumothorax Uneventful recovery Ganguly et al., 2012 [12] 8/F Rural/None Low-grade fever, occasional abdominal pain, and a non-productive cough Bilateral, R:7.4x6.7 L:8.5x6.4 Oral Albendazole, Postero-lateral thoracotomy None Albendazole Uneventful recovery Sabr et al., 2024 [13] 15/M Rural/Yes Dyspnea and a persistent cough Bilateral R:16x14 L:14x12 VATS None Albendazole for 6 months Uneventful recovery Arega et al., 2022 [14] 3/M NR/Yes Progressive dry cough, shortness of breath, and low-grade intermittent fever Bilateral R:9x7 L:8x7 Posterolateral thoracotomy and cystectomy None Albendazole Uneventful recovery Alawadhi et al., 2025 [15] 42/M Rural/None Fever, chills, productive cough, and malaise Right lower lobe/ 4x2.9 Conservative Secondary bacterial infection and pleural effusion N/A Improvement of symptoms M: Male, F: Female, NR: Not reported, CM: Centimeter, VATS: Video-assisted thoracoscopic surgery, N/A: Not applicable Imaging plays a central role in the diagnosis of hydatid disease. Chest X-rays and CT scans are particularly useful for identifying characteristic cystic lung lesions [13]. In uncomplicated pulmonary hydatid disease, the typical chest radiographic appearance consists of single or multiple well-defined, round masses with smooth borders and homogeneous density [9]. In the present case, chest radiography demonstrated a well-defined opacity in the right upper zone and a cavitary lesion in the left lower zone. The radiographic crescent sign, often linked to HCs, can also be observed in other conditions, including aspergilloma, cavitating malignancies, blood clots, and Rasmussen aneurysm [9]. The CT appearance of HCs can be variable and may occasionally mimic solid tumors due to associated inflammatory changes [9]. In cases such as the present one, particularly when the cyst is ruptured or infected, imaging may reveal a thick, irregularly enhancing wall and a prominent air–fluid level with undulating internal membranes, producing the characteristic water-lily sign. Management of bilateral pulmonary hydatidosis remains controversial. It can be performed either as a one-stage procedure or as a two-stage approach, typically spaced 4–5 weeks apart, beginning with the uncomplicated cyst [8]. Due to intolerance of single-lung ventilation, this case underwent a single-stage surgery, as some authors advocate a single-stage procedure, citing advantages such as reduced morbidity, shorter hospitalization, and lower overall costs [8]. VATS has been employed as a minimally invasive alternative to reduce the risks associated with open surgery. However, its use is limited to select cases due to concerns about postoperative complications, including cyst rupture, spillage of cystic contents, and the management challenges associated with bronchial fistulas [5]. Hybrid interventions have also been utilized, though open surgery remains more common [4]. Among the reviewed cases, open surgical approaches were employed in four patients, all of whom experienced uneventful recoveries [1,10,12,14]. VATS was utilized in seven cases, with no reported complications, suggesting favorable outcomes in carefully selected patients [8,9,11,13]. These findings highlight that both open surgery and VATS can achieve good outcomes when appropriately indicated, although VATS may offer advantages in terms of reduced invasiveness. In contrast, conservative approaches may carry a greater risk of complications depending on case complexity and selection. In the present case, a single-stage VATS approach was adopted, given its association with lower morbidity, shorter hospital stays, and reduced overall cost [4]. A key controversy in the surgical management of pulmonary HCs is whether capitonnage should be performed following cystotomy. Traditionally, it has been recommended to obliterate the residual cavity; however, some authors suggest it may be unnecessary, emphasizing that meticulous closure of bronchial openings alone can allow adequate re-expansion and healing of the lung parenchyma [4]. In the present case, capitonnage was performed on the right side but omitted on the left side, where the infected, thickened pericyst precluded safe suturing. The patient had an uneventful recovery. Adjunctive medical therapy with anthelmintic agents, such as albendazole, complements surgical management by reducing the risk of recurrence and targeting residual cystic elements [13]. In seven of the reviewed cases, albendazole was administered as postoperative therapy, and all patients had uneventful recoveries. The only exception was a case managed without surgical intervention, which reported only symptomatic improvement, not full recovery [15]. This pattern suggests that albendazole might be most effective as an adjunct to surgery rather than as a standalone treatment, supporting its role in reducing recurrence. This report has some limitations. First, serological confirmation was not obtained, which would have provided additional diagnostic support, although serology is not always sensitive in pulmonary hydatid disease. Second, the follow-up period was relatively short, which limits the assessment of long-term outcomes and recurrence. Conclusion Single-session bilateral VATS may be a feasible therapeutic approach for giant pulmonary hydatid cysts, even when complicated cysts are present. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the parents. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: FHK, AKH, and MMA: Major contributions to the study's conception and design, literature review, and manuscript drafting. HKA, AMM, and FHF: Contribution to the literature search, data collection, and manuscript preparation. HMH, HAA, SSA, KTS, and DOA: Critically revision of the manuscript and assisting in the preparation of the tables and figures. All authors have read and approved the final manuscript. Use of AI: ChatGPT-5.3 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Coexisting Granulomatous Mastitis and Breast Cancer: A Systematic Review
Abstract Introduction: Granulomatous mastitis (GM) is a rare inflammatory breast disease that mimics carcinoma. GM can coexist with breast cancer (BC), though the relationship remains unclear. This systematic review aims to examine the coexistence of GM and BC, focusing on the clinicopathological features of synchronous and metachronous cases. Methods: A systematic search of PubMed/MEDLINE and Google Scholar, up to the 30th November 2025, identified studies reporting individual patient-level data. Inclusion criteria were: (1) patients diagnosed with both BC and GM (concurrently or sequentially); (2) histopathological or imaging confirmation of both conditions. Exclusion criteria were: (1) animal studies; (2) conference abstracts; (3) non-recommended journal publications; and (4) non-English papers. Descriptive statistics were used to summarize categorical variables as frequencies and percentages, and continuous variables as means or medians with ranges. Results: Nineteen studies (23 female patients; median age of 42 years) were included. Most of the cases were premenopausal 17 (74.0%). Synchronous coexistence occurred in 15 (65.2%), with ipsilateral involvement in 11 (73.3%) of these. Granulomatous mastitis preceded BC in 6 (26.1%) (median interval 3 years), and BC preceded GM in 2 (8.7%). Core needle biopsy diagnosed GM in 9 (39.1%) and BC in 14 (60.9%); excisional biopsy was required in 7 (30.4%) of GM cases. Breast cancer treatment included mastectomy in 11 (47.8%) and breast-conserving surgery in 9 (39.1%). Follow-up ranged from 2–53 months. Conclusion: Granulomatous mastitis and BC can coexist, with GM potentially masking malignancy. Clinicians should maintain a low threshold for repeat biopsy in refractory cases. Introduction Granulomatous mastitis (GM) is a rare, chronic inflammatory breast disease, first described in 1972 as a lesion mimicking carcinoma [1,2]. It is characterized by non-caseating granulomatous inflammation centered on breast lobules, typically affecting women of childbearing age, often within five years of their last childbirth [3,4]. The incidence of idiopathic GM is estimated at 2.4 per 100,000 women aged 20-40 years, with higher rates among Asian, Hispanic, and Arab populations [5]. Although the exact etiology remains unclear, proposed mechanisms include autoimmune processes, hormonal imbalances, oral contraceptive use, hyperprolactinemia, pregnancy and lactation, alpha-1 antitrypsin deficiency, and infectious agents [6,7]. While GM is generally benign, several reports have documented its occurrence alongside breast carcinoma. The coexistence of GM and breast cancer (BC) presents a rare but clinically significant diagnostic and therapeutic challenge [7]. The literature contains case reports and small series of patients with concurrent or metachronous GM and BC, encompassing invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), and lobular carcinoma in situ (LCIS) [8,9]. The pathophysiological relationship between GM and BC is not fully understood. Two main hypotheses have been proposed. First, the granulomatous response may represent a secondary "sarcoid-like reaction" to breast carcinoma first described in 1911, reflecting immunological hypersensitivity to tumor-derived antigens [7,10]. Second, chronic inflammation from GM may predispose to dysplasia and subsequent malignant transformation [7,10]. This systematic review aims to examine the coexistence of GM and breast carcinoma, focusing on the clinicopathological features of synchronous and metachronous cases. Methods Study design This review followed Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [11]. Information sources and search strategy A systematic literature search was conducted in PubMed/MEDLINE and Google Scholar for published studies up to 30th of November 2025. The following medical keywords and search terms were used for Google Scholar: (cancer OR cancers OR cancerous OR carcinoma OR carcinomas OR neoplasm OR neoplasms OR malignancy OR malignancies OR malignant OR metastasis OR tumor OR tumors) AND ("granulomatous mastitis" OR GM). And these keywords were used in PubMed/MEDLINE: ("granulomatous mastitis"[tiab] OR GM [tiab] OR "Granulomatous Mastitis"[Mesh]) AND (cancer[tiab] OR cancers[tiab] OR carcinoma[tiab] OR carcinomas[tiab] OR neoplasm[tiab] OR neoplasms[tiab] OR malignancy[tiab] OR malignancies[tiab] OR malignant[tiab] OR metastasis[tiab] OR tumor[tiab] OR tumors[tiab] OR "Breast Neoplasms"[Mesh]). Inclusion Criteria Studies were included if they met the following criteria: 1) Studies reporting individual patient-level data, 2) patients diagnosed with both GM and BC, either concurrently or sequentially, 3) the diagnosis of both BC and GM was confirmed by diagnostic imaging, surgical findings, or histopathological examination. All included studies underwent eligibility verification [12]. Exclusion Criteria Exclusion criteria included all of the following: 1) Studies with no human subjects, 2) studies that were published in the form of conference abstracts, 3) studies published in non-recommended journals, and 4) non-English papers. Data extraction The extracted data included the following variables: The first author's name, year of publication, and country of study. Patient demographic and reproductive characteristics included age, parity, menopausal status, lactation history, oral contraceptive use, and smoking status. Clinical presentation data included the chief complaint, duration of symptoms before diagnosis, side and quadrant of the affected breast, and family history of BC. Regarding the relationship between GM and BC, the laterality of each pathology and the chronological sequence of the two diagnoses were recorded. Diagnostic data included the sampling and diagnosis method, type of GM, and imaging findings on mammography, ultrasound, and magnetic resonance imaging (MRI), along with the assigned Breast Imaging-Reporting and Data System (BI-RADS) category. Breast cancer-specific variables comprised the type and grade of cancer, hormone receptor status such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), cancer stage, and metastasis status. Finally, management data included the treatment approaches applied for both GM and BC, and the follow-up duration. Granulomatous Mastitis and BC were classified as synchronous when both were diagnosed concurrently or within 6 months of one another, and as metachronous when the interval between the two diagnoses exceeded 6 months [13]. Statistical Analysis Descriptive statistics were used to summarize categorical variables as frequencies and percentages. Continuous variables (e.g., age, follow-up duration) were summarized as means with ranges or medians with ranges, as appropriate. All analyses were conducted using Microsoft Excel (version 16.0). Results Study selection A total of 236 records were identified from PubMed/MEDLINE and Google Scholar. After removing 42 duplicates, 194 records were screened. Of these, 173 were excluded based on title and abstract review, leaving 21 reports to be sought for retrieval, all of which were successfully retrieved. Following eligibility assessment, 2 reports were excluded (one as it was a historical report predating the formal definition of GM, and the other one due to publication in a non-recommended journal). Ultimately, 19 studies were included in the final review (Figure 1). Characteristics of the included studies A comprehensive literature search yielded a total of 23 eligible cases from 19 published reports [2,4-10,14-24] documenting the coexistence of GM and BC. These cases were derived from case reports and case series published between 2012 and 2025. The included cases originated from multiple countries; most commonly from Iran (7, 30.4%) and China (5, 21.7%), followed by Iraq and Turkey (2, 8.7%), with single cases reported from Brazil, Chile, Japan, Australia, Malaysia, Tunisia, and Pakistan (Tables 1 & 2). Table 1. Demographic and clinical characteristics of patients with coexisting granulomatous mastitis and breast cancer Author (year) [ref] N Country Age (years) Presentation Duration of Symptoms Parity Menopausal Lactation OCP Smoking FH of BC Salih et al., 2025 [2] 1 Iraq 36 Breast pain 2w 3 Pre 4y, currently nursing No Passive No Freitas et al., 2020 [20] 1 Brazil 42 Breast nodule enlargement NA 2 Pre 5y No NA No Zavieh et al., 2024 [8] 3 Iran 42 Breast Pain and lump NA 2 Pre 48m, 20y ago Yes NA No 46 Mass NA 2 Pre 9y before GM No NA No 41 Mass NA NA Pre NA No NA No Zhu et al., 2024 [18] 3 China 51 Hard mass 1d NA Post NA NA NA NA 50 Recurrent mass NA NA Peri NA NA NA NA 45 Lump with redness, heat, pain, nipple retraction and discharge 2m NA Peri NA NA NA NA Oddó et al., 2019 [6] 1 Chile 44 Pain and swelling 2w NA NA NA NA Former No Tavakol et al., 2022 [9] 1 Iran 35 Pain & mass 1m 2 Pre NA No NA No Yoshida et al., 2023 [4] 1 Japan 34 Mass & redness NA NA Pre NA NA NA No Zangouri et al., 2022 [22] 1 Iran 38 Mass NA NA Pre 28m NA NA NA Çalış and Kilitçi, 2018 [19] 1 Turkey 77 Pain & swelling NA NA Post NA NA NA NA Xie et al., 2022 [23] 1 China 39 Enlarging mass, pain, redness NA 1 Pre NA NA NA No Evans et al., 2021 [17] 1 Australia 39 Mass increasing in size & tenderness NA 2 Pre NA NA NA No Salih et al., 2023 [16] 1 Iraq 30 Pain 7d 3 Pre 6m, 3y ago No No Yes Mazlan et al., 2012 [24] 1 Malaysia 34 Progressive loss of vision in the left eye NA NA Pre NA No No No Chen et al., 2025 [21] 1 China 31 Mass, pain NA NA Pre Currently Lactating, 4y3m NA NA NA AkbariRad et al., 2025 [7] 1 Iran 46 Stiffness NA 3 Pre NA No NA Yes Limaiem et al., 2013 [10] 1 Tunisia 77 Pain 6m NA Post NA No NA NA Özşen et al., 2018 [14] 1 Turkey 35 Swelling 8m* 0 Pre NA NA NA NA Mahmood et al., 2025 [5] 1 Pakistan 45 Painful breast swelling NA 7 Pre 2 y for each 7 children NA No No Kaviani et al., 2017 [15] 1 Iran 48 large palpable masses and nipple retraction 4m NA Pre None Yes NA No Abbreviations. Ref: reference; GM: granulomatous mastitis Pre: premenopausal; Post: postmenopausal; Peri: perimenopausal; FH: family history; BC: breast cancer; OCP: oral contraceptive pills; NA: not available; D: days; W: weeks; M: months; Y: years. *First experienced swelling in her right breast in March 2017, the case report was formally received for publication on November 26, 2017 Table 2. Summary of Clinical and Demographic Variables Variable N % Country Iran China Iraq Turkey Other countries 7 5 2 2 7 30.4 21.7 8.7 8.7 30.4 Age (years) 30-39 40-49 50-59 ≥60 10 9 2 2 43.5 39.1 8.7 8.7 Menopausal status Premenopausal Perimenopausal Postmenopausal N/A 17 2 3 1 74.0 8.7 13.0 4.3 Parity Nulliparous (0) Primiparous (1) Multiparous (2-3) Grand multiparous (≥7) N/A 1 1 8 1 12 4.3 4.3 34.8 4.3 52.2 Lactation History Currently lactating Previous lactation No lactation history N/A 2 6 1 14 8.7 26.1 4.3 60.9 Risk factors OCP use Yes No N/A 2 9 12 8.7 39.1 52.2 Smoking history Former Passive No N/A 1 1 3 18 4.3 4.3 13.0 78.3 Family history of BC Yes No N/A 2 13 8 8.7 56.5 34.8 Granulomatous Mastitis Characteristics Side Left breast Right breast Bilateral 14 8 1 60.9 34.8 4.3 Type Idiopathic GM Non-idiopathic GM 20 3 87.0 13.0 Breast cancer characteristics Laterality Ipsilateral to GM Contralateral to GM Bilateral GM 16 6 1 69.6 26.1 4.3 Type of carcinoma IDC DCIS Mixed (IDC+DCIS) LCIS 13 7 2 1 56.5 30.4 8.7 4.3 Cancer grade High-grade Intermediate-grade Low-grade N/A 12 3 2 6 52.2 13.0 8.7 26.1 Molecular subtype ER Positive Negative N/A 14 5 4 60.9 21.7 17.4 PR Positive Negative N/A 10 7 6 43.5 30.4 26.1 HER2 Positive Negative N/A 7 9 7 30.4 39.1 30.4 Triple-negative 3 13.0 Cancer stage Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 N/A 8 1 9 2 1 2 34.8 4.3 39.1 8.7 4.3 8.7 Temporal Relationship Synchronous Metachronous GM before BC BC before GM 15 8 6 2 65.2 34.8 26.1 8.7 Diagnosis Method GM diagnosis Core needle biopsy only Excisional / Incisional Biopsy (EB/IB) Only Mixed methods N/A 9 7 5 2 39.1 30.4 21.7 8.7 Breast Cancer Diagnosis Core needle biopsy only Excisional / Incisional Biopsy (EB/IB) Only Mixed methods N/A 14 5 2 2* 60.9 21.7 8.7 8.7 Treatment of Granulomatous Mastitis Surgical intervention only Conservative management only Mixed 3 8 12 13.0 34.8 52.2 Treatment of Breast Cancer Mastectomy Breast-conserving surgery Hormone therapy Radiotherapy Neoadjuvant chemotherapy Adjuvant chemotherapy 11 9 9 8 7 6 47.8 39.1 39.1 34.8 30.4 26.1 Abbreviations. N/A: not available; GM: granulomatous mastitis; BC: breast cancer; OCP: oral contraceptive pills; IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2. *Chen et al. (2025) was classified as N/A because the biopsy technique was not explicitly reported. Participants A total of 23 female patients with coexisting GM and BC were analyzed. The median age was 42 years (range 30–77 years). The majority were premenopausal (17, 74.0%), followed by postmenopausal (3, 13.0%), and perimenopausal (2, 8.7%); menopausal status was not applicable in 1 (4.3%). Parity data were available for 11 patients: 1 (9.1%) was nulliparous, 1 (9.1%) was primiparous, 8 (72.7%) were multiparous with 2–3 children, and 1 (9.1%) was grand multiparous with 7 children. Lactation history was documented in 9 patients (39.1%): 2 (22.2%) were currently lactating at presentation, 6 (66.7%) had previous lactation ranging from 6 months to 9 years, and 1 (11.1%) had no lactation history. Risk factors were incompletely reported. Oral contraceptive pill use was explicitly denied in 9 (39.1%) and confirmed in 2 (8.7%) (Tables 1 & 2). Main Findings Imaging findings were nonspecific and overlapping between GM and BC. Mammography was performed in 13 (56.5%) of cases, commonly showing asymmetric density, focal opacity, calcifications, or mass lesions. Ultrasound was used in 22 (95.7%) cases, frequently demonstrating irregular hypoechoic areas in 12 (54.5%), heterogeneous echogenicity in 4 (18.2%), skin thickening in 5 (22.7%), ductal dilatation in 3 (13.6%), and occasionally fluid collections or abscesses in 3 (13.6%). Magnetic resonance imaging was performed in 11 (47.8%) cases, revealing non-mass enhancement in 3 (27.3%), rim enhancement in 1 (9.1%), ductal dilatation in 3 (27.3%), and washout kinetic curves suggestive of malignancy in 4 (36.4%). BI-RADS categories ranged from 2 to 5. Among the 9 cases (39.1%) with a documented BI-RADS category, all 9 (100%) had at least one lesion categorized as BI-RADS 4 or 5, indicating high suspicion for malignancy. In 3 cases (13.0%), GM-associated inflammation initially obscured malignant features on imaging, and only after treatment of GM did the underlying cancer become more apparent (Table 3). Table 3. Imaging findings and BI-RADS categorization in coexisting GM and BC Author (year) [ref] MMG US MRI BI-RADS Salih et al., 2025 [2] N/A Heterogeneous area with fluid echogenicity and moderate surrounding edema; localized skin thickening and contour distortion at 2 o'clock (64x27 mm) Heterogeneous non-mass-like enhancement and a small 18-mm central mass; bilateral enlarged axillary lymph nodes N/A Freitas et al., 2020 [20] N/A BI-RADS 4c lesion initially; follow-up showed a residual nodule and a new palpable area A 3-cm irregular nodule with a Type 3 kinetic curve and a 2.4-cm axillary lymph node 4C(US) Zavieh et al., 2024 [8] Focal density in the central outer part of the breast 50x29x22 mm mass-like lesion with undefined borders and dilated ducts containing debris and extending toward the nipple. N/A 4 (US) N/A Hypoechoic irregular spiculated mass with indistinct margins N/A N/A N/A 22x20 mm irregular hypoechoic mass N/A 5 (US) Zhu et al., 2024 [18] N/A Glandular edema and dilated ducts Posterior edema of the glandular layer with ductal dilatation N/A enlarged ducts with dense calcification resembling gravel in the ducts Local glandular hypertrophy with multiple internal hypoechoic nodules Abnormal mass shadowing and ductal dilatation 4A (US) N/A Multiple fluid-filled dark areas N/A N/A Oddó et al., 2019 [6] Diffuse dense breast with focal areas of higher density; no microcalcifications Cutaneous thickening, increased echogenicity of subcutaneous tissue, and multiple collections N/A N/A Tavakol et al., 2022 [9] Large mass (150 mm) in the lateral part of the right breast; no distortion Right: Diffuse heterogeneous ill-defined area with internal microcalcification and skin thickening. Left: well-defined hypoechoic mass R: Asymmetrical parenchymal thickening, multiple rim-enhanced masses (14–35 mm), and extensive NME (140x80x60 mm) with a Type 3 curve L: 23x16mm lobulated mass 4B (US) / 4C (MRI) Yoshida et al., 2023 [4] N/A Irregular hypoechoic area measuring > 4 cm Widespread T2-weighted high-signal lesion with a fast washout pattern and pre-spectral edema Initial:4B (MRI) Follow-up: 4A (MRI) Zangouri et al., 2022 [22] Well-defined high-density mass Irregular hypoechoic mass with tubular extensions N/A N/A Çalış and Kilitçi, 2018 [19] Amorphous mass and focal asymmetric opacity with calcifications Fibroglandular tissue increases with no distinctive borders; inflammatory appearance with right axillary non-reactive lymphadenopathy N/A N/A Xie et al., 2022 [23] N/A Diffusely distributed irregular hypoechoic lesions; skin thickening and increased echogenicity in subcutaneous tissue N/A 4 (US) Evans et al., 2021 [17] Left (GM): Asymmetric density with hyperemia; Right (BC): Clusters of pleomorphic microcalcifications Left (GM): 60-mm irregularity (no collection); Right (BC): irregular lesions measuring 16x11x11 mm and 9x10x7 mm 60mm resectable area N/A Salih et al., 2023 [16] Left: Operative bed deformity, skin thickening, and two rounded scattered faint micro-calcifications below the scar. Right: Solitary benign-looking calcification. Full-length ectatic duct from nipple root to 5–7 o'clock; heterogeneous internal echo and mild surrounding edema Clumped focal non-mass-like enhancement (20x6 mm) within an ectatic duct; surgical bed showed additional heterogeneous NME (19x13 mm) 2 (MMG) / 4 (MRI) Mazlan et al., 2012 [24] Extensive scarring Extensive fibrous scarring noted during follow-up Breast scarring suspicious for malignancy; orbital apex tumor compressing the optic nerve. N/A Chen et al., 2025 [21] Heterogeneous density with uneven distribution; no definite mass Patchy hypoechoic area (8.3 × 1.0 cm) beneath the nipple with irregular shape, clear boundaries, partial ductal distribution, and uneven internal echoes. Color Doppler showed abundant peripheral strip-like blood flow. CEUS revealed rapid, high enhancement with small non-enhanced foci (~1.1 × 0.2 cm). Follow-up imaging confirmed sinus tract formation connecting multiple hypoechoic areas to the skin Multiple hyperintense T2 signal lesions; post-contrast nodules and patchy enhancements in the lower quadrant with a washout-type curve N/A AkbariRad et al., 2025 [7] N/A An ill-defined mass (32x26 mm) in the central region of the right breast N/A N/A Limaiem et al., 2013 [10] A 2.2 x 2.4 cm stellate mass with uneven edges. NA N/A N/A Özşen et al., 2018 [14] NA Heterogeneous, irregularly limited hypoechoic area (3 cm from the subareolar zone), with a 34x9 mm fluid pocket at the 12 o'clock position. N/A N/A Mahmood et al., 2025 [5] Suspicious UOQ lesion Left (Initial): 25.7mm irregular hypoechoic mass + axillary thickening (IDC). Bilateral (Interval): Skin thickening, parenchymal fuzziness, and ductal dilatation with internal avascular echoes (IGM onset) N/A L:4 (MMG) R:2 (US) Kaviani et al., 2017 [15] Distortion and mass-like lesions within extremely dense breast tissue Right: Large hypoechoic mass with irregular borders and multiple echogenic foci; Left: Hypoechoic spiculated mass (30x50 mm). Post-chemo: a single mass (20x12 mm) in the left breast without satellite lesions. N/A Abbreviation. Ref: reference; MMG: mammography; US: ultrasonography; MRI: magnetic resonance imaging; BI-RADS: Breast Imaging Reporting and Data System; N/A: not available; IDC: invasive ductal carcinoma; IGM: idiopathic granulomatous mastitis; CEUS: contrast-enhanced ultrasound; NME: non-mass enhancement; UOQ: upper outer quadrant; L: left; R: right; GM: granulomatous mastitis; BC: breast cancer; chemo: chemotherapy Synchronous coexistence of GM and BC occurred in 15 (65.2%) cases. Among these, the majority demonstrated ipsilateral involvement, with BC arising in the same breast as GM in 11 (73.3%) of synchronous cases. Contralateral GM relative to the cancer was observed in 3 (20.0%), while bilateral GM was observed in 1 (6.7%). The most common BC histologies in synchronous cases were DCIS alone, accounting for 6 (40.0%), and IDC alone in 6 (40.0%), followed by mixed IDC and DCIS in 2 (13.3%), and LCIS in 1 (6.7%). High-grade tumors were observed in 8 (53.3%) of synchronous cases, intermediate-grade in 2 (13.3%), low-grade in 2 (13.3%); grade was not reported in 3 (20.0%) (Tables 2 & 4). Table 4. Granulomatous mastitis and breast cancer characteristics Author (year) [ref] Side Quadrant Laterality (GM) Chronology (GM) Diagnosis method GM Type BC Type Grade ER PR HER2 AJCC Stage Salih et al., 2025 [2] L UOQ Ipsilateral Synchronous GM&BC: CNB Idio IDC+DCIS High + NA + 2A Freitas et al., 2020 [20] R UOQ Ipsilateral Synchronous (after BC during chemotherapy) GM&BC: CNB Non-Idio IDC High + + - 1A Zavieh et al., 2024 [8] L Lateral Contralateral Metachronous (2 years after BC treatment) GM: CNB and IB; BC:N/A Idio IDC N/A + + + 2 R N/A Ipsilateral Metachronous (4 years before BC) GM: N/A; BC: CNB Idio IDC N/A - - - N/A L N/A Contralateral Metachronous (13 years before BC) GM: N/A; BC: CNB Idio IDC N/A + + + N/A Zhu et al., 2024 [18] L LOQ+LIQ Ipsilateral Synchronous GM&BC: CNB Idio DCIS High - - - 0 L Lateral Ipsilateral Synchronous GM&BC: EB Idio DCIS High - - + 0 L N/A Ipsilateral Synchronous GM: EB; BC: CNB Non-Idio DCIS Low + + + 0 Oddó et al., 2019 [6] L UOQ + LOQ Ipsilateral Synchronous GM&BC: CNB and IB Idio DCIS Int + + N/A 0 Tavakol et al., 2022 [9] R UOQ + Lateral Ipsilateral Synchronous GM&BC: CNB Idio LCIS N/A N/A N/A N/A 0 Yoshida et al., 2023 [4] L LIQ Ipsilateral Synchronous GM: FNA and CNB; BC: EB Non-Idio DCIS Low + + N/A 0 Zangouri et al., 2022 [22] L N/A Ipsilateral Metachronous (1 year before BC) GM&BC: CNB Idio IDC High N/A N/A N/A 3A Çalış and Kilitçi, 2018 [19] R RA + UOQ Ipsilateral Synchronous GM&BC: CNB and EB Idio IDC+DCIS High - - + 2A Xie et al., 2022 [23] L Areolar + LOQ Ipsilateral Metachronous (BC masked by GM for 10 months)* GM: CNB; BC: EB Idio IDC Int + + - 2A Evans et al., 2021 [17] L UOQ Contra Synchronous GM: EB; BC: CNB Idio IDC High N/A + - 3A Salih et al., 2023 [16] L LIQ + LOQ Ipsilateral Metachronous (2 years before BC) GM&BC: EB Idio DCIS High + N/A N/A 0 Mazlan et al., 2012 [24] R N/A Ipsilateral Metachronous (8 years before BC) GM: IB; BC: CNB Idio IDC High + + - 4 Chen et al., 2025 [21] L LQ Contralateral Metachronous (3 years after radical mastectomy for BC) GM: EB; BC: Biopsy Idio IDC High - - - 2B AkbariRad et al., 2025 [7] L Lateral Contralateral Synchronous GM&BC: CNB Idio IDC High + - - 2B** Limaiem et al., 2013 [10] R SA Ipsilateral Synchronous GM: EB; BC: CNB Idio IDC Int + + - 2A Özşen et al., 2018 [14] R SA Ipsilateral Synchronous GM: CNB; BC: EB Idio DCIS N/A N/A N/A N/A 0 Mahmood et al., 2025 [5] Bilat PA + RA Bilateral Synchronous (after the 2nd cycle of chemotherapy for BC) GM&BC: CNB Idio IDC High + - + 2B Kaviani et al., 2017 [15] R Central Contralateral Synchronous GM: CNB and IB; BC: CNB Idio IDC N/A + N/A N/A 2A Abbreviation. Ref: reference; L: left; R: right; UOQ: upper outer quadrant; LOQ: lower outer quadrant; LIQ: lower inner quadrant; LQ: lower quadrant; SA: subareolar; RA: retroareolar; PA: periareolar; GM: granulomatous mastitis; BC: breast cancer; CNB: core needle biopsy; EB: excisional biopsy; IB: incisional biopsy; FNA: fine needle aspiration; IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; N/A: not available; Idio: idiopathic; Non-Idio: non-idiopathic; Int: intermediate grade; AJCC: American Joint Committee on Cancer; +, positive; -, negative. * Although the clinical interval between diagnoses was 10 months, this case was classified as metachronous by standard criteria. The authors noted that the malignancy was likely present at the initial presentation. The intense inflammatory response and edema associated with GM provided a diagnostic masking effect, leading to a 10-month diagnostic lag. **The exact number of metastatic axillary lymph nodes was not reported in this case. However, the authors explicitly confirmed the presence of right axillary lymph node metastasis in their summary table. In the absence of quantitative nodal data, the case was classified as N1 based on categorical evidence of axillary nodal involvement. In 6 (26.1%) cases, GM was diagnosed before BC, with intervals ranging from 10 months to 13 years (median approximately 3 years). All patients in this subgroup were premenopausal. The initial presentation of GM was typically a palpable breast mass, and all patients received treatment for GM including corticosteroids, methotrexate, or surgical drainage. Among these, 2 (33.3%) experienced recurrent GM before the cancer diagnosis. The subsequent BC was ipsilateral to the original GM in 5 (83.3%) and contralateral in 1 (16.7%). In 2 (8.7%) of the metachronous cases, BC was diagnosed before GM, with intervals ranging from 2 to 3 years after completion of BC treatment. All patients in this subgroup were premenopausal. In 1 (50.0%), GM developed in the contralateral breast three years after radical mastectomy. Another patient, 1 (50.0%), developed GM two years after completion of BC treatment, presenting with contralateral breast pain and a mass-like lesion (Tables 2 & 4). Management of GM was heterogeneous: conservative treatment (antibiotics, NSAIDs, corticosteroids, methotrexate) alone in 8 (34.8%) of all cases, surgical intervention alone in 3 (13.0%), and mixed approaches in 12 (52.2%). For BC, mastectomy was performed in 11 (47.8%) of cases, breast-conserving surgery in 9 (39.1%). Neoadjuvant chemotherapy was used in 7 (30.4%), adjuvant chemotherapy in 6 (26.1%), hormone therapy in 9 (39.1%), and radiotherapy in 8 (34.8%). Follow-up duration ranged from 2 to 53 months (Tables 2 & 5). Table 5. Management strategies for granulomatous mastitis and breast cancer with follow-up duration Author (year) [ref] Management of GM Management of BC Follow-up duration Salih et al., 2025 [2] AB, ibuprofen, mastectomy + reconstruction WLE, mastectomy + reconstruction, adjuvant CT (Docetaxel, Carboplatin), trastuzumab, ET N/A Freitas et al., 2020 [20] AB NAC, BCS, SLNB, ET 53m Zavieh et al., 2024 [8] Naproxen, open drainage NAC, mastectomy + reconstruction, RT, anti-HER2 therapy, ET N/A Corticosteroids NAC, mastectomy, SLNB, RT N/A Corticosteroids NAC, BCS, SLNB, RT Zhu et al., 2024 [18] Anti-inflammatory therapy, mirabilite compress, WLE BCS, SLNB N/A Anti-inflammatory therapy, aspiration, WLE BCS, SLNB N/A Aspiration, WLE BCS, SLNB N/A Oddó et al., 2019 [6] AB, steroids, MTX, multiple drainages, mastectomy Lumpectomy, total mastectomy >4m Tavakol et al., 2022 [9] Prednisolone, hydroxychloroquine Observation/surveillance 12m Yoshida et al., 2023 [4] Prednisolone, total mastectomy Excision, total mastectomy, ET 18m Zangouri et al., 2022 [22] Prednisolone, MTX N/A N/A Çalış and Kilitçi, 2018 [19] MRM MRM, ALND, adjuvant CT N/A Xie et al., 2022 [23] Rifampicin (6 months), BCS BCS, ALND, RT, ET, adjuvant CT N/A Evans et al., 2021 [17] AB, surgical drainage Oncoplastic WLE, SLNB, ALND, adjuvant CT, RT, ET N/A Salih et al., 2023 [16] Steroids, MTX, simple mastectomy Simple mastectomy, SLNB, ET 6m Mazlan et al., 2012 [24] Repeated drainages, prednisolone Craniotomy and orbital decompression (metastatic disease) 6m Chen et al., 2025 [21] Two surgical resections Mastectomy, ALND, adjuvant CT 36m AkbariRad et al., 2025 [7] Prednisone, MTX NAC, mastectomy, RT, ET N/A Limaiem et al., 2013 [10] Radical mastectomy Radical mastectomy, ALND 2m Özşen et al., 2018 [14] Steroids, surgical excision Surgical excision N/A Mahmood et al., 2025 [5] NSAIDs, steroids, MTX NAC, MRM, adjuvant CT, RT N/A Kaviani et al., 2017 [15] Observation NAC*, BCS, SLNB, RT, ET N/A Abbreviation. Ref: reference; AB: antibiotics; ALND: axillary lymph node dissection; BCS: breast-conserving surgery; GM: granulomatous mastitis; BC: breast cancer; CT: chemotherapy; ET: endocrine therapy; HER2: human epidermal growth factor receptor 2; MRM: modified radical mastectomy; MTX: methotrexate; NAC: neoadjuvant chemotherapy; NSAIDs: non-steroidal anti-inflammatory drugs; RT: radiotherapy; SLNB: sentinel lymph node biopsy; WLE: wide local excision; N/A: not available. *Neoadjuvant Chemotherapy was primarily for the BC, which incidentally aided the resolution of the observed GM mass as well. Discussion It is estimated that approximately 25% of all cancers, including those of the colon, esophagus, stomach, and liver, arise in the setting of chronic inflammation or infection; yet the extent to which this paradigm applies to breast cancer remains uncertain [14]. Because GM produces chronic inflammation within the breast, the coexisting GM and BC cases in this review provide a direct clinical setting in which this question can be examined. Whether the granulomatous response in these cases represents a sarcoid-like reaction to an underlying carcinoma, or whether chronic GM-related inflammation contributes to malignant transformation, remains the central unresolved question that the present findings can help inform [7,10]. In a previous literature review of patients with lobular GM and BC, cases were categorized as GM preceding cancer (45%), concurrent with cancer (45%), and following cancer (10%) [7]. The present analysis shows a higher proportion of synchronous cases (65.2%) and a lower proportion of GM first cases (26.1%). The median age of 40 years reported by that same review aligns closely with the median age of 42 years in this analysis, and both reviews found a predominance of premenopausal women (approximately 75% in both) [7]. The most common presenting symptoms in the present review were palpable breast mass, pain, swelling, erythema, and abscess formation. A previous review reported similar symptoms: palpable mass (100%), swelling (78%), pain (56%), erythema (33%), and abscess (33%) in patients with GM preceding BC [7]. Salih et al. reported a 30-year-old woman who presented with left breast pain for seven days, along with a large palpable lump and axillary lymphadenopathy, initially diagnosed as recurrent GM after a previous episode [16]. Evans et al. noted a distracting presentation of GM in one breast that delayed investigation of contralateral BC, highlighting that GM can be the dominant clinical feature even when malignancy is present elsewhere [17]. Regarding imaging findings, this review found that mammography commonly showed asymmetric density, focal opacity, and calcification. Reported calcification patterns included dense calcification resembling gravel, microcalcifications, focal asymmetric opacity with calcifications, and operative bed deformity with skin thickening [16,18,19]. In contrast, one report described diffuse dense breasts with focal areas of higher density but no evident microcalcifications [6]. On ultrasound, the current review identified irregular hypoechoic areas, skin thickening, ductal dilatation, and fluid collections; additional reports described a heterogeneous area with fluid echogenicity and moderate surrounding edema [2], as well as a BI-RADS 4c lesion with a new palpable area developing during chemotherapy [20]. On MRI, the current review noted non-mass enhancement, rim enhancement, and washout kinetic curves. Reported MRI findings in individual cases included a widespread T2-weighted high-signal lesion with a fast washout pattern and pre-spectral edema (classified as BI-RADS 4B initially and 4A after treatment) [4]; posterior edema of the glandular layer with ductal dilatation [18]; and a clumped focal non-mass-like enhancement with additional heterogeneous non-mass-like enhancement in the surgical bed, classified as MR-4 [16]. The role of core needle biopsy (CNB) in diagnosing coexisting GM and BC remains a subject of debate within the included cases. On one hand, CNB proved sufficient for diagnosing GM in nine (39.1%) and BC in 14 (60.9%) of cases, supporting its use as a first-line sampling tool. Several included cases reached definitive dual diagnoses through CNB alone, suggesting that when adequately targeted, CNB can successfully identify both conditions [2,7,9,18]. On the other hand, excisional or incisional biopsy was ultimately required in 30.4% of GM cases and 21.7% of BC cases, pointing to the inherent sampling limitations of CNB in an inflamed, heterogeneous breast. In some reports, DCIS was identified only after excisional surgery: in one patient, excision followed failure of medical GM therapy; in another, residual post-treatment imaging abnormalities prompted excision after CNB had initially confirmed GM alone [4,14]. Taken together, these findings suggest that while CNB is a reasonable and often adequate initial approach, its diagnostic yield in the setting of GM-associated malignancy is inconsistent, and a low threshold for escalation to excisional sampling should be maintained, particularly in refractory or recurrent cases. Management of GM across the included cases was notably heterogeneous, reflecting the absence of a standardized treatment protocol for this condition. This variability is consistent with the review of AkbariRad et al. who reported that among patients who developed GM before BC, initial GM therapy included systemic corticosteroids alone in 40%, combined with methotrexate in 30%, incision and drainage in 20%, and antibiotics in 10%, with complete resolution requiring a median of 18 months [7]. Several cases in the present review illustrate the refractory nature of GM in this context. Mahmood et al. described a stepwise escalation from NSAIDs to prednisolone and ultimately methotrexate before GM was controlled [5], and Chen et al. required two surgical resections for GM that persisted in the contralateral breast of a BC survivor [21]. Among the three GM cases reported by Zavieh et al., one was managed with naproxen and open drainage, and the other two with corticosteroids alone [8]. The coexistence of GM complicated BC management in several cases. One report described a new palpable area emerging during neoadjuvant chemotherapy that initially raised concern for tumor progression but was ultimately attributed to GM [20], and Mahmood et al. reported GM onset during the second cycle of chemotherapy for BC, necessitating concurrent management of both conditions [5]. These findings highlight that when GM and BC coexist, treatment planning must account for both conditions simultaneously, as the inflammatory process can obscure tumor response assessment and complicate surgical decision-making. Our review has several limitations. First, it relied exclusively on case reports and small case series. Second, incomplete reporting of key variables (e.g., parity, lactation, follow-up) precluded subgroup analyses. Third, most cases originated from Iran and China, limiting generalizability. Conclusion Granulomatous mastitis and BC can coexist synchronously or metachronously, and overlapping imaging features together with the limitations of core needle biopsy frequently delay the diagnosis of malignancy. Clinicians should maintain a low threshold for repeat biopsy or excisional sampling whenever GM fails to respond to standard therapy or recurs. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: BAA, ZDH and LLH: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. DJHR, SJH, ADA, SMA, STL: Literature review, critical revision of the manuscript, and processing of the tables. HAS, SSA, GMF, DKA: Data extraction, data organization, and critical revision. All authors have read and approved the final version of the manuscript. Use of AI: Claude Opus 4.8 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Rational Drug Design Targeting Multidrug-Resistant Microorganisms: A Narrative Review
Abstract Antimicrobial resistance remains a major global health challenge and continues to erode the clinical utility of many existing antibiotics. This review outlines recent advances in rational antibacterial discovery, with emphasis on fully synthetic, structure-guided scaffolds designed to target essential bacterial processes such as cell division, lipid A biosynthesis, DNA replication, and protein synthesis. While many candidate molecules show strong enzymatic inhibition and promising antibacterial activity in vitro, their progress is often limited by poor Gram-negative permeability, active efflux, a narrow spectrum, and off-target toxicity. Recent efforts are therefore focusing on scaffold optimization, prodrug and conjugation strategies, dual-target agents, and combination regimens to improve delivery, broaden activity, and reduce resistance emergence. In parallel, early evaluation of whole-cell potency, efflux liability, pharmacokinetics, and safety appears increasingly important for identifying viable leads. Overall, the evidence suggests that future success in antibacterial development will likely depend on integrating target potency with physicochemical and pharmacological properties from the earliest stages of design. Introduction Antimicrobial resistance (AMR) has emerged as one of the foremost threats to global public health, driven by the rapid evolution and horizontal dissemination of resistance determinants among pathogenic bacteria [1,2]. The proliferation of multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes has rendered many empirical therapies obsolete, a crisis exacerbated by the inherent limitations of semisynthetic modification in generating novel scaffolds [1]. Epidemiological projections corroborate this exigency; the World Health Organization estimates that antimicrobial resistance, which was associated with approximately 4.95 million deaths in 2019, will cause 10 million deaths annually by 2050 [3]. The clinical threat is disproportionately attributed to the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). This group necessitates the development of agents capable of circumventing established resistance mechanisms [4]. The ubiquity of resistance in Methicillin-resistant S. aureus (MRSA) isolates has precipitated a clinical environment in which standard-of-care antibiotics, including vancomycin and linezolid, increasingly fail, necessitating agents that act via novel mechanisms to prevent established resistance pathways [5]. The persistence of S. aureus in cystic fibrosis patients, facilitated by biofilm formation and adaptive virulence factors, underscores the limitations of current therapeutic regimens and highlights the urgent need for novel chemical entities that can disrupt bacterial cell-division machinery [6]. The contemporary stagnation in antimicrobial innovation is attributed not to a paucity of effort, but to the structural obsolescence of a discovery paradigm historically tethered to the finite chemical diversity of natural products [1]. Although natural product isolation defined the mid-20th-century discovery era, the subsequent reliance on semisynthetic modification has proven recalcitrant to the rapid evolution of resistance mechanisms [1]. Specifically, semisynthetic derivatization of the lincosamide class has failed to circumvent the methylation of ribosomal RNA conferred by erm and cfr enzymes, thereby necessitating fully synthetic strategies to access novel chemical space [1]. Concurrently, the financial retrenchment of the pharmaceutical sector has created a critical gap in the development of agents with novel mechanisms of action [7]. Consequently, the ubiquity of derivative compounds in clinical pipelines, inherently susceptible to cross-resistance, has necessitated a paradigm shift toward fully synthetic, rationally designed scaffolds devoid of structural homology to extant pharmacophores [4]. The integration of whole-genome sequencing with high-throughput screening has illuminated a plethora of potential antibacterial targets; however, translating these genomic coordinates into viable clinical candidates remains hindered by high attrition rates in late-stage development [7]. While systems biology has successfully elucidated essential metabolic targets in Mycobacterium tuberculosis, specifically DfrA, FolB, and Tmk, the physicochemical recalcitrance of the bacterial envelope frequently renders these enzymatic inhibitors impotent in vivo, necessitating rigorous in silico validation to mitigate downstream failure [7]. The prohibitively high attrition rate in lead identification is frequently attributed to the physicochemical inability of candidate molecules to permeate the Gram-negative outer membrane or evade active efflux mechanisms, which constitute formidable barriers to intracellular accumulation [8]. To mitigate these physicochemical liabilities before synthesis, structure-based drug design protocols have been deployed to interrogate virulence factors, recently yielding novel coumarin-based antagonists targeting the Salmonella typhi effector protein SipA [9]. The permeation of the Gram-negative cell envelope constitutes the rate-limiting step in contemporary antibiotic development, necessitated by the dual-membrane architecture wherein the outer membrane functions as a stringent permeability checkpoint. Unlike Gram-positive counterparts, these organisms possess a lipopolysaccharide-rich outer leaflet and size-selective porin channels that severely restrict the passage of small molecules, necessitating the optimization of physicochemical properties to achieve adequate intracellular accumulation. Molecules that successfully traverse the outer membrane are frequently effluxed by efflux pumps, which prevent accumulation at the target site. To overcome this exclusion, rational design strategies have evolved to exploit active transport mechanisms via molecular mimicry. For instance, the conjugation of DNA gyrase inhibitors to siderophore mimics facilitates the hijacking of bacterial iron-uptake machinery, thereby causing active transport into the periplasm of E. coli. This "Trojan Horse" strategy exemplifies the paradigm shift from serendipitous discovery to molecular engineering, wherein permeation is structurally conferred rather than incidental [8]. This review delineates the trajectory of rational antimicrobial design, prioritizing novel chemical entities that exploit phylogenetically conserved yet underutilized targets to bypass established resistance mechanisms [10,11]. Search Strategy A literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify studies on the rational design and discovery of novel antimicrobial agents against MDR bacterial pathogens. Publications from 2012 to 2026 were searched, with selected seminal earlier studies included where relevant. Search terms covered three domains: (i) MDR pathogens and antimicrobial resistance (e.g., MRSA, VRE, Acinetobacter baumannii, Pseudomonas aeruginosa, and Mycobacterium tuberculosis); (ii) design approaches (e.g., rational drug design, structure-based drug design, virtual screening, machine learning, and antimicrobial peptide design); and (iii) molecular targets and antimicrobial classes (e.g., FtsZ, LpxC, DNA gyrase, GyrB, dihydrofolate reductase, ATP synthase, antimicrobial peptides, polymyxins, vancomycin, and lincosamides). Articles were selected based on relevance, scientific significance, recency, and representation of major targets and design strategies, with emphasis on studies reporting activity against clinically relevant MDR pathogens. Reference lists of key articles were also screened to identify additional relevant studies. All the references were checked for validity [12]. Rational Design of Small Molecules Cell Division Inhibitors (FtsZ) Filamenting temperature-sensitive mutant Z (FtsZ), the prokaryotic homologue of eukaryotic tubulin, functions as the central orchestrator of bacterial cytokinesis and represents a validated target for antimicrobial intervention [5]. Driven by Guanosine triphosphatase (GTP) hydrolysis, FtsZ polymerizes at the cellular midline to assemble the Z-ring, a dynamic scaffold that recruits divisome components to facilitate septal constriction [6]. Despite preserving the structural fold characteristic of eukaryotic tubulin, FtsZ shares negligible sequence homology (<20%) with its mammalian counterpart, a divergence that minimizes the risk of antimitotic-related neurotoxicity and provides a high margin of selectivity for host safety [6]. This evolutionary distance is particularly significant from a safety-engineering perspective: it implies that potent FtsZ binders need not engage tubulin at therapeutically relevant concentrations, thereby circumventing the peripheral neuropathy and myelosuppression that have hampered repositioning of classical antimitotic agents as antibacterials. As of early 2025, the Protein Data Bank contains 97 FtsZ structures from 12 bacterial species, furnishing an increasingly detailed structural atlas that is driving structure-based inhibitor design across multiple pharmacophore classes [13]. Pharmacological interrogation of FtsZ typically exploits two distinct modalities: orthosteric blockade of the GTP-binding pocket to arrest polymerization, or allosteric modulation of the interdomain cleft (PC pocket), which often stabilizes aberrant polymeric filaments, precipitating cytokinetic failure [14, 15]. The benzamide scaffold remains the most clinically advanced pharmacophore targeting the interdomain cleft, recently optimized to prevent the metabolic instability and solubility limitations inherent to earlier generations. The structure-activity relationship (SAR) of TXH9179, a thiazolopyridine-benzamide derivative incorporating a 6-acetylene functionality, was elucidated via crystallographic analysis (PDB: 8HTB), revealing that the acetylene moiety enables the molecule to adopt a "straight" binding conformation within the S. aureus FtsZ cleft. This conformation maximizes hydrophobic contacts without necessitating the steric rearrangement of residues Met226, Thr309, and Ile311 required by the bent conformation of the trifluoromethyl analogue, TXA707. This structural optimization translated into superior potency, with TXH9179 exhibiting a minimum inhibitory concentration (MIC) of 0.25 μg/mL against a panel of MRSA, vancomycin-intermediate S. aureus, and vancomycin-resistant S. aureus isolates, representing a 4-fold improvement over the comparator, TXA707. To address formulation challenges, the carboxamide prodrug TXH1033 was synthesized for enzymatic hydrolysis by serum acetylcholinesterases. Oral administration of this agent (72 mg/kg) in a murine peritonitis model resulted in 100% survival, significantly outperforming the previous lead prodrug TXA709 [5]. Extending this strategy to Gram-negative pathogens, the second-generation FtsZ inhibitor/acinetobactin conjugate RUP7 linked an oxazole-benzamide pharmacophore to acinetobactin, the native siderophore of A. baumannii [16]. Under iron-limiting conditions, RUP7 exhibited enhanced uptake, likely via the BauABCDEF acinetobactin transport system, and showed potent bactericidal synergy with PBP3-targeting β-lactams such as aztreonam and ceftazidime [16]. This "Trojan horse" strategy exploits bacterial iron-acquisition pathways to overcome the outer membrane permeability barrier that has historically limited benzamide activity against Gram-negative organisms. Efforts to expand the benzamide chemotype also identified four benzodioxane-benzamide derivatives (FZ95, FZ100, FZ116, and FZ118) as the first members of this class with bactericidal activity against Streptococcus pneumoniae [17]. With MICs of 25-80 μg/mL, these compounds disrupted both cell division and elongation, consistent with inhibition of FtsZ polymerization at the interdomain cleft [17]. Together with earlier activity against efflux-deficient E. coli, these findings highlight the benzodioxane-benzamide scaffold as a versatile platform for broader-spectrum FtsZ inhibitor development. Parallel efforts to rigidify the benzamide scaffold involved the introduction of non-planar heterocyclic linkers, specifically through a series of 4,5-dihydroisoxazole-containing benzamides. This campaign identified racemate A16 as a potent polymer stabilizer, and subsequent chiral resolution demonstrated that the S-enantiomer (A16-S) is the eutomer, with an MIC of ≤ 0.125 μg/mL against MRSA ATCC 43300. These findings confirm that stereochemical geometric constraints are critical for maintaining an optimal fit within the hydrophobic cleft [18]. This principle appears broadly applicable: the equivalent chiral selectivity observation has been made independently across the dihydroisoxazole, thiazolopyridine, and benzodioxane series, implying that the PC pocket imposes a stringent chiral filter on binding partners regardless of the linker chemotype employed. Natural products provide a complementary source of FtsZ-targeting scaffolds, although their clinical development has often been limited by mammalian cytotoxicity arising from off-target interactions with eukaryotic tubulin [6]. Sanguinarine and berberine exemplify this challenge: both isoquinoline alkaloids possess antibacterial activity but also exhibit significant toxicity due to their ability to inhibit tubulin polymerization [6]. Recent studies have shown that sanguinarine acts through a distinctive mechanism, inducing unfolding of S. aureus FtsZ and reducing the conformational flexibility required for polymer assembly, rather than simply inhibiting GTPase activity. This mechanism translated into MIC values of 8-16 μg/mL against multidrug-resistant MRSA isolates [19]. Such findings suggest that compounds capable of destabilizing FtsZ structure may represent an underexplored allosteric strategy distinct from the polymer-stabilizing activity of benzamide derivatives. Another promising natural product is magnolol, a hydroxylated biphenyl neolignan derived from Magnolia officinalis. Identified through cell-based screening, magnolol exhibited activity against Gram-positive pathogens, including MRSA and vancomycin-resistant Enterococcus (MIC 8-16 μg/mL), with biochemical studies confirming inhibition of both FtsZ GTPase activity and polymerization. Its antibacterial efficacy was further supported in a Galleria mellonella infection model [20]. Although natural products generally remain less potent than optimized synthetic benzamides, they serve as valuable starting points for medicinal chemistry. For example, alkoxy benzene-berberine derivatives achieved MIC values of 2-16 μg/mL against MRSA and vancomycin-resistant Enterococcus while partially reducing the cytotoxicity associated with the parent alkaloid [20]. Collectively, these studies highlight natural products as a rich source of structurally distinct FtsZ inhibitors and attractive templates for semi-synthetic optimization. While benzamide inhibitors traditionally target the interdomain cleft, recent pharmacophore hybridization strategies have yielded cationic indolyl-acrylamides designed to target the GTP-binding site of FtsZ and reduce the outer membrane impermeability of Gram-negative pathogens. Among these novel scaffolds, the indolyl-acrylamide derivative 12e was synthesized to optimize hydrophobic and electrostatic interactions within the nucleotide-binding pocket. The incorporation of an ethylenediamine tail conferred superior potency; 12e achieved an MIC of 1.2 μg/mL against A. baumannii BAA-747, and 4.3 μg/mL against the XDR clinical isolate A-564, representing a 13-fold improvement over cefepime. Mechanistic characterization attributed this efficacy to a dual mode of action: the compound inhibited FtsZ GTPase activity by 51% at 32 μg/mL and simultaneously caused membrane permeabilization. This dual mode of action, inhibiting FtsZ GTPase activity by 51% at 32 μg/mL while simultaneously permeabilizing the bacterial membrane, is clinically significant because it reduces the probability that single-step mutations in ftsZ will generate full resistance. Subsequent homologation to the butyl-derivative 12j enhanced potency against XDR A. baumannii (MIC 1.2 μg/mL) despite attenuated GTPase inhibition (30.5%), implying that increased lipophilicity shifts the primary mode of action toward membrane disruption [3]. This mechanistic fluidity complicates resistance prediction but may be advantageous in the context of extensively drug-resistant pathogens, where any additional membrane stress is bactericidal. The exploration of fused heterocyclic systems has yielded additional high-potency inhibitors targeting the “Phosphatidylcholine hydrophobic pocket”. Compound C9, a 1-methylquinazoline derivative decorated with a 4-fluorostyryl side chain that interacts with the T7-loop, exhibited potent bactericidal activity against clinical isolates of S. aureus (MIC 0.125 μg/mL) and Bacillus subtilis (MIC 0.0625 μg/mL), with time-kill kinetics confirming rapid bacterial eradication [14]. However, C9 was identified as a substrate of the acrB efflux pump in E. coli, evidenced by a dramatic MIC shift from 256 μg/mL in wild-type strains to 16 μg/mL in ΔAcrB mutants [14]. Expanding on the quinolinium scaffold, Compound A3, a 4-methylpiperidine derivative that functions as a polymer stabilizer, promoted lethal filamentation with an MIC of 1.0 μg/mL against MRSA and 4.0 μg/mL against Vancomycin-Resistant E. faecium, while demonstrating strong synergy with methicillin (FICI = 0.31) [21]. The mechanistic basis of this synergy is interpretable: FtsZ-mediated filamentation sensitizes the bacteria by extending and distorting the division septum, thereby increasing access of the cell wall-active agent. Moving to tricyclic architectures, the benzofuroquinolinium derivative Compound 5 was reported to target the GTP-binding pocket rather than the interdomain cleft, a binding-site alteration that conferred broad-spectrum activity, inhibiting NDM-1-producing E. coli (MIC = 1.0 μg/mL) with no observed resistance after 25 passages [15]. Similarly, Compound 16e, a hybrid of 1-methyl-2-phenylpyridin-1-ium and indole, was introduced as an agent operating via a dual mechanism, allosteric stabilization of the FtsZ T-state and dissipation of the proton motive force, resulting in MIC values of 0.0625 μg/mL for S. aureus and 1.0 μg/mL against A. baumannii [22]. Concurrently, structure-based virtual screening campaigns targeting the allosteric interdomain cleft of FtsZ have precipitated the identification of non-canonical scaffolds. C11, a benzothiophene-oxazole derivative that binds to the allosteric interdomain cleft, exhibited a potent MIC of 2 μg/mL against S. aureus and demonstrated remarkable synergy with carbapenems to restore susceptibility in MRSA strains. This compound inhibited FtsZ polymerization with an IC50 of 47.97 μM and efficiently eradicated mature biofilms at 4 μg/mL [6]. The therapeutic viability of these next-generation inhibitors is further corroborated by their favorable selectivity profiles; C11 maintained >90% viability in A549 epithelial cells at 25 μM, while the quinolinium derivative A3 exhibited negligible hemolytic toxicity (IC5 = 64 μg/mL), thereby circumventing the eukaryotic cytotoxicity often associated with tubulin-homologous targets [6,21]. Critically, the low risk of on-target host toxicity resulting from the limited (<20%) structural homology between FtsZ and tubulin contrasts sharply with the mammalian toxicity observed for natural product inhibitors such as sanguinarine and berberine, highlighting the advantages of structure-guided synthetic drug discovery over direct natural product development [13,23]. Current evidence suggests that the most promising route toward clinically viable FtsZ inhibitors integrates high-resolution structural characterization of inhibitor-FtsZ complexes for rational potency optimization, prodrug or conjugation approaches to overcome pharmacokinetic and permeability barriers, and mechanism-based combination therapies, particularly with cell wall-active antibiotics, to limit resistance development and expand activity against challenging Gram-negative pathogens. Lipid A Biosynthesis (LpxC) The zinc-dependent metalloenzyme LpxC (UDP-3-O-acyl-N-acetylglucosamine deacetylase) constitutes a critical therapeutic target, as it catalyzes the first committed step of the Raetz pathway, an obligate sequence for Lipid A biogenesis and the structural integrity of the Gram-negative outer membrane. Distinguished by its structural conservation across diverse pathogenic species and the absence of mammalian homologues, LpxC presents a theoretical framework for high-selectivity inhibition [24]. However, the medicinal chemistry of LpxC inhibition has historically been plagued by a reliance on hydroxamate-based zinc-binding groups, which often exhibit poor selectivity against host metalloproteins, leading to severe cardiovascular toxicity [25]. The persistence of this toxicity liability across structurally diverse hydroxamate series has led to a broad consensus in the field that the warhead itself, rather than the hydrophobic tail, is the primary driver of off-target metalloprotein engagement, necessitating either radical scaffold departures or precisely engineered steric constraints around the chelating motif [26]. To overcome these off-target effects, contemporary discovery efforts have bifurcated: one trajectory pursues the structural rigidification of the hydroxamate scaffold to enhance selectivity [27]. While the other necessitates the complete dereplication of the hydroxamate warhead in favor of alternative chelating architectures [25]. The therapeutic potential of the hydroxamate pharmacophore was first evaluated clinically via ACHN-975, a novel inhibitor of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) that progressed to Phase 1 trials. In vitro characterization revealed potent enzymatic inhibition (IC50: 0.68 nM) concomitant with broad-spectrum activity against 250 clinical P. aeruginosa isolates (MIC90: 0.25 μg/mL). Despite achieving rapid bactericidal kinetics, defined by a 3-log10 reduction in colony-forming units within 4 hours, the clinical progression of this agent was terminated due to dose-limiting hypotension driven by peak plasma concentrations (Cmax) rather than total exposure. Optimization campaigns subsequently produced LPXC-516 (IC50: 0.71 nM), a lead candidate exhibiting superior efficacy in neutropenic murine lung infection models; however, development was precluded by the reemergence of cardiovascular toxicity, suggesting this liability is intrinsic to the hydroxamate zinc-binding motif utilized in this scaffold series [24]. The mechanistic interpretation is that hydroxamate geometry permits bidentate chelation of zinc in a manner geometrically compatible with both LpxC and human matrix metalloproteinases, and that no amount of peripheral lipophilic tail engineering can fully overcome this promiscuity when the warhead retains full conformational flexibility [26]. To circumvent the promiscuity inherent to flexible hydroxamate linkers, structure-based design was employed to engineer Compound 1(−), a derivative anchored by a chiral L-threonine scaffold. Optimization of the hydrophobic tail with a rigid propargyl ether ensured tunnel occupancy, while a beta-gem-dimethyl group stabilized the zinc-binding group. The resulting compound demonstrated exceptional affinity (IC50 = 0.001 μM) and efficacy against P. aeruginosa (MIC90 = 2 μg/mL), with excellent selectivity against human matrix metalloproteinases (MMPs) and histone deacetylases (IC50 > 30 μM). Yet, a critical limitation persisted. Despite dissociating LpxC inhibition from mammalian cytotoxicity (CC50​ > 295 μM in HepG2 cells), the compound's spectrum remained recalcitrant to expansion, exhibiting negligible activity against broader Enterobacteriaceae [27]. This spectrum gap is particularly consequential given the 2024 WHO priority pathogen list update, which added multiple MDR Gram-negative Enterobacteriaceae as critical priority organisms, underscoring the need for LpxC inhibitors with pan-Gram-negative coverage rather than species-selective activity [26]. The cardiovascular toxicity intrinsic to the hydroxamate pharmacophore necessitated structural divergence, culminating in the engineering of TP0586532, an inhibitor that utilizes an N-hydroxyformamide zinc-binding group anchored to a 2-hydroxymethyl imidazole scaffold. This compound exhibited an IC50 of 0.101 μM against Escherichia coli LpxC and demonstrated broad-spectrum potency against carbapenem-resistant K. pneumoniae (MIC90 = 4 μg/mL) and mcr-1 positive colistin-resistant E. coli (MIC = 2 μg/mL). Notably, the replacement of the hydroxamate warhead resulted in a selectivity index exceeding 700-fold against human MMPs, and in vivo safety assays corroborated the absence of hypotension or QT prolongation in guinea pig models [25]. The crystallographic structure of TP0586532 bound to P. aeruginosa LpxC (PDB: 7DEM) provided the foundation for a second generation of 2-(1-S-hydroxyethyl)imidazole inhibitors, now the most actively developed non-hydroxamate LpxC chemotype [26]. Building on this scaffold, Forge Therapeutics disclosed compounds 46 and 47 in 2022, both exhibiting improved antibacterial activity over TP0586532 in preclinical pneumonia models, while Blacksmith Pharmaceuticals reported compound 48 in 2024, optimized specifically for P. aeruginosa lung infections [26]. In parallel, incorporation of an aromatic acetylene substituent into the P4 region generated compound 49, which displayed enhanced oral bioavailability against Gram-negative pathogens [26]. Together, these advances reflect growing industrial commitment to non-hydroxamate LpxC inhibitors, motivated by the favorable safety and efficacy profile first demonstrated by TP0586532. Academic efforts have simultaneously pursued scaffold-hopping strategies to identify alternative zinc-binding group architectures. Chen and colleagues recently reported hydrazone-containing derivatives of the clinical reference inhibitor CHIR-090 that retained antibacterial activity against E. coli while exhibiting low HepG2 cytotoxicity and favorable plasma protein binding [28]. The hydrazone moiety was designed to engage the hydrophobic tunnel of LpxC and modulate physicochemical properties, with docking studies indicating key interactions with Trp191 and Cys63 [28]. Notably, these same residues are targeted by the oxazolidinone-based inhibitor 23j, previously identified by Kurasaki and colleagues through a scaffold-hopping campaign that yielded nanomolar LpxC inhibition and potent activity against both E. coli and K. pneumoniae with low susceptibility to efflux [29]. The recurrent engagement of Trp191 and Cys63 across structurally distinct inhibitor classes suggests that these residues constitute a pharmacophoric hotspot that may serve as a valuable focus for future LpxC inhibitor design. While the non-hydroxamate strategy appears to have resolved the toxicity bottleneck, the genetic plasticity of the target persists as a challenge. Resistance frequencies as high as 9.3×10−7 were observed in K. pneumoniae, attributed to mutations in the fabZ gene, which regulates the supply of fatty acid substrates to the LpxC pathway [25]. The mechanistic basis of FabZ-mediated resistance is now well established. Increased FabZ activity redirects acyl-acyl carrier protein (ACP) flux toward phospholipid biosynthesis, thereby reducing competition for LpxC substrates and restoring the lipid A/phospholipid balance disrupted by LpxC inhibition. As a result, bacterial cells can compensate for the enzymatic blockade without directly modifying the drug target itself [26]. Notably, this resistance mechanism appears to be chemotype-independent, having been reported across hydroxamate, N-hydroxyformamide, and sulfonamide-hydroxamic acid LpxC inhibitor classes. These findings suggest that FabZ upregulation represents a broadly conserved adaptive response to LpxC inhibition and highlight the potential need for combination therapies or FabZ co-targeting strategies to overcome resistance [26]. DNA Replication (Gyrase B & ParE Inhibitors) The maintenance of genomic topology, a prerequisite for replication, transcription, and decatenation, is governed by the bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV [8]. While the clinical utility of fluoroquinolones relies on the stabilization of the DNA-enzyme cleavage complex, the emergence of resistance has necessitated the exploration of inhibitors targeting the N-terminal ATPase domains of GyrB and ParE [4,8]. These subunits are integral to the transduction of free energy derived from ATP hydrolysis, a process that drives the introduction of negative supercoils into the DNA lattice [30]. Consequently, competitive inhibition at the ATPase active site, a locus distinct from the fluoroquinolone binding pocket, circumvents the resistance mechanisms conferred by mutations in gyrA and parC, thereby restoring potency against recalcitrant MDR isolates [31]. Despite the strong mechanistic rationale for targeting GyrB and ParE, clinical translation has proven challenging. Numerous ATPase inhibitor series have advanced into preclinical or clinical development, yet most have ultimately been limited by toxicity concerns, unfavorable pharmacokinetic properties, insufficient antibacterial spectrum, or the rapid emergence of resistance. Consequently, no GyrB/ParE ATPase inhibitor has achieved regulatory approval to date, highlighting the difficulty of converting potent target-based inhibition into safe, durable, and broadly effective antibacterial therapy [32]. Recent structural interrogations of the benzothiazole scaffold have necessitated a granular mapping of the E. coli GyrB ATP-binding pocket to identify exploitable subsites for enhanced ligand affinity. Specifically, the topology of the "hydrophobic floor," a lipophilic region defined by residues Ile78, Pro79, Ile94, and Ala98, was delineated as offering a distinct trajectory for inhibitor extension. Through the synthesis of benzothiazole-pyrrole-2-carboxamide derivatives, it was elucidated that N-benzylation of the carboxamide moiety (Compound 3) enables the inhibitor to accommodate the conformational plasticity of this sub-site, a behavior corroborated by potential energy surface calculations. Compound 3 manifested superior potency against E. coli DNA gyrase (IC50 = 19 ± 3 nM); this efficacy is attributed to the maintenance of the canonical Asp73 hydrogen bond network concomitant with the establishment of stabilizing interactions within the hydrophobic floor, specifically involving Lys103 [30]. A complementary quantum theory of atoms in molecules analysis by Zidar and colleagues further refined the understanding of ligand–target interactions within this scaffold. Studying a series of N-(benzothiazol-2-yl)pyrrolamide derivatives, the authors quantified the electron-density contributions of individual binding contacts and demonstrated that substituents oriented toward the hydrophobic floor contribute disproportionately to overall binding affinity relative to their size. These findings provide a high-resolution mechanistic framework for structure-based optimization and suggest that strategic elaboration of floor-facing substituents may represent a particularly productive direction for future fragment-growing campaigns within this chemical series [33]. While benzothiazole scaffolds exhibit exceptional enzymatic affinity, their translation into whole-cell activity against Gram-negative pathogens is frequently abrogated by the synergistic exclusion of the outer membrane barrier and active efflux mechanisms. To overcome these permeation deficits, siderophore-mediated active transport was exploited, conjugating the benzothiazole core to a hydroxypyridinone moiety designed to mimic ferric-siderophore complexes and facilitate uptake via bacterial iron-transport machinery. The resultant conjugate, 18b, retained low-nanomolar inhibitory potency against E. coli GyrB (IC50: 22 ± 6 nM) and demonstrated confirmed iron(III) chelation capacity through nuclear magnetic resonance spectroscopic titration. Microbiological profiling revealed that while 18b remained recalcitrant against wild-type E. coli (MIC >50 µM), significant potency was restored against the efflux-deficient ΔtolC strain JW5503 (MIC 12.5 µM) under iron-depleted conditions. These data elucidate that although the siderophore moiety facilitates periplasmic access, the elevated topological polar surface area (149.4 Å²) conferred by the conjugate renders the molecule a substrate for rapid efflux, necessitating further physicochemical optimization to ensure intracellular accumulation [8]. This result mirrors an identical bottleneck encountered in benzamide FtsZ inhibitor conjugates and underscores a field-wide challenge: siderophore conjugation reliably improves outer membrane penetration but cannot compensate for poor efflux pump evasion when the conjugated payload is itself an efflux substrate. Future design iterations for both target classes will likely require explicit efflux liability profiling as a primary filter rather than a late-stage assay [8,16]. Ligand-based virtual screening has led to the discovery of diverse chemotypes targeting the ATPase domain, identifying the 2,3-diaminoquinoxaline scaffold as a potent inhibitor class. The lead compound, 6c, interacts electrostatically with Arg84 and forms hydrogen bonds with Lys118 and Glu58 within the S. aureus GyrB active site. This molecule demonstrated robust antibacterial activity against MRSA clinical isolates (MIC of 0.5 µg/mL), equivalent to that of vancomycin. Conversely, the arylaminotriazine hit AG-205/33156020 exhibited superior enzymatic inhibition (IC50: 1.1 µM) but weaker whole-cell activity (MIC: 4–8 µg/mL), confirming the challenge of membrane permeation in this target class [4]. The disconnect between enzymatic potency and whole-cell MIC observed across these series is not surprising given the absence of a defined permeability pharmacophore in most ATPase inhibitor design campaigns; the field increasingly recognizes that lipophilicity and molecular weight must be treated as first-class design parameters, not afterthoughts [32]. To evade the metabolic instability and suboptimal pharmacokinetics of the clinical candidate zoliflodacin (ETX0914), a systematic derivatization of the benzisoxazole scaffold was undertaken, specifically targeting the oxazolidinone ring, which is prone to oxidative degradation. The introduction of a spirocyclopropane moiety at the C5 position yielded compound 33e, which demonstrated potent activity against MRSA (MIC <0.03–0.06 µg/mL) and Neisseria gonorrhoeae (MIC90: 0.125 µg/mL). Molecular docking elucidated that 33e retains the pharmacophoric hydrogen bond with Asp437 necessary to stabilize the DNA-cleavage complex, while the spirocyclopropane motif establishes additional hydrophobic contacts with Asn476. Subsequent bioisosteric modulation, replacing the oxazolidinone with a thiazolidinone core, culminated in compound 39e; this analogue exhibited superior metabolic stability and achieved a four-fold improvement in in vivo efficacy (ED50: 2.54 mg/kg) compared to the parent zoliflodacin in a murine model of systemic MRSA infection [31]. The clinical relevance of the zoliflodacin scaffold has since been directly validated: a global Phase III non-inferiority trial demonstrated that a single 3 g oral dose of zoliflodacin achieved a microbiological cure rate of 90.9% in urogenital gonorrhea, non-inferior to the ceftriaxone/azithromycin dual standard-of-care regimen, and the FDA accepted a New Drug Application for the agent in 2025 [34]. Crucially, zoliflodacin activity was unaffected by mutations in gyrA, gyrB, parC, or parE that elevate fluoroquinolone MICs, providing the first clinical-scale confirmation that the spiropyrimidinetrione binding mode on GyrB is genuinely orthogonal to fluoroquinolone resistance mechanisms [35]. This clinical milestone validates GyrB cleavage-complex stabilization as a viable antibacterial strategy and is likely to reinvigorate efforts to develop next-generation spiropyrimidinetriones with improved Gram-negative activity. A major challenge in GyrB/ParE inhibitor development has been mitigating mitochondrial toxicity without compromising antibacterial activity. Addressing this issue, Zhao and colleagues developed a hydroxyisopropyl pyridazine-substituted pyrrolamide (compound 28) that retained potent GyrB inhibition while markedly reducing mitochondrial toxicity, likely through improved selectivity over the human mitochondrial topoisomerase. This strategy provides a promising framework for future optimization of GyrB-targeting scaffolds [36]. Recent strategies have also explored dual-targeting agents to mitigate resistance development, leading to the synthesis of coumarin-1,3,4-thiadiazole hybrids designed to inhibit both GyrB and the enoyl-ACP reductase (FabI). Compound 7i, featuring a meta-nitro substitution, demonstrated significant activity against A. baumannii (MIC: 16 µg/mL). It has been suggested that this molecule occupies the ATPase domain of GyrB via π-anion interactions with Asp163, while simultaneously blocking the NADH-binding cleft of FabI. This dual-mechanism approach offers a viable strategy for overcoming the limitations of single-target ATPase inhibitors [37] Ribosome Inhibitors The bacterial 70S ribosome Peptidyl Transferase Center remains a validated target, yet the utility of traditional lincosamides is compromised by erm-encoded rRNA methyltransferases. These enzymes dimethylate nucleotide A2058, creating a steric clash that confers cross-resistance to MLSB antibiotics. To overcome the limitations of semi-synthetic modifications, component-based total synthesis was employed to access novel chemical space that could bypass these barriers [1]. The absence of any new lincosamide entering clinical trials since 1970 highlights the formidable challenge posed by MLS_B resistance and supports the shift toward fully synthetic scaffolds capable of accessing chemical space beyond the reach of traditional semi-synthetic approaches [38]. This approach necessitated replacing the clindamycin pyrrolidine core with a rigidified oxepanoproline scaffold, designed to pre-organize the antibiotic for ribosomal binding. The initial rigidified prototype, OPP-1, failed to inhibit constitutively methylated strains, necessitating the addition of a hydrophobic moiety. This optimization yielded Iboxamycin (IBX), featuring a C7'-α-isobutyl extension. Crystallographic analysis revealed that IBX induces a conformational shift, displacing the methylated A2058 nucleotide by approximately 2 Å while anchoring into a hydrophobic cleft defined by residues A2451 and C2452. These compensatory hydrophobic interactions provide sufficient binding affinity to override the steric hindrance conferred by methylation [1]. Although iboxamycin substantially overcomes Erm- and Cfr-mediated resistance, its activity can still be partially compromised by ABCF ribosomal protection proteins, which displace the antibiotic through ribosome remodeling rather than target modification. Nevertheless, studies suggest that the high ribosomal affinity of iboxamycin limits the effectiveness of this resistance mechanism under clinically relevant conditions [39,40]. Additionally, Cfr-mediated C8-methylation of A2503 confers only moderate resistance to IBX (MIC of 2–8 μg/mL compared to 0.06 μg/mL for cfr-negative strains), a partial resistance profile that the Myers group explicitly used to guide the next cycle of optimization [40]. This active site remodeling conferred exceptional potency against MDR pathogens, including c-ermA-positive S. aureus (MIC 1 μg/mL) and lsaA-expressing Enterococcus faecalis (MIC 0.06 μg/mL). Departing from the spectrum of traditional lincosamides, IBX demonstrated expanded activity against Gram-negative pathogens, including carbapenem-resistant A. baumannii and E. coli. SAR analysis confirmed the critical role of the C7'-α stereochemistry; the β-epimer exhibited reduced potency against Gram-negative isolates, underscoring the need for precise geometric alignment to enhance target engagement [1]. The safety profile of IBX is attributed to the ubiquity of a G2058 residue in human mitochondrial rRNA, which precludes antibiotic binding. Consequently, the compound exhibited no cytotoxicity against HepG2 cells and did not inhibit mitochondrial protein synthesis. In a murine model of Streptococcus pyogenes infection, IBX conferred 100% survival at 3 mg/kg, with 24% oral bioavailability, thereby validating the displacement mechanism as a viable strategy for overcoming methylation-based resistance [1]. Building on the success of iboxamycin, subsequent generations have leveraged conformational pre-organization to further enhance potency, spectrum, and resistance evasion. Cresomycin introduced a bridged macrobicyclic scaffold that locks the molecule into its bioactive conformation, improving activity against multidrug-resistant Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa, while retaining efficacy against multiple resistance mechanisms [41]. The latest analogue, BT-33, further optimized this strategy through structural modifications that strengthen ribosomal interactions and increase conformational rigidity, resulting in enhanced potency, improved pharmacokinetics, and favorable preclinical efficacy against multidrug-resistant pathogens [38]. Collectively, the progression from iboxamycin to cresomycin and BT-33 exemplifies a rational structure-guided medicinal chemistry program that has transformed a resistance-limited antibiotic class into a promising broad-spectrum antibacterial platform. Cell Wall Biosynthesis & Metabolic Pathways The escalating morbidity attributed to the "ESKAPE" pathogens, particularly MDR S. aureus and A. baumannii, has precipitated a paradigm shift away from conventional antibiotics toward novel targets that lack mammalian homologues. Concomitantly, rational drug design has necessitated the deployment of molecular hybridization, a strategy generating dual-mechanism scaffolds engineered to subvert established resistance pathways by simultaneously interrogating distinct pharmacological targets [37]. This strategic shift is further supported by the 2024 WHO Bacterial Priority Pathogen List, which continues to identify several ESKAPE pathogens, including carbapenem-resistant Acinetobacter baumannii and vancomycin-resistant Enterococcus faecium, as high-priority threats with limited treatment options, underscoring the urgent need for antibiotics with novel mechanisms of action [42]. To identify novel therapeutic candidates within the S. aureus core genome, researchers employed hierarchical subtractive genomics to filter for proteins that are essential to the pathogen yet non-homologous to the human host [43]. Through hierarchical subtractive genomics, two critical, non-host homologous targets were elucidated in MDR S. aureus: Aspartate-semialdehyde dehydrogenase (Asd) and Anthranilate synthase component II (TrpG). Asd is pivotal for the aspartate biosynthesis pathway, including the diaminopimelate and lysine biosynthetic processes, which are crucial for microorganisms' essential amino acids and cell biosynthesis. In silico screening of the Traditional Chinese Medicine library identified ZINC85492658 as the lead candidate, exhibiting a superior binding affinity (ΔGbind = −57.72 kcal/mol) for the Asd active site; notably, thermodynamic decomposition revealed this interaction is driven primarily by Van der Waals forces (−61.84 kcal/mol) rather than Coulombic attraction, which presented an unfavorable energy penalty [43]. Similarly, for the metabolic target TrpG, the Traditional Chinese Medicine library yielded ZINC70455378 (ΔGbind = -35.33 kcal/mol), suggesting that targeting the biosynthesis of aromatic amino acids can effectively starve the bacterium of essential metabolic building blocks. These findings corroborate the potential of small-molecule inhibitors to target essential metabolic pathways, thereby compromising bacterial growth and survival by disrupting the synthesis of critical amino acids and metabolites [43]. A key limitation of this approach is that computational predictions do not necessarily translate into whole-cell antibacterial activity. As neither lead compound has been validated by enzymatic inhibition or MIC testing, the subtractive genomics pipeline should be viewed as a target prioritization and hit-identification strategy rather than a complete drug discovery workflow. Nonetheless, it remains a valuable tool for efficiently narrowing the pool of potential drug targets in multidrug-resistant pathogens and guiding subsequent experimental validation [44]. A significant challenge in targeting the later stages of cell wall synthesis is the VanA-type resistance mechanism in Enterococci, where the D-Ala-D-Ala terminus is reprogrammed to D-Ala-D-Lac, reducing vancomycin affinity by 1000-fold. Researchers circumvented this resistance by engineering lipophilic vancomycin analogues that incorporate a quaternary ammonium cation. This modification confers a dual mechanism of action: the glycopeptide backbone retains Lipid II binding, while the lipophilic tail precipitates rapid membrane depolarization and permeabilization. The tetradecyl-derivative (Compound 6) demonstrated remarkable potency against vancomycin-resistant E. faecium, achieving an MIC of 0.7 μM, a >1000-fold improvement over native vancomycin. Furthermore, the octyl-derivative (Compound 4) exhibited superior safety profiles (non-hemolytic up to 1000 μM) and efficacy in a neutropenic mouse thigh infection model against MRSA, demonstrating a 3-log kill potency compared to the ED1-log kill potency of vancomycin. Crucially, this membrane-disrupting modality prevented the evolution of resistance in MRSA even after 52 serial passages, attributed to the difficulty of bacteria to remodel their entire membrane architecture [45]. This concept was further supported by the aryl sulfonium-modified vancomycin derivatives reported by Xie and colleagues, which displayed markedly enhanced activity against both MRSA and VRE through a dual mechanism involving membrane disruption and inhibition of cell wall biosynthesis. The lead compound demonstrated potent in vivo efficacy and favorable pharmacokinetic properties, highlighting the therapeutic potential of combining target engagement with membrane-directed activity [46]. Together with quaternary ammonium lipidated analogues, these findings suggest that introducing positively charged, membrane-interacting functionalities may represent a broadly applicable strategy for overcoming glycopeptide resistance and expanding the design space of next-generation vancomycin derivatives. Beyond the peptidoglycan layer, the integrity of the bacterial membrane relies on the Type II Fatty Acid Synthesis pathway, specifically the enoyl-acyl carrier protein reductase (FabI). Researchers rationally designed novel coumarin-1,3,4-thiadiazole Schiff base hybrids to target FabI, exploiting the enzyme's hydrophobic active site. SAR analysis revealed that the electronic character of the phenyl ring substituents dictated strain selectivity. Compound 7i, featuring a meta-nitro substitution, demonstrated superior potency against carbapenemase-producing A.baumannii (MIC 16 μg/mL), effectively circumventing the resistance mechanisms that rendered the strain recalcitrant to ciprofloxacin (MIC >2 μg/mL) [37]. Molecular docking corroborated this activity, revealing that 7i occupies the NADH-binding cleft of the A. baumannii FabI reductase with a binding energy of -9.7 kcal/mol, stabilized by specific hydrogen bonding with Ile22 and π-cation interactions with Lys166. Conversely, the introduction of a thiophene bioisostere (Compound 7m) shifted the spectrum toward Gram-positive pathogens, achieving an MIC of 32 μg/mL against S. aureus via enhanced π-π stacking within the hydrophobic pocket. These data indicate that hybridization of pharmacophores can yield "broad-spectrum" scaffolds that are tunable to specific MDR pathogens through precise substituent modification [37]. The clinical advancement of afabicin has validated FabI and the FASII pathway as tractable antibacterial targets; however, its lack of Gram-negative activity highlights the persistent challenge of outer membrane permeability. This limitation was addressed through permeation-guided optimization, culminating in fabimycin, which demonstrated potent activity against multidrug-resistant Gram-negative pathogens and efficacy in multiple animal infection models [47]. These findings illustrate how rational permeability engineering can extend the utility of validated targets to Gram-negative bacteria and provide an important framework for future FabI inhibitor development. Peptide Engineering & Peptidomimetics De Novo Amphipathic Peptides The renaissance of antimicrobial peptide (AMP) therapeutics is predicated on the transition from the isolation of natural products to the rational, de novo design of synthetic sequences [48, 49]. Unlike traditional antibiotics that target specific enzymatic pockets, de novo amphipathic peptides are engineered to exploit the fundamental electrostatic and hydrophobic disparities between prokaryotic and eukaryotic membranes [50]. The central design philosophy governs the segregation of cationic residues (typically Arginine or Lysine) to drive initial electrostatic attraction to anionic bacterial lipids (Lipid A, phosphatidylglycerol), and hydrophobic residues (Tryptophan, Leucine, Isoleucine) to facilitate insertion into the non-polar acyl core of the bilayer [11,51,52]. A key advantage of membrane-targeting agents is their high barrier to resistance. Because bacterial membrane composition is governed by multiple essential biosynthetic pathways, extensive remodeling is often biologically costly, making resistance less readily acquired than for antibiotics directed against single enzymatic targets. This property is increasingly recognized as an important contributor to the long-term therapeutic potential of antimicrobial peptides and other membrane-active agents [53]. The optimization of the "idealized amphipathic helix" requires a precise calibration of sequence length and amino acid composition to maximize the Minimum Optimal Length (MOL) parameter [51]. Excessive length is unnecessary for potency; by engineering the 12-residue peptide WR12 (composed exclusively of Arginine and Tryptophan), researchers achieved potent bactericidal activity (MIC: 4 μg/mL against MDR P. aeruginosa) comparable to the 24-residue parent peptide WLBU2 [48]. The positioning of Tryptophan residues at the hydrophilic-hydrophobic interface is critical, as the indole ring anchors the peptide to the membrane surface, facilitating the insertion of the helical core [51]. A critical divergence in SAR involves the selection of cationic residues. While Arginine provides robust membrane binding via bidentate hydrogen bonding with phosphate headgroups, this strong interaction often extends to zwitterionic mammalian membranes, resulting in toxicity [49]. In a systematic comparison of 12-mer helical peptides, the Arg-rich analogue (Peptide 8a) exhibited high hemolytic activity (HC50 = 45 μg/mL), whereas the Lysine-substituted analogue (Peptide 8b) retained broad-spectrum potency (MIC 3.1–6.2 μg/mL against MRSA and A. baumannii) but exhibited a significantly improved safety profile (HC50= 280 μg/mL) [49]. Building on the importance of amphipathic organization, Zhang and colleagues redesigned the classical (XXYY)n α-helical template to better align with the natural 3.6-residue-per-turn geometry of α-helices. The resulting template enhanced the segregation of cationic and hydrophobic faces, producing peptides with improved antimicrobial selectivity. The lead peptide, H-R, demonstrated potent activity against multidrug-resistant bacteria and biofilms, low propensity for resistance development, and favorable in vivo efficacy and safety, highlighting a broadly applicable framework for antimicrobial peptide design [54]. Furthermore, to address proteolytic instability, a "leucine-centric" design was applied to the peptide P-α-02-B. By substituting specific Leucine residues with D-Isoleucine, the derivative H-10 was developed, which displayed exceptional stability (t1/2 > 6h against chymotrypsin) without compromising antimicrobial potency (MIC: 1.56–3.13 μM against MDR isolates) [11]. An important consideration in D-amino acid engineering is that complete enantiomerization does not necessarily improve therapeutic performance. Although full D-substitution can enhance proteolytic stability while preserving in vitro antimicrobial activity, it may also disrupt secondary structure formation in membrane-like environments and reduce in vivo efficacy. Consequently, selective D-substitution at protease-sensitive sites is often a more effective strategy than global inversion of peptide chirality [55]. The bactericidal efficacy of these de novo peptides is driven by rapid membrane permeabilization, often occurring within minutes of exposure. Confocal microscopy and scanning electron microscopy analyses of the Long Short-Term Memory-designed peptide NN2_0050 revealed massive cytoplasmic leakage and a flaccid, ridged morphology in E. coli, confirming a lytic mechanism of action [49]. Similarly, the engineered peptide PAX E35 induced irreversible membrane permeabilization in colistin-resistant P. aeruginosa (PA239) in under 10 minutes, as evidenced by propidium iodide uptake [51]. Molecular dynamics simulations provide an atomistic resolution of this interaction. It was observed that the lead peptide 8b undergoes a structural transition from a random coil in aqueous solution to a stable amphipathic α-helix upon contact with the lipid bilayer. The simulations indicated that hydrophobic side chains (Leu/Ile) drive deep insertion into the anionic bacterial membrane, whereas interactions with zwitterionic mammalian lipids remain superficial, explaining the selectivity [50]. These findings are consistent with recent machine learning-assisted AMP discovery studies, which have identified charge and hydrophobicity as the principal determinants of antimicrobial activity. By combining XGBoost-based prediction with physicochemical feature analysis, Bhangu and colleagues achieved high classification accuracy and successfully identified experimentally active novel peptides, demonstrating the utility of ML for accelerating AMP hit discovery while emphasizing the continued necessity of experimental validation to confirm biological activity [56]. Conversely, the peptide PEP-36, designed via a recurrent neural network, showed no in vitro activity due to helical unraveling at the membrane surface, yet achieved the highest survival rate (66.7%) in a murine sepsis model, suggesting an alternative in vivo mechanism potentially linked to immunomodulation [2]. This observation highlights a broader limitation of AMP discovery pipelines: conventional in vitro screening may overlook peptides whose primary activity depends on immunomodulatory or intracellular mechanisms rather than direct membrane disruption. Accordingly, future machine learning frameworks should incorporate predictions of host-directed and immunomodulatory activity alongside antimicrobial potency to better capture clinically relevant AMP candidates [53]. A major recent advance in the field has been the application of large-scale metagenomics and machine learning to mine the global microbiome for novel AMP sequences. Using this approach, Santos-Júnior and colleagues developed the AMPSphere resource, identifying more than 860,000 nonredundant candidate AMPs from environmental and host-associated microbiomes, most of which have no counterpart in existing databases [57]. Experimental validation confirmed antimicrobial activity for the majority of tested candidates, many of which were active against drug-resistant pathogens through membrane-disruptive mechanisms while sparing commensal bacteria. By dramatically expanding the pool of discoverable AMP sequences, AMPSphere represents a significant shift in the scale and efficiency of AMP hit identification and provides a valuable foundation for future antimicrobial development [57]. The clinical viability of de novo peptides is defined by the Therapeutic Index (TI), which is calculated as the ratio of the hemolytic concentration (HC50) to the antimicrobial potency (MIC). It was demonstrated that while maximizing cationicity increases potency, it often compromises safety; the Lysine-clustered analogue 6K-1426 exhibited drastic mammalian cytotoxicity (IC50 = 1.178 μM in HaCaT cells). In contrast, the rationally designed QUB-1426 achieved a perfect amphipathic balance, yielding a TI of 30.76 and 100% survival in an in vivo Galleria mellonella infection model [52]. Similarly, the D-amino acid substituted peptide H-10 demonstrated a TI of 30.33 and a favorable pharmacokinetic profile, reducing bacterial load by >3 log units in murine organs following intravenous administration [11]. Importantly, therapeutic indices exceeding 10 are generally regarded as a key benchmark for systemic development. The emergence of multiple independent AMP discovery strategies, including rational design, machine learning-guided optimization, D-amino acid engineering, and metagenomic mining, that consistently achieve therapeutic indices in the 10–30 range, suggests that the field is nearing the requirements for clinical translation. At present, the principal barriers are less related to antimicrobial potency or selectivity and more to pharmacokinetics, manufacturing scalability, and regulatory development pathways, emphasizing the need to complement sequence optimization with advances in formulation and translational development [53,56]. Peptidomimetics & Backbone Modifications The clinical translation of natural AMPs is severely hampered by their rapid degradation by both bacterial proteases and host serum enzymes, resulting in poor pharmacokinetic profiles that preclude systemic administration. Furthermore, MDR pathogens frequently evolve surface modifications, such as the aminoarabinose (L-Ara4N) modification of Lipid A in P. aeruginosa, to electrostatically repel cationic peptides [58]. To overcome these barriers, peptidomimetics employ non-natural backbones that evade enzymatic recognition while retaining the specific amphipathic topology required for membrane disruption. By shifting the side chain from the α-carbon to the amide nitrogen, N-substituted glycines (peptoids) render the oligomer backbone invisible to proteases while maintaining the spatial arrangement of pharmacophores [59]. Peptoids achieve intrinsic, chemotype-independent protease resistance through their N-substituted glycine backbone, which is not recognized by endogenous proteases, unlike residue-specific D-amino acid substitution strategies [60]. Hybridization of these protease-resistant scaffolds with natural amino acids optimizes selectivity; notably, the alternating α-amino acid/α-peptoid hybrid 4 exhibited potent activity against NDM-1-producing E. coli (MIC = 2 μM) while maintaining a favorable therapeutic index (TI > 21) against HeLa cells, a profile superior to the significant cytotoxicity observed in homologous all-β3-amino acid oligomers (IC50 ≈ 31 μM) [59]. Extending peptoid applications to previously neglected pathogens, a 2024 study demonstrated potent activity against MDR ocular pathogens, including XDR P. aeruginosa resistant to all clinically available antibiotics, including polymyxins. Selected peptoids retained acceptable mammalian cell selectivity, highlighting their potential for topical ophthalmic therapy, where proteolytic stability and reduced concerns regarding systemic toxicity are particularly advantageous [61]. To circumvent the limitations of purely electrostatic targeting, a phosphate-recognition strategy was implemented by conjugating antimicrobial peptoids with zinc-dipicolylamine (ZnDPA) and bivalent Zn2BPMP motifs. This design facilitates specific coordination with anionic bacterial surface components, such as lipopolysaccharides and lipoteichoic acids, thereby enhancing membrane selectivity independent of cationic charge density. The resulting conjugate, 8_Zn4, exhibited potent activity against Colistin-resistant E. coli (MIC = 6.3 μM) and Carbapenem-resistant A. baumannii (MIC = 1.6 μM). The Zn-mediated recognition mechanism conferred a superior safety profile, effectively abolishing hemolytic activity (0% at 100 μM) and yielding a selectivity index exceeding 32. In a murine sepsis model, the mono-BPMP analog 5_Zn2 (0.5 mg/kg) not only achieved 50% survival at 48 hours but also suppressed the cytokine storm (TNF-α/IL-6) associated with Gram-negative sepsis, validating the therapeutic potential of metal-coordinated peptidomimetics [62]. The dual antimicrobial and anti-inflammatory activity of 5_Zn2 is clinically significant because the morbidity and mortality of Gram-negative sepsis are driven largely by dysregulated host inflammation rather than bacterial burden alone. Consequently, an agent that simultaneously reduces bacterial load and mitigates immunopathology may offer advantages over conventional combinations of separate antimicrobial and anti-inflammatory therapies [62]. Stereochemical inversion and backbone modification constitute pivotal strategies for fortifying peptide stability while preserving the membrane-disruptive pharmacophore. A leucine-centric design was utilized to engineer H-10, a derivative containing a site-specific D-Ile substitution. This stereochemical modification conferred exceptional proteolytic stability, with a half-life (t1/2) exceeding 6 hours against chymotrypsin, compared to the rapid degradation of the L-isomer parent. H-10 displayed rapid bactericidal action against MDR S. aureus (MIC = 1.56 μM) and demonstrated a low propensity for resistance development; MIC values remained unchanged after 15 passages, whereas resistance to polymyxin B and rifampicin emerged rapidly under identical conditions [11]. Similarly, a "bond switch" strategy was introduced, replacing a standard amide bond with an isopeptide linkage at Lysine-9. This modification disrupted the α-helical structure locally, preventing the deep membrane insertion into zwitterionic mammalian bilayers that drives toxicity. The resulting analog, Amp1EP9, retained potent activity against P. aeruginosa (MIC = 3.12 μM) but exhibited 0% hemolysis at 80 μM and remained stable in human plasma for over 2 hours [63]. Complementing site-specific modifications, a 2024 study applied all-hydrocarbon stapling to the HIV-derived Tat peptide to generate membrane-active stapled antimicrobial peptides with broad-spectrum antibacterial activity. Stapling stabilized the helical conformation, enhanced membrane insertion, and markedly suppressed resistance development, with no resistance detected after 30 serial passages in E. coli, K. pneumoniae, or A. baumannii, while preserving low hemolytic activity [64]. Similar findings across multiple stapled peptide series suggest that helically pre-organized scaffolds disrupt bacterial membranes more uniformly and irreversibly than flexible linear analogues, thereby reducing the likelihood that adaptive mutations can restore membrane integrity and confer resistance [65]. The translational chasm between in vitro potency and in vivo efficacy remains a formidable barrier in peptidomimetic development, often precipitated by discordant serum stability and tissue kinetics. Compound 5x was developed as a polymyxin analogue, in which the diaminobutyric acid (Dab-3) residue was replaced with diaminopropionic acid (Dap-3) and a polar N-phenyl pyridone side chain. While this modification successfully eliminated in vitro renal cytotoxicity (hRPTEC TC50 > 100 μM compared to 22 μM for Polymyxin B), the compound failed to demonstrate superior efficacy in a murine neutropenic thigh model, highlighting that reductions in nephrotoxicity must be balanced against tissue accumulation and bactericidal kinetics [66]. Conversely, the polymyxin scaffold was successfully optimized by incorporating a hydrophobic octylglycine motif at position R7 (FADDI-002). This lipophilic modification circumvented the electrostatic repulsion conferred by lipid A L-Ara4N modifications, retaining potency against colistin-resistant P. aeruginosa (MIC 2–8 mg/L) and significantly attenuating bacterial burden in a lung infection model [58]. The most clinically advanced next-generation polymyxin analogue is SPR206 (EVER206), which was designed to retain antibacterial activity while reducing the nephrotoxicity associated with the fatty acyl tail of native polymyxins. In 2025, Outeda-García and colleagues reported potent activity against both colistin-susceptible and colistin-resistant A. baumannii clinical isolates, with MIC₅₀/MIC₉₀ values of 0.12/0.25 mg/L, and observed resistance in only 1 of 118 isolates [67]. Notably, pmrCAB mutations that mediate colistin resistance did not affect SPR206 susceptibility, indicating evasion of a major resistance mechanism and underscoring its potential against emerging colistin-resistant strains [67]. Currently in Phase 2 clinical development for serious Gram-negative infections, SPR206 represents the most advanced example of rational optimization of the polymyxin scaffold. Beyond peptide backbone modification, translating amphiphilic topologies into non-peptidic small-molecule scaffolds and high-molecular-weight polymers offers a strategy to circumvent the scalability and stability limitations inherent to traditional AMPs. Compound 27, an amphiphilic derivative of the cystic fibrosis drug ivacaftor, was synthesized to mimic the cationic/hydrophobic balance of AMPs. This compound demonstrated broad-spectrum activity (MIC = 0.195–3.125 μg/mL) and inhibited S. aureus biofilm formation (99.6% inhibition) [68]. The development of Compound 27 illustrates an attractive scaffold-repurposing strategy, as its parent molecule, ivacaftor, is already clinically approved and supported by extensive human safety data. Consequently, these amphiphilic derivatives may benefit from a more streamlined translational and regulatory pathway than entirely novel antimicrobial scaffolds [68]. More broadly, scaffold repurposing represents a complementary strategy to siderophore conjugation and AMP-mimetic polymers for overcoming the manufacturing costs and regulatory barriers that have historically limited AMP development [68]. In the polymeric domain, the guanidinium-functionalized acrylamide copolymer g-D50 demonstrated that environmental context dictates efficacy; contrary to the activity loss often observed with canonical peptides in complex media, g-D50 displayed a 4-fold increase in potency against S. aureus (MIC: 4.3 μM) in synthetic wound fluid relative to standard broth [69]. This counterintuitive enhancement of activity in wound fluid, likely driven by conformational changes induced by the ionic and protein-rich environment, highlights a key advantage of AMP-mimetic polymers over linear peptides. Unlike conventional AMPs, whose activity is often diminished under physiological conditions, polymeric architectures can be engineered to exploit these environments and maintain or even enhance membrane-disruptive activity, effectively transforming a major pharmacological constraint into a design opportunity [69]. Metabolic and Respiratory Inhibitors The inhibition of oxidative phosphorylation and essential folate metabolism represents a strategic pivot from traditional replication-dependent targets, offering a mechanism to eradicate both metabolically active and non-replicating persister cells responsible for chronic infection relapse [10]. While the folate biosynthetic pathway remains a cornerstone of bacteriostatic therapy, the respiratory chain, specifically the F-ATP synthase complex, provides a bactericidal avenue by collapsing the proton motive force and depleting the intracellular ATP pool required for bacterial viability [10]. Clinical validation of bioenergetic targeting was established by bedaquiline (BDQ), the first-in-class diarylquinoline approved for MDR tuberculosis. BDQ inhibits mycobacterial F₁F₀-ATP synthase through interactions with the c-subunit rotor ring and ε-subunit, blocking ATP production irrespective of bacterial metabolic state. This mechanism accounts for its activity against both actively replicating bacilli and dormant persisters, populations that are largely refractory to conventional antibiotics [70]. The rational design of novel chemical entities within this sphere focuses on overcoming two primary barriers: the structural evolution of plasmid-encoded resistance enzymes and the intrinsic impermeability of the bacterial cell envelope. Targeting the mycobacterial F-ATP synthase (F0F1-ATPase) yielded the N-acyl phenothiazine derivative PT6, a hybrid scaffold integrating a benzimidazolone core to optimize interfacial binding between the enzyme's A and B chains [10]. It has been revealed that PT6 engages the target via critical π-π stacking interactions with the Phe69 residue of chain B and hydrogen bonding to Glu65, a binding mode that yields a potent IC50 of 0.788 μM against the isolated enzyme. Unlike traditional antibiotics that fail against dormant populations, this direct interference with bioenergetics results in rapid intracellular ATP depletion and bactericidal activity against MDR and rifampicin-resistant M. tuberculosis strains, with MIC values of 17.62 μM and 8.76 μM, respectively. The requirement for this pharmacophore hybridization is evidenced by the control compound PT1; lacking the fluoro-benzyl tail, PT1 exhibited an 8-fold potency reduction, corroborating the necessity of lipophilic optimization to access the membrane-embedded rotor complex [10]. An important advance in understanding ATP synthase selectivity came from a 2024 cryo-EM study of M. tuberculosis and human ATP synthase complexes with BDQ and its clinical analogue TBAJ-587. The structures showed that both compounds bind multiple sites at the bacterial a-subunit/c-ring interface, where their quinolinyl and dimethylamino moieties form extensive protein contacts. Comparison with the human enzyme revealed a structurally analogous binding pocket, providing a molecular explanation for BDQ-associated mitochondrial toxicity and a high-resolution framework for designing analogues that exploit species-specific residues to enhance bacterial selectivity [71]. A recent addition to the F-ATP synthase inhibitor pipeline is PRP020, a squaramide derivative reported in 2025 that targets mycobacterial ATP synthase at a site distinct from the BDQ-binding pocket, as demonstrated by ATP-driven inverted membrane vesicle acidification assays [72]. Structural studies showed that the aniline moiety engages Phe58 of the c-subunit through π–π interactions, while the methylenedioxy group and thiazol-5-ylmethanamine moiety establish additional contacts with Asn174, Phe69, and Tyr68. Unlike earlier squaramide analogues, PRP020 exhibited improved metabolic stability and low mammalian cytotoxicity, while retaining potent activity against diverse mycobacteria, including M. avium, an intrinsically drug-resistant pathogen of particular concern in cystic fibrosis patients [72]. Importantly, its non-overlapping binding site raises the possibility of combination therapy with BDQ, potentially enhancing target inhibition while reducing the impact of BDQ-resistance mutations [72]. In the metabolic domain, the rapid evolution of plasmid-encoded dihydrofolate reductase variants, such as DfrA1 and DfrA5, has necessitated the development of propargyl-linked antifolates (PLAs) that can accommodate active-site mutations such as D27E and L28Q [73]. Structural analysis of the PLA UCP1228 confirms that its flexible propargyl linker accommodates steric constraints to stabilize the ternary complex, maintaining nanomolar affinity (Ki = 20.08 nM) against the resistant DfrA5 isoform, where trimethoprim affinity is abrogated [73]. However, the utility of these lipophilic scaffolds is heavily modulated by efflux pump activity. In Gram-positive S. aureus, replacing the hydrophobic biphenyl moiety of early PLAs with a pyridyl ring (Compound 1) successfully evaded efflux, maintaining a low Mutant Prevention Concentration of 1.25 μg/mL [74]. Conversely, in Gram-negative E. coli, the biphenyl-containing PLAs (UCP1223 and UCP1228) remained susceptible to the AcrAB-TolC system, evidenced by a dramatic 16-fold improvement in MIC potency (from 10 μg/mL to 0.625 μg/mL) upon deletion of the acrB gene [73]. To overcome efflux-mediated limitations, Anderson, Wright, and colleagues developed zwitterionic PLA analogues inspired by the favorable Gram-negative penetration of zwitterionic antibiotics such as fluoroquinolones and tetracyclines. Incorporation of partial zwitterionic character improved mycobacterial permeability and yielded compounds with MIC values ≤1 μg/mL against MDR and XDR M. tuberculosis, including the most potent PLA derivatives reported to date against clinical MDR-TB isolates [75]. Building on these advances, a 2025 pharmacokinetic study systematically characterized the in vivo exposure, half-life, and tissue distribution of seven PLA antibiotics in mice, providing a quantitative framework for dose optimization and further scaffold refinement toward systemic therapeutic applications [76]. The clinical viability of these metabolic and respiratory inhibitors ultimately rests on their ability to distinguish between prokaryotic targets and their mammalian homologs. The respiratory inhibitor PT6 demonstrated a superior safety profile, achieving a selectivity index of >253 for mycobacterial ATP synthase over the mammalian mitochondrial homolog, and showed no cytotoxicity against Vero cell lines at concentrations up to 200 μg/mL [10]. The structural basis of this selectivity has been elucidated by the 2024 cryo-EM studies of Guo and colleagues, which revealed that residues flanking the BDQ-binding cavity differ between bacterial and human ATP synthases, creating exploitable determinants of species selectivity. These insights provide a high-resolution framework for the rational design of next-generation F-ATP synthase inhibitors beyond BDQ and its close analogues [71]. This high selectivity underscores the potential of targeting the distinct interfacial residues of bacterial F-ATP synthase without compromising mammalian cellular respiration. Collectively, these propargyl-linked antifolates demonstrate that while high-affinity binding to mutant enzymes is achievable, future optimization must prioritize physicochemical properties that reduce substrate recognition by MDR efflux transporters to ensure intracellular accumulation [73,74]. The convergence of cryo-EM structural data, zwitterionic permeability design rules, and comparative pharmacokinetic profiling represents a shift in the metabolic inhibitor field from largely empirical SAR optimization to genuinely mechanism-informed, structure-guided drug design, mirroring the paradigm transformation that crystallographic ribosome and topoisomerase structures brought to their respective fields in earlier decades. Membrane-Active Small Molecules (Non-Peptides) The clinical translation of host defense peptides has long been stalled by high production costs and susceptibility to proteolytic degradation. To bypass these hurdles, medicinal chemistry has shifted its focus to 'peptidomimetics.' The primary objective is to generate low-molecular-weight architectures with cationic domains for electrostatic attraction to anionic bacterial surfaces, coupled with hydrophobic moieties that facilitate lipid bilayer insertion and subsequent membrane permeabilization [77]. In a seminal investigation of this strategy, the design and synthesis of a novel class of bis-cyclic imidazolidine-4-one derivatives was elucidated. Synthesized through the dimerization of γ-substituted-N-acylated-N-aminoethyl peptides, Compound 3 relies on a rigid bis-imidazolidine core, cationic primary amines, and hydrophobic decyl (C10) chains. Critical SAR analysis revealed that the length of the lipophilic tail dictated the spectrum of activity. Unlike C12 analogs, which were excluded by the Gram-negative outer membrane, the optimized C10 chains enabled Compound 3 to retain broad-spectrum potency, with MICs of 2 μg/mL against MRSA and 5 μg/mL against E. coli and K. pneumoniae. This finding reinforces a broader principle in the field: excessive hydrophobicity not only promotes hemolysis but can paradoxically narrow the antibacterial spectrum by triggering self-aggregation or by generating molecules too bulky to traverse the Gram-negative outer membrane barrier [77]. Membrane-targeting antimicrobial agents are probably less likely to promote bacterial resistance than conventional antibiotics, which makes fine-tuning of these physicochemical parameters especially strategically important. To confirm membrane disruption as the primary mechanism, Wang and colleagues employed complementary fluorescence and imaging assays. The membrane potential-sensitive dye DiSC3(5) revealed rapid, concentration-dependent depolarization of the E. coli cytoplasmic membrane, while Propidium Iodide uptake confirmed inner membrane permeabilization and loss of membrane integrity [77]. Transmission electron microscopy further demonstrated extensive membrane disintegration in MRSA, providing direct morphological evidence of membrane lysis. Together, these findings established membrane disruption as the principal antibacterial mechanism of Compound 3. Mechanistic insights from related membrane-active compounds have further expanded understanding of this therapeutic strategy. In 2023, Melcrová and colleagues showed that the cationic tripeptide AMC-109 acts through a two-step process involving preferential association of self-assembled cationic aggregates with anionic bacterial membranes, followed by disruption of membrane nanodomains that govern protein organization and cell wall synthesis. Unlike classical pore-forming agents, AMC-109 exerts its effects through nanodomain dissolution, illustrating the mechanistic diversity available within membrane-targeting peptidomimetic scaffolds. A review by Ganesan and colleagues similarly highlighted membrane-targeting small molecules as a promising but underexploited strategy for combating drug-resistant S. aureus [78]. A notable feature of Compound 3 was its high selectivity for bacterial over mammalian membranes. The compound exhibited negligible hemolytic activity, with a hemolysis threshold exceeding 250 μg/mL and a selectivity index greater than 125 relative to its antibacterial MIC [77]. This selectivity reflects fundamental differences in membrane composition. Bacterial membranes are enriched in negatively charged phospholipids that promote electrostatic attraction of cationic compounds, whereas mammalian erythrocyte membranes are predominantly zwitterionic and contain substantial cholesterol, which enhances membrane rigidity and limits amphipathic insertion [78]. The reported selectivity index substantially exceeds the values generally considered necessary for therapeutic development. The resistance profile of Compound 3 further distinguishes it from conventional antibiotics. No increase in MIC was observed against MRSA after 13 serial passages, whereas norfloxacin rapidly selected for resistance [77]. Similar findings were reported by Hamad and colleagues in 2024, where the membrane-disrupting compound SIMR 2404 failed to generate resistance after 24 serial passages, while ciprofloxacin resistance emerged readily under identical conditions [79]. These observations support the view that membrane-active agents impose a substantially higher evolutionary barrier than target-specific antibiotics because resistance would require extensive remodeling of membrane composition rather than mutation of a single cellular target. Nevertheless, resistance is not impossible. Alterations in membrane lipid composition, increased carotenoid production, and enhanced lysyl-phosphatidylglycerol biosynthesis have all been associated with reduced susceptibility in experimental systems, underscoring the importance of long-term serial passage studies during preclinical development. The comprehensive summary of the novel lead compounds and their targets is provided in Supplementary Table S1. Future Perspectives Future antibacterial discovery will likely need to move beyond target identification and focus on closing three recurring gaps: permeability, efflux, and toxicity. These barriers can be addressed more concretely by integrating physicochemical filtering, early whole-cell testing, and resistance profiling into the discovery pipeline at the start, rather than after target potency is established. First, compounds should be optimized for bacterial entry and intracellular retention by deliberately tuning molecular size, polarity, ionization, and scaffold rigidity. In parallel, transporter-hijacking strategies such as siderophore conjugation or prodrug design may help improve uptake into Gram-negative bacteria, although these approaches will probably require careful balancing against efflux liability. Second, resistance risk can be reduced by favoring mechanisms that are less vulnerable to single-step escape and by using combination therapy where appropriate. Dual-target agents, target–membrane hybrid compounds, and pairing of new inhibitors with cell wall-active antibiotics may provide more durable activity than single-mechanism compounds alone. Third, safety concerns should be addressed earlier through selectivity profiling against human homologues and off-target enzymes, especially for chemotypes with known toxicity liabilities. For example, non-hydroxamate replacements, stereochemical refinement, and prodrug strategies may help preserve antibacterial potency while improving tolerability. Overall, the field will probably progress most efficiently if future candidates are evaluated as complete therapeutic systems rather than as isolated enzyme inhibitors. That shift would make it more likely that promising scaffolds advance from biochemical activity to clinically useful antibacterial agents. Conclusion The reviewed strategies suggest that future antibacterial development may be most successful when target potency is paired with improved permeability, reduced efflux susceptibility, and lower toxicity. A more integrated design approach, supported by combination therapy and early resistance assessment, will likely be important for translating promising scaffolds into clinically relevant candidates. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: KAA, FHF, and FHK: Major contributors to the conception of the study, literature search, study design, and manuscript writing. KFHH, AGH, RAM, SJH, ADA, KKM, SLE, SHM, and MQM: Literature review, data extraction, data organization, and preparation of the manuscript. DOA, HOA, and SHK: Critical revision of the manuscript, interpretation of the findings, and supervision of the study. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-5.3 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Multifocal Fibrosing Thyroiditis: A High-Volume Center Experience
Abstract Introduction: Multifocal fibrosing thyroiditis (MFT) is a rare and underrecognized fibroinflammatory lesion of the thyroid characterized by multiple discrete fibrotic foci with reactive epithelial changes. Its morphologic overlap with papillary thyroid carcinoma (PTC) and its reported coexistence with PTC have generated ongoing debate regarding its clinical and biological significance. The primary aim of this study is to characterize the clinicopathologic features of MFT across a large single-center experience. Methods: A retrospective case series was conducted at a single endocrine center between October 2022 and January 2026. All patients with histopathologically confirmed MFT were included. Demographic, clinical, laboratory, radiologic, surgical, and histopathologic data were collected and analyzed descriptively. Results: Twenty-seven patients were identified, with a mean age of 45.1 ± 8 years, of whom 22 (81.5%) were female. Twenty-four patients underwent total thyroidectomy (88.9%). Concurrent PTC was identified in 11 cases (40.7%). Among the 11 PTC cases, 8 (72.7%) were unifocal, and 3 (27.3%) were multifocal. Conclusion: Multifocal fibrosing thyroiditis is a rare thyroid lesion with distinctive histopathologic features. Greater awareness of this entity may improve diagnostic accuracy and clarify its clinical significance. Introduction Multifocal fibrosing thyroiditis (MFT) is a rare and underrecognized fibroinflammatory lesion of the thyroid gland characterized by multiple discrete fibrotic foci composed of a paucicellular central fibrotic core surrounded by a more cellular peripheral zone containing reactive-appearing follicular epithelial atypia and variable chronic inflammatory infiltrates [1]. Since its original description in 1990 [2], the etiology and pathogenesis of MFT have remained speculative. Various hypotheses have been proposed, including localized parenchymal injury, stromal remodeling, and a reactive process occurring in the setting of other thyroid pathology; however, no definitive mechanism has been established [1,3]. Frequently, MFT is discovered incidentally during histopathologic examination of thyroidectomy specimens resected for suspicious nodules, multinodular goiter, or coexisting thyroid malignancy rather than as a primary clinical diagnosis [1]. Recently, it has been suggested that MFT is analogous to a radial scar lesion in breast tissue both in morphology and pathogenesis, as the fibrotic lesion is a risk factor for the development of carcinoma [4-6]. Radial scars are often found incidentally on breast biopsies or mastectomies performed for other indications [5]. Multifocal fibrosing thyroiditis, like radial scars, shows a stellate configuration with fibro-elastotic center entrapping epithelial structures, and proliferative regenerative change in the surrounding parenchyma [4]. Although the clinicopathological significance of MFT remains incompletely defined, MFT has increasingly been reported in association with papillary thyroid carcinoma (PTC), raising questions regarding its potential role as a reactive or premalignant process [1,3]. This study aims to present a case series of MFT and to provide a brief review of the existing literature. The references were assessed for credibility using the most current evaluation criteria [7]. Methods Study Design and Setting This retrospective case series included patients managed between October 2022 and January 2026. The hospital is a regional referral center for endocrine surgery, assessing 75,000 patients with thyroid disorders over the 3-year study period. Inclusion and Exclusion Criteria Inclusion criteria comprised all patients with a histopathologically confirmed diagnosis of MFT [8] following surgical intervention. Patients with incomplete medical records, insufficient follow-up data, or lacking definitive histopathological confirmation were excluded from the study. Data Collection Data were extracted from the hospital's electronic medical records and pathology databases. The collected variables included demographic information, clinical presentation, medical history, details of surgical procedures, histopathological findings, and tumor characteristics (size, presence of extra-thyroidal extension, lymphatic-vascular invasion). Preoperative imaging, such as high-resolution neck ultrasonography, was reviewed to assess tumor localization and extent. Biochemical parameters, including thyroid function tests and serum thyroglobulin, were recorded preoperatively and during follow-up. Histopathological Analysis For histopathological analysis, 5‑μm‑thick tissue sections were fixed in 10% neutral buffered formalin at room temperature for 1–3 days, routinely processed, paraffin-embedded, and sectioned. Sections were stained with hematoxylin and eosin using an automated staining system. Surgical Intervention All patients underwent surgical intervention under general anesthesia, performed by experienced endocrine surgeons. The choice of surgical procedure, ranging from total thyroidectomy, thyroid lobectomy, or partial lobectomy, was determined based on preoperative imaging, intraoperative findings, and clinical judgment. Efforts were made to preserve critical anatomical structures, including the recurrent laryngeal nerve and adjacent vascular structures. In cases with suspected malignancy or invasive characteristics, wider excision margins were pursued to minimize residual disease. Lymph node dissection was performed when there was clinical or radiological suspicion of nodal involvement. Data Analysis Collected data were entered into Microsoft Excel 2021 and subsequently analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 27.0. Descriptive statistics were employed to summarize the data, with continuous variables presented as mean ± standard deviation. Categorical variables were expressed as frequencies and percentages. Normality of continuous variables (age, thyroid stimulating hormone [TSH], free thyroxine [free T4]) was assessed using the Shapiro-Wilk test and showed normal distribution. Accordingly, continuous variables are presented as mean ± standard deviation (SD). Results This study included 27 patients with histologically confirmed MFT (Figure 1) (composing 0.04% of all thyroid disorders). The mean age was 45.1 ± 8 years, with a range of 26 to 68 years, comprising 22 female patients (81.5%) and 5 male patients (18.5%). The most frequent clinical presentation was generalized weakness, observed in 7 patients (25.9%). Eighteen patients (66.7%) reported no significant past medical history. Regarding past surgical history, 19 patients (70.4%) had undergone previous surgical procedures, while 8 patients (29.6%) had no history of prior surgery. The most frequently reported prior operation was caesarean section, documented in 13 patients (48.1%), with 6 patients undergoing other surgeries (Table 1). <img id="image_3" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-45110937031781588554429.jpg" alt="Figure 1. (A) Section shows nodule with central fibrous hypocellular area (dark stars) with presence of adjacent benign thyroid follicles (yellow stars) with the interface of the nodule with thyroid tissue showing more compact follicles with inflammatory cells (dark arrows). Hematoxylin and Eosin stain. 4X (B) Higher power view of the same area showing central fibrosis (dark star) with benign thyroid follicles filled with colloid material (dark arrows), and in between both there are smaller size follicles showing some nuclear clearing and inflammatory cell infiltration (blue arrows). Hematoxylin and Eosin stain. 10X" width="1920" height="1080" /> Table 1. Demographics data and clinical presentation. Variables Frequency Sex Female Male 22 (81.5%) 5 (18.5%) Age groups (years) 26-36 37-47 48-58 59-69 Mean ± SD 2 (7.4%) 16 (59.3%) 8 (29.6%) 1 (3.7%) 45.1 ± 8 years Smoking status Active smoker Passive smoker Non-smoker 3 (11.1%) 4 (14.8%) 20 (74.1%) Family history Positive for PTC Negative 3 (11.1%) 24 (88.9%) Past medical history Negative Hypertension only HTN + CKD DM + HTN HTN + GIST PCOS TB 18 (66.7%) 3 (11.1%) 2 (7.4%) 1 (3.7%) 1 (3.7%) 1 (3.7%) 1 (3.7%) Past surgical history C/S Other Negative 13 (48.1%) 6 (22.2%) 8 (29.6%) Clinical presentation Generalized weakness Weight loss Palpitation Anterior neck swelling Lateral neck swelling Globus sensation Voice change Incidental 7 (25.9%) 5 (18.5%) 4 (14.8%) 2 (7.4%) 3 (11.1%) 2 (7.4%) 1 (3.7%) 3 (11.1%) SD: standard deviation; PTC: papillary thyroid carcinoma; HTN: hypertension; DM: diabetes mellitus; GIST: gastro intestinal stromal tumor; PCOS: polycystic ovarian syndrome; CKD: chronic kidney disease; TB: tuberculosis; PSH: past surgical history; C/S: caesarean section Preoperative thyroid function test was conducted, with a mean TSH of 2.07 ± 1.4, ranging from 0.005 to 5.14 uIU/ml, and serum free T4 of 16.45 ± 2.5, ranging from 12.3 to 22 pmol/L. Neck ultrasound examinations were conducted for 25 patients (92.6%). In 24 patients (88.9%), at least one nodule was recorded with Thyroid Imaging Reporting and Data System (TI-RADS) classifications ranging from TR3 to TR5. Five patients (18.5%) had TR3 nodules, while TR4 nodules were identified in 16 patients (59.3%). TR5 nodules were observed in 3 patients (11.1%). Fine needle aspiration cytology (FNAC), conducted on 17 patients (62.9%), demonstrated varying probabilities of malignancy, ranging from Bethesda I to Bethesda VI. Surgical management primarily involved total thyroidectomy, which was performed in 24 patients (88.9%). Thyroid lobectomy, with or without parathyroidectomy, was undertaken in 3 patients (11.1%), including 2 procedures on the right lobe (7.4%) and 1 on the left lobe (3.7%). In 11 patients (40.7%), concurrent thyroid carcinoma was present, all of which were papillary type PTC (100%) (Table 2). Table 2. Preoperative Evaluation, Histological Diagnosis, and Surgical Management. Variables Frequency TSH (uIU/ml) <0.4 0.4-4 4.1-10 Mean ± SD 4 (14.8%) 20 (74.1%) 3 (11.1%) 2.07 ± 1.4 Free T4 (pmol/L) 12-22 Mean ± SD 27 (100.0%) 16.45 ± 2.51 Ultrasound One nodule MNG Thyroiditis with nodule Findings suggestive of GD Not done 2 (7.4%) 21 (77.8%) 1 (3.7%) 1 (3.7%) 2 (7.4%) TI-RADS TR-1 TR-2 TR-3 TR-4 TR-5 Not available 0 (0.00%) 0 (0.00%) 5 (18.5%) 16 (59.3%) 3 (11.1%) 3 (11.1%) FNA Bethesda classification B I B II B III B IV B V B VI Not done 3 (11.1%) 5 (18.5%) 2 (7.4%) 0 (0.00%) 1 (3.7%) 6 (22.2%) 10 (37.0%) Procedure Total Thyroidectomy Right lobectomy + Right CLND Right partial lobectomy Left lobectomy 24 (88.9%) 1 (3.7%) 1 (3.7%) 1 (3.7%) Histological Diagnosis MFT PTC and MFT 16 (59.3%) 11 (40.7%) TSH: thyroid stimulating hormone; FNA: fine needle aspiration; MNG: multinodular goiter; GD: Graves’ disease; MFT: multifocal fibrosing thyroiditis; PTC: papillary thyroid carcinoma; CLND: central lymph node dissection Out of the 11 patients positive for PTC, tumor focality was predominantly unifocal, observed in 8 cases (72.7%), while multifocality was identified in 3 cases (27.3%). The mean tumor size among these 11 patients was 0.94 ± 0.88 cm, ranging from 0.2 to 3 cm. Postoperative serum thyroglobulin levels were available for 11 patients, all of which were ≤0.040 ng/ml (Table 3). Table 3. Tumor Characteristics Among Malignant Cases (n = 11 of 27) Variables Frequency Tumor size (cm), mean ± SD 0.94 ± 0.88 Tumor Focality Unifocal Multifocal 8 (72.7%) 3 (27.3%) Laterality Right lobe Left lobe Right lobe + isthmus Left lobe + isthmus 7 (63.6%) 2 (18.2%) 1 (9.1%) 1 (9.1%) Post-operative thyroglobulin (ng/ml) ≤0.04 >0.04 11 (100.0%) 0 (0.0%) Lymphovascular invasion Present Not identified 1 (9.1%) 10 (90.9%) Perineural invasion Seen Not seen 0 (0.0%) 11 (100.0%) SD: standard deviation Discussion Multifocal fibrosing thyroiditis continues to pose diagnostic and conceptual challenges, as its morphologic features may overlap with those of PTC, potentially leading to diagnostic confusion and overtreatment [1,3,9]. Clinically, patients with MFT most frequently present with thyroid nodules, though generalized weakness, thyroid function abnormalities, or incidental discovery during evaluation for other indications may also occur [1,9]. Given its often incidental identification in thyroidectomy specimens resected for unrelated indications, the true incidence and clinical significance of MFT remain incompletely defined [1,3]. The demographic characteristics of the current series are consistent with those of previously published series. In the study conducted by Fellegara G and Rosai J, 55 patients were evaluated, including 51 females (92.7%) and 4 males (7.3%), with ages ranging from 15 to 71 years and a mean age of 47.03 years [9]. Similarly, this series comprised 27 patients, of whom 22 (81.5%) were female, and 5 (18.5%) were male, with a mean age of 45.1 ± 8 years. Another study by Orsatti et al. included 7 patients, all of whom were female [1]. These findings collectively support a clear female predominance. With regard to clinical presentation, the most common reason for seeking medical care in the current study was generalized body weakness, reported in 7 patients (25.9%). However, Fellegara G and Rosai J noted that detection of one or more thyroid nodules was the most frequent reason for medical evaluation [9]. Concerning thyroid functional status, in the current series, 3 patients (11.1%) had subclinical hypothyroidism and 4 patients (14.8%) had hyperthyroidism. In comparison, Fellegara G and Rosai J reported hyperthyroidism in 10 patients (18.2%) and hypothyroidism in 1 patient (1.8%) [9]. Surgical management in the current series predominantly involved total thyroidectomy, performed in 24 patients (88.9%). The remaining procedures included 1 left lobectomy (3.7%), 1 right partial lobectomy (3.7%), and 1 right lobectomy with right central lymph node dissection (3.7%). In contrast, Fellegara G and Rosai J reported that 29 patients (52.7%) underwent total thyroidectomy, 9 (16.3%) underwent right lobectomy, and 8 (14.6%) underwent left lobectomy [9]. One of the most important and debated aspects of MFT is its reported association with PTC. Although MFT is regarded as a benign fibroinflammatory process, multiple studies have documented its coexistence with PTC in a proportion of cases. In the current study, 11 patients (40.7%) were diagnosed with PTC. Similarly, Orsatti et al. reported an association rate of 38.5% between MFT and PTC [1]. In contrast, a study conducted by Frank et al. evaluated 7 cases in which both MFT and PTC were present and did not identify a close topographic relationship between fibrotic foci and carcinoma [3]. Furthermore, none of the MFT lesions showed BRAF mutations. Although they could not rule out the potential that MFT would be a very early step in the pathogenesis of PTC, the authors concluded that there was no indication of a pathogenetic link between MFT and PTC based on these data [3]. In the current series, among the 11 cases of PTC, 8 (72.7%) were unifocal, and 3 (27.3%) were multifocal. This distribution is comparable to that reported by Frank K et al., in which 5 of 7 cases (71.4%) were unifocal, and 2 (28.6%) were multifocal [3]. The pathogenesis of MFT remains incompletely understood and speculative. Several mechanisms have been proposed, including localized ischemic injury, autoimmune-mediated follicular damage, and a reparative response to repeated microtrauma [1]. The morphologic resemblance to radial scar type lesions in other organs has further prompted speculation that MFT may represent a patterned stromal response within a biologically susceptible thyroid gland [4,9,10]. Although the relatively high coexistence rate with PTC has raised concern regarding a potential preneoplastic role, available molecular data have not demonstrated clonal alterations within MFT lesions [1,3]. In our study, several limitations should be acknowledged. First, its retrospective design inherently introduces potential selection and information bias. Second, the details of the follow-up data were not sufficient. Third, molecular analysis was not performed in this study, preventing further exploration of potential pathogenetic mechanisms. Conclusion Multifocal fibrosing thyroiditis is a rare fibroinflammatory thyroid lesion that predominantly affects females and may coexist with PTC; therefore, accurate histopathologic recognition is essential to avoid diagnostic confusion and guide appropriate management. Further molecular and multicenter studies are needed to clarify the biological significance of this association. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: In accordance with our institution's oral policy, retrospective case series involving anonymized histopathological material and de-identified patient data do not require formal ethical approval. Consent for participation: Not applicable. Consent for publication: Informed consent for publication was obtained from the patients. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: AMS, KMS, SHA, IJH, and DAK: managed the cases, and performed critical revision. AMA and RMA: pathologists who contributed to the pathological analysis. AJQ: a radiologist who contributed to the radiological analysis. MHA and AAQ: contributed to conception of the idea, data collection and interpretation, and critical revision. AHA, MLF, and HAM: contributed to conception of the idea, literature review, table preparation, and critical revision. LLH: contributed to conception of the idea, literature review, and drafting of the manuscript. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Data are available from the corresponding author upon reasonable request.
Fine-Needle Aspiration Cytology and Salivary Gland Tumors: A Cross-Sectional Study
Abstract Introduction Salivary gland neoplasms are relatively rare and diverse, requiring accurate preoperative diagnosis. Although the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has improved diagnostic consistency, fine-needle aspiration cytology (FNAC) performance remains variable. This study aims to assess FNAC’s diagnostic accuracy in salivary gland tumors and determinants affecting its performance. Methods This cross-sectional study was conducted at a tertiary care center and included patients with suspected salivary gland tumors. The FNAC was performed using a 22–24-gauge needle. All cases underwent histopathological examination. FNAC accuracy was assessed by comparing findings with final histopathological diagnosis, calculating sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Two diagnostic settings were defined based on MSRSGC categories Results Among 272 FNAC cases, 232 (85.3%) originated from the parotid gland. The mean patient age was 44.90 years, with 151 (55.5%) females. Histopathological examination identified 11 (4.0%) non-neoplastic lesions, 241 (88.6%) benign tumors, and 20 (7.4%) malignant tumors. FNAC sensitivity was 84.6% in Setting 1 and 88.2% in Setting 2. The FNAC success was significantly lower for submandibular gland lesions (OR = 0.218, p-value= 0.002). Conclusion Salivary gland FNAC is a minimally invasive, safe, and cost-effective diagnostic technique that may serve as an appropriate first-line investigation in the evaluation of major salivary gland lesions. Introduction Salivary gland neoplasms are relatively rare, with an annual incidence of 3.0 per 100,000 individuals [1]. These neoplasms account for approximately 6% of head and neck cancers and about 0.3% to 0.5% of all malignancies [2]. Primary salivary gland carcinomas constitute 20–35% of these cases, encompassing 21 clinically and biologically distinct entities [1,3]. Additionally, secondary salivary gland carcinomas, including metastatic solid tumors and lymphomas, may present in the lymph nodes of the parotid gland [1]. The risk of malignancy (ROM) associated with a salivary gland mass varies by its anatomical location. Specifically, it ranges from 20% to 25% for masses in the parotid gland, 40% to 50% in the submandibular gland, and 50% to 81% in the sublingual and minor salivary glands of the upper aerodigestive tract [4]. Given the wide variety of neoplasms affecting the salivary glands, a comprehensive and systematic diagnostic approach is essential to determine the most appropriate treatment. Preoperative differentiation between benign and malignant tumors is crucial for planning the extent of the surgical procedure [5]. However, imaging techniques alone have been shown to be insufficient in accurately distinguishing benign from malignant salivary gland tumors. Therefore, invasive preoperative diagnostic testing is often necessary. Both European and American guidelines for salivary gland neoplasms recommend the routine use of fine-needle aspiration cytology (FNAC) in the presence of a lesion in one of the major salivary glands, due to its simple application and low complication rates [6,7]. False diagnoses may occur when interpreting common neoplasms, such as pleomorphic adenoma and Warthin’s tumor. Moreover, a major challenge in FNAC is the possibility of obtaining unsatisfactory aspirates. Some specimens cannot be adequately assessed due to insufficient cellularity or poor quality, which can undermine the diagnostic accuracy. Immunostaining with Ki-67 fraction can be helpful in distinguishing malignant from benign tumors. Myoepithelial markers, such as S-100 and smooth muscle actin, are valuable for identifying the myoepithelial component, while markers like EMA and CEA assist in highlighting ductal structures [2]. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC), introduced in 2018, was developed to standardize cytopathological reports for salivary gland tumors and improve the accuracy of FNAC. While the MSRSGC has significantly enhanced diagnostic outcomes, performance measures for salivary gland FNAC remain controversial, with sensitivity ranging from 71% to 93% and specificity from 96% to 99% [1,8,9]. The factors influencing the success of FNAC, contributing to the broad variability in performance measures, remain largely unclear. Therefore, this study aims to evaluate the diagnostic role of FNAC in major salivary gland tumors and investigate factors influencing its accuracy. The references were assessed for eligibility [10]. Methods Study Design and Setting This cross-sectional study was carried out at a tertiary care hospital from March 2019 to December 2024 and patients were included consecutively based on their presentation over 5 years with clinically suspected salivary gland lesions. Patient Selection and Data Collection Patients included in the study with histopathologically confirmed benign or malignant salivary gland tumors. Exclusion criteria encompassed individuals with lesions of non-salivary gland origin, missing FNAC samples, and incomplete clinical or imaging data. Sociodemographic data, including age, sex, occupation, marital status, smoking status, and chief complaint, were collected. Additionally, relevant clinical details, including ultrasound tumor size, tumor size based on histopathology, side of involvement, FNAC findings, parotid involvement, type of operation, histopathology results, and follow-up information, were extracted and analyzed. All cases were classified according to the MSRSGC. The longest diameter (cm) of the lesion, as reported in the final pathology report, was used for analyses related to the lesion size. Fine Needle Aspiration Cytology (FNAC) The FNAC was performed for all enrolled patients with suspected salivary gland lesions. The procedure was conducted under ultrasound guidance using negative-pressure aspiration with a 22–24-gauge needle attached to a 10-cc syringe under aseptic conditions. For cystic lesions, the solid or mural component was targeted under aseptic conditions. For cystic lesions, the cyst was first aspirated and the lesion was then reassessed sonographically for any residual solid component; when a solid component was identified, immediate re-aspiration of that component was performed, with material preferentially collected for cell block preparation to optimize cellular yield. Aspirated material was immediately smeared onto glass slides, and each specimen was gently spread between two slides to obtain adequate cytological preparations. When sufficient material was available, the residual specimen was processed for cell block preparation, also stained with hematoxylin and eosin, to facilitate further histopathological assessment and ancillary studies. Immunocytochemistry was used when the cytological diagnosis was inconclusive or required further confirmation. Specimen adequacy required both sufficient cellularity (quantitative) and lesional representativeness (qualitative); a specimen was considered adequate when it contained well-preserved lesional cells, whereas aspirates showing only obscuring artifact, non-mucinous cyst fluid without epithelial cells, or normal salivary tissue from a targeted mass were classified as non-diagnostic. Non-diagnostic specimens were repeated, either on the same day or at a subsequent visit. Histopathological Examination Following FNAC, all patients underwent surgical excision of the lesion, and the resected tissue was sent for histopathological examination. The specimens were fixed in 10% formalin, routinely processed, and embedded in paraffin. Serial sections were cut and stained with hematoxylin and eosin. Special histochemical stains were applied at the discretion of the reporting pathologist in defined scenarios: periodic acid-Schiff with diastase (PAS-D) to confirm diastase-resistant mucin in lesions suspected of mucoepidermoid carcinoma and to demonstrate zymogen granules where acinic cell carcinoma was in the differential; PAS to highlight basement-membrane-like material in basaloid or cribriform lesions suspected of adenoid cystic carcinoma and to identify glycogen in clear-cell lesions; and PAS to screen for fungal organisms in cases of granulomatous inflammation. Final diagnoses were based on hematoxylin and eosin morphology supplemented by immunohistochemistry where indicated, with special stains serving only as confirmatory adjuncts. Statistical Analysis The diagnostic performance of FNAC was evaluated by comparing its findings with the histopathological diagnoses. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated. In accordance with a previous study [9], two settings were defined for calculating the performance measures. In Setting 1, the MSRSGC categories V and VI, which correspond to 'suspicious for malignancy' and 'malignant' respectively, were considered as positive index tests. Conversely, MSRSGC categories II and IVa, representing 'non-neoplastic' and 'neoplasm-benign', were classified as negative tests. In Setting 2, MSRSGC categories III, IVb, V, and VI, encompassing 'atypia of undetermined significance (AUS)', 'salivary gland neoplasm of uncertain malignant potential (SUMP)', 'suspicious for malignancy', and 'malignant', were designated as positive index tests. Similarly, MSRSGC categories II and IVa were maintained as negative tests. FNAC was considered successful when the specimen was adequate for cytological interpretation, corresponding to MSRSGC categories II–VI. Conversely, FNAC was classified as unsuccessful when the result was non-diagnostic, consistent with MSRSGC category I. Data analysis was performed using SPSS software (version 26.0). Univariate logistic regression was employed to identify factors influencing the success of FNAC. A p-value of <0.05 was considered statistically significant. Results A total of 272 salivary gland FNAC cases were included. Among these, 232 (85.3%) originated from the parotid gland, while 40 (14.7%) involved the submandibular gland. The patient cohort had a mean age of 44.90±15.0 years, with 151 (55.5%) being female (Table 1). Table 1. Demographic, Clinical, and Surgical Characteristics of the Study Population Variables N, Mean (%, SD) Age 44.90±15.0 Age group 10-20 20-30 30-40 40-50 50-60 60-70 70-80 >80 16 (5.9) 32 (11.8) 64 (23.5) 59 (21.7) 61 (22.4) 28 (10.3) 10 (3.7) 2 (0.7) Gender Male Female 1 (9.1%) 121 (44.5) 151 (55.5) Marital Status Single Widow Married 37 (13.6) 1 (0.4) 234 (86.0) Smoking Status Non-smoker Active Passive Ex-smoker 191 (70.2) 59 (21.7) 20 (7.4) 2 (0.7) Side Right Left Bilateral 134 (49.3) 136 (50.0) 2 (0.7) Gland Parotid gland Submandibular gland 232 (85.3) 40 (14.7) Type of operation Superficial parotidectomy Submandibular gland excision Total parotidectomy Submandibular gland excision + Neck dissection Parotid gland excision 211 (77.6) 35 (12.9) 19 (7.0) 5 (1.8) 2 (0.7) Tumor size (Longest dimension) (cm) 2.56±1.17 Follow-up Normal Dead 271 (99.6) 1 (0.4) The most common category was MSRSGC IVa (neoplasm-benign), accounting for 223 (82.0%) of cases. The highest risk of neoplasm was observed in MSRSGC categories IVb (SUMP), III (AUS), and VI (malignant), each demonstrating a rate of 100.0%. In contrast, the lowest risk of neoplasm was recorded in MSRSGC II (non-neoplastic) cases, at 0.0%. Regarding the ROM, MSRSGC VI (malignant) cases showed a rate of 100.0%, whereas MSRSGC II (non-neoplastic) and MSRSGC IVa (benign neoplasm) demonstrated ROM values of 0.0% and 0.9%, respectively (Table 2). Table 2. Diagnostic Classification Based on the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) Category Final Diagnosis Total n, (%) RON (%) ROM (%) Non-neoplastic Benign Malignant Non-diagnostic, I 4 13 3 20 (7.4) 80.0 15.0 Non-Neoplastic, II 1 0 0 1 (0.4) 0.0 0.0 AUS, III 0 5 1 6 (2.2) 100.0 16.7 Neoplasm-benign, IVa 5 216 2 223 (82.0) 97.8 0.9 Neoplasm-SUMP, IVb 0 7 3 10 (3.7) 100.0 30.0 SFM, V 1 0 7 8 (2.9) 87.5 87.5 Malignant, VI 0 0 4 4 (1.5) 100.0 100.0 Total 11 241 20 272 (100.0%) 96.0 7.4 M:Male, F:Female, S.Ca:Serum calcium, TG:Thyroglobulin, N/A:Not applicable Histopathological follow-up revealed 11 (4.0%) cases of non-neoplastic lesions, 241 (88.6%) cases of benign tumors, and 20 (7.4%) cases of malignant tumors. Among the benign tumors, pleomorphic adenoma was the most common entity, identified in 169 (62.1%) cases, followed by Warthin tumor in 47 (17.3%) cases (Figures 1 and 2). Regarding malignant tumors, mucoepidermoid carcinoma was the most frequently diagnosed subtype, accounting for 8 (2.9%) cases, followed by squamous cell carcinoma in 3 (1.1%) cases and adenoid cystic carcinoma in 2(0.7%) cases (Figure 3) (Table 3). <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-45069763911781506482056.png" alt="Figure 1. Cytological features of a parotid gland nodule. (A) Low-power view (Hematoxylin and Eosin, ×4) showing hemorrhagic material (dark stars) admixed with cellular elements (yellow stars). (B) Higher-power view of the same area (Hematoxylin and Eosin, ×10) demonstrating bland-appearing epithelial and myoepithelial cells arranged in small groups and as single cells with plasmacytoid features (dark arrows) within a myxoid stroma (dark stars). These cytomorphological features are consistent with pleomorphic adenoma of the parotid gland." width="1376" height="768" /> <img id="image_2" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-4544387821781506513633.png" alt="Figure 2. Cytological features of a parotid gland mass. (A) Low-power view (Hematoxylin and Eosin, ×4) showing hemorrhagic material (dark stars) admixed with cellular elements (yellow stars). (B) Higher-power view of the same area (Hematoxylin and Eosin, ×10) demonstrating bland-appearing oncocytic epithelial cell layers (dark arrows) with underlying mature lymphoid cell aggregation (yellow stars). These cytomorphological features are consistent with warthin tumor of the parotid gland." width="1376" height="768" /> Table 3. Patient demographics and clinical data. Lesions Number of cases (%) Non-neoplastic 11 (4.0) Sialadenitis 8 (2.9) Lymphoepithelial Cyst 2 (0.7) Lymphoid Hyperplasia 1 (0.4) Neoplastic 4 (36.3%) Benign tumors 241 (88.6) Pleomorphic Adenoma 169 (62.1) Warthin Tumor 47 (17.3) Oncocytoma 8 (0.4) Benign Salivary Gland Tissue 4 (1.5) Vascular Hamartoma 3 (1.1) Basal Cell Adenoma 2 (0.7) Canalicular Adenoma 2 (0.7) Giant Cell Tumor 2 (0.7) Myoepithelioma 1 (0.4) Lipoma 1 (0.4) Schwannoma 1 (0.4) Intra-parotid Cavernous Hemangioma 1 (0.4) Malignant tumors 20 (7.4) Mucoepidermoid Carcinoma 8 (2.9) Squamous Cell Carcinoma 3 (1.1) Adenoid Cystic Carcinoma 2 (0.7) Adenocarcinoma 1 (0.4) Salivary Duct Carcinoma 1 (0.4) Epithelial-Myoepithelial Carcinoma 1 (0.4) Mammary Analogue Secretory Carcinoma 1 (0.4) Non-Hodgkin’s Lymphoma 1 (0.4) Acinic Cell Carcinoma 1 (0.4) Basaloid Cell Carcinoma 1 (0.4) <img id="image_3" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-86601138331781506672488.png" alt="Figure 3. Cytological features of adenoid cystic carcinoma of the parotid gland. (A) Low-power view (Hematoxylin and Eosin, ×4) showing a cellular aspirate composed of basaloid cells arranged in a prominent cribriform growth pattern (dark arrows). (B) High-power view of the same area (Hematoxylin and Eosin, ×10) demonstrating basaloid cells forming cribriform structures (dark arrows) with associated basement membrane–like eosinophilic material (yellow arrows)." width="1376" height="768" /> In setting 1, for distinguishing malignant from benign tumors, which excluded tumors classified as AUS and SUMP, the diagnostic performance was as follows: sensitivity 84.6%, specificity 99.6%, accuracy 98.7%, PPV 91.7%, and NPV 99.1%. In Setting 2, which included AUS and SUMP cases, the sensitivity increased to 88.2%, while specificity, accuracy, PPV, and NPV were 94.5%, 94.1%, 53.6%, and 99.1%, respectively (Table 4). Table 4. Evaluation of the Milan System's Diagnostic Performance in Salivary Gland Cytopathology Setting Sensitivity, % Specificity, % Accuracy, % PPV, % NPV, % Setting 1 84.6 99.6 98.7 91.7 99.1 Setting 2 88.2 94.5 94.1 53.6 99.1 PPV: positive predictive value, NPV: negative predictive value Regression analysis showed that tumor size was not a statistically significant predictor of FNAC success; however, it was associated with an increased odds of successful FNAC, with each additional centimeter corresponding to a 50% increase in the odds of success (OR = 1.50). In contrast, FNAC success was significantly lower for lesions located in the submandibular gland compared with the parotid gland (OR = 0.218, 95% CI: 0.083–0.575; p-value= 0.002) (Table 5). Table 5. Univariate Logistic Regression Analysis of Factors Affecting FNAC Success Variable B (SE) OR (95% CI) p-value Tumor size (cm) 0.405 (0.254) 1.500 (0.911–2.469) 0.111 Gland Parotid gland Submandibular gland -1.522 (0.494) 1 0.218 (0.083-0.575) 0.002 B: Logistic regression coefficient, SE: Standard error, OR: Odds ratio, CI: confidence interval Discussion Fine-needle aspiration is a safe, minimally invasive, and cost-effective diagnostic modality widely used for the preoperative evaluation of lesions across various organs. However, its diagnostic utility in salivary gland lesions remains a subject of ongoing debate [11]. Salivary gland neoplasms can occur across a broad age range. A study by Rameeza et al., which included 104 patients, reported a mean age of 45 years, with peak incidence in the fourth decade of life [11]. Similarly, Kakoty et al. also identified the fourth decade as the most affected age group [12]. In contrast, studies conducted by Koirala et al. and Omhare et al. found a higher incidence in the third decade [13,14]. In the present study, the mean age was 44.90 years, with the highest prevalence observed in the fourth decade of life, consistent with the findings of previous reports. Studies examining the role of FNAC in diagnosing salivary gland tumors have demonstrated variability in sex distribution. A ten-year retrospective study from Greece reported a male predominance, with a male-to-female ratio of 1.28:1 (46 males vs. 36 females) [15]. Similarly, a systematic review of 45 cases of secretory carcinoma also demonstrated a male predominance, with 25 (55.6%) males and 20 (44.4%) females [16]. Conversely, other investigations have described either a balanced or female-predominant distribution. An analysis of 37 FNAC specimens demonstrated an equal gender distribution (17 males vs. 20 females) [17]. Likewise, a study of 81 cases reported a slight female predominance, with 51.85% of cases occurring in females, corresponding to a male-to-female ratio of 1:1.33 [18]. In this study, comprising 272 cases, a slight female predominance was observed, with 55.5% of cases occurring in females, yielding a male-to-female ratio of 1:1.25. The relative proportions of benign, malignant, and non-neoplastic salivary gland tumors vary across published series. A large study from Southern Iran involving 405 cases reported that 74.5% were benign and 25.4% malignant. The most frequently observed benign tumors were pleomorphic adenoma (70.5%) and Warthin’s tumor (21.5%), whereas mucoepidermoid carcinoma (26.2%) and adenoid cystic carcinoma (22.3%) predominated among malignant tumors. Additionally, the study found that benign tumors predominantly affected the parotid gland and were more common in younger individuals, whereas malignant tumors were more frequently observed in older age groups [19]. Similarly, an analysis of 318 patients with primary salivary gland carcinomas identified adenoid cystic carcinoma, mucoepidermoid carcinoma, and squamous cell carcinoma as the most prevalent malignant entities, with the parotid gland being the most commonly affected site [20]. Another study of 124 cases found benign neoplasms in 31.45% (39 cases) and malignant tumors in 15.32% of cases, with pleomorphic adenoma and mucoepidermoid carcinoma representing the most common benign and malignant entities, respectively; 68.9% of neoplasms arose in the parotid gland [14]. In the current study, benign tumors accounted for 88.6% of cases, while 7.4% were malignant. The lower proportion of malignant tumors observed in this cohort compared with several published series may be attributable to differences in referral patterns, patient selection, and the predominance of parotid gland lesions, which are more likely to be benign than lesions arising in other major salivary glands. This distribution may have contributed to the relatively high specificity and negative predictive value observed in the present study and should be considered when interpreting the diagnostic performance of FNAC. Additionally, pleomorphic adenoma was the most prevalent benign tumor in this study, followed by Warthin’s tumor, whereas among malignant neoplasms, mucoepidermoid carcinoma was the most common, followed by squamous cell carcinoma. Additionally, the parotid gland was identified as the most frequently affected site, accounting for about 85.3% of cases. In this study, the ROM for MSRSGC category I (non-diagnostic) was 15.0%, consistent with the 15% benchmark recommended in the second edition of the MSRSGC [21]. This rate exceeds the 11.4% reported in the large meta-analysis by Wang et al., which analyzed 7,168 FNAC cases [9], and is also higher than the 3.2% inadequacy rate observed in the study by Kim et al., where salivary gland FNAC were performed by a single radiologist with six years of experience [22]. However, the current study ROM remains lower than the 23.9% reported in another series [1]. In contrast, among 223 cases classified as MSRSGC category IVa (benign neoplasm), the ROM was merely 0.9%, which is lower than the 2.8% reported in Wang et al.'s meta-analysis [9], and comparable to the 1.0% documented in another study [1]. These findings further support the high diagnostic accuracy and reliability of FNAC when adequate sampling and expert cytological interpretation are achieved. The FNAC is integral to the preoperative assessment of salivary gland tumors, offering a minimally invasive and cost-effective approach to differentiate benign from malignant lesions. Nevertheless, reported diagnostic performance varies across studies. A large series of 1,289 cases evaluated FNAC in two diagnostic settings and demonstrated sensitivity and specificity of 87.5% and 97.7% in one setting, and 91.6% and 81.6% in the other, underscoring its overall reliability while highlighting the potential for false-positive results [1]. Similarly, Naz et al. reported a sensitivity of 77.7% and specificity of 86.3%, reflecting moderate effectiveness in detecting malignancy and relatively higher accuracy in confirming benign disease [23]. Despite its utility, FNAC exhibits limitations in certain histological subtypes. A 2024 systematic review and meta-analysis reported a notably low sensitivity of 27.7% (95% CI: 16.6–42.5%) for secretory carcinoma, largely due to significant cytomorphological overlap with other benign and malignant entities; FNAC alone provided a definitive diagnosis in only 6.6% of cases, emphasizing the need for adjunctive diagnostic modalities [16]. Likewise, Kim et al. documented a sensitivity of 64.2% for high-grade salivary gland malignancies, illustrating the challenges in accurately distinguishing aggressive tumors from benign lesions in complex scenarios [22]. In the present study, FNAC performance was assessed in two analytical settings. When only definitive cytological diagnoses were considered (Setting 1), sensitivity and specificity were 84.6% and 99.6%, respectively. Inclusion of indeterminate categories (Setting 2) yielded sensitivity and specificity of 88.2% and 94.5%, respectively. Variations in diagnostic accuracy across studies likely reflect differences in tumor heterogeneity, cytopathologist expertise, specimen adequacy, case mix, and institutional protocols. A large single-center study from Germany identified lesion size as an independent predictor of sample adequacy in salivary gland FNAC, reporting a 22% increase in diagnostic success for each additional centimeter in lesion diameter [1]. In contrast, another investigation found no significant association between tumor size and FNAC success [22]. Conversely, a separate study demonstrated that sensitivity, specificity, and overall accuracy were higher in parotid lesions measuring 2.1–4.0 cm compared with those smaller than 2 cm [24]. In the present study, although lesion size did not reach statistical significance, it was associated with improved adequacy, with each additional centimeter increasing the odds of successful FNAC by 50%. Regarding lesion location, the aforementioned German study reported significantly lower FNAC success rates for submandibular gland lesions compared with parotid lesions [1]. By contrast, Kim et al. did not observe a significant relationship between gland location and diagnostic performance, possibly reflecting their smaller sample size [22]. The current study’s finding aligns with the German data, demonstrating significantly reduced FNAC success in the submandibular gland relative to the parotid gland. This discrepancy may be explained by the submandibular gland’s deeper anatomical position within the submandibular triangle, which can limit accessibility and compromise sampling. Collectively, these results underscore the importance of meticulous technique and careful procedural planning when performing FNAC in anatomically challenging regions. This study has several limitations that warrant consideration. First, its retrospective design inherently introduces potential selection and information biases, which may affect the interpretation of the findings. Second, the exact number of needle passes performed during each FNAC procedure was not consistently documented. Although institutional protocol generally recommends a single-pass technique, the possibility that additional passes were undertaken in selected cases cannot be excluded. Future prospective studies with standardized procedural documentation are needed to clarify the impact of the number of needles passes on sample adequacy and diagnostic accuracy in salivary gland FNAC. Conclusion Salivary gland FNAC is a minimally invasive, safe, and cost-effective diagnostic technique that may serve as an appropriate first-line investigation in the evaluation of major salivary gland lesions. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: As the study design was a retrospective cohort study based on the analysis of existing clinical records, formal ethical approval was not required in accordance with institutional policy. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from all patients or from their legal guardians in cases involving minors. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: AJQ, AMA, KMS, and AMM: Major contributors to the conception and design of the study, literature review, and manuscript writing. STA, MLF, HAM, ISS, IJH, MBA, RSA, SHQ, AAQ, SHH, and HAA: Literature review, critical revision of the manuscript, and preparation of the tables and figures. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Pediatric Pilonidal Sinus Disease: A Single-Center Cohort Study of Clinical and Surgical Outcomes
Abstract Introduction: Pilonidal sinus disease is increasingly recognized in the pediatric population, yet evidence on its clinical characteristics and surgical outcomes in children and adolescents remains limited. Given this gap, this study aimed to characterize the clinical presentation and surgical outcomes of natal cleft pilonidal sinus in a large pediatric cohort. Methods: This retrospective cohort study included patients aged ≤18 years diagnosed with natal cleft pilonidal sinus over a five-year period. Clinical and sociodemographic data were extracted from medical records. All patients underwent minimal excision under local anesthesia with healing by secondary intention. Results: A total of 1,751 patients were included, with a median age of 17 years and a near-equal sex distribution. Family history was positive in 65.8% of cases. Abscess formation was inversely associated with time to presentation (p < 0.001), while granuloma presence was associated with longer disease duration (p < 0.001). Females demonstrated higher abscess rates than males (30.2% vs 20.9%; p < 0.001). A positive family history was associated with earlier presentation (p = 0.007). Healing was achieved in 95.1% of cases, with a recurrence rate of 20.0% at a median follow-up of 36 months. Conclusion: In pediatric pilonidal sinus disease, abscess and granuloma formation were associated with symptom duration, higher abscess rates in females, and earlier presentation with positive family history. Minimal excision under local anesthesia with outpatient secondary-intention healing warrants prospective comparative evaluation. Introduction Pilonidal sinus disease (PND) is an inflammatory condition caused by the entrapment of hair and debris within the natal cleft [1]. It predominantly affects young adults, with an estimated annual incidence of 26 cases per 100,000 individuals. The condition is most commonly seen in males during their second and third decades of life, with a male-to-female ratio of approximately 3:1 [2]. In the pediatric population, nearly 1.2 per 1,000 children are affected, with a mean age of 15 years (range: 12–19 years), and the overall prevalence appears to have increased in recent decades [3]. The disease rarely manifests before puberty, a pattern attributed to hormonal influences on the pilosebaceous glands, which become active during this developmental period [4]. While the natal cleft represents the most common site of involvement, the condition has also been documented in other anatomical locations, including the umbilicus, interdigital webs, suprapubic area, nose, groin, axilla, penis, clitoris, occiput, and prepuce [5]. The accumulation of foreign bodies and fragmented hair in moist areas of the body subsequently leads to infection and sinus formation [5]. Recognized associated factors in the pediatric population include gluteal fold hair, obesity, poor personal hygiene, and prolonged sitting, a habit particularly common among school-aged children [6]. Clinically, PND typically presents with localized inflammatory features along the sinus tract, including pain, warmth, tenderness, fluctuance, erythema, and purulent discharge. The condition is associated with recurrence and often poses significant challenges to achieving complete resolution [7]. The management of pediatric PND remains a significant clinical challenge, largely due to the absence of an established gold standard surgical technique and a paucity of high-quality evidence to guide treatment decisions [8,9]. Consequently, reported recurrence rates following surgery in children and adolescents vary considerably, ranging from 0% to 42%, and remain substantial regardless of the surgical approach employed [9,10]. This study aims to characterize the clinical presentation and surgical outcomes of pediatric PND in a large single-center cohort, addressing the limited pediatric-specific evidence in this field. Only peer-reviewed literature was cited after careful verification of all references [11]. Methods Study Design This retrospective single-center cohort study included pediatric patients diagnosed with natal cleft pilonidal sinus disease (NCPND) from 2020 to 2025 at a private medical facility. All patients were evaluated, treated, and followed up at the same institution. Verbal informed consent for the use of anonymized clinical data and its publication was obtained from all patients and their guardians. Eligibility Criteria and Dataset Patients aged ≤ 18 years who presented with NCPND during the study period were included. Diagnosis was established clinically based on history and physical examination, with ultrasonography being performed in cases of diagnostic uncertainty. Typical presentations included pain, swelling, discharge, itching, or midline pits in the natal cleft region (Figure 1. A). Patients managed under spinal or general anesthesia were excluded. Clinical and sociodemographic data were obtained from medical records and treating healthcare providers. Variables recorded included age, sex, presenting symptoms, past medical and surgical history, examination findings, ultrasonography findings (when performed), indications for excision under local anesthesia (LA), postoperative complications, outcome, and duration of follow-up. Time to presentation was defined as the interval between first symptom recognition and initial clinic presentation, based on patient/parent history recorded at the first encounter. As data were extracted retrospectively from existing records, individual variables were analyzed on an available-case basis, and recurrence was assessed only in the patients with a documented follow-up visit (444 [25.4%] lacked follow-up and were excluded from recurrence analysis). Surgical Management All procedures were performed by consultant surgeons experienced in NCPND, under the supervision of senior attending surgeons and following a standardized protocol. All patients underwent comprehensive preoperative assessment to determine suitability for LA, including monitoring of vital signs, hematological assessment, and routine viral screening, the latter performed per institutional policy for all surgical patients irrespective of anesthetic technique. All procedures were performed with the patient in the prone position using strict aseptic technique. In patients with non-acutely infected NCPND, the procedure consisted of minimal excision of the pilonidal sinus tract(s) and associated diseased tissue through a small elliptical or circular incision (specimen size approximately 1–3 cm), preserving surrounding healthy tissue, with the wound left open to heal by secondary intention (Figure 1. B). Patients presenting with acutely infected pilonidal abscesses were managed in two stages. The first stage involved incision and drainage of the abscess, followed by daily wound dressing with gauze drainage. The second stage consisted of definitive excision of the sinus tract once the acute infection had resolved. Postoperative care included analgesics as needed and daily wound dressing with normal saline until complete healing was achieved. Complete healing was defined as full epithelialization of the wound without discharge, infection, or pain and with no need for further wound care, assessed at scheduled follow-up visits with final determination at approximately 4–8 weeks. Recurrence was defined as the reappearance of pilonidal disease (sinus formation, persistent discharge, abscess, or the need for repeat intervention) at the previously treated site, diagnosed clinically during follow-up. <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/blobid0-141aaff4315bbfbac4d0d4a84f05dd06.jpg" alt="Figure 1. (A) Preoperative view of the sacrococcygeal region showing a chronic pilonidal sinus within the natal cleft, with multiple epithelialized midline pits visible. (B) Immediate postoperative view following excision, with the sinus tracts completely removed and wounds left open for healing by secondary intention." width="1920" height="1080" /> Statistical Analysis The database was locked prior to analysis; data were organized using Microsoft Excel 2019 and analyzed using the Statistical Package for Social Sciences (SPSS) version 25.0. The Shapiro-Wilk and Kolmogorov-Smirnov tests were used to assess the normality of continuous variables. Continuous variables are therefore presented as median and interquartile range (IQR), while categorical variables are presented as frequencies and percentages. The chi-square test was used to assess associations between categorical variables, with Cramer's V reported as a measure of effect size. The Mann-Whitney U test was used to compare continuous variables between two independent groups. Recurrence-free survival was estimated by the Kaplan–Meier method, with time measured from the date of excision to recurrence. Patients without recurrence were censored at their last documented follow-up. Multivariable binary logistic regression was used to identify factors independently associated with abscess formation and with recurrence, with sex, time to presentation, and family history (FHX) as covariates (reference categories: <1 week and female). Results are reported as adjusted odds ratios with 95% confidence intervals, with model fit assessed by the Hosmer–Lemeshow test. Obesity was defined as BMI ≥30 kg/m², consistent with the adult threshold, which was considered appropriate given that the cohort was predominantly composed of older adolescents with a median age of 17 years. A p-value of < 0.05 was considered statistically significant. Results years, with a median age of 17 years (IQR = 3). Body mass index ranged from 14.1 to 43.5 kg/m², with a median of 24.4 (IQR = 5.4); by category, 884 patients (50.5%) were of normal weight, 525 (30.0%) were overweight, 221 (12.6%) were obese, and 121 (6.9%) were underweight. Overall, 881 cases were males (50.3%), and 870 were females (49.7%). Previous surgical history was positive in 124 patients (7.1%), while 1,627 (92.9%) had no history of surgical intervention. Family history for PND was positive in 1,152 cases (65.8%) and negative in 599 (34.2%). Regarding smoking status, 1,641 participants (93.7%) were non-smokers, 100 (5.7%) were active smokers, and 10 (0.6%) were passive smokers. A sedentary lifestyle was present in 1,686 participants (96.3%), while 65 (3.7%) were non-sedentary. Sitting on hard surfaces was reported in 199 patients (11.4%), and frequent car travel in 39 (2.2%), while 1,712 (97.8%) did not travel by car frequently. Body hair characteristics included a small amount in 622 cases (35.5%) and hairy in 1,129 (64.5%). Among 1,704 patients, straight hair was present in 1,409 (82.7%), wavy hair in 182 (10.7%), and curly hair in 113 (6.6%) (Table 1). Table 1. Patient demographics and characteristics Age (years), median (IQR) 17 (3) BMI (kg/m²), median (IQR) 24.4 (5.4) BMI Classification Underweight Normal weight Overweight Obese 121 (6.9%) 884 (50.5%) 525 (30.0%) 221 (12.6%) Sex Male Female 881 (50.3%) 870 (49.7%) Surgical History Yes No 124 (7.1%) 1,627 (92.9%) Family History for PND Positive Negative 1,152 (65.8%) 599 (34.2%) Smoking Status Non-smoker Smoker Passive smoker 1,641 (93.7%) 100 (5.7%) 10 (0.6%) Sedentary Lifestyle Yes No 1,686 (96.3%) 65 (3.7%) Sitting on Hard Surfaces Yes No 199 (11.4%) 1,552 (88.6%) Frequent Car Travel Yes No 39 (2.2%) 1,712 (97.8%) Body Hair Small amount Hairy 622 (35.5%) 1,129 (64.5%) Type of Body Hair (n=1704) Straight Wavy Curly 1,409 (82.7%) 182 (10.7%) 113 (6.6%) IQR: interquartile range; BMI: body mass index; PND: pilonidal sinus disease Most patients were symptomatic (n = 1,729; 98.7%), with 22 (1.3%) asymptomatic; the latter were diagnosed incidentally during examination. Time to presentation was 1–12 months (n = 698; 39.9%), more than 1 year (n = 397; 22.7%), 1 week to <1 month (n = 364; 20.8%), and less than 1 week (n = 292; 16.6%). Among symptomatic patients, pain was reported in 1,573 patients (91.0%), itching in 1,080 (62.5%), discharge in 984 (57.0%), of whom 753 (43.5%) had purulent discharge, and swelling in 685 (39.6%). On examination, a sinus tract was identified in 1,726 patients (98.6%), abscess formation in 447 (25.5%; 95% CI 23.5–27.6), and granuloma in 313 (17.9%; 95% CI 16.2–19.7). As for treatment outcomes, healing was assessed at the treating center for all 1,751 patients and was achieved in 1,666 (95.1%; 95% CI 94.0–96.1), while 85 (4.9%) did not achieve complete healing. Recurrence assessment required follow-up data, which were available for 1,307 patients (74.6%); the remaining 444 (25.4%) lacked follow-up. Among the 1,307 patients with follow-up data, 262 (20.0%; 95% CI 18.0–22.3) experienced recurrence and 1,045 (80.0%) did not, over a median follow-up of 36 months (IQR = 25); of those who recurred, 246 (94.0%) did so after documented initial healing, while 16 (6.0%) represented persistent disease in patients who had not achieved initial healing (Table 2). Table 2. Clinical presentations, diagnosis, management and outcome Variable Frequency/percentages Symptom Status Symptomatic Asymptomatic 1,729 (98.7%) 22 (1.3%) Time to Presentation After PND 1–12 months More than 1 year 1 week–<1 month Less than one week 698 (39.9%) 397 (22.7%) 364 (20.8%) 292 (16.6%) Symptoms (n=1729) Pain Itching Discharge Swelling 1,573 (91.0%) 1,080 (62.5%) 984 (57.0%) 685 (39.6%) Examination Findings Sinus tract Abscess formation Granuloma 1,726 (98.6%) 447 (25.5%) 313 (17.9%) Number of Sinus Openings 1 2 3 4 5 6 ≥7 377 (21.5%) 402 (23.0%) 335 (19.1%) 236 (13.5%) 134 (7.7%) 98 (5.6%) 169 (9.6%) Healing Status Achieved Not achieved 1,666 (95.1%) 85 (4.9%) Recurrence (n = 1,307) Present Absent 262 (20.0%) 1,045 (80.0%) Recurrence by healing status (n = 262) After initial healing Persistent disease (no initial healing) 246 (94.0%) 16 (6.0%) PND: pilonidal sinus disease A significant association was found between granuloma presence and time to presentation (χ² = 77.198, df = 3, p < 0.001; Cramer's V = 0.21), with granuloma present in 4.8% of patients presenting within one week, 11.3% within 1 week to <1 month, 21.1% within 1–12 months, and 28.0% after more than one year. Abscess formation was similarly associated with time to presentation (χ² = 431.851, df = 3, p < 0.001; Cramer's V = 0.50), present in 67.1% of patients within one week, 38.2% within 1 week to <1 month, 9.5% within 1–12 months, and 11.6% after more than one year (Table 3). Furthermore, females demonstrated a higher rate of abscess formation compared to males (30.2% vs 20.9%; χ² = 20.105, df = 1, p < 0.001; Cramer's V = 0.11). However, FHX was not significantly associated with recurrence (20.8% vs 18.6%; χ² = 0.867, p = 0.352; Cramer's V = 0.03), nor was obesity (18.6% vs 20.3%; χ² = 0.257, p = 0.612; Cramer's V = 0.014) (Table 4). Patients with a positive FHX of NCPND presented at a younger age than those without FHX (median 16 vs 17 years; U = 318,462, p = 0.007) (Table 5). Kaplan–Meier recurrence-free probability declined from 90.9% at 24 months to 59.6% at 60 months (Figure 2). <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-13255777111781423491905.png" alt="Figure 2. Kaplan–Meier estimate of recurrence-free probability over 60 months of follow-up. The shaded area represents the 95% confidence interval. Patients without recurrence were censored at their last documented follow-up. Numbers at risk are shown beneath the x-axis. " width="2138" height="1483" /> Table 3. Effect of granuloma and abscess formation on time to presentation Variable < 1 week 1 week–<1 month 1–12 months > 1 year χ² p-value Cramer's V Granuloma Absent 278 (95.2%) 323 (88.7%) 551 (78.9%) 286 (72.0%) 77.198 <0.001 0.21 Present 14 (4.8%) 41 (11.3%) 147 (21.1%) 111 (28.0%) Abscess Absent 96 (32.9%) 225 (61.8%) 632 (90.5%) 351 (88.4%) 431.851 <0.001 0.50 Present 196 (67.1%) 139 (38.2%) 66 (9.5%) 46 (11.6%) χ²: Chi-Square statistic Table 4. Associations of abscess formation with sex, and of recurrence with family history and obesity Variable Category Status n (%) χ² p-value Cramer's V Yes No Abscess formation by sex Male 184 (20.9%) 697 (79.1%) 20.105 <0.001 0.11 Female 263 (30.2%) 607 (69.8%) FHX by Rx Positive FHX 178 (20.8%) 678 (79.2%) 0.867 0.352 0.03 Negative FHX 84 (18.6%) 367 (81.4%) Obesity by Rx Obese 32 (18.6%) 140 (81.4%) 0.257 0.612 0.014 Not Obese 230 (20.3%) 905 (79.7%) Table 5. Association between family history and age at presentation in pilonidal sinus disease Comparison Category Age, median (IQR), years U p Age at Presentation Positive FHX 16 (2) 318,462 0.007 Negative FHX 17 (3) IQR: interquartile range; U: Mann-Whitney U test; FHX: family history In multivariable logistic regression for abscess formation, earlier presentation and female sex were independently associated with higher odds of abscess. Relative to presentation within one week, the adjusted odds of abscess were markedly lower at 1 week to <1 month (OR 0.30, 95% CI 0.22–0.42), 1–12 months (OR 0.05, 95% CI 0.04–0.07), and beyond one year (OR 0.07, 95% CI 0.04–0.10; all p < 0.001). Male sex was associated with lower odds of abscess relative to female sex (OR 0.63, 95% CI 0.49–0.81, p < 0.001), whereas FHX was not independently associated with abscess (OR 1.20, 95% CI 0.92–1.56, p = 0.177). The model showed good fit (Hosmer-Lemeshow p = 0.42; Nagelkerke R² = 0.32) (Table 6). In the model for recurrence, restricted to the 1,307 patients with available follow-up data (262 events), none of the examined factors was independently associated with the outcome. Neither time to presentation (overall p = 0.72), sex (OR 1.15, 95% CI 0.87–1.51, p = 0.320), nor FHX (OR 1.17, 95% CI 0.87–1.57, p = 0.293) predicted recurrence, and the model was not statistically significant overall (Omnibus p = 0.68), explaining negligible variance (Nagelkerke R² < 0.01). Model calibration was nonetheless adequate (Hosmer–Lemeshow p = 0.98). These findings indicate that recurrence was not predicted by the baseline clinical characteristics examined (Table 7). Table 6. Multivariable logistic regression for abscess formation Variable Adjusted OR 95% CI p-value Sex (male vs female) 0.63 0.49–0.81 <0.001 Time to presentation (ref: <1 week) 1 week–<1 month 0.30 0.22–0.42 <0.001 1–12 months 0.05 0.04–0.07 <0.001 >1 year 0.07 0.04–0.10 <0.001 Family history (positive vs negative) 1.20 0.92–1.56 0.177 OR: odds ratio; CI: confidence interval. Reference categories: female sex and presentation within one week. Model fit: Hosmer–Lemeshow p = 0.42; Nagelkerke R2 = 0.32. Table 7. Multivariable logistic regression for recurrence Variable Adjusted OR 95% CI p-value Time to presentation (ref: <1 week) 1 week–<1 month 0.78 0.51–1.22 0.276 1–12 months 0.88 0.60–1.29 0.499 >1 year 0.82 0.54–1.26 0.363 Sex (male vs female) 1.15 0.87–1.51 0.320 Family history (positive vs negative) 1.17 0.87–1.57 0.293 OR: odds ratio; CI: confidence interval. Reference categories: female sex and presentation within one week. Overall model not significant (omnibus p = 0.68); Hosmer–Lemeshow p = 0.98; Nagelkerke R2 < 0.01. Discussion This large single-center cohort of 1,751 pediatric patients characterized the clinical associations and surgical outcomes of NCPND managed by minimal excision under local anesthesia. The principal findings were that abscess formation was strongly associated with earlier presentation and female sex, granuloma with longer symptom duration, and positive FHX with younger age at presentation, while no baseline factor independently predicted recurrence. Complete healing was achieved in 95.1% of patients, with a crude recurrence rate of 20.0%. Surgical options in treating PND include excision with primary closure, secondary intention healing, off-midline flap procedures, and minimally invasive techniques, each with distinct trade-offs between healing time and complication rates [9,12]. More recently, minimally invasive approaches have gained popularity due to minimal postoperative pain and earlier return to normal activities, as well as significantly shorter operative times [1,8]. In this study, a near-equal male-to-female ratio was observed (50.3% male vs. 49.7% female), contrasting with the 3:1 to 4:1 male predominance ratio reported in adults [13]. However, this finding is consistent with other pediatric series, including the 1:1.14 ratio reported by Ozcan et al., as well as distributions reported by Nasr and Ein (52.9% male) and Esposito et al. (55.6% male) [8,13,14]. Nevertheless, female predominance has also been described by other studies, such as Lee et al. (55.6% and 82.2% female across treatment groups) and Kalyoncu Ayçenk (62.0% female) [1,6]. Collectively, these discrepancies suggest that the traditional male predominance may be less pronounced in pediatric populations, particularly in younger age groups. Family history emerged as a notably prominent finding in the present study, with FHX documented in 65.8% of patients, a proportion considerably higher than that reported in comparable studies of adolescent and young adult populations. Yildiz et al. identified a positive FHX in 52.4% of their teenage cohort, while Kalyoncu Ayçenk reported this in 32.0% of patients, and the meta-analysis by Xu et al. yielded a pooled prevalence of 29.6% across included studies [6,15,16]. Notably, FHX was self-reported by patients and guardians, based on FHX in any relative, and not independently verified. This method is prone to recall bias and may over-report prevalence, likely contributing to the higher rate observed here. The clinical significance of hereditary predisposition has been well demonstrated by Yildiz et al., who found that familial transmission was significantly more prevalent in patients with NCPND compared to healthy controls (OR: 8.652, p = 0.005) [15]. This elevated prevalence may reflect a more pronounced genetic predisposition within the studied population, or regional or ethnic variation in heritability. In the study herein, patients with a positive FHX of NCPND presented at a significantly younger age (median 16 vs 17 years; U = 318,462, p = 0.007), although this one-year difference, while statistically significant, is likely of limited clinical relevance. A similar trend was reported by Doll et al. in an adult cohort, where patients with a positive FHX underwent surgery at a younger age compared to those without FHX (22.4 vs 23.9 years, p = 0.038), supporting the concept of earlier disease manifestation in genetically predisposed individuals [17]. Although the Doll et al. study was conducted in adults, the consistency of this finding in the present pediatric cohort suggests that FHX exerts a similar influence on disease onset across age groups. In contrast, FHX was not significantly associated with recurrence (20.8% vs 18.6%; χ² = 0.867, p = 0.352), which differs from the long-term recurrence trends reported by Doll et al., likely attributable to the considerably shorter follow-up period in the present study [17]. A sedentary lifestyle was recorded in 96.3% of patients; however, this was based on patient self-report and parental report rather than a standardized cutoff such as the ≥6 hours/day threshold used by Yildiz et al., who reported prolonged sitting in 45.2% of their cohort. The absence of a quantitative definition likely explains the higher proportion observed here [15]. Regarding body hair characteristics, 64.5% of patients were observed to be hairy, though formal assessment of hirsutism was not performed. This is consistent with the broader literature, in which dense body hair is recognized as a significant risk factor for NCPND (OR: 3.29), and hirsutism has been identified as a predisposing factor in multiple studies [2,8,16]. Notably, straight hair was the most common hair type in this cohort (82.7%), in contrast to curly hair, which Xu et al. identified as a risk factor [16]. However, this likely reflects the underlying hair-type distribution of the regional population rather than a true contradiction. Granuloma presence was associated with longer disease duration (χ² = 77.198, p < 0.001; Cramer's V = 0.21), being identified in 4.8% of patients presenting within one week compared to 28.0% of those presenting after more than one year. This supports the interpretation of granuloma as a marker of chronic disease. According to the established pathogenesis, granuloma formation develops gradually as a foreign body reaction to hair penetration into the subcutaneous tissue, leading to progressive inflammation and tract epithelialization over time, which explains why granulomas are more frequently identified in long-standing disease [18]. In contrast, a strong inverse association was observed between time to presentation and abscess formation (χ² = 431.851, p < 0.001; Cramer's V = 0.50), with abscess markedly less common with later presentation, occurring in 67.1% of patients presenting within one week compared with 11.6% of those presenting after more than one year. This relationship persisted on multivariable analysis, with progressively lower odds of abscess at each later interval (OR 0.30 at 1 week to <1 month, 0.05 at 1–12 months, and 0.07 beyond one year, relative to presentation within one week; Nagelkerke R² = 0.32), indicating it was not attributable to the other characteristics examined. This pattern reflects the acute nature of abscess formation, which arises from rapid bacterial proliferation within an obstructed sinus pit, resulting in pain, swelling, and a purulent collection that prompts early presentation [18,19]. Although these mechanisms have been primarily described in adult populations, the present findings indicate that the same disease behavior is observable in pediatric patients, reinforcing the relevance of these pathogenic principles across age groups. Among the present cohort, females demonstrated higher abscess rates than males (30.2% vs 20.9%; χ² = 20.105, p < 0.001; Cramer's V = 0.11). Directly comparable pediatric abscess-prevalence data by sex are scarce; the closest available comparison, Stoeckel et al., reported a higher frequency of incision and drainage in females (6.0% vs 3.0%, p = 0.01), though as a procedural rather than a prevalence metric, so the two are not directly comparable [20]. Chiu et al. similarly observed sex-related differences in pain intensity, drainage, and granuloma formation among pediatric patients, proposing hormonal influences during puberty as a potential underlying mechanism [21]. Taken together, these findings suggest that the higher abscess rate observed among females in this cohort reflects a sex-specific clinical pattern in adolescents rather than greater disease burden. In the present study, healing by secondary intention following minimal excision under LA was achieved in 95.1% of patients. The published literature consistently reports longer healing times with secondary intention compared to primary closure, though primary closure carries its own morbidity, most notably wound dehiscence [9]. Additionally, primary closure was performed as an inpatient procedure, with a median hospital stay of up to 15.8 days reported in one case series [3]. The outpatient approach employed here avoided inpatient admission, although the two-stage management of abscesses entailed repeat outpatient visits. While this may represent a clinically meaningful advantage in patient burden and resource use, in the absence of a comparator arm it is inferred rather than demonstrated and would require prospective comparative evaluation to confirm. Recurrence remains the principal challenge in pediatric NCPND. The crude rate of 20.0% at a median follow-up of 36 months is consistent with the 26.0% pooled risk for excision with open healing reported by Hardy et al. [9] and with comparable series [13,14]. This crude figure, however, reflects events observed during available follow-up: Kaplan–Meier analysis showed recurrence-free probability falling from 90.9% at 24 months to 59.6% at 60 months, corresponding to a cumulative recurrence of 40.4% as later recurrences accrued beyond the second postoperative year. This trajectory closely mirrors the largest longitudinal pediatric datasets, in which five-year recurrence reaches approximately 46.0% and is roughly fourfold higher than in adults [10], indicating that the high long-term recurrence reflects an age-related disease pattern rather than a shortcoming of the technique, and underscoring the need for prospective evaluation with sustained follow-up. Obesity was not associated with recurrence in this cohort (18.6% vs 20.3%; p = 0.612), consistent with most pediatric data. Esposito et al. found no association on multivariable analysis (OR 0.934, p = 0.795), and Ozcan et al. reported no significant BMI difference between patients with and without recurrence (p = 0.167) [13,22]. This suggests that obesity, although implicated in the development of pilonidal disease, may not influence recurrence once disease is established. This study has several limitations inherent to its retrospective, single-center design, including the potential for selection bias and limited generalizability. As data were drawn from a single private facility, the cohort may be subject to referral and socioeconomic bias and may not reflect the broader pediatric population. The exclusion of patients managed under spinal or general anesthesia may also have introduced selection bias, as the cohort was limited to those suitable for local anesthesia and may not represent patients with more extensive or complex disease. The absence of a control group precluded formal comparative risk factor analysis, and several recognized risk factors, including obesity, sedentary lifestyle, and hirsutism, were recorded descriptively rather than systematically measured, limiting their interpretation. Key exposure variables, including FHX and time to presentation, were self-reported and unverified, introducing potential recall bias. Additionally, the large sample size may have inflated statistical significance for some findings, and clinical interpretability should be considered accordingly. Furthermore, incomplete follow-up data for a subset of patients may introduce attrition bias and limit the accuracy of recurrence estimates. Recurrence may also be underestimated, as follow-up relied on documented clinical encounters rather than active surveillance. Conclusion In conclusion, abscess and granuloma formation in pediatric NCPND were associated with symptom duration, higher abscess rates in females, and earlier presentation with positive FHX. Minimal excision under local anesthesia with outpatient secondary-intention healing warrants prospective comparative evaluation. Declarations Conflicts of interest: The authors declare no conflicts of interest. Ethical approval: As the study design was a retrospective cohort study based on the analysis of existing clinical records, formal ethical approval was not required in accordance with institutional policy. Consent for participation: Not applicable. Consent for publication: Verbal informed consent for publication of anonymized data was obtained from all patients and their legal guardians. Funding: No funding was received for conducting this study. Acknowledgements: None. Authors' contributions: AMS: involved in study conceptualization, design, and methodology, the management and surgery of all cases, and critical review and follow-up of cases. ISS and MSJ: involved in study conceptualization, design, and methodology, as well as critical review of the manuscript. MTH: involved in methodology, writing the first draft of the manuscript, data curation and analysis, and visualization. OAA, HAHM, KQA, and THH: involved in data curation and critical review of the manuscript. AAQ, BLF, AOH, and KZH: involved in critical review of the manuscript and follow-up of patients. HOA: involved in critically reviewing the manuscript. All authors read and approved the final version of the manuscript. Use of AI: The authors used Claude Opus 4.7 and Claude Opus 4.8 (Anthropic, PBC, San Francisco, CA, USA) to check the language and flow of the manuscript; the authors have reviewed the manuscript and take full responsibility for its content. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Preoperative Thyroglobulin and Thyroid Pathologies: A Single Center Experience
Abstract Introduction: Thyroid nodules are frequently found in the general population, though malignancy is confirmed in only a minority of cases. Distinguishing between benign and malignant nodules before surgery is vital for appropriate clinical management. The utility of preoperative serum thyroglobulin (Tg) levels as a diagnostic marker in thyroid carcinomas remains controversial. This study aimed to provide a descriptive overview of patients with markedly elevated preoperative Tg levels (>500 ng/mL) and their corresponding histopathological outcomes. Methods: A retrospective, single-center study was conducted at Smart Health Tower, which included patients who underwent surgical interventions for thyroid disorders between 2019 and 2025, with preoperative serum Tg levels exceeding 500 ng/mL. Patients were excluded if they had incomplete medical records. Patient demographics, clinical features, preoperative findings, surgical details, and final histopathology were retrieved from electronic medical records. Results: A total of 260 patients were included, predominantly female (73.08%), with a median age of 49 years (QR: 38–61). Neck swelling was the most common symptom (63.08%). Ultrasonography showed follicular nodular disease in 60.0%. Fine-needle aspiration cytology revealed Bethesda II in 20.0%, IV in 13.85%, and VI in 11.15% of cases. Total thyroidectomy was performed in 74.62% of cases. Histopathology showed benign lesions in 70.77% and malignant lesions in 29.23% of the cases. Conclusion: Preoperative Tg levels may be elevated in both benign and malignant thyroid disorders; however, Tg may not possess adequate diagnostic precision to be used as a sole indicator of malignancy. Introduction Thyroid nodules are highly prevalent in the general population, with ultrasonography identifying them in up to 60% of individuals. Despite their frequency, approximately 5% are malignant [1, 2]. Primary thyroid carcinoma is the most common endocrine malignancy and is broadly classified into follicular epithelial-derived and non-follicular epithelial-derived tumors. Tumors of follicular epithelial origin include differentiated thyroid carcinoma (DTC), poorly differentiated carcinoma, and undifferentiated (anaplastic) carcinoma. DTC, which encompasses papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, and oncocytic (previously Hürthle), accounts for approximately 95% of all thyroid malignancies [3, 4]. Accurate preoperative identification of thyroid nodules as benign or malignant is essential for guiding appropriate treatment decisions [3]. Initial evaluation commonly involves thyroid ultrasound, which plays a vital role in differentiating benign from malignant nodules. Complementary diagnostic techniques, such as contrast-enhanced ultrasound and ultrasonic elastography, provide additional insight. Among these, ultrasound-guided fine needle aspiration (FNA) is considered the most reliable method for diagnosing DTC prior to surgery. However, the accuracy of both ultrasound and FNA can be affected by factors including nodule size, sonographic features, and the clinician’s experience [5]. Reliable serum biomarkers are also essential for diagnosing and managing DTC. Thyroglobulin (Tg), a large glycoprotein composed of 2750 amino acids with a molecular weight of approximately 330 kilodaltons, is synthesized and secreted by thyroid follicular epithelial cells. It is primarily localized within thyroid follicular structures, with only minimal quantities circulating in the bloodstream under normal physiological conditions [6]. In patients with DTC who have undergone total thyroidectomy, particularly those who receive radioactive iodine (I-131) therapy, serum Tg functions as a valuable biomarker for assessing residual thyroid tissue, disease recurrence, and distant metastases, as its presence in the circulation postoperatively is typically indicative of persistent or recurrent disease [3]. The clinical significance of preoperative Tg levels as a diagnostic and prognostic tool in thyroid carcinomas remains a subject of ongoing debate [3]. This study aimed to provide a descriptive overview of patients with markedly elevated preoperative Tg levels (>500 ng/mL, reference range 3–40 ng/mL) and their corresponding histopathological findings following thyroid surgery. All references were evaluated for eligibility using reputable predatory journal lists to ensure scholarly integrity [7]. Methods Study Design This retrospective, single-center study was conducted at the Smart Health Tower (Sulaymaniyah, Iraq) and included patients who underwent surgical interventions for thyroid disorders between 2019 and 2025. The study received approval from the Kscien Organization’s Ethics Committee under registration number 40 in 2025. Inclusion Criteria The study included only patients who had elevated preoperative serum Tg levels exceeding 500 ng/mL. The threshold of 500 ng/mL was selected because it represents a markedly abnormal elevation well beyond the ranges commonly reported in both benign and malignant thyroid disease in previous studies [8–14]. In addition, this value corresponded to the upper reporting limit of our institutional laboratory assay, which does not quantify Tg concentrations above 500 ng/mL. Exclusion Criteria Patients were excluded if they had incomplete medical records. Data Collection Demographic and clinical data were retrieved from electronic medical records. The variables collected included age, sex, occupation, relevant medical history, presenting symptoms, results of preoperative imaging and laboratory investigations, Bethesda category, type of surgery performed, and final histopathological diagnosis. Statistical Analysis All collected data were entered into Microsoft Excel and subsequently analyzed using IBM SPSS (Statistical Package for the Social Sciences), version 27.0. Continuous variables were presented as means with standard deviations or medians with quartile ranges, as appropriate, while categorical variables were summarized using frequencies and percentages. Results Patient Demographics A total of 260 patients were included in this study. The majority were female (n = 190, 73.08%), while the remaining 70 patients (26.92%) were male. The median age was 49 years (QR: 38–61). The highest frequency of patients was observed in the 40–49 age group (n = 61, 23.46%), followed by the 50–59 age group (n = 53, 20.38%). In terms of smoking, 216 patients (83.08%) were non-smokers. The most common occupation among the patients was homemaker (n = 150, 57.69%) (Table 1). Table 1. Patient Demographics and Medical Backgrounds Parameters Frequency (%) Gender Female Male 190 (73.08%) 70 (26.92%) Age (year) < 20 20 – 29 30 – 39 40 – 49 50 – 59 60 – 69 70 – 79 > 80 Median (QR) Mean ± SD 5 (1.92%) 18 (6.92%) 50 (19.23%) 61 (23.46%) 53 (20.38%) 48 (18.46%) 24 (9.23%) 1 (0.38%) 49 (38 – 61) 49.14 ± 14.76 Smoking status Active smoker Passive smoker Former smoker Non-smoker 30 (11.54%) 13 (5.00%) 1 (0.38%) 216 (83.08%) Occupation Homemaker Teacher Unemployed Retired Police officer Student Butcher Engineer Farmer Healthcare personnel Others 150 (57.69%) 15 (5.77%) 11 (4.23%) 11 (4.23%) 6 (2.31%) 5 (1.92%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 58 (22.31%) Medical history* Unremarkable Hypertension Diabetes mellitus Heart disease Asthma Deaf Stroke 243 (93.46%) 13 (5.0%) 7 (2.69%) 4 (1.54%) 1 (0.38%) 1 (0.38%) 1 (0.38%) Past surgical history Unremarkable Total thyroidectomy Right thyroid lobectomy CABG 238 (91.54%) 19 (7.30%) 2 (0.77%) 1 (0.38%) *: Some patients had multiple medical conditions, CABG: Coronary artery bypass graft, IQR: Interquartile range, SD: Standard deviation Medical and Surgical History Two hundred forty-three patients (93.46%) had no past medical conditions. Hypertension was present in 13 patients (5.0%). Most patients (n = 238, 91.54%) had no prior surgical history. Nineteen patients (7.30%) had previously undergone total thyroidectomy, and 2 (0.77%) had undergone right thyroid lobectomy (Table 1). Presenting Symptoms and Laboratory Findings The most common presenting symptom was neck swelling, reported in 164 patients (63.08%), while 76 patients (29.23%) were asymptomatic. All patients had preoperative elevated serum Tg levels exceeding 500 ng/mL. Thyroid-stimulating hormone (TSH) levels were within the normal range in 178 patients (68.46%) (Table 2). Table 2. Clinical Presentations and Diagnostic Evaluations Parameters Frequency (%) Presentations Neck swelling Weakness Dyspnea Voice change Others Asymptomatic 164 (63.08%) 11 (4.23%) 3 (1.15%) 3 (1.15%) 3 (1.15%) 76 (29.23%) Thyroglobulin (ng/mL) > 500.0 260 (100.0%) TSH level (mIU/L) Below normal range (<0.4) Within normal range (0.4–4.0) Above normal range (>4.0) 43 (16.54%) 178 (68.46%) 39 (15.0%) Ultrasonography findings TFND Right thyroid lobe nodule Left thyroid lobe nodule Multiple suspicious LNs Remnant thyroid tissue Gravis disease Recurrent TFND Isthmus nodule Thyroiditis N/A 156 (60.0%) 44 (16.92%) 32 (12.31%) 10 (3.85%) 5 (1.92%) 4 (1.54%) 4 (1.54%) 1 (0.38%) 1 (0.38%) 3 (1.15%) TI-RADS classification * TR3 (Mildly Suspicious) TR4 (Moderately Suspicious) TR5 (Highly Suspicious) TR2 (Not Suspicious) TR1 (Benign) N/A 172 (66.15%) 53 (20.38%) 22 (8.46%) 5 (1.92%) 1 (0.38%) 14 (5.38%) FNA (Bethesda Categories) ** Bethesda II Bethesda IV Bethesda VI Bethesda III Bethesda I Bethesda V N/A 52 (20.0%) 36 (13.85%) 29 (11.15%) 10 (3.85%) 7 (2.69%) 10 (3.85%) 119 (45.77%) *: TI-RADS classifications were assigned to multiple nodules in certain patients, **: Some patients underwent FNA more than once, TFND: Thyroid follicular nodular disease, N/A: Not available, TI-RADS: Thyroid imaging reporting and data system, FNA: Fine needle aspiration, LN: Lymph node Ultrasonographic and Fine-Needle Aspiration Findings Ultrasonographic evaluation revealed thyroid follicular nodular disease (TFND) in 156 patients (60.0%), right thyroid lobe nodules in 44 (16.92%), and left lobe nodules in 32 (12.31%). According to the TI-RADS classification, most nodules were TR3 (n = 172, 66.15%), followed by TR4 (n = 53, 20.38%) and TR5 (n = 22, 8.46%). FNA findings based on the Bethesda system were available for 141 patients (54.23%). The most frequent categories were Bethesda II (n = 52, 20.0%), Bethesda IV (n = 36, 13.85%), and Bethesda VI (n = 29, 11.15%) (Table 2). Surgical Intervention Surgical intervention consisted predominantly of total thyroidectomy (n = 194, 74.62%). Central neck dissection was performed in 18 patients (6.92%), while lateral neck dissection was carried out in 11 patients (4.23%) (Table 3). Table 3. Surgical Procedures, Diagnoses, and Outcomes Parameters Frequency (%) Type of operation Total Thyroidectomy Thyroid lobectomy Thyroid nodulectomy Completion lobectomy Isthmusectomy Revision of thyroid remnant 194 (74.62%) 46 (17.69%) 15 (5.77%) 2 (0.77%) 2 (0.77%) 1 (0.38%) Central neck dissection Bilateral central neck dissection Right central neck dissection Left central neck dissection Not performed 8 (3.08%) 6 (2.31%) 4 (1.54%) 242 (93.07%) Lateral neck dissection Left lateral neck dissection level Right lateral neck dissection level Bilateral lateral neck dissection level Not performed 5 (1.92%) 5 (1.92%) 1 (0.38%) 249 (95.77%) Histopathological diagnosis TFND PTC Conventional variant of PTC Conventional variant of PTMC Conventional and follicular variants of PTC Follicular variant of PTC Tall cell variant of PTC Conventional and trabecular variants of PTC Infiltrative follicular subtype of PTC Hyperplastic nodule Adenomatoid nodule Minimally invasive follicular carcinoma NIFTP Follicular adenoma Graves' Disease Hashimoto's thyroiditis Oncocytic adenoma Oncocytic cell carcinoma Differentiated high-grade thyroid carcinoma Hyalinizing trabecular adenoma Benign cystic thyroid colloid nodule Collision tumors (PTC and high-grade FTC) Collision tumors (PTC and Oncocytic cell carcinoma) Follicular thyroid carcinoma FT-UMP Insular thyroid carcinoma Infarcted oncocytic cell lesion Invasive EFVPTC MTC 115 (44.23%) 56 (21.54%) 38 (67.86%) 9 (16.07%) 3 (5.35%) 2 (3.57%) 2 (3.57%) 1 (1.79%) 1 (1.79%) 28 (10.77%) 10 (3.85%) 9 (3.46%) 7 (2.69%) 6 (2.31%) 6 (2.31%) 4 (1.54%) 3 (1.15%) 3 (1.15%) 2 (0.77%) 2 (0.77%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) 1 (0.38%) Malignancy Status Benign Malignant 184 (70.77%) 76 (29.23%) EFVPTC: Encapsulated follicular variant of papillary thyroid carcinoma, FT-UMP: Follicular tumor of uncertain malignant potential, MTC: Medullary thyroid carcinoma, NIFTP: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features, PTMC: Papillary thyroid microcarcinoma, PTC: Papillary thyroid carcinoma Histopathological Findings Histopathological analysis showed that the most common diagnosis was TFND (n = 115, 44.23%), followed by PTC in 56 patients (21.54%). Among PTC cases, the conventional variant was the most frequent (n = 38, 67.86%). Hyperplastic nodules were reported in 28 patients (10.77%), and adenomatoid nodules in 10 (3.85%). In total, 184 patients (70.77%) were diagnosed with benign pathology, whereas 76 patients (29.23%) were confirmed to have malignant disease (Table 3). Discussion The production of Tg is influenced by various internal physiological factors, such as hyperthyroidism due to Graves' disease, TSH levels, and the size of the thyroid gland and nodules [15]. Tg binds covalently to iodine and is stored in the follicular lumen until stimulated by TSH, which triggers its reabsorption into thyroid cells and its enzymatic breakdown into the active thyroid hormones, T3 and T4. These hormones are then released into the bloodstream and can be measured using peripheral blood assays. While T3 and T4 are the primary hormones secreted, small amounts of Tg also enter the circulation and can be detected at low levels in healthy individuals with normal thyroid function. However, in individuals with DTCs originating from follicular cells, Tg appears to be actively secreted [15]. Since Tg is produced solely by thyroid follicular cells, measuring its levels in the blood following a total thyroidectomy for thyroid cancer has become a standard approach for identifying persistent or recurrent disease. A serum Tg concentration of 1.0 ng/mL or higher is considered a highly reliable indicator of tumor recurrence [15]. Ultrasonography and FNA are primary diagnostic tools used to distinguish benign from malignant thyroid nodules before surgery. While FNA is commonly employed for this purpose, both methods have notable limitations, particularly in accurately differentiating benign from malignant follicular tumors [3]. As a result, approximately 20% to 30% of thyroid nodules still require surgical intervention to obtain a definitive pathological diagnosis following FNA [3]. The current study's findings support this observation, as FNA results were available for only about half of the patients (54.23%), and a substantial proportion of nodules, especially those classified as Bethesda category IV or VI, still required surgical confirmation. Preoperative serum Tg levels are advantageous due to their convenience, rapid availability, and consistent reproducibility. However, their effectiveness in differentiating benign from malignant thyroid nodules before surgery has not been conclusively established. Despite this, many studies have investigated the potential of preoperative Tg levels for this purpose in diverse patient populations [3]. Several studies have demonstrated a significant association between elevated preoperative Tg levels and the presence of thyroid malignancy. Melik et al. (2022) prospectively measured Tg levels in 203 patients undergoing total thyroidectomy and found that patients with PTC had significantly higher Tg levels (105.05 ng/mL) compared to those with benign disease (76.80 ng/mL). A receiver operating characteristic analysis identified a cutoff value of 102 ng/mL, with the difference reaching statistical significance (P < 0.05) [8]. Similarly, Petric et al. (2012) observed higher preoperative Tg levels in PTC patients relative to those with benign nodules [9]. Jin et al. (2022) further supported this association in a cohort study that included 500 PTC patients, 376 with benign nodules, and 125 healthy controls. After excluding patients positive for Tg antibodies, they reported significantly higher Tg levels in PTC patients (42.87 ng/mL) compared to those with benign nodules (33.13 ng/mL) and healthy individuals (14.90 ng/mL), though the difference between the benign and healthy groups was not significant [10]. In the present study, PTC was the most prevalent subtype among malignant cases with thyroglobulin levels exceeding 500 ng/mL, accounting for 73.68% of such cases. The conventional variant was the most common among these, representing 67.86% of the PTC cases. In a broader evaluation, Lu et al. (2024) conducted a systematic review and meta-analysis. They found that, among patients with indeterminate cytology and negative Tg antibodies, those with malignant nodules had significantly higher serum Tg levels than those with benign nodules (OR = 2.59, 95% CI: 1.59–4.21, P < 0.001) [3]. Conversely, several studies have reported the opposite trend, with lower preoperative Tg levels observed in patients with DTC compared to those with benign thyroid nodules. Zhang et al. (2022) analyzed 1,519 DTC cases and 571 benign cases, finding significantly lower Tg levels in the DTC group (15.7 ng/mL vs. 52.1 ng/mL, P < 0.001) [11]. Aydogu et al. (2023) similarly found that patients with benign nodules had higher Tg levels than those with DTC (85.0 ng/mL vs. 27.15 ng/mL, P < 0.001) [12]. Kang et al. (2022) reported consistent findings, noting lower average Tg levels in DTC patients (238 ± 77 ng/mL) compared to those with benign nodules (532 ± 97 ng/mL, P = 0.02) [13]. Patel et al. (2019) echoed this trend, with a median Tg level of 167.5 ng/mL in benign cases compared to 30.8 ng/mL in malignant ones (P < 0.001) [14]. The present study found that only 29.23% of the cases were diagnosed with thyroid malignancy, primarily PTC, while the majority (70.77%) had benign pathology, predominantly TFND. These results align with those of Zhang et al. [11], Aydogdu et al. [12], Kang et al. [13], and Patel et al. [14], highlighting the limited specificity of preoperative Tg in differentiating malignant from benign thyroid conditions. The high Tg levels observed in both malignant and benign cases suggest that, although Tg may provide supplementary information in certain clinical contexts, it lacks sufficient diagnostic accuracy to be relied upon as a standalone marker for malignancy in the preoperative setting. These findings support the conclusion that preoperative Tg testing alone is unreliable for distinguishing between benign and malignant thyroid nodules. A key strength of the study is the inclusion of a relatively large sample size from a single tertiary center with standardized surgical and pathological protocols, ensuring consistency in data collection and analysis. Additionally, excluding cases with incomplete records enhanced data reliability, and comparing cytological, radiological, and histopathological findings enabled a comprehensive assessment. However, several limitations should be acknowledged. The retrospective design inherently carries a risk of selection and information bias. As a single-center study, the findings may not be generalizable to other populations or institutions with differing referral patterns or laboratory assays. Furthermore, thyroglobulin levels above 500 ng/mL could not be quantified precisely due to the assay’s upper limit, which may have limited the ability to explore potential dose response relationships. Finally, the absence of long-term postoperative follow-up data precluded evaluation of the prognostic significance of preoperative thyroglobulin levels. Conclusion Preoperative Tg levels may be elevated in both benign and malignant thyroid disorders; however, Tg may not possess adequate diagnostic precision to be used as a sole indicator of malignancy. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Ethical approval was obtained from the “Kscien Organization’s Ethics Committee under registration number 40 in 2025. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: FHK, HAN, and AMS: Major contributors to the conception and design of the study, supervision of the project, and drafting and critical revision of the manuscript for important intellectual content. SFA: Contributes to data analysis and interpretation and participates in manuscript revision. ReMA, RaMA, and AMA: Involve in study design and assist with initial drafting and revision of the manuscript. HOB, ROM, ANQ, SHH, AAQ, HAA, and BAA: Contribute to data acquisition and collection. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Data are available from the corresponding author upon reasonable request.
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Late-Onset Alkaptonuria in an Elderly Male: A Case Report and Literature Review
Abstract Introduction: Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by homogentisate 1,2-dioxygenase deficiency, leading to homogentisic acid accumulation. While AKU typically presents in children and young adults, this report aims to present an unusual late-onset presentation of AKU in an elderly male. Case presentation: A 65-year-old male presented with 20 years of black skin discoloration and chronic knee and pelvic pain. Despite early signs, including dark-colored urine, the condition was repeatedly misdiagnosed as melasma and primary osteoarthritis. Computed tomography scan revealed vertebral ankylosis and sacroiliac arthritis, and histopathological examination confirmed ochronotic pigment deposition. Due to financial constraints, the patient declined joint replacement surgery and was managed with diclofenac 100 mg twice daily and dietary restrictions. Literature review: Among six case reports of AKU reviewed in the literature, selected with a focus on misdiagnosis or delayed diagnosis, the majority of cases (3/6, 50%) occurred in the 8th–9th decades of life. Although AKU affects both sexes equally, five of the six reviewed cases (83.3%) were male. Conclusion: This case highlights the unusual late-onset alkaptonuria and the risk of prolonged misdiagnosis, emphasizing the importance of early recognition and multidisciplinary management. Introduction Alkaptonuria (AKU) is a rare, autosomal recessive metabolic disorder, with an estimated prevalence ranging from 1 in 200,000-1,000,000 live births worldwide [1,2]. The primary risk factor for AKU is having two copies of the affected homogentisate 1,2-dioxygenase (HGD) gene, which requires both parents to be carriers of mutations in the HGD gene. Consanguineous marriages significantly increase the risk of AKU due to the higher probability of both parents carrying the same recessive gene inherited from a common ancestor. This is particularly evident in certain populations where consanguinity is more common, such as in Slovakia and the Dominican Republic, which have higher prevalences of AKU (1 in 19,000) compared to the global average [3]. It is caused by a deficiency of the enzyme HGD, primarily produced by liver and kidney parenchymal cells. HGD is responsible for converting homogentisic acid (HGA) into maleylacetoacetic acid as part of the tyrosine degradation pathway [1]. As a result, HGA accumulates in the body and is excreted in urine, which causes the urine to turn dark brown or black upon exposure to oxygen and alkalinization. This characteristic change in urine color can occur early in the disease, but it may not be immediately noticeable. Fresh urine often appears normal, and it may take several hours after voiding for the color change to develop [2,4]. There are three main manifestations of this condition: the presence of HGA in the urine, ochronosis (the deposition of HGA in connective tissue and cartilage), and spondyloarthropathy affecting both the axial and appendicular skeleton, particularly arthritis of the spine and large joints [2]. Although AKU is typically diagnosed in children and young adults, this report describes a rare case identified in a 65-year-old male. The case is structured according to the CaReL guidelines [5]. All references used in the report have been evaluated for eligibility [6]. Case presentation Patient Information A 65-year-old male presented with black discoloration on his face and body, which had been present for 20 years, along with bilateral knee pain and pelvic pain. Medical attention was sought primarily for persistent knee pain. The patient lived in a remote district with limited access to specialized medical services. Although he had sought consultations previously for his lifelong history of dark urine, no definitive diagnosis had been made. His condition was repeatedly misdiagnosed, with the skin pigmentation attributed to melasma and post-inflammatory hyperpigmentation, while the bilateral knee and pelvic pain was considered primary osteoarthritis. He was not born to a consanguineous marriage. His past medical history was notable only for the presence of dark urine since birth. He had previously undergone a total right knee replacement. A positive family history was reported, with his brother and cousin affected by the same condition. Clinical Findings The patient's vital signs were normal. The examination revealed blue-black pigmentation on the face, the dorsum of the hands, and the feet (sun-exposed areas). The lesions also involved the sclera (Osler's sign) and the ear cartilage (Figure 1). On musculoskeletal examination, the patient had a fixed flexion deformity of both knees and reduced range of motion in both hips. Further examination could not be performed due to severe pain. Diagnostic Assessment Rheumatoid factors (IgM, IgG), anti-cyclic citrullinated peptide, and uric acid were normal. Computed Tomography (CT) scan revealed vertebral ankylosis, sacroiliac joint arthritis, and diffuse osteopenia, which were consistent with AKU-related ochronotic osteoarthritis (Figure 2). The patient underwent a facial skin punch biopsy. The histopathologic examination revealed deposition of round and elongated yellow-brown material in the dermis, accompanied by surrounding fibrosis and basophilic degeneration of collagen. Based on these findings, the diagnosis of ochronosis was confirmed (Figure 3). The delayed diagnosis was due to the lack of correlation between the skin pigmentation and musculoskeletal symptoms. <img id="image_4" src="[binary]" alt="Figure 2. A) Coronal CT image of the abdomen with IV contrast showing diffuse osteoporosis, multilevel disc calcification and disc space narrowing (yellow arrows), syndesmophyte formation at multiple levels (blue arrows), and scoliosis. B) Axial and coronal CT images of the abdomen with IV contrast demonstrating bilateral sacroiliac joint space narrowing and ankylosis (yellow arrows), along with features of hip osteoarthritis (blue arrows)." width="2069" height="2019" /> Therapeutic Intervention Total knee and bilateral hip replacement was planned, but the patient refused the procedure due to financial constraints. Instead, he was prescribed diclofenac 100 mg twice daily to manage his severe pain. He was recommended to avoid sun exposure to prevent further skin pigmentation. A dietary restriction of foods rich in phenylalanine, tyrosine, and protein was also advised. Follow-up Regular follow-ups with an orthopedist, cardiologist, and ophthalmologist were recommended for comprehensive monitoring for related complications. The cardiologist performed an echocardiogram, which revealed mitral regurgitation, tricuspid regurgitation, a small ventricular septal defect, and mild pulmonary hypertension. Since the condition was stable, follow-up appointments were advised every three months to ensure early detection of any progression or complications. Discussion In the AKU, patients are frequently misdiagnosed with spondyloarthritis or other degenerative musculoskeletal diseases [7]. This systemic condition can impact connective tissues and joints, potentially leading to complications such as cardiac valvular disease and kidney stones [1]. The literature review of six case reports of AKU presenting with joint pain showed that most cases were either diagnosed late or initially misdiagnosed (Table 1) [1,7-11]. In most cases, the condition was identified in the fourth or fifth decade of life [11]. Although AKU is an autosomal recessive disorder that affects both sexes equally [8], some studies suggest that males may develop more severe symptoms [2,9]. In contrast, the current literature review shows that five of the six reported AKU cases involved male patients, and the majority (3/6, 50%) occurred in the 8th–9th decades of life [1,7-11]. Table.1 Summary of Six Reported Cases of Alkaptonuria Author (Year) Gender Age (Y) Misdiagnosis or Delay Hereditary/Family History Ochronosis Treatment Tseliou et al. (2018) [1] Male 81 Misdiagnosed as Ankylosing Spondylitis Yes Yes Analgesics, Vitamin C, Diet Shah and Kumar (2024) [7] Male 38 Misdiagnosed as ankylosing spondylitis N/A Yes Physiotherapy, Palliative Singh et al. (2023) [8] Female 80 Late Diagnosis N/A Yes Vitamin C Gupta et al. (2021)​ [9] Male 58 Misdiagnosis N/A Yes Vitamin C, Diet Gundersen et al. (2024)​ [10] Male 70s Delayed Diagnosis Yes Yes Nitisinone, Diet Sharma et al. (2015) [11] Male 6 None (early detection) No No Vitamin C Y: Years; N/A: Not available In patients with AKU, the urine appears normal but gradually darkens over time due to the oxidation and polymerization of HGA. However, diagnosis is often delayed until adulthood when symptoms such as arthritis or ochronosis develop, as acidic urine may not darken even after prolonged exposure to air [12]. According to the literature, AKU is frequently misdiagnosed or identified late, with ankylosing spondylitis being a common initial misdiagnosis. Although the patient exhibited early signs, such as darkened urine, a definitive diagnosis was not made until ochronosis became evident [1,9]. Multiple case reports have documented ochronosis in patients with AKU, making it an important diagnostic indicator [1]. However, misdiagnosis of ochronosis-related symptoms as other degenerative conditions remains a common challenge [1]. For instance, and Kumar Upadhyaya reported a case in which a 38-year-old male was initially treated for ankylosing spondylitis before ultimately being diagnosed with ochronosis [7]. In the present case, ochronotic pigmentation persisted for 20 years with bilateral knee and pelvic pain but was repeatedly misdiagnosed despite multiple consultations. While early detection of ochronosis can facilitate the diagnosis of AKU, many cases experience delays due to its rarity and overlapping clinical features with other musculoskeletal disorders such as ankylosing spondylitis [7, 8]. The hereditary nature of AKU has been well-documented through various case reports, highlighting its strong genetic component. Gundersen et al. and Tseliou et al. reported cases highlighting the genetic influence on disease manifestation through siblings with similar symptoms [1,10]. The present case also provides evidence for this hereditary pattern. However, in some cases, no family history of the disease has been reported [7]. This variability complicates early diagnosis, especially when the carrier status is unknown. Despite being a genetically inherited disorder, AKU frequently goes undiagnosed or misdiagnosed due to its rarity and the wide range of clinical manifestations [1, 8]. The gold-standard test for confirmation is detecting HGA in a 24-hour urine sample using gas chromatography-mass spectrometry [7]. Genetic analysis of mutations in the HGD gene also aids in diagnosis and family counseling. In low-income countries, simpler biochemical tests may be used when GC-MS or genetic testing is unavailable [8]. In this case, most laboratory tests, including rheumatoid factors (IgM, IgG) and uric acid, were within normal ranges, indicating that inflammatory and metabolic markers may remain unchanged in AKU. Radiographic imaging helps confirm the diagnosis by revealing characteristic skeletal changes, such as joint space narrowing, osteoporosis, osteophytosis, and vertebral calcifications [9]. The CT scan in this case identified vertebral ankylosis, sacroiliac joint arthritis, and diffuse osteopenia, consistent with ochronotic osteoarthritis. These findings underscore the crucial role of imaging in diagnosing AKU and differentiating it from other forms of arthritis [4]. A skin biopsy can serve as a diagnostic tool for AKU by detecting ochronotic pigment deposition in collagen-containing tissues. This method can confirm diagnosis even in cases with limited clinical history [13]. In this case, ochronosis was confirmed through histopathological examination. Although AKU does not reduce life expectancy, it significantly impacts quality of life. Currently, no curative treatment exists, and management focuses on alleviating symptoms. Nonsteroidal anti-inflammatory drugs and physiotherapy help relieve arthropathies, while surgery may be necessary in severe cases. Dietary restrictions on tyrosine- and phenylalanine-rich foods, such as dairy products, eggs, soy, nuts, and meat, offer limited benefits [8]. High-dose vitamin C (1 g/day) has mild antioxidant properties that may slow HGA deposition in cartilage, but its effectiveness remains minimal. In this case, the patient required total knee and bilateral hip replacements but declined the procedure due to its high cost. Instead, a restricted diet low in phenylalanine, tyrosine, and protein was recommended. Despite these strategies, no definitive treatment is available, highlighting the need for further research [9]. This case report is limited by two limitations: the lack of availability of nitisinone, which precluded its therapeutic application, and the inability to quantify HGA levels due to the unavailability of the requisite diagnostic infrastructure. Conclusion This case highlights the unusual late-onset presentation of alkaptonuria and underscores the potential for prolonged misdiagnosis. Although no curative treatment is available, early recognition and multidisciplinary management are essential for improving patient outcomes and preventing complications. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the patient. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: RSA, SOS, SFA, LJM, SMM and RMA: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. RBJ, OMH, SKA, AKG and LAS: Literature review, critical revision of the manuscript, and processing of the figures. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Male Breast Cancer: A Single Center Case Series
Abstract Introduction: Male breast cancer is a rare malignancy, and despite increasing its prevalence, little is known about its prognosis, and management continues to rely largely on guidelines developed for female breast cancer. This study presents a single-center experience focusing on the diagnosis, therapeutic strategies, and prognostic outcomes associated with male breast cancer. Methods: The study was carried out between May 2020 and January 2025. All the male patients diagnosed with breast cancer were identified from the center's database. The study included those with complete medical records, encompassing demographics, clinical presentation, imaging findings, outcome, and follow-up data. Results: Fifteen male breast cancer cases were analyzed (mean age 59.47 ± 12.97 years). The left breast was affected in 60%, and 80% presented with a painless lump. Tumor size ranged 0.6–5.4 cm (mean 2.53 ± 1.50 cm). Modified radical mastectomy was performed in 86.66%. Invasive ductal carcinoma predominated (93.33%), with lymph node involvement in 40% and bone metastasis in 6.67%. Immunohistochemistry results were available for 5 patients (33.33%); all of them were estrogen receptor and progesterone receptor positive and human epidermal growth factor receptor 2 negative. Adjuvant chemotherapy and radiotherapy were used in 33.33%, while 20% received triple modality therapy. Mean follow-up was 2.8 ± 1.52 years (range 1–5), with one recurrence. Conclusion: Male breast cancer may present as a breast mass and is often diagnosed as invasive ductal carcinoma. Modified radical mastectomy accompanied by adjuvant therapy might offer favorable outcomes. Introduction Male breast cancer (MBC) is a rare condition, representing about 1% of all malignancies in men and of all breast cancer cases globally. Moreover, MBC accounts for less than 0.2% of cancer-related mortality among men. Breast cancer occurs less frequently in males, with a male-to-female ratio of approximately 1:100. This lower incidence is primarily attributed to the limited amount of breast tissue and differences in hormonal profiles between men and women [1-3]. Data from the Surveillance, Epidemiology, and End Results (SEER) program show an increase in male breast cancer incidence from 1.0 per 100,000 in the late 1970s to 1.2 per 100,000 in 2000–2004, with a median age at diagnosis of 67 years [2,4]. Like female patients, certain germline mutations increase the risk of breast and other cancers in men. Approximately 15% to 20% of men with breast cancer report a family history of breast or ovarian cancer, and around 10% carry a known hereditary mutation associated with breast cancer predisposition. BRCA2 is the gene most strongly associated with MBC, with affected individuals facing a lifetime risk ranging from 1% to 6%, higher than the approximate 0.1% risk in the general male population [4]. Additional genetic risk factors may contribute to the development of MBC, such as alterations in the ratio of estrogen to testosterone, as seen in individuals with Klinefelter syndrome [5]. Management of MBC is largely adapted from treatment protocols established for female breast cancer (FBC), owing to the limited availability of prospective, male-specific clinical trials. Notably, male patients represented only 0.087% of participants across 131 breast cancer clinical trials [6]. The current study presents a single-center experience regarding the diagnosis, management, and prognosis of MBC patients. All the references have been evaluated, and non-peer-reviewed sources have been excluded [7]. Methods Study Design and Setting This study was a single-center case series carried out at the Breast Clinic of Smart Health Tower between May 2020 and January 2025. This study was approved by the Ethics Committee of Kscien organization (Approval No. 2025-36). Participants and Eligibility Criteria The study included patients with a confirmed histopathological diagnosis of MBC who had complete medical records and provided consent for the publication of their data. Data Collection Data were retrieved from the hospital’s registry. The parameters included demographic details, clinical presentation, diagnostic findings, management, outcome, and follow-up. Intervention The patients underwent surgery under general anesthesia in the supine position, following skin preparation and antiseptic measures. The surgical approach was tailored to the specific requirements of each case, utilizing elliptical, Stewart, or alternative incision techniques as appropriate. After the incisions, procedures such as wide local excision, modified radical mastectomy (MRM), or nipple-areolar sparing mastectomy were performed. In all cases, the long thoracic and thoracodorsal nerves were preserved. Lymph node management involved either sampling or dissection of levels I, II, and III. Hemostasis was secured, and a Redivac drain was placed for each patient. Finally, the surgical site was closed in anatomical layers. For histopathology, 5-µm-thick tissue sections were fixed in 10% neutral buffered formalin at room temperature for 24 hours and subsequently embedded in paraffin. The slides were prepared and stained with hematoxylin and eosin (Bio Optica Co.) for 1–2 minutes at room temperature, then examined using a light microscope (Leica Microsystems GmbH). Data Processing and Statistical Analysis All collected data were recorded and organized using Microsoft Excel 2021. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS), version 25.0. Descriptive statistics were applied to summarize the results. Continuous variables were reported as means with standard deviations or medians with interquartile ranges, while categorical variables were presented as frequencies and percentages. Results Patient Demography A total of 15 MBC cases were diagnosed and managed during the period of conducting the study. Ages ranged from 40 to 85 years (59.47 ± 12.97). All participants were manual workers. 1 patient (6.67%) was an active smoker, 1 (6.67%) was a passive smoker, and none reported alcohol consumption. The history of breast cancer was positive in 1 patient (6.67%) who had undergone mastectomy (Table 1). Table 1. Demographic Data and Patient History Variables Frequency (%) Age 40-49 50-59 60-69 >70 Mean ± SD 2 (13.33%) 8 (53.33%) 2 (13.33%) 3 (20.00%) 59.47 ± 12.97 Occupations Manual labor 15 (100%) Smoking status Active smoker Passive smoker Non-smoker 1 (6.67%) 1 (6.67%) 13 (86.66%) Medical history Breast cancer Hypertension Hypertension & diabetes mellitus Negative 1 (6.67%) 2 (13.33%) 1 (6.67%) 11 (73.33%) Surgical history Mastectomy Herniotomy PNS surgery Hemorrhoidectomy Laparoscopic cholecystectomy & eye surgery Negative 1 (6.67%) 2 (13.33%) 1 (6.67%) 1 (6.67%) 1 (6.67%) 9 (60.00%) Family history of breast cancer Positive Negative 1 (6.67%) 14 (93.33%) SD: standard deviation, PNS: pilonidal sinus Clinical Presentation and Diagnosis The left side was involved in 9 patients (60%), while the right side was affected in 6 patients (40%). Clinical presentations included a painless breast lump in 12 patients (80%) and an axillary lump, breast discharge, and breast pain in each of the remaining patients (6.67%). Gynecomastia was present in 2 cases (13.33%). The duration of symptoms ranged from one week to two years, with a median of 0.69 (5.77) months. On ultrasonography, tumor sizes ranged from 0.6 cm to 5.4 cm, with a mean size of 2.53 ± 1.50 cm. Tumors were located centrally in 10 patients (66.66%), in the upper outer quadrant in 3 patients (20%), and in the upper inner quadrant and axilla each in 1 patient (6.67%) (Table 2). Mammography was performed for 5 patients (33.33%), all of whom had microcalcifications with variations in margin appearance (Figure 1). Computed tomography revealed lymphadenopathy in 5 (33.33%) patients (Figure 2). Table 2. Clinical Findings of Male Breast Cancer patients Variable Frequency (%) Affected side Right Left 6 (40.00%) 9 (60.00%) Clinical presentation Painless breast lump Axillary lump Breast discharge Breast pain 12 (80.00%) 1 (6.67%) 1 (6.67%) 1 (6.67%) Presence of gynecomastia Yes No 2 (13.33%) 13 (86.67%) Duration of symptoms, months (median (IQR)) 0.69 (5.77) Tumor size (cm), mean ± SD 2.53 ± 1.50 Tumor location Central Upper outer quadrant Upper inner quadrant Axilla 10 (66.66%) 3 (20.00%) 1 (6.67%) 1 (6.67%) IQR: Interquartile range, cm: Centimeter, SD: Standard deviation Management and Outcome Thirteen patients (86.66%) underwent MRM. Of these, 6 patients (40%) had MRM with axillary sampling only, while 7 patients (46.66%) underwent MRM combined with axillary lymph node dissection (ALND) at different levels (5 cases with ALND levels I and II, one with ALND levels I, II, and III, and one with ALND level I). One case (6.67%) underwent bilateral nipple-areola sparing mastectomy with radiotherapy and axillary sampling. Additionally, wide local excision with axillary sampling was performed in one patient (6.67%) (Figures 3-5). Histopathology confirmed invasive ductal carcinoma (IDC) in 14 cases (93.33%), either in isolation or in association with other pathological findings (Figure 6). Seven patients (46.67%) had grade II tumors, while six patients (40.0%) had grade III tumors. Regarding lymph node status, 9 patients (60.0%) had no evidence of lymph node involvement, whereas 6 patients (40.0%) showed varying degrees of lymphatic spread. Bone metastasis was recorded in one patient (6.67%). Immunohistochemistry results were available for 5 patients (33.33%); all of them were estrogen receptor and progesterone receptor positive and HER2 negative. Ki-67 proliferation index was reported in 3 patients (20%), with values ranging from 40% to 41%. The most used adjuvant therapy included a combination of chemotherapy and radiotherapy in 5 cases (33.33%), and a combination of chemotherapy, radiotherapy, and hormonal treatment in 3 cases (20%). The follow-up period ranged from 1 to 5 years (2.8 ± 1.52 years), and only one case of recurrence was reported (Table 3). <img id="image_1" src="[binary]" alt="Figure 3. A) Preoperative image showing an advanced ulcerated, nodular, and fungating breast tumor with an irregular surface, likely indicative of late-stage male breast cancer. B) Intraoperative image following a radical mastectomy, revealing an extensive excision of subcutaneous tissue and underlying structures. C) Excised specimen, including the tumor and surrounding skin, placed next to a scalpel for size reference. D) Postoperative image showing skin graft reconstruction with multiple sutures securing the graft to cover the large defect after mastectomy." width="2010" height="1638" /> <img id="image_1" src="[binary]" alt="Figure 4. A) Preoperative image of a male patient showing visible enlargement of the right breast, centrally extending toward the upper outer quadrant, with no other apparent skin changes. B) Intraoperative image of a skin-sparing and nipple areola complex sparing mastectomy, with an incision above the nipple-areolar complex, exposing subcutaneous fat and underlying tissues. C) Postoperative image showing bilateral mastectomy scars (left prophylactic mastectomy) with nipple preservation." width="3572" height="892" /> <img id="image_1" src="[binary]" alt="Figure 5. A) Preoperative image showing a male breast with post-core biopsy pigmentation. The lesion extends from the nipple-areolar complex toward the lateral central part, appearing irregular and enlarged. B) Intraoperative view after wide local excision, exposing subcutaneous fat and muscle. Clean surgical margins are evident. C) Excised specimen, including skin, subcutaneous fat, and nipple, with a scalpel for scale reference. D) Postoperative image showing a well-sutured wound with mild bruising and no signs of complications." width="3860" height="3046" /> Table 3. Management and Follow-Up of Male Breast Cancer Patients Variables Frequency (%) Surgical approaches MRM & axilla sampling MRM + ALND WLE NASM 6 (40.00%) 7 (46.66%) 1 (6.67%) 1 (6.67%) Histopathological findings IDC of NST IDC of NST + DCIS IDC of NST with High Grade DCIS + Paget IDC of Papillary Type and Extensive DCIS High-grade sarcoma favoring undifferentiated pleomorphic sarcoma 7 (46.66%) 5 (33.33%) 1 (6.67%) 1 (6.67%) 1 (6.67%) Tumor grades Grade I (Well-differentiated) Grade II (Moderately differentiated) Grade III (Poorly differentiated) Grade IV (Undifferentiated) N/A 0 (0.00%) 7 (46.67%) 6 (40.00%) 0 (0.00%) 2 (13.33%) Immunohistochemical findings ER+/PR+/HER2- N/A 5 (33.33%) 10 (66.67%) Lymph node involvement No involvement Single node Multiple nodes 9 (60.00%) 4 (26.67%) 2 (13.33%) Distant metastasis Bones None 1 (6.67%) 14 (93.33%) Adjuvant therapy Chemotherapy & radiotherapy Radiotherapy & hormone therapy* Chemotherapy & radiotherapy & hormone therapy* Chemotherapy alone Radiotherapy alone Hormone therapy alone* No adjuvant therapy 5 (33.33%) 1 (6.67%) 3 (20.00%) 1 (6.67%) 1 (6.67%) 1 (6.67%) 3 (20.00%) Follow-up (years), mean ± SD 2.8 ± 1.52 Outcome Recurrence Remission 1 (6.67%) 14 (93.33%) MRM: modified radical mastectomy, ALND: axillary lymph node dissection, WLE: wide local excision, NASM: nipple-areolar sparing mastectomy, IDC: invasive ductal carcinoma, NST: non-specific type, DCIS: ductal carcinoma in situ, ER: estrogen receptor, PR: progesterone receptor, HER2: human epidermal growth factor receptor 2, SD: standard deviation, N/A: not available. *Tamoxifen Discussion Breast cancer in males accounts for <1% of all cancers and <1% of breast cancers, with higher incidence in North America and Israel, lowest in Thailand, and the highest European rates reported in Italy [8]. The mean age of diagnosis in this study was comparable to that reported in the literature [2,4]. Smoking and alcohol consumption were infrequent among the MBC patients. It has been suggested that alcohol consumption is not associated with an increased risk of MBC, while the role of smoking as a potential risk factor remains controversial [8]. However, a study of 53 MBCs by Herrero et al. observed that 77% of the patients were ex-smokers and 17% had a history of alcoholism [9]. Only one patient in the current series reported smoking. In the current study, 6.67% of the patients reported a family history of breast cancer. Soliman and Hetnał reported that 7.7% of the patients had a positive family history of breast cancer, while Herrero et al. found that 23% of the patients had a family history of breast or ovarian cancer [9,10]. A study involving 152 MBCs and 304 FBC patients from 1990 to 2014 revealed that a positive family history was significantly more common in MBC cases compared to FBC (30.9% vs. 18.4%) [11]. Gynecomastia is a common condition present in 30–50% of healthy men. Although gynecomastia is not considered a usual risk factor, the issue is still controversial. Gynecomastia has been reported in 6–30% of MBC cases [12]. Two of the patients in the present study had gynecomastia, and both were diagnosed with IDC. In a study of 642 MBC patients, gynecomastia was associated with a significantly increased risk of developing breast cancer. Even after adjusting for multiple variables, the association remained strong [12]. In the current study, 60% of the cancers were located on the left side, while 40% were right-sided. Although the sample size is limited, this distribution is consistent with existing literature, which generally shows a slight predominance towards the left side. In a large analysis, 4,190 MBC were diagnosed in the left breast versus 3,868 in the right breast, giving a laterality ratio of 1.08 (95% CI: 1.03–1.13) [13]. However, in a smaller sample-sized study by Ilhan et al., breast cancer was located almost equally on the right side in 11 (52.3%) cases and on the left side in 10 (47.7%) cases [12]. A breast mass was the most common presenting symptom (80%), consistent with previous findings [10,12]. Soliman and Hetnał [10] reported a 100% incidence of breast mass in 39 MBC cases, with axillary involvement in 30%, which was higher than that in the present study. Similarly, Ilhan et al. found breast mass in 85.7% of their 21 cases [13]. Nipple discharge was observed in 6.67% of cases, consistent with Ambareen et al., who reported a comparable incidence of 6% [2]. Initial diagnosis of MBC often occurs at a later stage than in FBC, and MBC often exhibits more advanced disease features, such as a larger tumor size [14]. Studies have reported mean sizes of 3.5, 2.4, and 6 [2, 7, 14]. The mean tumor size in the current study was 2.53 ± 1.50 cm, comparable to previous findings [2,8]. Regarding tumor location, MBC most commonly occurs in the subareolar region, whereas FBC typically presents in the upper-outer quadrant of the breast [8]. This pattern was also observed in the present study, with 66.66% showing centrally located tumors. Similarly, Ilhan et al. reported central tumor location in 90.4% of cases [12]. In contrast, Zhao et al. found a lower rate, with only 37.5% of tumors located centrally [11]. Approximately 90% of male breast malignancies are classified as IDCs, which are characteristically associated with elevated expression of hormone receptors. This biomolecular profile renders them highly amenable to hormone-based therapeutic interventions, often resulting in favorable clinical outcomes [15]. In contrast, invasive lobular carcinoma is exceedingly uncommon in the male population, primarily due to the absence of terminal ductal lobular units in the male breast. Its occurrence is typically restricted to individuals with increased exposure to endogenous or exogenous estrogens [14]. In the present study, 93.33% (14 of 15) of cases were IDC, either of the non-specific type or in conjunction with other histopathological subtypes. In a case series on MBC, histological grade II was the most frequently reported, accounting for 54–58% of cases, followed by grade III (17–33%) and grade I (12–20%) [16]. The distribution of tumor grade in the current study generally aligns with these trends, but demonstrated a higher proportion of grade III tumors, highlighting the need for tailored treatment strategies and further investigation into the biological mechanisms underlying increased tumor aggressiveness in MBC. Compared to FBC, MBC tends to present with higher lymph node involvement and distant metastases at the time of diagnosis [1]. In the present study, 60% of cases showed no evidence of lymph node involvement, whereas 40% exhibited varying degrees of lymphatic spread, and bone metastasis was recorded in one case. Similarly, Zhao et al. reported a nodal involvement rate of 44.1%. However, El Fouhi et al. reported a nodal involvement rate of 82% [11,15]. Typically, men with breast cancer are treated with MRM, often accompanied by ALND or sentinel lymph node biopsy. However, in selected cases, breast-conserving surgery, as well as nipple-sparing or skin-sparing mastectomies, may also be considered [14]. Performing ALND is linked to considerable postoperative morbidity, including lymphedema, infection, and sensory disturbances such as axillary paresthesia [17]. In the present study, thirteen patients (86.66%) underwent MRM, seven of whom (46.66%) underwent MRM accompanied by ALND, and one patient underwent nipple-areolar sparing mastectomy. This is comparable to a previous study in which 90% of MBC patients opted for MRM [1]. Chemotherapy regimens for MBC are comparable to those used in FBC [5]. In a prospective study conducted by the American National Cancer Institute between 1974 and 1988, involving 31 MBC patients with lymph node metastases treated with adjuvant chemotherapy, overall survival rates at 5, 10, and 20 years were reported as 80%, 65%, and 42%, respectively [5]. In the present study, nine patients (60%) received chemotherapy, either alone or in combination with other adjuvant therapies, with most achieving favorable outcomes during follow-up. Given that over 90% of MBC cases are hormone receptor-positive, endocrine therapy plays a central role in treatment. Tamoxifen remains the most utilized anti-estrogen agent in both FBC and MBC management [17]. In the present study, immunohistochemistry results were available for only five patients (33.3%), all of whom were hormone receptor positive and received tamoxifen. The apparent discrepancy with the higher rates reported in the literature likely reflects the absence of receptor status data for the remaining ten patients rather than a true difference in tumor biology. Adjuvant radiotherapy is recommended for patients with axillary lymph node metastasis or who are undergoing breast-conserving surgery. Postoperative radiotherapy is also recommended for patients with tumors larger than 5 cm [5]. In the present study, 10 patients (66.67%) received radiotherapy, either alone or with other adjuvant therapies, with most achieving good outcomes during follow-up. Management of MBC is controversial due to reliance on female-based data [6]. Key debates involve mastectomy versus breast-conserving therapy, unclear indications for radiotherapy, and the choice and duration of endocrine therapy (tamoxifen vs aromatase inhibitors ± GnRH analogues). The role of genomic assays in guiding chemotherapy, systemic therapy strategies in advanced disease, risks of under- or overtreatment, and psychosocial effects of radical surgery also remain unresolved [6]. Breast cancer in males exhibits distinct recurrence patterns influenced by tumor biology, stage, and treatment. In a cohort of 38 patients with estrogen receptor-positive, HER2-negative tumors, the distribution of the 21-gene recurrence score (RS) closely resembled that observed in FBC. Low RS (≤17) was found in 68.4% of cases, intermediate RS (18–30) in 23.7%, and high RS (≥31) in 7.9% [18]. According to a study, the rate of locoregional recurrence in MBC is approximately 10.1%, while distant recurrence has been reported in up to 21% of cases [18]. Only one case of recurrence was reported in the present study, after a median follow-up of 2.8 years. This study had a few limitations. First, the follow-up periods were relatively short compared to other studies on the topic. Second, genetic testing and data on affected patients were lacking. Conclusion Male breast cancer may present as a breast mass and is often diagnosed as invasive ductal carcinoma. Modified radical mastectomy accompanied by adjuvant therapy might offer favorable outcomes. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: This study was approved by the Ethics Committee of Kscien organization (Approval No. 2025-36). Consent for participation: Not applicable. Consent for publication: Informed consent for publication was obtained from the patients. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: AMS, ROM, FHK, and MMA: Major contribution to the conception and design of the study, literature search, and manuscript drafting. HOB, SHS, HHF, NSS, HOA, SOA, and MKA: literature review, study design, data organization, table preparation, and critical revision of the manuscript. LRAP, FHF, AMA, RMA, and AHA: literature review and figure preparation. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Fregoli Syndrome: A Case Report and Literature Review
Abstract Introduction: Fregoli syndrome is a rare misidentification disorder that can disrupt behavior, endanger safety, and impair quality of life. Its occurrence in young adults is exceptionally uncommon. This report presents a case of Fregoli delusion in a young adult without the usual underlying causes, such as schizophrenia. Case presentation: A 25-year-old male presented with a two-month history of persecutory delusions, believing that strangers, friends, and professors were disguising themselves to follow and harass him. His psychiatric history was unremarkable, and there was no family history of mental illness. The patient was diagnosed with Fregoli delusion and prescribed Risperidone 2 mg/day, alongside cognitive-behavioral therapy to challenge his delusions. After three months of treatment, he showed gradual improvement, with reduced intensity of delusions but occasional paranoid thoughts. Literature review: Seven cases of Fregoli delusion were reviewed. Patient ages ranged from 43 to 77 years, with predominant female prevalence (71.4%). Psychiatric histories included delusional schizophrenia, paranoid schizophrenia, and unspecified psychiatric conditions. Medical histories included hypertension, myocardial infarction, Parkinson’s, and diabetes mellitus. Presenting symptoms varied with delusional misidentification, auditory/visual hallucinations, suicidal ideations, delirium, and paranoia. Treatment approaches included risperidone alone or in combination with electroconvulsive therapy, aripiprazole & promazine, and more. Symptom improvement was seen in four cases, and one case achieved full resolution of symptoms. Conclusion: Fregoli syndrome is a rare condition of multiple etiologies that can present in young patients. Risperidone, combined with cognitive behavioral therapy, may yield fruitful results. Introduction Delusional Misidentification Syndrome (DMS) is typically classified into three main types: Capgras syndrome, Fregoli syndrome, and intermetamorphosis syndrome. In Capgras syndrome, individuals believe familiar people have been replaced by impostors who closely resemble them. The rarest of the three, intermetamorphosis syndrome, is characterized by the perception that certain individuals' identities and physical appearance have changed [1]. Fregoli syndrome was first described in 1927. It is characterized by the persistent belief that different people, often strangers, are, in fact, a single familiar individual who is changing their appearance or disguising themselves to deceive or follow the affected person. Unlike other DMSs, Fregoli syndrome involves the misperception that one individual repeatedly assumes different identities [2]. The syndrome is named after Leopoldo Fregoli, an Italian actor renowned for his ability to switch roles, costumes, and accessories rapidly during his performances, reflecting the delusional belief of a single person constantly altering their appearance [2]. For more than 80 years, DMSs have presented significant challenges for mental health professionals. These difficulties stem from a limited understanding of their underlying causes, the absence of consistently effective treatments, and concerns regarding the potential risks associated with these conditions [2]. There has been considerable interest and ongoing debate regarding the causes and underlying mechanisms of DMSs. Researchers and clinicians have explored various explanations, ranging from psychodynamic theories to neurological and organic impairments. Some theories suggest that DMSs arise from deep-seated psychological conflicts or defense mechanisms, while others point to structural or functional abnormalities in the brain, particularly in regions associated with recognition, memory, and perception [1]. Fregoli syndrome, in particular, is often associated with neurological or psychiatric disorders, including schizophrenia, traumatic brain injury, and dementia [1]. This report presents a rare case of Fregoli syndrome in a young adult without any of the commonly reported underlying causes. The report was developed following the CaReL guidelines, and only reliable, peer-reviewed sources were included while excluding any unreliable references or data [3,4]. Case presentation Patient Information A 25-year-old male, with no prior psychiatric history, was brought in by his father with a two-month history of persecutory delusions. He had a persistent belief that various individuals, including friends and strangers, were disguising themselves to follow and harass him. These delusional beliefs were accompanied by marked irritability, anxiety, and sleep disturbances. He denied any previous episodes of psychosis, including hallucinations or delusions. There was no history of substance use, and his medical history was unremarkable. In addition, there was no known family history of psychiatric illness, and he denied any recent psychosocial stressors or physical abuse. Mental State Examination The patient was well-groomed and cooperative but alert and guarded, frequently scanning the room as if expecting pursuit. His mood was anxious and suspicious with restricted affect. Speech was normal in tone, volume, and rate. The thought process was coherent yet dominated by persecutory misidentification delusions consistent with Fregoli syndrome. No hallucinations were reported, and orientation to time, place, and person was intact. Insight was poor, as he regarded his delusions as true, and judgment was impaired accordingly. The baseline Positive and Negative Syndrome Scale score was 91. Medical and Neurological Workup The patient underwent a thorough medical and neurological workup to rule out secondary causes of psychosis or DMS. All baseline laboratory investigations (complete blood count, liver and renal function tests, thyroid profile, serum electrolytes, random blood sugar, and HbA1c) were normal. His magnetic resonance imaging (MRI) showed no abnormal findings. All this supported a primary psychiatric disease hypothesis, ruling out an organic origin from the outset. Diagnosis Based on the history, mental status examination, and investigations, the patient was diagnosed with Fregoli delusion, a form of DMS, which falls under the category of delusional disorder with persecutory themes. Treatment The patient was initiated on a low dose of antipsychotic medication, specifically risperidone at 2 mg per day for 12 weeks, to address his delusional thoughts. In parallel, cognitive-behavioral therapy (CBT) was commenced. The patient completed 12 weekly CBT sessions (≈50 minutes each) with a licensed clinical psychologist trained in CBT for psychosis. The program combined psychoeducation on the nature of delusions, cognitive restructuring to challenge misinterpretations of identity and persecution, and behavioral experiments with reality-testing exercises to reduce conviction in delusional beliefs. To promote treatment adherence, the patient attended regular psychiatric follow-up appointments and received strong support from family members. Family psychoeducation sessions were conducted to enhance understanding of the patient’s condition, reduce levels of expressed emotion, and foster a collaborative and supportive caregiving environment. Follow-up After 12 weeks of treatment, the patient achieved partial remission, characterized by reduced conviction and frequency of delusional beliefs. Positive and Negative Syndrome Scale total score improved from 91 at baseline to 68, indicating moderate symptomatic improvement. Clinically, he developed uncertainty about his persecutory delusions, resumed university attendance, and began socializing. No extrapyramidal or metabolic side effects were observed. The patient was advised to continue Risperidone at 2 mg/day for a minimum of 6 months post-remission, with plans to reassess for dose tapering after 9–12 months, provided there is sustained recovery. CBT sessions were recommended to continue biweekly for another three months to consolidate gains and monitor for relapse indicators. The treatment plan also includes monthly psychiatric reviews and continued family involvement. Discussion The current understanding of Fregoli syndrome is primarily based on reported cases and therefore remains insufficient. It has been suggested that DMSs may be secondary to brain damage, including infarctions, traumatic injuries, or other types of brain lesions [5]. A recent meta-analysis by Dias et al. showed that among patients who underwent neuroimaging, it was particularly notable that right-sided lesions were common. Also, there was an overrepresentation of patients with lesions in the frontal lobe. It also showed that nearly half of all patients with Fregoli syndrome are found to have a secondary cause of psychosis [2]. This suggests that clinicians should maintain a high level of suspicion for a neurological rather than a primary psychiatric cause when evaluating patients with Fregoli syndrome. As a result, appropriate neuroimaging investigations, such as MRI, should be considered to identify any underlying neurological abnormalities. In a recent study that examined brain connectivity related to delusions of misidentification, it was found that the majority of the patients had lesions in brain areas functionally connected to the right frontal cortex. This finding was specific to misidentification delusions when compared to other neurological syndromes [6]. This highlights the critical importance of the right frontal regions. Seven cases of Fregoli syndrome have been reported (Table 1) [1, 5, 7–11]. Four demonstrated abnormal brain MRI findings, including atrophy and infarctions [1, 7, 8, 10]. In contrast, the MRI in the present case was unremarkable. Table 1. Baseline characteristics of Fregoli syndrome cases Author/year Age (years) Sex Medical history Psychiatric history Family psychiatric history Presenting symptoms Brain MRI Treatment Outcome Follow-up (years) Moriyama et al./2007 [1] 68 F Cerebrovascular accident Delusional schizophrenia N/A Delusional misidentifications RI Risperidone Resolved N/A Hentati et al./2022 [5] 50 F Hypertension Irritability, misidentifications, auditory & visual hallucinations Unremarkable Delirium, Auditory hallucinations Normal Risperidone Improved symptoms 2 Salviati et al/2014 [7] 61 F DMt2, PN & Retinopathy Unremarkable Unremarkable Disorientation, Rapid speech, Delusions & Paranoia CSE Aripiprazole & Promazine No improvement N/A Hanan/2022 [8] 55 M Unremarkable Paranoid schizophrenia N/A Paranoia, Hallucinatory behavior & irritability Right-side DBA in the frontal lobe N/A N/A N/A Kumar/2018 [9] 43 F Unremarkable Unspecified Depression Delusional thoughts N/A Risperidone, bilateral modified ECTs & trihexyphenidyl Improved symptoms N/A Ferreira et al./2017 [10] 77 F Hypertension, Myocardial infarction, Vascular dementia & Chronic kidney disease Unremarkable Unremarkable Euthymic mood, Fregoli delusion, Auditory hallucinations, Anxiety & Poor insight GA & CSI Quetiapine, Aripiprazole & Zotepine Improved symptoms 4 Ogata et al., 2025 [11] 50 M Parkinson’s disease & dopamine dysregulation syndrome Auditory hallucinations and persecutory delusions Unremarkable Inability to walk, delusions, self-doubt, and accusatory auditory hallucinations, Despondency, reduced food intake, self-hatred, and suicidal ideation N/A Quetiapine Improved symptoms 0.8 M: Male, F: Female, N/A: Not applicable, GA: General Atrophy, CSI: Cortical Sequelar Infarctions, DMt2: Diabetes Mellitus type 2, PN: Peripherial Neuropathy, CSE: Chronic Subcortical Encephalopathy, DBA: Diffuse Brain Atrophy, ECT: Electroconvulsive Therapy, RI: Regional Infarction Dysfunction in the right hemisphere and frontal lobe is linked to the distortion of familiarity, as well as to deficits in reality testing and memory integration. These cognitive impairments are likely to result in misleading and incorrect interpretations, potentially giving rise to Fregoli syndrome and other misidentification delusions [12]. Additionally, DMSs can be a manifestation of an underlying psychiatric condition, with schizophrenia being the most commonly associated disorder. Prior psychiatric history was remarkable in four of the reviewed cases, as two of them were previously diagnosed with schizophrenia, and two cases had experienced hallucinations [1,5,8,11]. Contrary to the reviewed cases and the majority of the literature, the present case had no previous head injuries or underlying neurological issues and no history of psychiatric illnesses, and his age of presentation is much younger than the reviewed cases, adding another angle of uncertainty to this disorder. A wide range of presenting symptoms of Fregoli delusion have been reported, for example: psychotic symptoms (such as delusions, disorganized thoughts, and paranoia), cognitive disturbances (such as delirium and poor insight), mood symptoms (such as anxiety and suicidal ideations), and neurological impairment (such as inability to walk) [1,7,8-11]. Assaultive behavior has been reported in association with Fregoli delusion; for instance, one patient fatally strangled his cellmate during an episode of misidentification [8]. Several treatment approaches for DMSs have been described. However, there is limited published evidence on the effectiveness of atypical antipsychotics or antidepressants in managing DMSs [10]. This indicates that the currently available treatments may not be entirely effective for these patients. Typical and atypical antipsychotics, anticholinergics, and electroconvulsive therapy are among the treatments utilized. Risperidone was the most utilized drug in the reviewed cases, and it was the drug of choice in the current patient [1,5,9]. Salviati et al. reported a case of Fregoli syndrome in a patient triggered by an acute pneumonia associated with urinary infection, where antipsychotic treatment was ineffective until the infection resolved [7]. This suggests that such delusions may arise as a result of infections rather than being solely linked to neurological or psychiatric conditions. CBT was not utilized in any of the reviewed cases. However, it may help by challenging cognitive distortions and assisting patients in recognizing and questioning misinterpretations related to identity misrecognition [13]. It can also enhance reality testing by strengthening their ability to distinguish between reality and delusional perceptions. Additionally, CBT can aid in managing associated symptoms such as anxiety or paranoia, providing strategies to cope with distress linked to the delusion [13]. More research is essential to solidify the efficacy of its uses. Fregoli syndrome can significantly impact personal, professional, and social life, causing familial conflicts and distress for both the patient and their loved ones. Therefore, greater efforts are needed to understand DMS phenomena, develop effective treatments, and establish long-term management strategies. One limitation of the present report is the unavailability of the MRI image, which could have strengthened its rigor. Another limitation is the relatively short follow-up period. Conclusion Fregoli syndrome is a rare condition of multiple etiologies that can present in young patients. Risperidone, combined with cognitive behavioral therapy, may yield fruitful results. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the patient’s father. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: YNA, MMA and FHK: Major contribution to the conception and design of the study, literature search, and manuscript drafting. FHF, HSM, JIH and AMM: Literature review, study design, data collection, and critical revision of the manuscript. HMH, SHM and BAA: Literature review, table processing. All authors have read and approved the final version ofthe manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Atypical Presentations of Pilonidal Sinus Disease: A Case Series with Literature Review
Abstract Introduction: Pilonidal sinus (PNS) typically arises in the sacrococcygeal region but can occasionally present in atypical locations, including the axilla, intermammary region, umbilicus, interdigital web, and neck, often leading to delayed diagnosis and suboptimal management. This study aims to examine clinical features, surgical management, and outcomes of PNS in these uncommon sites. Methods: This retrospective case series was conducted at a single center over eight years and examined patients with extra-sacrococcygeal PNS confirmed by histopathology. Clinical, surgical, and follow-up data were retrieved from patient records. Data were analyzed using SPSS 25.0 and presented as descriptive statistics (frequencies, percentages, means, and ranges). Results: This study included 4 patients, with an equal sex distribution (2 females, 50%; 2 males, 50%) and a mean age of 24 years (range: 16–31). Presenting symptoms included discharge, itching, pain, redness, and mass formation. None had significant past medical history, and one patient (25%) had prior surgery at the same site. Affected sites were equally distributed: breast (25%), axilla (25%), penile (25%), and scalp (25%). All patients underwent surgical intervention, and histopathology revealed tracts lined with epidermis, surrounded by mixed inflammatory cells, foreign body giant cells, and hair shafts in granulation tissue. During the follow-up period (mean follow-up: 13.5 months), no recurrence was observed. Conclusion: Atypical presentations of PNS, although rare, can occur in diverse anatomical regions. Surgical excision with primary closure might be an effective treatment approach, potentially leading to favorable clinical outcomes and a low recurrence rate. Introduction Pilonidal sinus (PNS) is a common inflammatory disorder that typically occurs in the natal cleft, resulting from hair penetration into the skin, forming a tract lined with granulation tissue, which may develop into a pus-filled cavity [1,2]. The condition was first described by Mayo in 1833, who identified a hair-containing cyst just below the coccyx. The term "pilonidal" was coined by Hodge in 1880 and is derived from its Latin roots. Despite being recognized for nearly two centuries, the pathogenesis of PNS remains a subject of ongoing debate [3]. Notable contributions by Karydakis and Bascom have shifted the understanding of PNS from a congenital neural tube abnormality to an acquired condition, emphasizing the role of environmental and lifestyle factors [4,5]. PNS risk factors include poor hygiene, a deep natal cleft, excessive hair growth, and a sedentary lifestyle. Although often asymptomatic, PNS may present as a recurrent abscess or a non-healing draining sinus [4]. The condition predominantly affects the sacrococcygeal area of hirsute males, with an estimated incidence of 26 per 100,000 people [6]. However, in rare cases, PNS can develop in atypical locations, including the axilla, intermammary region, umbilicus, interdigital webs, occiput, scalp, endoanal canal, groin, suprapubic area, clitoris, penis, and prepuce [2,3,7]. Given the scarcity of literature on atypical presentations of PNS, the current study aims to examine the clinical features and management of PNS in atypical locations (extra-sacrococcygeal). The eligibility of the references has been confirmed [8]. Methods Study Design This retrospective case series was conducted over eight years at a single private facility, focusing on patients with atypical PNS who were evaluated, treated, and followed up. Ethical approval for this study was obtained from the Ethical Committee of the Kscien Organization (Approval No. 31/2025). Clinical, surgical, and follow-up data were collected through a systematic review of electronic medical records, surgical pathology reports, and consultation with treating healthcare providers when necessary. Informed consent was obtained from all patients or their guardians for the publication of their anonymized data. Setting and Participants The study included patients with atypical (extra-sacrococcygeal) PNS presentations who were admitted to the hospital during the study period. Clinical and sociodemographic data were collected from patient records. The following variables were recorded: age, gender, signs and symptoms, past medical and surgical history, clinical examination findings, ultrasound (US) findings, surgical indications, type of surgery performed, histopathological results, complications, and follow-up duration. Inclusion and Exclusion Criteria Eligible participants were those with confirmed PNS diagnoses through HPE. Patients with incomplete clinical or sociodemographic data or those whose diagnosis could not be confirmed through histopathology were excluded. Patients with primary sacrococcygeal PNS or those lacking follow-up data were also excluded from the study. Surgical Management All patients underwent thorough preoperative planning and assessments to evaluate their suitability for local anesthesia. Preoperative evaluations included US, monitoring of vital signs, viral screening, and hematological assessment, including a complete blood count and hemoglobin level measurement. Surgical procedures were performed with patients in the supine position. The surgical approach involved wide local excision of the PNS followed by primary closure. Following wide local excision, Salih’s preparation (a mixture of sclerosing agent and Lawsonia inermis) was applied to the wound bed and sinus margins prior to primary closure. This was performed to enhance wound healing and reduce the risk of infection [9]. Postoperative pain was managed with oral paracetamol at a dose of 1,000 mg, administered every 6–8 hours as needed, for a minimum of five days. Statistical Analysis The data were organized and analyzed using Microsoft Excel 2019. Descriptive analysis was conducted using the Statistical Package for Social Sciences (SPSS) version 25.0. The results are presented as frequencies, percentages, means, and ranges. Results Clinical and Histopathological Features This study included four patients, comprising 2 females (50%) and 2 males (50%), with a mean age of 24 years (range: 16–31 years) (Table 1). Patients presented with various symptoms, including discharge, itching, pain, and erythema. None of the patients had significant past medical history. One patient (25.0%) had a history of prior surgery at the same site. The affected sites varied, with the breast, axilla, penile, and scalp region each in one case (Figures 1 and 2). Ultrasound imaging was performed in three of four cases (75%), and the findings revealed simple breast cysts with associated midline and inframammary PNS, infected dermal–subdermal cysts with mild edema, and chronic PNS in the left temporal scalp region (Table 1). All patients underwent surgical intervention, including excision of sinuses or complete removal of masses/nodules. HPE revealed tracts lined with epidermis, surrounded by mixed inflammatory cells, foreign body giant cells, and hair shafts embedded in granulation tissue. Table 1. Summary of Reported and Present Cases of Atypical Pilonidal Sinus Case / Authors [Ref] Age (Y) Sex Sign & Symptoms Location PMH PSH Examination Findings Imaging (US) Surgical Indication Type of Surgery Histopathology Follow-Up Salih & Kakamad [2] 39 M Perianal discharge and pruritus Endoanal Negative Surgically treated PNS and anal fistula External opening at 11 o’clock, 3.5 cm from anal verge with induration and surrounding excoriation Single fistulous tract extending into anal canal Discharge and pain during defecation Fistulectomy Chronic inflammation with scattered foreign body giant cells consistent with PNS Symptom-free at 5 weeks Salih & Kakamad [3] 19 M Chronic nodule Scalp Negative Negative 2×2 cm mobile nodule in left parieto-occipital region with central punctum Not performed Intermittent discharge Complete excision Mixed inflammatory cells with foreign body giant cell reaction containing hair No recurrence at 3 months Salih et al. [7] 22 F Painful submental mass Submental Negative Operation at same site 6 years prior Tender 2×2 cm mass attached to skin, no external opening Well-defined hyperechoic lesion suggestive of dermoid cyst Painful mass Complete excision Mixed inflammatory cells with foreign body giant cell reaction containing hair No recurrence at 2 years Salih et al. [10] 27 M Painless postauricular discharge Auricle Negative Negative NA Not performed Discharge Excision of sinuses NA No recurrence Salih et al. [11] 25 F Bilateral Multiple discharging sinuses Breast Negative Negative Multiple discharging sinuses with induration and tenderness Not performed Discharge Excision of sinuses Chronic foreign body granuloma surrounding hair No recurrence at 6 months Salih & Kakamad [12] 22 M Pain and purulent discharge Auricle Negative Negative 2 cm scar with single central opening Not performed Pain and discharge Complete excision Mixed inflammatory cells with foreign body giant cell reaction containing hair No recurrence Salih et al. [13] 20 F Yellowish discharge Neck Negative Negative 10 openings on nape, 7×4 cm induration and erythema Not performed Multiple sinuses with discharge Excision of sinuses Free hair shaft embedded within chronic inflammation and granulation tissue Healthy at 2 months Salih et al. [14] 35 F Discharging lesion Breast Negative Negative Local redness with multiple discharging sinuses, 3–4 cm from nipple Not performed Remission and relapse Excision of sinuses Hair shaft surrounded by granulation tissue No recurrence at 6 months Salih et al. [15] 22 F Pain, discharge, and erythema Breast Negative Negative Single sinus with clear discharge, surrounding old scar Not performed Discharge Wide local excision Inflammatory reaction and foreign body giant cells surrounding hair shaft No recurrence Salih et al. [16] 16 F Chronic discharging sinus Breast NA Negative Single discharging sinus, 8×9 cm induration Not performed Discharge Excision of sinuses Inflammatory cell collection with pus and scattered hair shafts No recurrence at 4 months Salih et al. [17] 25 M Mass with chronic discharge Auricle Negative Negative 1×1 cm firm, tender nodule attached to skin Not performed Discharge Mass excision PNS No recurrence at 8 months Present study (Case 1) 31 F Intermammary mass with erythematous nodules Breast Negative Negative Midline swelling without ulceration or discharge Simple breast cysts with midline and inframammary PNS Painful mass Complete excision Mixed inflammatory cells with foreign body giant cell reaction containing hair No recurrence at 4 years Present study (Case 2) 27 F Right axillary mass, 4-year duration Axilla Negative Negative Linear scar with mild hyperpigmentation, chronic PNS Infected dermal-subdermal cysts with mild edema Painful mass Excision of sinuses Mixed inflammatory cells with foreign body giant cell reaction containing hair No recurrence at 1 month Present study (Case 3) 22 M Perianal discharge and pruritus Penile Negative Negative Linear scar, chronic PNS without active inflammation NA Sinus Excision of sinus PNS No recurrence at 2 months Present study (Case 4) 16 M Painless scalp discharge Scalp Negative Skin laceration at same site NA Left temporal scalp chronic PNS Sinus Excision of sinus PNS No recurrence at 3 months F: Female, M: Male, PMH: past medical history, PSH: past surgical history, PNS: pilonidal sinus, US: ultrasound, NA: not available, Y: Years <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-86876132511762682908972.png" alt="Figure 1. Preoperative image demonstrating a localized indurated area with post-inflammatory hyperpigmentation in the right axillary region (A); intraoperative view showing sinus tract exposure through a limited incision (B); and the excised specimen revealing hair-containing fibrofatty tissue characteristic of pilonidal material (C). " width="1640" height="664" /> <img id="image_2" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-47853266621762682962748.png" alt="Figure 2. Intermammary pilonidal sinus - preoperative view showing a midline skin indentation with mild erythema over the lesion site (A); intraoperative views demonstrating elliptical skin incisions with exposed sinus tracts (B); and the excised fibrofatty tissue containing sinus material from the intermammary region (C)." width="1640" height="664" /> Outcomes and Follow-up All 4 cases had favorable outcomes with no recurrence. Follow-up duration ranged from 1 month to 4 years, with the mean follow-up period being 13.5 months. No significant complications or adverse events occurred, and postoperative recovery was uneventful, with no need for further interventions. Discussion The pilonidal disease has a spectrum of clinical manifestations, ranging from asymptomatic to large, symptomatic abscesses. The exact cause of PNS remains unclear, with two main theories, acquired and congenital, offering potential explanations for its development. The formation of PNS generally requires three key factors: the presence of hair in the skin, a region of wrinkled skin (such as the natal cleft or a scar), and a combination of hormonal and hygiene-related factors [5]. This condition is less frequent before puberty and after the age of 40 years, likely due to the influence of sex hormones during these periods. It is also three times more common in males than females. Studies have shown that individuals who sit for prolonged periods and bathe less frequently are at a significantly higher risk of developing PNS, with a 219-fold increased risk compared to those without these risk factors [2,10]. Among the 11 cases reported in the literature, the mean patient age was 24.7 years (range: 16–39 years). The most commonly affected site was the breast (36.4%), followed by the auricle (27.3%), with single cases involving the endoanal, scalp, submental, and neck regions (each 9.1%). The sex distribution showed a slight male predominance, with 6 males (54.5%) and 5 females (45.5%) (Table 1) [2,3,7,10–17]. In line with these findings, the current case series included 4 patients with an equal sex distribution (2 males, 50%; 2 females, 50%) and a comparable mean age of 24 years (range: 16–31 years). The differential diagnosis for atypical PNS includes a broad range of conditions, such as hernia, endometriosis, urachal cyst, pyogenic granuloma, epidermoid cyst, dermoid cyst, and infected sebaceous cyst. Clinical signs often include pain, warmth, and swelling, indicating inflammation. This condition is multifaceted, causing physical discomfort and emotional distress for those affected, leading to direct healthcare costs and indirect societal costs due to lost work hours [11,12]. Among the cases reviewed, the most common presenting symptom was discharge (9/11, 81.8%), followed by pain (3/11, 27.3%) and mass or nodule formation (2/11, 18.2%) [2,3,7,10–17]. In the current series, two (50%) presented with masses (intermammary and axillary), and two (50%) presented with discharge (perianal and scalp), with pruritus, erythema, painless presentation, and chronicity each observed in a single case (25%). PNS is most commonly diagnosed based on the clinical presentation, with laboratory or radiologic investigations generally unnecessary [10]. However, US can reveal strands of hair associated with the lesion. Fine needle aspiration cytology can help to rule out a neoplastic process, particularly when the suspicion for PNS disease is low [10]. Ultrasonography was performed in only 2 of the 11 cases reviewed (18.2%). One case demonstrated a single fistulous tract extending into the anal canal, while another revealed a well-defined hyperechoic lesion suggestive of a dermoid cyst. In the remaining 9 cases (81.8%), ultrasound evaluation was not carried out [2,3,7,10–17]. In the current series, ultrasound was performed in three of four cases (75%). Findings included simple breast cysts with associated midline and inframammary PNS, infected dermal–subdermal cysts with mild edema, and chronic PNS in the left temporal scalp region A variety of both surgical and non-surgical approaches are utilized in managing PNS. Surgical interventions include simple incision and drainage, marsupialization, open wound management, primary closure, and rhomboid excision followed by a Limberg flap. Non-surgical methods typically involve the injection of sclerosing and wound-enhancing agents into the sinus tract. Managing atypical PNS often necessitates more tailored approaches, such as resection with or without primary closure. Postoperative complications and recurrences are common, with significant risk factors identified, including obesity, a family history of PNS, male sex, tobacco use, inadequate hygiene, sinus size, and the specific surgical technique employed [3, 4]. The ideal management of PNS should aim to alleviate patient discomfort, reduce hospital stays, minimize recurrence rates, address complications, and limit prolonged work absences [4]. Furthermore, the treatment should be safe, effective, and free from adverse consequences. Surgical approaches, however, may not align with these optimal treatment goals, as they can result in discomfort and prolonged work absences. While surgery remains the recommended approach for atypical PNS, it also facilitates a definitive diagnosis through HPE. Shareef et al. conducted a study involving 12 female patients, all presenting with discharge lasting from four weeks to two years. Nine of these patients underwent resection with direct closure, without a flap, while the remaining three had their PNS excised and allowed to heal secondarily. Recurrence was observed in three of the patients [13-18]. Among the cases reviewed, excision of sinuses was the most commonly performed procedure (5/11, 45.5%), followed by complete excision (3/11, 27.3%). Fistulectomy, wide local excision, and mass excision were each performed in a single case (9.1%) [2,3,7,10–17]. In the current series, surgical management included excision of a single sinus in two cases (50%), complete excision in one case (25%), and excision of multiple sinuses in one case (25%). All 15 cases, including 11 reviewed in the literature and 4 from the current series, remained symptom-free with no recurrence during follow-up. This study has several limitations. First, the retrospective design may introduce selection bias and limit the ability to establish causal relationships. Second, the small sample size limits the generalizability of the findings. Third, the follow-up period varied among the patients, which could affect the assessment of long-term outcomes. Finally, the study was conducted at a single center, which may not reflect the broader population. Conclusion This case series highlights the rare occurrence of PNS in atypical locations, with clinical and HPE findings that resemble typical cases. Surgical excision might result in favorable outcomes without recurrence. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Ethical approval was obtained from the Ethical Committee of the Kscien Organization (Approval No. 31/2025) Consent for participation: Not applicable. Consent for publication: Informed consent was obtained from all patients or their guardians for the publication of their anonymized data. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: SL, HHK, DAI, and AMM: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. KMS, SHH, KAN, HAA, AAQ and AMA: Literature review, critical revision of the manuscript, and processing of the tables and figures. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Challenging Management of Postoperative Empyema: A Case Report with Literature Review
Abstract Introduction: Pleural empyema is the collection of pus within the pleural cavity, typically arising as a complication of pneumonia, chest trauma, thoracic surgery, or bacterial invasion of the pleural space. This report presents a case of post-surgical pleural empyema caused by Pseudomonas aeruginosa, successfully managed with a targeted combination of fosfomycin and colistin, with intrapleural lavage. Case presentation: A 37-year-old male developed epigastric pain 12 days after a laparoscopic near-total gastrectomy. A chest computed tomography scan revealed a right-sided pleural empyema. Ultrasound-guided drainage was performed, followed by the intrapleural instillation of alteplase to facilitate breakdown of the loculated empyema. Pseudomonas aeruginosa was identified as the causative agent. Based on antimicrobial susceptibility, the patient received intravenous fosfomycin and colistin, along with daily pleural lavage using colistin. Inflammatory markers declined, and the patient showed notable clinical improvement. Literature review: A review of five cases of Pseudomonas aeruginosa pleural empyema was conducted, including two carbapenem-resistant and one extensively drug-resistant case. The mean patient age was 53.8 years, and 60% (3/5) were female. Four of the five cases (80%) were confirmed using computed tomography, and all patients received antimicrobial therapy, most frequently ceftolozane/tazobactam (60%), ciprofloxacin (60%), and colistin (40%). Surgical management was required in 60% of cases, whereas bacteriophage therapy was utilized in 20%. During follow-up, 60% of patients remained stable, 20% experienced repeated hospital admissions during which antibacterial therapy was withheld, and 20% died due to infectious disease. Conclusion: Pleural lavage combined with antibiotics such as fosfomycin and colistin may provide an effective treatment for postoperative pleural empyema, with early intervention being critical to prevent clinical deterioration. Introduction Pleural empyema is the accumulation of pus within the pleural cavity. Although its pathogenesis is not entirely clear, it typically arises from pneumonia, chest trauma, postoperative complications following thoracic surgery, or bacterial invasion from adjacent infection [1]. Epidemiological data from France report an incidence of approximately 0.78 cases per 10,000 people annually [2]. Mortality is not uncommon, with overall rates around 17%, and most patients require hospitalization [2]. Approximately 25–50% of patients with pneumonia develop a parapneumonic effusion, which may progress to empyema in some cases [3]. The factors contributing to the progression of pneumonia to empyema remain poorly understood [4]. However, pleuritic pain, higher severity scores for community-acquired pneumonia, multilobar involvement on imaging, and elevated inflammatory markers have been associated with an increased risk of progression. In contrast, administration of systemic corticosteroids at the time of admission has been linked to a reduced risk, possibly by decreasing pleural inflammation [5]. The use of corticosteroids in community-acquired pneumonia remains debated: the Infectious Diseases Society of America recommends them only for septic shock unresponsive to vasopressors, whereas European guidelines suggest their use more broadly in cases of shock [5]. Pseudomonas aeruginosa is a widely distributed Gram-negative bacterium that can be found in various environmental settings and hosts [6]. It can cause various infections in humans, especially affecting the respiratory tract of patients with cystic fibrosis [7]. Its clinical impact is amplified by intrinsic antibiotic resistance, mediated through biofilm formation, antibiotic-modifying enzymes, multiple efflux pumps, and low cell permeability, making infections particularly challenging in immunocompromised or chronically ill patients [6]. This report presents a case of pleural empyema due to Pseudomonas aeruginosa approximately two weeks after a laparoscopic near-total gastrectomy, successfully managed with a combination of fosfomycin and colistin alongside intrapleural lavage. This report was prepared in accordance with CaReL guidelines, and all references cited have been carefully assessed for credibility [8, 9]. Case presentation Patient Information A 37-year-old male smoker presented with epigastric pain, low-grade fever, anorexia, and generalized weakness following 12 days after laparoscopic near-total gastrectomy with spleen-preserving D2 lymph node dissection for gastric cancer. The patient had a recent influenza infection three weeks prior to surgery. Other than the gastrectomy, no significant medical or surgical history was reported. Clinical Findings Upon examination, he appeared agitated and fatigued, with a generally ill appearance. Vital signs showed tachycardia (heart rate 105 bpm) and tachypnea (25 breaths per minute), while oxygen saturation and blood pressure remained within normal limits. Chest auscultation revealed diminished breath sounds over the right lower lung. Diagnostic Approach Laboratory investigations revealed markedly elevated inflammatory markers, with a C-reactive protein (CRP) level of 180 mg/L (Normal range: < 3 mg/L) and an erythrocyte sedimentation rate (ESR) of 95 mm/hr (Normal range: < 15 mm/hr). Chest computed tomography (CT) confirmed the presence of a right-sided pleural empyema (Figure 1), while abdominal CT ruled out an anastomotic leak. These findings suggested the empyema likely resulted from postoperative pneumonia progressing to a complicated pleural infection rather than a direct surgical complication. Therapeutic Intervention Ultrasound-guided drainage was performed, and a chest tube was inserted, initially draining 100 cc of pus. The following day, 50 mg of alteplase diluted in 100 cc of normal saline was administered through the tube. After a 4-hour dwell time, drainage increased to 500 cc, indicating effective fibrinolysis and breakdown of loculated empyema. Empirical broad-spectrum antibiotic therapy with meropenem (1 g every 8 hours) was initiated pending culture results, and the patient maintained a regular oral diet. Culture Results and Targeted Antimicrobial Therapy ​Microbiological analysis of the drained pus, performed using the advanced VITEK-II Compact (bioMérieux) diagnostic system, identified Pseudomonas aeruginosa as the causative agent. Antimicrobial susceptibility testing showed that the strain was multidrug-resistant (MDR), with sensitivity limited to colistin, aztreonam, and fosfomycin (Table 1). The patient received intravenous fosfomycin (4 g every 8 hours for 7 days) and colistin (initially 3 million units every 8 hours for 7 days, followed by 1 million units every 8 hours for 12 days). Pleural lavage with colistin was performed every 12 hours for 5 days, once daily for 7 days, and then on alternate days for an additional 7 days to enhance local antibiotic concentrations. Table 1. Antimicrobial susceptibility testing results Antimicrobials Inhibition zone (mm) Interpretation Antimicrobials Inhibition zone (mm) Interpretation Cefixime 0 Resistant Moxifloxacin 0 Resistant Cefuroxime 0 Resistant Levofloxacin 0 Resistant Cefotaxime 0 Resistant Doxycycline 0 Resistant Ertapenem 0 Resistant Minocycline 0 Resistant Cefpodoxime–clavulanate 0 Resistant Tigecycline 0 Resistant Aztreonam 20 Sensitive Nitrofurantion 0 Resistant Rifampin 0 Resistant Streptomycin 0 Resistant Colistin 19 Sensitive Azithromycin 0 Resistant Fosfomycin 24 Sensitive Clarithromycin 0 Resistant Monitoring and Outcome Daily clinical assessments and serial inflammatory marker measurements were performed. Vital signs normalized, CRP returned to normal, and ESR decreased to 40 mm/hr. Follow-up cultures from the chest drain were negative. Given significant clinical improvement, the chest tube was removed, and the patient was discharged in stable condition. He was subsequently referred to an oncology for ongoing management of gastric cancer. At 10 months post-treatment, there was no evidence of recurrence. The patient has completed adjuvant chemotherapy and continues to undergo regular follow-up with upper gastrointestinal endoscopy and chest and abdominal CT scans. Discussion Empyema has increasingly been recognized as a reservoir for resistant bacteria, largely because many antibiotics penetrate the pleural space at subtherapeutic concentrations, thereby promoting resistance development [10]. Clinically, the disease progresses through three distinct stages—uncomplicated parapneumonic effusion, complicated parapneumonic effusion, and established empyema—which highlight its dynamic pathophysiology and the need for timely intervention [1]. In parallel with this progression, the incidence of MDR and XDR Pseudomonas aeruginosa has risen substantially. This trend is driven by the organism’s ability to cause severe healthcare-associated infections, its exceptional capacity to accumulate and spread resistance determinants within the host, and the global dissemination of high-risk clones. As a result, infections caused by these strains pose significant clinical challenges and are associated with increased morbidity and mortality due to limited therapeutic options [11]. The severity of empyema and its outcomes are reflected in epidemiologic data. Bobbio et al. studied adults hospitalized with pleural infections in France between 2013 and 2017, identifying 25,512 empyema cases with an annual incidence of 7.15–7.75 per 100,000 inhabitants. Mortality rates varied substantially depending on underlying conditions, reaching 30% in cancer patients, 18% after lung resection, and 11% among patients without these comorbidities [2]. This variability underscores the importance of understanding pathogen behavior in the context of patient-specific risk factors. Among the common pathogens, Pseudomonas aeruginosa remains a notable cause of hospital-acquired pneumonia and is frequently detected in airway colonization, especially in previously treated individuals. The development of MDR phenotypes not only complicates therapy but may also alter the organism’s virulence characteristics [12]. Its adaptability is further demonstrated by its ability to colonize diverse hospital environments, including soap solutions and saline, facilitating persistent contamination and transmission. Consequently, treatment strategies must be tailored to the organism’s susceptibility pattern and the clinical scenario, often relying on agents such as colistin, ceftazidime, meropenem, and amikacin. However, therapeutic success is hindered by multiple resistance mechanisms, ranging from chromosomal mutations to horizontally acquired β-lactamases [13]. A review of five similar cases of empyema illustrates this complexity. The cases involved patients aged 22–77 years, with Pseudomonas aeruginosa identified in all isolates. While two isolates were carbapenem-resistant and one was XDR, resistance profiles were not reported for the remaining two. Imaging modalities, most commonly CT, confirmed empyema or associated cavitary lesions. All patients received antimicrobial therapy, with ceftolozane/tazobactam, colistin, and ciprofloxacin being most frequently used. Surgical interventions such as thoracotomy or video-assisted thoracoscopic surgery were required in 60% of patients, while adjunctive measures like bacteriophage therapy were rarely used (20%). Only one patient died, emphasizing both the severity of these infections and the potential for successful outcomes when appropriate therapy is provided (Table 2) [10, 14-17]. In the present case, treatment with intravenous fosfomycin in combination with colistin was guided by the antimicrobial susceptibility profile and resulted in a favorable clinical response. Evidence supports the synergy of this combination, in a study of 87 carbapenem-resistant Pseudomonas aeruginosa isolates, the fosfomycin and colistin regimen exhibited synergistic or partially synergistic effects in nearly half of the isolates and significantly reduced colistin MIC values compared with monotherapy [18]. These findings suggest that fosfomycin may enhance colistin’s efficacy and therapeutic window. Conversely, when resistance to fosfomycin does occur, it is typically mediated through FosA overexpression or inactivation of the glycerol-3-phosphate transporter responsible for drug uptake [19]. . Table 2. Review of five cases of empyema caused by Pseudomonas aeruginosa Author, year of publication Age (years) Sex Clinical finding Diagnosis Imaging Antimicrobial susceptibility Treatment Outcome Sousou et al. 2024[14] 61 M Left-sided chest pain and shortness of breath, worsening dyspnea on exertion. Influenza A initially, later empyema from P. aeruginosa. CT: large left pleural effusion. US: extensively multiloculated, dense pleural fluid. Sensitivity: cefepime & ciprofloxacin Video-assisted thoracoscopic surgery, & left thoracotomy with complete decortication. First given cefepime then ciprofloxacin. Stable Parra et al. 2022 [15] 22 F respiratory failure with necrotizing pneumonia Pleural empyema due to carbapenem-resistant P. aeruginosa. Radiologically compatible with necrotizing pneumonia. Resistance: ceftolozane/tazobactam & ceftazidime-avibactam. Intravenous ceftazidime later ceftolozane/tazobactam, then changed to ciprofloxacin & nebulized colistin. Deceased Borghesi et al. 2021[16] 64 M Increased discharge from the pleural drainage. Chronic left pleural empyema caused by a carbapenem-resistant P. aeruginosa. A CT scan of the thorax was suggestive of interstitial pneumonia. Resistance: all β-lactams & quinolones. Sensitivity: ceftolozane/tazobactam, gentamicin, amikacin & colistin. ceftolozane/tazobactam & gentamicin. Surgical debridement procedure, cefiderocol, colistin & Fosfomycin. Stable Kufel et al. 2020 [10] 45 F Leukocytosis, respiratory failure, fever, & increased tracheal secretions. Empyema caused by XDR P. aeruginosa. CT: loculated left & right pleural effusions. Sensitivity: cefiderocol, but later 2 cefiderocol-resistant morphologies of XDR P. aeruginosa were found. Ceftazidime-avibactam, polymyxin B, & fluconazole, later fluconazole & cefiderocol. Esophageal stent replacement, video-assisted thoracoscopic surgery with left lung thoracotomy & decortication, & esophageal rupture repair with muscle flap placement. Repeated hospital admissions; antibacterial therapy withheld Maddocks et al. 2019 [17] 77 F Pleuritic chest pain, respiratory distress, drowsiness & fever, parenchymal cavitation. Ventilator-associated pneumonia and empyema caused by P. aeruginosa. CT: cavitation, consolidation, empyema, & subcutaneous emphysema. X-ray: right lung field consolidation, & later pneumothorax. Sensitivity: piperacillin tazobactam, ciprofloxacin, & meropenem. But later resistant to meropenem, imipenem, piperacillin-tazobactam in vitro, & fluoroquinolone. First meropenem, then gentamicin, & ciprofloxacin later ceftolozane/tazobactam. Bacteriophage therapy: two Myoviridae & two Podoviridae. Stable P. aeruginosa: Pseudomonas aeruginosa; M: Male; F: Female; CT: Computed tomography; US: Ultrasonography; XDR: Extensively drug-resistant The relevance of this combination is supported by a comparable case involving a 64-year-old patient with chronic post-pleuropneumonectomy empyema caused by carbapenem-resistant Pseudomonas aeruginosa [16]. In that case, surgical debridement followed by cefiderocol, fosfomycin, and colistin—along with pleural lavage using colistin—resulted in clinical improvement, highlighting the potential role of both systemic and local therapy. Monitoring inflammatory markers, especially C-reactive protein, further assists in assessing response, as a rapid decline typically correlates with resolution of infection [20], consistent with the trajectory observed in the present case. Given the rise of resistance, interest has grown in adjunctive and alternative therapeutic approaches. Bacteriophage therapy is particularly notable, as combining phages with antibiotics can produce synergistic antimicrobial effects, a finding supported by multiple in vitro studies [13]. Although limited by narrow host ranges, phages may offer options for otherwise untreatable infections [21]. This was exemplified by Maddocks et al., who treated a 77-year-old patient with ventilator-associated pneumonia and empyema due to Pseudomonas aeruginosa using the AB-PA01 phage cocktail after resistance emerged during antibiotic therapy. Intravenous and nebulized administration led to gradual clinical improvement, demonstrating the potential of phage–antibiotic combinations in refractory cases [17]. Further emerging strategies include vaccines and monoclonal antibodies targeting virulence factors such as the type III secretion system. Candidates like IC43, KB001-A, and KBPA-101 are being investigated for preventive and therapeutic roles in high-risk populations [11]. In the current case, such alternatives were not required, as the selected antibiotic regimen successfully controlled the infection without the need for surgical intervention. A limitation of this study is the unavailability of certain clinical data, including abdominal CT images obtained to exclude an anastomotic leak and specific laboratory values. Conclusion Pleural lavage combined with antibiotics such as fosfomycin and colistin may provide an effective treatment for postoperative pleural empyema, with early intervention being critical to prevent clinical deterioration. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the patient. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: HHK, AKA, AHH, FHK, NAM and TOS: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. AHA, MNH, YHH, DAI, SHM and HMH: Literature review, critical revision of the manuscript, and processing of the figure and tables. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Clinicopathological Profile of Malignant Tumors at a Tertiary Center in Iraq: A Five-Year Analysis
Abstract Introduction: Cancer incidence and mortality are increasing worldwide, disproportionately affecting low- and middle-income countries due to limited healthcare access. This study aims to analyze the prevalence and clinicopathological characteristics of cancers diagnosed at a tertiary care center, offering crucial data to inform regional cancer control efforts. Methods: This retrospective study was conducted at a single tertiary center, analyzing histopathological reports from January 2020 to January 2025. Data were collected from digital and physical archives by a trained team, including only confirmed malignant diagnoses. Variables extracted included patient demographics, cancer types, tumor characteristics, and procedure details. Data integrity was ensured through double-entry and expert review. Statistical analysis using SPSS 27.0 summarized categorical variables as frequencies, percentages and continuous variables as means or medians. Results: A total of 9,375 cases were analyzed (median age 48 years), with females comprising 75.74% (7,101 cases). The age-standardized incidence rate was 82.20 per 100,000. Head and neck cancers accounted for 2,903 cases (30.97%), primarily thyroid (2,208 cases), followed by thoracic malignant tumors with 2,556 cases (27.26%). Invasive ductal carcinoma was most frequent cancer type (2,392 cases, 25.5%). Larger tumors correlated significantly with positive margins and lymph node involvement (p < 0.05). Conclusion: The study highlights a unique cancer profile, with younger age at diagnosis and higher rates of head, neck, and thyroid cancers. These findings underscore the need for targeted screening and prevention strategies adapted to regional healthcare systems. Introduction Cancer remains one of the foremost causes of morbidity and mortality globally, representing a growing public health challenge of increasing magnitude and complexity. According to the International Agency for Research on Cancer, an estimated 20 million new cancer cases and 9.7 million cancer-related deaths were recorded worldwide in 2022 [1,2]. These figures underscore the profound global burden of cancer, with approximately one in five individuals developing the disease during their lifetime. Notably, one in nine men and one in twelve women are estimated to die from cancer [3]. Projections indicate that by 2070, the global incidence of cancer will surpass 34 million new cases annually, with lower-income countries experiencing a disproportionate impact marked by an anticipated 400% increase in cancer incidence over the next five decades [4]. Among the malignancies expected to contribute most significantly to this rise are breast, lung, and colorectal cancers. Current epidemiological models forecast that colorectal cancer cases will increase from 1.9 million in 2020 to 3.2 million by 2040, while breast cancer incidence is projected to reach a similar level by 2050, rising from 2.26 million cases in 2020 [5,6]. Substantial disparities in cancer burden are evident across countries with different income levels and health system capacities. In high-income nations, rising incidence rates of breast and thyroid cancers have been partially attributed to improved access to healthcare services and widespread implementation of early detection and screening programs [7]. Conversely, low- and middle-income countries tend to report higher incidence rates of cancers associated with infectious etiologies, such as cervical and liver cancers. These regions also face significantly higher cancer mortality rates, largely due to limited access to preventive services, early diagnosis, and effective treatment options [8,9]. Furthermore, marked differences in mortality-to-incidence ratios are observed across human development index categories. Data from Globocan 2020 indicate that mortality-to-incidence ratios are nearly twice as high in low- human development index countries compared to very high- human development index countries, 0.75 versus 0.36 for men, and 0.69 versus 0.30 for women [10]. Given the magnitude of the global cancer burden and the critical role of accurate epidemiological data in informing cancer control strategies, institution-level studies are essential. The current study aims to evaluate the prevalence and clinicopathological characteristics of cancers diagnosed via histopathological examination at a tertiary care center. By analyzing cases over a five-year period, this study seeks to provide insights into the local cancer profile, and identify the most frequently diagnosed cancer types. All referenced data sources have been verified for eligibility [11]. Methods Study Design and Setting This retrospective study was conducted at Smart Health Tower, Iraq. All histopathological reports issued between January 2020 and January 2025, were considered for inclusion. Data Collection Data were retrieved from both the digital and physical archives of the pathology department. A team of more than ten trained individuals participated in the collection process to ensure completeness and accuracy. Only reports that provided complete documentation of the required parameters were included in the analysis. Inclusion and Exclusion Criteria All histopathological reports confirming a malignant diagnosis and issued within the specified time frame were included in the study. Reports were excluded if they lacked a definitive diagnosis of cancer, were incomplete, or were duplicates. Variables and Data Extraction The following variables were extracted from each eligible report: patient age at diagnosis, sex, nationality, anatomical location of the lesion, cancer type, definitive diagnostic approach (histology, cytology, or immunohistochemistry), resection margin status (free or involved), tumor size in millimeters, and lymph node involvement (present or absent). All variables were systematically documented in a structured database for analysis. Data Quality and Management To maintain data integrity, a double-entry process was implemented. Two independent researchers entered the data separately, and any discrepancies between entries were resolved by reviewing the original reports. Only de-identified data were used. Ethical Considerations As this study involved retrospective analysis of anonymized medical records, the requirement for informed consent was waived. Confidentiality and data protection standards were strictly followed throughout the study. Ethical approval was obtained from the Kscien Organization (Approval No. 41/2025). Statistical Analysis Data analysis was performed using SPSS (Statistical Package for the Social Sciences) software (version 27.0). Descriptive statistics were used to summarize the data. Categorical variables, such as sex, type of cancer, and the anatomical system or organ affected, were reported as frequencies and percentages. Continuous variables, including age and tumor size, were presented as means with standard deviations or medians with quartile ranges, depending on data distribution. Comparisons of tumor size between groups (e.g., free vs. positive resection margins, lymph node involvement vs. no involvement) were performed using the Mann–Whitney U test, as tumor size was not normally distributed. A p-value < 0.05 was considered statistically significant. Results A total of 9,375 patients were analyzed (median age: 48.0 years; QR: 39.0–60.0). The age-standardized incidence rate was 82.20 (411.01/5) per 100,000 population per year (Table 1). Cancer incidence per 100,000 population rose with age, from 10.08 in the 0–10 group to a peak of 1,803.04 in the 71–80 group (Figure 1). Females comprised the majority at 7,101(75.74%). Of all evaluated cases, 6,635 (70.8%) were diagnosed by histology, 2,016 (21.5%) by cytology, and 724 (7.7%) underwent additional immunohistochemical analysis. Lymph node involvement was identified in 25.0% of cases, while nodes were not sampled in 49.3%. Invasive ductal carcinoma was the most frequently diagnosed cancer at 2,392 (25.5%) cases, followed by papillary thyroid carcinoma at 1,186 (12.7%) cases and unspecified adenocarcinoma at 639 (6.8%) (Table 2). Table 1. Age-Specific Cancer Incidence Rates Age group, n (%) n (%) Population Ratio Crude Rate per 100,000 Weighted Rate <10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 >80 NA 50 (0.53) 142 (1.51) 699 (7.46) 1,819 (19.40) 2,506 (26.73) 1,828 (19.50) 1,359 (14.50) 747 (7.97) 223 (2.38) 2 (0.02) 495,803 489,567 426,132 326,470 243,584 134,611 84,910 41,430 25,543 - 21.9 21.6 18.8 14.4 10.7 5.9 3.7 1.8 1.1 - 10.08 29.0 164.03 557.17 1028.8 1357.9 1600.52 1803.04 873.03 - 2.207 6.264 30.838 80.2325 110.0816 80.116 59.219 32.455 9.60 - Total 9,375 (100.0) 2,268,050 100.0 - 411.01 NA: Not available Table 2. Baseline Characteristics Variables Frequency (%) Age, Median (QR) 48.0 (39.0-60.0) Gender Female Male 7,101 (75.74) 2,274 (24.26) Nationality Iraqi Turkish Bangladeshi British Pakistani NA 9,363 (99.87) 4 (0.04) 1 (0.01) 3 (0.03) 1 (0.01) 3 (0.03) Anatomical location of the lesion Breast & Head & Neck Gastrointestinal tract Cardiothoracic / Cardiovascular Dermatology Pulmonology / Respiratory Orthopedics ENT & Maxillofacial Oncology Neurology / Neurosurgery Radiology Ophthalmology Pediatrics 6,952 (74.1) 1,243 (13.3) 387 (4.1) 167 (1.8) 152 (1.6) 152 (1.6) 140 (1.5) 92 (1.0) 34 (0.4) 32 (0.3) 17 (0.2) 7 (0.1) Definitive diagnosis approach Histology Cytology Immunohistochemistry 6,635 (70.8) 2,016 (21.5) 724 (7.7) Resection free margin Yes No Can not be assessed NA 2,324 (24.8) 995 (10.6) 1,980 (21.1) 4,076 (43.5) Tumor size (mm), Median (QR) 6.0 (2.0-15.0) Lymph node involvement Yes No NA 2,344 (25.0) 1,431 (15.3) 5,600 (59.7) Type of cancer Invasive ductal carcinoma Papillary thyroid carcinoma Adenocarcinoma (unspecified) Ductal carcinoma in situ Metastatic carcinoma (all sites) Basal cell carcinoma Invasive lobular carcinoma Urothelial carcinoma Squamous cell carcinoma (all sites) Medullary thyroid carcinoma Hodgkin lymphoma (all types) Follicular thyroid carcinoma Invasive mammary carcinoma Sarcoma (all types) Malignant melanoma Other (each <0.1%) 2,392 (25.5) 1,186 (12.7) 639 (6.8) 443 (4.7) 311 (3.3) 209 (2.2) 205 (2.2) 193 (2.1) 139 (1.5) 60 (0.6) 69 (0.7) 55 (0.6) 53 (0.6) 26 (0.3) 8 (0.1) 3,387 (36.1) QR: Quartile range, ENT: Ear, Nose, and Throat, NA: Not available Head and neck lesions were the single largest category (2,903 cases, 30.97%), followed by thoracic region (2,556 cases, 27.26%). Multi‐regional involvement was 17.30%, while abdominal (7.03%), pelvic (5.43%), extremity (upper 7.94%, lower 0.77%), axial skeleton (1.19%), and integumentary/soft tissue (2.11%) sites made up the rest (Table 3). Within the head and neck, the thyroid gland and associated lymph nodes constituted the majority of cases 2,208 (99.68%). In the thoracic region, the breast was the most frequently affected site 1,980 (77.5%), while the pulmonary system accounted for 468 cases (18.3%). Abdominal organs represented 659 cases (7.03%) (Table 3). Table 3. Frequency of Malignant Lesions Across Anatomical Regions Variables Frequency (%) Head and neck 2,903 (30.97) Endocrine (Head and Neck) Thyroid Thyroglossal duct Thymus 2,215 (76.3) 2,208 (99.68) 5 (0.23) 2 (0.09) Cervical Region Cervical/Cervical lymph node Neck Larynx Throat Vocal Cord Pharynx Head Tonsil Trachea Supraglottic Nasopharyngeal 363 (12.5) 236 (65.01) 52 (14.32) 16 (4.41) 13 (3.58) 12 (3.31) 9 (2.48) 6 (1.65) 6 (1.65) 5 (1.38) 4 (1.10) 4 (1.10) Facial Region Nose Eye Lip Tongue Mandible Cheek Face Palate Mouth Forehead Jaw Chin Maxilla 174 (6.0) 59 (33.91) 30 (17.24) 21 (12.07) 19 (10.92) 10 (5.75) 8 (4.60) 7 (4.02) 7 (4.02) 6 (3.45) 3 (1.72) 2 (1.15) 1 (0.57) 1 (0.57) Salivary System Parotid/Parotid Gland Submandibular Submental 74 (2.5) 42 (56.76) 30 (40.54) 2 (2.70) Cranial and Neural Brain Skull 45 (1.6) 30 (66.7) 15 (33.3) Auricular Ear Auricle 32 (1.1) 29 (90.63) 3 (9.37) Thoracic Region 2556 (27.26) Breast Breast Intermammary 1,980 (77.5) 1,978 (99.90) 2 (0.10) Pulmonary System Lung Bronchi Pleura 468 (18.3) 387 (82.70) 58 (12.39) 23 (4.91) Mediastinum Esophagus Mediastinum/Mediastinal lymph node 62 (2.4) 37(59.68) 25(40.32) Chest Wall Chest/Chest wall Clavicle Rib Sternum Suprasternal 39 (1.5) 20 (51.28) 7 (17.95) 6 (15.38) 4 (10.26) 2 (5.13) Cardiovascular Heart Aorta 7 (0.3) 4 (57.14) 3 (42.86) Abdominal Region 659 (7.03) Hepatobiliary and Upper GI tract Liver Stomach Pancreas Gallbladder Duodenum Spleen Bile Duct 288 (43.7) 157 (54.51) 93 (32.29) 15 (5.21) 10 (3.47) 5 (1.74) 5 (1.74) 3 (1.04) Large Intestine Colon Appendix Cecum 153 (23.2) 144 (94.12) 5 (3.27) 4 (2.61) Retroperitoneal Organs Kidney Adrenal Gland Retroperitoneum 112 (17.0) 101 (90.18) 9 (8.04) 2 (1.78) Peritoneal and Mesenteric Structures Peritoneum Omentum Mesentery 98 (14.9) 81 (82.65) 15 (15.31) 2 (2.04) Small Intestine Ileum Jejunum 8 (1.2) 7 (87.5) 1 (12.5) Pelvic sites 509 (5.43) Urological Bladder Prostate Male Genital Urethra 315 (61.9) 181 (57.46) 100 (31.75) 24 (7.62) 10 (3.17) Colorectal Rectum Sigmoid Anal 98 (19.3) 61 (62.25) 33 (33.67) 4 (4.08) Gynecological region Uterus Ovary Vagina Vulva 76 (14.9) 43 (56.58) 20 (26.32) 6 (7.89) 7 (9.21) Pelvic Pelvis 20 (3.9) 20 (100.0) Upper Extremity 744 (7.94) Shoulder Girdle Axilla Shoulder 715 (96.1) 713 (99.72) 2 (0.28) Arm region Upper-arm Humerus Hand Brachial 29 (3.9) 19 (65.52) 4 (13.79) 4 (13.79) 2 (6.90) Lower Extremity 72 (0.77) Leg region Leg Foot Knee 37 (51.4) 26 (70.27) 8 (21.62) 3 (8.11) Hip and Thigh Thigh Hip 35 (48.6) 28 (80.0) 7 (20.0) Axial Skeleton 112 (1.19) Spine Vertebrae Spine Sacrum Paravertebral tissue 37 (33.0) 15 (40.54) 8 (21.62) 8 (21.62) 6 (16.22) Lymphatic System Regional Nodes 75 (67.0) 75 (100.0) Integumentary and Soft Tissue 198 (2.11) Integument Skin Others 175 (88.4) 171 (97.71) 4 (2.29) Gastrointestinal Region Intestine/ Small intestine Bowel/ Small bowel 23 (11.6) 18 (78.26) 5 (21.74) Multi-Region Combination 1622 (17.30) Thoracic Region Breast + Axilla / Supraclavicular / Clavicular regions Axilla + Supraclavicular/ Inguinal lymph nodes Lung + Bronchi / Pleura / Mediastinal / Carinal / Subcarinal lymph nodes 1232 (76.0) 1210 (98.21) 15 (1.22) 7 (0.57) Head and Neck Combinations Thyroid gland + Cervical / Neck lymph nodes Cervical lymph nodes + Larynx / Tongue / Tonsil / Nose / Oral cavity Cervical lymph nodes + Ear / Parotid / Submandibular glands Cervical lymph nodes + Axillary lymph nodes Lip + Face / Submental / Cervical lymph nodes Nose + Mouth / Ear 333 (20.5) 303 (91.0) 8 (2.40) 7 (2.10) 6 (1.80) 6 (1.80) 3 (0.90) Pelvic Region Sigmoid + Rectum Uterus + Ovaries Ovary + Colon / Peritoneum / Omentum Rectum + Liver / Bladder 33 (2.0) 13 (30.40) 9 (27.27) 8 (24.24) 3 (9.09) Abdominal Region Stomach + Duodenum / Pylorus / Colon / Spleen / Gallbladder Colon + Liver / Kidney / Jejunum / Anus Ileum + Omentum + Peritoneum Kidney + Liver Liver + Omentum Pancreas + Spleen 18 (1.1) 8 (44.44) 6 (33.33) 1 (5.56) 1 (5.56) 1 (5.56) 1 (5.56) Lymphatic Focused Sites Thyroid gland + Pretracheal / Paratracheal lymph nodes Thigh + Inguinal lymph nodes 6 (0.4) 5 (83.3) 1 (16.7) Among the diagnostic procedures, excisional and incisional biopsy was the most frequently performed (2,300 cases, 24.5%), followed by fine needle aspiration (1,247 cases, 13.3%) and core needle biopsy (1,222 cases, 13.0%). In contrast, therapeutic interventions included total thyroidectomy with or without lymph node dissection (1,492 cases, 15.9%), wide local excision alone (415 cases, 4.4%), wide local excision with lymph node dissection (385 cases, 4.1%), mastectomy with lymph node dissection (275 cases, 2.9%), and mastectomy without lymph node dissection (270 cases, 2.9%) (Table 4). Table 4. Frequency of Major Surgical and Biopsy Procedures Among Patients Procedure/Operation Frequency (%) Excisional and Incisional Biopsy 2300 (24.5) Fine Needle Aspiration 1247 (13.3) Total Thyroidectomy (with/without LND) 1492 (15.9) Core Needle Biopsy 1222 (13.0) Wide Local Excision 415 (4.4) Wide Local Excision with LND 385 (4.1) Mastectomy with LND 275 (2.9) Mastectomy 270 (2.9) Mass Excision (with/without Lymph Node) 233 (2.5) Mastectomy with Lymph Node Biopsy 209 (2.2) Transurethral Resection of Bladder Tumor 171 (1.8) Wide Local Excision with Lymph Node Biopsy 161 (1.7) Thyroid Lobectomy (with/without LND or Isthmectomy) 145 (1.5) Lymph Node Dissection 103 (1.1) Mass Resection (with/without Lymph Node) 102 (1.1) Bronchial Biopsy 77 (0.8) Colectomy 69 (0.7) Nephrectomy 67 (0.7) Lobectomy (with/without Lymph Node Biopsy) 65 (0.7) Hysterectomy with Salpingo Oophorectomy 31 (0.3) Bronchial Washing 22 (0.2) Orchiectomy 18 (0.2) Transurethral Resection of the Prostate 17 (0.2) Sigmoidectomy 16 (0.2) Whipple Operation 15 (0.2) Pneumonectomy 14 (0.1) Gastrectomy (Subtotal / Total ± Splenectomy) 24 (0.3) Glossectomy (Total/Partial) (with/without LND) 12 (0.1) Dilatation and Curettage 12 (0.1) Esophagogastroduodenoscopy 9 (0.1) Colonoscopy 8 (0.1) Cystectomy 8 (0.1) Superficial or Total Parotidectomy (with/without LND) 26 (0.3) Thyroid Isthmectomy 14 (0.1) Lymph Node Biopsy 8 (0.1) Hysterectomy 8 (0.1) Lymph Node Resection 6 (0.1) Lumpectomy (with/without LND) 6 (0.1) Subtotal Colectomy 6 (0.1) Appendectomy 6 (0.1) Breast Revision Surgery (with/without Lymph Node Biopsy) 5 (0.1) Thyroid Nodulectomy 11 (0.1) Cholecystectomy 4 (0.04) Metastasectomy 4 (0.04) Amputation 3 (0.03) Hepatectomy 3 (0.03) Nephrectomy with LND 3 (0.03) Pelvectomy 3 (0.03) Prostatectomy (with/without LND) 4 (0.04) Segmentectomy 3 (0.03) Thyroid Nodulectomy with LND 3 (0.03) Tonsillectomy 3 (0.03) Adrenalectomy 2 (0.02) Esophagectomy 2 (0.02) Eye enucleation 2 (0.02) Microdochectomy 2 (0.02) Pancreatectomy 2 (0.02) Polypectomy 2 (0.02) Vulvectomy 2 (0.02) Splenectomy 2 (0.02) Total Laryngectomy with LND 2 (0.02) Tonsillectomy with Lymph Node Biopsy 2 (0.02) Hepatic lobectomy 1 (0.01) Maxillectomy 1 (0.01) Oophorectomy 1 (0.01) Pancreatectomy with Splenectomy 1 (0.01) Pap test 1 (0.01) Paracentesis 1 (0.01) Parathyroidectomy 1 (0.01) Pneumonectomy with LND 1 (0.01) Subtotal Thyroidectomy 1 (0.01) Wedge Resection 1 (0.01) NA 2 (0.02) LND: Lymph node dissection, NA: Not available The median tumor size was 5.1 mm (QR 2.2–22.0 mm) in cases with free resection margins, compared to 8.5 mm (QR 4.0–17.0 mm) in cases with positive margins, with the difference being statistically significant (p < 0.001) (Figure 2). Patients with lymph node involvement had significantly larger tumor sizes (median: 5 mm, QR: 2.3–20 mm, mean: 13.4 mm) compared to those without lymph node involvement (median: 4 mm, QR: 1.5–15 mm, mean: 10.6 mm) (p = 0.018) (Figure 3). Discussion Despite advances in global cancer surveillance, accurately capturing the true burden of cancer survivorship remains challenging, particularly in low- and middle-income countries. Although survival data from these regions have expanded in recent years, they often lack sufficient granularity for effective local health planning and policy development [12]. Against this backdrop, the present study provides detailed institution-level prevalence data from a tertiary care center in Iraq, offering valuable insights into the demographic, epidemiological, and clinical characteristics of cancer patients in this setting. Age is a well-established risk factor for cancer development [13]. In the present study, the median age at diagnosis was 48.0 years, reflecting an earlier onset compared with most Western populations. This pattern aligns with broader epidemiological data from the Middle East, where cancers tend to present one to two decades earlier than in Western countries. Comparable medians have been reported in Jordan (55–56 years) [14,15] and Palestine (55 years) [16], while in a study from Basra, Iraq, which analyzed 2,163 cancer cases in 2017, the mean age was 51.4 ± 19.6 years [17]. In contrast, data from the U.S. National Cancer Institute’s Surveillance, Epidemiology, and End results program indicate a median cancer diagnosis age of 67 years, with individual cancers occurring at even older ages, lung (71), prostate (68), colorectal (66), and breast (63 years) [18]. Peak cancer incidence in this study occurred in the 71–80 age group, with 1,803 per 100,000 population, indicating that age-related cancer burden is increasingly affecting Iraq’s population. This pattern is consistent with national cancer registry data, which report the highest incidence among individuals aged 70–79 years [19]. In high-income countries, peak incidence occurs at slightly older ages and higher rates, such as 2,500 per 100,000 in U.S. adults aged 80–84 years [20] or adults ≥75 years comprising 36% of new UK cases [21]. In this study, the declining pattern in cancer incidence observed after the age of 80 was likely due to competing mortality, whereby many elderly individuals die from other conditions before cancer can be diagnosed; diagnostic underestimation, as very old patients are less likely to undergo extensive investigations; and population structure, since the >80 group made up only 1.1% of the total population, making the rates more sensitive to small changes in case numbers. The age-standardized incidence rate (ASR) in this study was 82.20 per 100,000 population, consistent with low- and middle-income country figures but lower than the 2022 global ASR of 198 per 100,000 [22]. Regional ASRs vary: high-incidence countries like Cyprus, Israel, and Turkey report 196–340 per 100,000, while Jordan reports moderate ASRs of 131–137 per 100,000 [23]. The overall Arab countries’ ASR is ~132 per 100,000 [22], whereas high-income nations may exceed 300 per 100,000, with Australia at ~468 per 100,000 [24]. The relatively low ASR in this study may reflect Iraq’s younger demographic, limited screening, underreporting, registry limitations. In this single-center series, head and neck lesions constituted the largest category, with 2,903 cases (30.97%), followed by thoracic lesions with 2,556 cases (27.26%). This distribution differs markedly from national cancer trends. Iraqi registries consistently identify breast and lung cancers as the most common malignancies, with bladder cancer leading in men; notably, breast cancer alone accounted for 19.5% of all malignancies in 2012 [25]. Similarly, a nine-year study from Karbala found head and neck tumors to represent only 2.7% of cancers [26]. Globally, head and neck cancers rank among the ten most common malignancies, with around 900,000 new cases annually [26]. In the UK, they are the eighth most common cancer, comprising 3% of new cases (approximately 12,400 per year), with peak incidence between 60–64 years [21]. Since the early 1990s, incidence rates in the UK have risen by over 35%, with a nearly 47% increase among females [27, 28]. The unusually high proportion of head and neck lesions in this study most likely reflects referral patterns rather than the true population-based incidence. The thoracic category represented the second most common group in the current series, accounting for 27.26% of cases. This pattern is consistent with Iraq’s known cancer burden, where breast cancer is the most prevalent malignancy among women, comprising approximately 19–34% of female cancers [25]. A study from the Basra Cancer Control Centre analyzing 2,163 cases also highlighted bladder and lung cancers as the leading malignancies among men [17]. National statistics further confirm breast and lung cancers as the two most common cancer types overall. The prominence of thoracic cases in the present study is therefore not unexpected. Globally, lung cancer remains a major health challenge, with an estimated 2.2 million new cases and 1.8 million deaths reported in 2020, making it the leading cause of cancer-related mortality worldwide. Recent data from the International Agency for Research on Cancer (2025) indicate that lung adenocarcinoma has become the predominant histological subtype, with rising incidence particularly among younger populations and females [29,30]. Cancers of the abdomen (7.03%) and pelvis (5.43%) were less frequent compared to global trends. Worldwide, colorectal cancer is among the top three cancers in incidence and mortality, comprising approximately 10% of global cancer cases [10]. The lower proportion in this dataset might reflect underdiagnosis, referral patterns, or differences in lifestyle factors like diet and obesity, which are known contributors to colorectal carcinogenesis [31]. Similarly, the relatively low prevalence of integumentary/soft tissue cancers (2.11%) is consistent with global data, where soft tissue sarcomas are rare, accounting for less than 1% of all cancers in developed countries [32]. Globally, thyroid cancer was the tenth most common malignancy in 2020, with about 586,000 new cases (≈3% of all cancers), predominantly affecting women [33]. In this study, however, thyroid cancer comprised nearly a quarter of cases, far exceeding regional expectations. For comparison, a Saudi tertiary center reported overall rate of 9% (12% in women) [34], whereas Iraqi registry data from 2012 did not list thyroid as one of the leading sites [25]. Globocan 2020 ranked thyroid cancer as the second most common cancer in Iraqi women (5.8%) [10]. This unusually high proportion likely reflects referral bias, as the center specializes in endocrine disorders and thyroid surgery. Conversely, several major cancers were underrepresented. Lung, colorectal, bladder, liver, and prostate cancers each accounted for only 1–4% of cases, compared with much higher global and national figures. Worldwide, lung cancer alone contributed 12.4% of new cases in 2022 and remains the leading cause of cancer death [3], whereas it was only 4.13% (387/9,375) here. Colorectal cancer was 1.5% (98/9,375) compared to 9.6% globally and 6.2% in Iraq [3,10]. Similarly, rates for bladder (1.9%), liver (1.7%), and prostate (1.1%) were well below both global averages and Iraqi data [3,10]. These discrepancies again point to strong referral and selection factors rather than true incidence. The predominance of invasive ductal carcinoma in this cohort is consistent with global epidemiology, as it remains the most common form of breast cancer, representing 70–80% of invasive cases [35–37]. In the United States alone, about 276,000 women are diagnosed annually, with most cases occurring in those over 50 years [36]. Invasive lobular carcinoma, the second most common subtype, accounted for 2.2% of cases here, similar to SEER data showing its position behind ductal carcinoma [38]. Long-term analyses indicate stable ductal carcinoma rates but increasing lobular and mixed ductal-lobular subtypes over recent decades [39]. Ductal carcinoma in situ, observed in 4.7% of cases, reflects the influence of screening programs, with contemporary data showing it accounts for 20–25% of newly diagnosed breast cancers in the U.S., largely mammography-detected [40]. Papillary thyroid carcinoma comprised 12.7% of cases, aligning with global trends of increasing thyroid cancer incidence. It constitutes about 84% of all thyroid cancers, with a 3:1 female predominance, and its incidence rose from 9.9 to 16.1 per 100,000 between 2003 and 2017 before stabilizing in recent years [41]. Revisions in diagnostic criteria, particularly reclassifying certain follicular variants as in situ tumors, have slowed reported growth. Regional data illustrate heterogeneity, with a study from Jordan reporting papillary carcinoma increases from 89.6% to 94% of thyroid cases [42]. Follicular and medullary thyroid carcinomas were less frequent but remain important subtypes with distinct epidemiological features; notably, follicular carcinoma incidence rose by over 30% between the 1980s and 2000s [43]. Skin cancers were also represented, with basal cell carcinoma (2.2%) and squamous cell carcinoma (1.5%). Basal cell carcinoma is the most common skin cancer globally, with steadily rising incidence over the past decades [44]. Squamous cell carcinoma shows wide geographic variation, with plateauing or declining rates in Australia, stable rates in the U.S., but increases in Europe [45]. Hodgkin lymphoma, comprising 0.7% of cases, remains rare but is the most common cancer among adolescents. Recent U.S. rates are 3.8 per 100,000 in men and 2.9 per 100,000 in women, with a modest overall decline since 2000 [46]. Globally, incidence varies, highest in Southern Europe and lowest in Eastern Asia, with rising trends in younger populations, females, and Asian countries [47]. Urothelial carcinoma (2.1%) reflects its role as the predominant bladder cancer subtype, comprising ~90% of cases. In the U.S., ~84,870 new bladder cancers are reported annually, with a 4:1 male predominance [48]. Upper tract urothelial carcinoma, while rare (~2 per 100,000), contributes 5–10% of urothelial malignancies [49]. Biopsy and diagnostic procedures constituted the overwhelming majority of interventions (53.42%, n=5,017), with incisional and excisional biopsy being the most common procedure (24.5%, n=2,300), followed by fine needle aspiration (13.3%, n=1,247) and core needle biopsy (13.0%, n=1,222). This pattern reflects the critical importance of tissue diagnosis in cancer management, consistent with international guidelines that emphasize histopathological confirmation as the cornerstone of cancer diagnosis [50]. The high frequency of fine needle aspiration biopsy aligns with Iraqi studies demonstrating its effectiveness, with reported sensitivity rates of 87.3-96% and specificity rates of 83-100% for breast lesions, making it a preferred initial diagnostic tool due to its minimal invasiveness and cost-effectiveness [51,52]. Studies from other Middle Eastern centers have similarly reported high utilization of fine needle aspiration and core needle biopsies, particularly for superficial lesions and thyroid nodules [53]. Thyroid surgery represented the second most common category (18.36%, n=1,733), with total thyroidectomy (with/without lymph node dissection) being the predominant procedure (15.9%). The preference for total thyroidectomy over thyroid lobectomy (1.5%) and isthmectomy (0.1%) aligns with international guidelines for differentiated thyroid cancer, particularly for tumors larger than 4 cm or those with aggressive histological features. The high frequency of total thyroidectomy in this series is consistent with the current trend toward more aggressive surgical management for thyroid cancer in developing countries, where patients often present at more advanced stages [54]. Breast surgery accounted for 8.20% of procedures, with mastectomy-related procedures representing 754 cases. The predominance of mastectomy over breast-conserving surgery reflects the pattern observed throughout Iraq, where modified radical mastectomy remains the standard approach for breast cancer treatment. Studies from the Kurdistan region of Iraq show that 60.2% of breast cancer patients undergo mastectomy compared to 39.8% receiving breast-conserving surgery, with the proportion of breast-conserving surgery slowly increasing from 36.3% in 2016 to 43.7% in 2021 [55]. This mastectomy preference contrasts with international trends in developed countries where breast-conserving surgery is increasingly favored for early-stage disease [56]. This study has several limitations. First, potential referral bias may affect the representativeness of the findings, as the unusually high proportion of head and neck and thyroid cancers likely reflects the center’s specialized role rather than true population-based cancer incidence. The five-year study period and single-center setting further limit the generalizability of the results to broader populations. Finally, the absence of survival data and cancer staging information restricts the ability to assess outcomes and prognosis within the studied population. Conclusion The study highlights a unique cancer profile, with younger age at diagnosis and higher rates of head, neck, and thyroid cancers. These findings underscore the need for targeted screening and prevention strategies adapted to regional healthcare systems and population risks. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Ethical approval for this study was obtained from the Ethical Committee of Kscien Organization (Approval No. 41/2025). Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: AMM, and FHK: Major contribution to the conception and design of the study, literature search, and manuscript drafting. ARA, DAH, FA, MSE, HSA, LQR, MAK, DGH and HHR: literature review, study design, data collection, and critical revision of the manuscript. BAA, and SJH: literature review, table and figure processing. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Data are available from the corresponding author upon reasonable request.
Pembrolizumab and Sarcoma: A meta-analysis
Abstract Introduction: Pembrolizumab is a monoclonal antibody that promotes antitumor immunity. This study presents a systematic review and meta-analysis of the efficacy and safety profile of this treatment as monotherapy or in combination with other drugs for the treatment of sarcomas. Methods: A literature search was conducted across Google Scholar, PubMed/MEDLINE, and EMBASE from February 15th to April 15th. Eligible studies were clinical trials that reported efficacy or outcomes of pembrolizumab in sarcoma patients, either alone or in combination with other drugs. In contrast, those lacking sufficient data or not meeting trial criteria were excluded. Results: Ten clinical trials met the eligibility criteria, including 419 sarcoma patients (53.7% male; median age 55.4). Pembrolizumab was administered either as monotherapy in 23% of cases or in combination with other agents in 77% of cases. The progressive disease rate was 83% with monotherapy and 36% with combination therapy. Objective response rates varied, with the highest observed in the pembrolizumab plus talimogene laherparepvec combination (35%) and the lowest in pembrolizumab monotherapy (ranging from 0% to 11.2%). Median progression-free survival ranged from 1.4 (Pembrolizumab + Cyclophosphamide) to 7.8 months (Pembrolizumab + Lenvatinib in undifferentiated pleomorphic sarcoma). Combination therapy was associated with significantly better tumor response (<0.001). However, rates of endocrine, gastrointestinal, some hepatic, and dermatological adverse events were significantly associated with combination therapy compared to monotherapy (p < 0.05). Conclusion: Pembrolizumab-based combination therapies have the potential to enhance treatment efficacy in sarcoma, although they may be associated with an increased risk of adverse events. Introduction Sarcomas are rare tumors that develop from mesenchymal tissue and are known for their diverse histological subtypes. Although they are uncommon, they carry particular clinical significance due to their relatively higher incidence in adolescents and young adults. The primary treatment is surgical resection, often combined with chemotherapy or radiotherapy, either before (neoadjuvant) or after (adjuvant) surgery, depending on the specific subtype [1]. Immunotherapy has introduced a breakthrough in cancer treatment. Unlike traditional approaches such as chemotherapy and radiation, which can harm healthy cells and lead to significant side effects, immunotherapy takes a more targeted and refined approach. It helps the body’s immune system recognize and attack cancer cells, offering a potentially more effective and less toxic alternative [2]. Cancer immunotherapy includes a variety of treatment methods, such as immune checkpoint inhibitors, adoptive cell transfer, cytokine therapies, and cancer vaccines [3]. What sets immunotherapy apart is its ability to produce long-lasting effects, sometimes leading to extended remission or even complete disappearance of the disease in some patients [4]. In addition, immunotherapy is often better tolerated than traditional treatments, since it tends to focus more precisely on cancer cells while causing less harm to healthy tissues [2]. Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor, blocking its interaction with the ligands PD-L1 and PD-L2, which are often expressed by tumor cells. By interrupting this pathway, pembrolizumab removes a key mechanism of immune suppression, allowing cytotoxic T cells to become more active and better able to attack cancer cells [5]. PD-1 is an immune checkpoint receptor found on activated T cells. When it binds to PD-L1 or PD-L2, it downregulates immune activity by inhibiting T-cell function and helping tumor cells avoid destruction. Research has shown that tumors often increase PD-L1 expression as a strategy to escape immune detection, weakening the body’s ability to fight cancer [6]. Despite significant research, sarcomas remain difficult to treat effectively. Soft tissue sarcomas, in particular, have a 5-year survival rate of only about 65%, highlighting the ongoing need for more effective therapeutic options [1]. Pembrolizumab has shown durable antitumor activity across several solid tumor types, along with a generally favorable safety and tolerability profile [7]. This systematic review and meta-analysis aims to assess the antitumor efficacy and safety of pembrolizumab, both as a standalone therapy and in combination with other agents, in treating different types of sarcomas through a systematic review and meta-analysis of clinical trials. Only data from peer-reviewed sources were included, ensuring the reliability of the data [8]. Methods Study design The study is a systematic review and meta-analysis encompassing clinical trials assessing the effectiveness of pembrolizumab in treating sarcomas. It encompasses trials where pembrolizumab is used alone as well as in combination with other treatments. The drug combinations were as follows: group A (Pembrolizumab + Doxorubicin), group B (Pembrolizumab + Axitinib), group C (Pembrolizumab + Eribulin), group D (Pembrolizumab + Talimogene Laherparepvec), group E (Pembrolizumab + Epacadostat), group F (Pembrolizumab + Olaratumab), group G (Pembrolizumab + Levatinib), and group H (Pembrolizumab + Cyclophosphamide). The search process was conducted from February 15th to April 15th 2025, in full compliance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data sources and search strategy A thorough search was performed using Google Scholar, PubMed/MEDLINE, and EMBASE. A set of keywords was utilized to retrieve pertinent studies, specifically: (anti-PD-1; PD-1 inhibitor; Keytruda; MK-3475; Lambrolizumab; Pembrolizumab; Sarcoma; Sarcomas; Spindle cell sarcoma; Spindle cell sarcomas). Eligibility criteria Eligible studies consisted of clinical trials evaluating the efficacy of pembrolizumab in treating sarcomas, either as a standalone therapy or in combination with other treatments. Studies were excluded if they were not clinical trials, did not investigate pembrolizumab for sarcoma treatment, or failed to provide adequate data on treatment efficacy or patient outcomes. Study selection process The study selection process was conducted independently by two researchers who carefully screened the titles and abstracts of all identified studies. Each study was assessed based on the predefined inclusion and exclusion criteria. In instances of disagreement regarding a study’s eligibility, a third researcher was consulted to resolve the conflict and reach a consensus. Data items Data extracted from the eligible studies encompassed a wide range of information, including the first author’s name, year of publication, trial phase, sarcoma subtype, number of enrolled patients, sex distribution, treatment regimen, median patient age, reported adverse events, and various clinical outcome measures, including progression-free survival, overall survival, complete response, partial response, stable disease and progressive disease. Data analysis and synthesis The extracted data were organized using Microsoft Excel (2019) and analyzed with SPSS version 25.0 (IBM Corp.). Descriptive statistics were reported as frequencies, percentages, medians, and ranges. Categorical variables were compared using the Chi-square or Fisher's exact test, as appropriate. Continuous variables, including overall survival and progression-free survival (PFS), were analyzed using the non-parametric Mann-Whitney U test. Results Study selection process and eligibility criteria A total of 103 records were initially identified through the search process. Among these, 42 were excluded because they were unretrievable, two were removed as duplicates, and one was excluded for not qualifying as a full research article. Then, the titles and abstracts of the remaining 58 studies were screened, resulting in the exclusion of 20 records that were deemed irrelevant. After that, 38 studies underwent full-text screening, of which 27 were excluded based on exclusion criteria. Subsequently, 11 studies were assessed for eligibility, and one was excluded because it did not provide complete data. In the end, 10 studies were included for final review and analysis (Figure 1) [7, 9-17]. Characteristics of included trials All the studies included were clinical trials, consisting of eight Phase II trials, one Phase I trial, and one study that encompassed both Phase I and II designs. The raw data, along with key characteristics of each study, are summarized in Tables 1, 2, and 3. Analysis of progressive disease rates in sarcoma patients treated with pembrolizumab monotherapy, based on two studies, revealed an overall rate of 83% (95% CI: 26%–100%). In contrast, a meta-analysis of patients receiving pembrolizumab in combination with other therapeutic agents showed a substantially lower progressive disease rate of 36% (95% CI: 23%–51%) (Figure 2). <img id="image_2" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-5288121221751108819164.png" alt="Figure 2. Forest plot of studies evaluating progressive disease rates with (A) Pembrolizumab monotherapy vs. (B) Pembrolizumab combination therapies*. CI, confidence interval *Olaratumab combination trial was excluded due to unavailable progressive disease data [16]." width="4096" height="2408" /> Table 1. Baseline characteristics of clinical trials evaluating pembrolizumab and combination therapies for sarcoma First Author /Year [reference] Trial Phase Type of sarcoma Therapy regimens No. of patients Sex Median Age Male Female Pollack et al,2020 [10] I/II Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Doxorubicin 45-75mg 37 22 15 58.4 Wilky et al, 2019 [11] II Soft tissue sarcoma Pembrolizumab 200mg/q3w (IV) Axitinib 5mg (Orally) 33 18 15 44 Tawbi et al,2017 [9] II Soft tissue sarcoma + Osteosarcoma Pembrolizumab 200mg/q3w (IV) 84 53 31 53a/ 33b Haddox et al,2024 [17] II Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Eribulin 1.4mg/m2 (iv) 57 24 33 60.4* Kelly et al,2020 [13] II Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Talimogene Laherparepvec ≤4ml×102 (intratumourally) 20 12 8 58.3 Kelly et al, 2023 [14] II Soft tissue sarcoma Pembrolizumab 200mg/q3w (IV) Epacadostat 100mg (orally) 30 18 12 54 Schöffski et al, 2023 [16] Ia/b Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Olaratumab 15-20mg/kg (IV) 41 15 26 56.83* Movva et al,2024 [12] II Soft tissue sarcoma + Bone sarcoma Pembrolizumab 200mg/q3w(IV) Levatinib 20mg (orally) 48 22 26 50 Toulmonde et al, 2018 [15] II Soft tissue sarcoma Pembrolizumab 200mg/q3w (IV) Cyclophosphamide 50mg (Orally) 57 33 24 59.5 Boye et al,2021 [7] II Osteosarcoma Pembrolizumab 200mg/q3w (IV) 12 8 4 43 *: mean age, a: median age in soft tissue sarcoma, b: median age in bone sarcoma, q3w: every three weeks, IV: intravenous Table 2. Patient response according to RECIST 1.1. First Author /Year [reference] Patient No. (Evaluable for response) Prior chemotherapy Therapy Regimen Outcome ORR (%) Yes No CR PR SD PD NE Pollack et al,2020 [10] 37 9 28 Group A 0 7 22 7 1 19 Wilky et al, 2019 [11] 30 27 6 Group B 0 8 9 13 3 24 Tawbi et al,2017 [9] 80 80 0 Pembrolizumab alone 1 8 24 47 4 11.2 Haddox et al,2024 [17] 56 2.5(1.5)a 0 Group C 1b 10 22 23 1 19.3 Kelly et al,2020 [13] 20 19 1 Group D 0 7 7 6 0 35 Kelly et al, 2023 [14] 30 24 6 Group E 0 1 13 16 0 3.3 Schöffski et al, 2023 [16] 41 37 0 Group F 0 6 N/A N/A N/A 14.6 Movva et al,2024 [12] 46 43 5 Group G 0 8 31 7 2 15.2 Toulmonde et al, 2018 [15] 48 55 2 Group H 0 1 16 31 9 2 Boye et al,2021 [7] 12 12 0 Pembrolizumab alone 0 0 0 12 0 0 RECIST: Response Evaluation Criteria in Solid Tumors, ORR: Objective response rate, CR: complete response, PR: Partial response, SD: Stable disease, PD: progressive disease, NE: not evaluable. (a): mean (SD), (b) The patient had radiotherapy-associated angiosarcoma. Table 3. Efficacy and survival outcomes of patients receiving pembrolizumab alone and in combination. First Author /Year [reference] Patient No. Therapy Regimen RMD (months) Median follow-up (months) Median PFS (months) Median Overall survival (months) Pollack et al, 2020 [10] 37 Group A N/A N/A 8.1 27.6 Wilky et al, 2019 [11] 33 Group B 6.6 14.7 4.7 18.7 Tawbi et al, 2017 [9] 84 Pembrolizumab alone 7.6a/9.9b 19.1a/17.8b 4a/2b 11.2a/12b Haddox et al, 2024 [17] 57 Group C N/A 14c/11.6d/7e 2.5c/7.3d/2.9e 13.5c/22d/N/Ae Kelly et al, 2020 [13] 20 Group D 13 13 4 N/A Kelly et al, 2023 [14] 30 Group E N/A 29.7 1.7 16.9 Schöffski et al, 2023 [16] 41 Group F 16.2 N/A 1.4f/2.8g/2.7h 11.4f/16.4g/14.8h Movva et al, 2024 [12] 48 Group G 2.5 20 2.2c/5.7A/7.8B/6.4C/4.3D 10.3A/N/AB/14.5C/13.8D/6.4E Toulmonde et al, 2018 [15] 57 Group H N/A 6.8 1.4 9.2 Boye et al, 2021 [7] 12 Pemb. alone N/A N/A 1.7 6.6 RMD: response median duration, PFS: progression-free survival, a: soft tissue sarcoma, b: bone sarcoma, c: Leiomyosarcoma, d: Liposarcoma, e: Undifferentiated pleomorphic sarcoma/other, f: Olaratumab plus Pembrolizumab, g: Olaratumab plus Pembrolizumab, h: Olaratumab Pembrolizumab, A: undifferentiated pleomorphic sarcoma, B: vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), C: synovial sarcoma or malignant peripheral nerve sheath tumor, D: bone sarcomas (osteosarcoma and chondrosarcoma). Baseline characteristics and treatment group distribution A total of 419 patients were included across the eligible studies, of which 225 (53.7%) were males. The median age (IQR) of the patients was 55.4 (14.4). Most patients had an Eastern Cooperative Oncology Group (ECOG) status of zero (156, 37.23%), followed by a score of one (139, 33.17%). Performance status was not reported for 124 patients (29.6%). Histologically, leiomyosarcoma was the most frequently reported subtype, accounting for 99 cases (25.85%), whereas conventional chondrosarcoma was the least common, identified in only three cases (0.78%). Three hundred twenty-nine (78.52%) patients exhibited both metastatic and locally advanced properties. Patients were categorized into two groups: 96 patients (23%) received pembrolizumab as a monotherapy, while 323 patients (77%) were treated with pembrolizumab in combination with other therapies. The types of sarcoma included in the trials were soft tissue sarcoma (354, 84.5%) and bone sarcoma (65, 15.5%) (Table 4). Table 4. Clinical characteristics and response profiles. Variables Frequency/percentage Median age (IQR) 55.4 (14.4) Sex Male Female 225 (53.7%) 194 (46.3%) ECOG Status ECOG status (0) ECOG status (1) Not mentioned 156 (37.23%) 139 (33.17%) 124 (29.6%) Sarcoma types Soft tissue sarcoma Bone sarcoma 354 (84.5%) 65 (15.5%) Histological subtypes Angiosarcoma Synovial sarcoma Dedifferentiated liposarcoma Pleomorphic liposarcoma Leiomyosarcoma Undifferentiated pleomorphic sarcoma Gastrointestinal stromal tumor Alveolar soft-part sarcoma Osteosarcoma Dedifferentiated chondrosarcoma Ewing sarcoma Conventional chondrosarcoma Others Evaluable patients (383) 17 (4.44%) 22 (5.74%) 40 (10.44%) 4 (1.04%) 99 (25.85%) 63 (16.45%) 11 (2.87%) 13 (3.39%) 36 (9.4%) 10 (2.61%) 15 (3.92%) 3 (0.79%) 50 (13.05%) Sarcoma stage Locally advanced Metastatic Both 11 (2.63%) 79 (18.85%) 329 (78.52%) Treatment group Pembrolizumab alone Pembrolizumab combination 96 (23.0%) 323 (77.0%) Objective response rate (ORR) was 19% for patients treated with pembrolizumab plus doxorubicin, 25% for pembrolizumab plus axitinib, and 11.2% for pembrolizumab alone in a cohort of 80 patients. Pembrolizumab plus eribulin yielded an ORR of 19.3%, while the combination with talimogene laherparepvec had the highest ORR at 35%. In contrast, pembrolizumab plus epacadostat showed a low ORR of 3.3%, and pembrolizumab plus olaratumab achieved an ORR of 14.6% (Table 2). Response median duration was available for five trials and ranged from 6.6 to 13 months. Median progression-free survival ranged from 1.4 months to 7.8 months, and median overall survival ranged from 6.6 to 27.6 months (Table 3). Efficacy and adverse events in different treatment groups Anemia affected 30% of patients overall. It was persistent with Group C (52.6%) and Group D (30%). Lymphopenia was notable in pembrolizumab monotherapy (27%). Vomiting and diarrhea were most frequent with Group B (66.6%) and (57.5%), respectively. Hypothyroidism was high in Group B (63.6%) and Group G (29.1%). Elevated liver enzymes (ALP, AST, ALT) were widespread, especially with Group G (89.5%) and Group A (59.3%). Cough and dyspnea were seen across most regimens, but cough was particularly high with Group B (33%). Headache was a relatively common complaint, notably with Group F (24.3%). Cardiac events were rare, but hypertension was notable in Group B (48.4%) and Group G (56%). Alopecia was most common in Group A (42.4%) and Group C (24.5%). Fatigue was the most common general adverse event, affecting more than half of all patients and reaching up to 80% in Group D (Table 5). Table 5. Adverse events of pembrolizumab monotherapy and pembrolizumab combination therapies Adverse events Total (%)* Pemb. (96)** G. A (37) G. B (33) G. C (57) G. D (20) G. E (30) G. F (41) G. G (48) G. H (57) Hematological Thrombocytopenia 19 (4.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (5%) 1 (3.3%) 0 (0.0%) 17 (35.4%) 0 (0.0%) Lymphopenia 36 (8.6%) 26 (27.0%) 2 (5.4%) 0 (0.0%) 3 (5.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 5 (8.7%) Febrile neutropenia 13 (3.1%) 4 (4.1%) 3 (8.1%) 0 (0.0%) 6 (10.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Anemia 126 (30.0%) 43 (10.2%) 5 (13.5%) 0 (0.0%) 30 (52.6%) 6 (30%) 6 (20%) 11 (26.8%) 13 (27%) 12 (21%) Gastrointestinal Nausea 138 (33.0%) 22 (23.0%) 32 (86.4%) 22 (3.0%) 25 (43.8%) 6 (30%) 4 (13.3%) 6 (14.6%) 15 (31.2%) 6 (10.5%) Vomiting 56 (13.4%) 11 (11.4%) 11 (29.7%) 22 (66.6%) 6 (10.5%) 4 (20%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Anorexia 72 (17.2%) 14 (14.5%) 18 (48.6%) 12 (36.3%) 24 (42.1%) 0 (0.0%) 4 (13.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Constipation 55 (13.1%) 17 (17.7%) 5 (13.5%) 9 (27.2%) 15 (26.3%) 0 (0.0%) 0 (0.0%) 9 (22%) 0 (0.0%) 0 (0.0%) Diarrhea 96 (23.0%) 15 (15.6%) 8 (21.6%) 19 (57.5%) 12 (21.0%) 0 (0.0%) 2 (6.6%) 12 (29.2%) 21 (4.16) 7 (12.2%) Decreased appetite 7 (1.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 7 (17.1%) 0 (0.0%) 0 (0.0%) Xerostomia 26 (6.2%) 0 (0.0%) 11 (29.7%) 0 (0.0%) 8 (14.0%) 0 (0.0%) 4 (13.3%) 0 (0.0%) 0 (0.0%) 3 (5.2%) Abdominal pain 27 (6.4%) 13 (13.5%) 2 (5.4%) 0 (0.0%) 3 (5.2%) 0 (0.0%) 1 (3.3%) 8 (19.5%) 0 (0.0%) 0 (0.0%) Colitis 5 (1.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 3(5.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (4.2%) 0 (0.0%) Colonic perforation 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0 (0.0%) Endocrine Hypothyroidism 61 (14.6%) 2 (2.1%) 7 (18.9%) 21 (63.6%) 5 (8.7%) 4 (20%) 4 (13.3%) 0 (0.0%) 14 (29.1%) 4 (7%) Hyperthyroidism 18 (4.3%) 7 (7.2%) 3 (8.1%) 0 (0.0%) 4 (7.0%) 0 (0.0%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 2 (3.5%) Hot flushes 3 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (3.3%) 0 (0.0%) 0 (0.0%) 2 (3.5%) Hepatobiliary Elevated ALP, AST, AP 162 (38.7%) 57 (59.3%) 0 (0.0%) 18 (1.6%) 27 (47.3%) 4 (20%) 12 (40%) 1 (2.4%) 43 (89.5%) 0 (0.0%) Increased bilirubin 15 (3.6%) 3 (3.1%) 0 (0.0%) 0 (0.0%) 4 (7.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 8 (16.6%) 0 (0.0%) Increased lipase 28 (6.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 17 (29.8%) 0 (0.0%) 3 (10%) 8 (19.5%) 0 (0.0%) 0 (0.0%) Increased serum amylase 16 (3.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 11 (19.2%) 3 (15%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Respiratory Cough 65 (15.5%) 24 (25.0%) 3 (8.1%) 11 (33%) 7 (12.2%) 3 (15%) 1 (3.3%) 9 (22%) 7 (14.6%) 0 (0.0%) Dyspnea 57 (13.6%) 19 (19.8%) 4 (10.8%) 0 (0.0%) 10 (17.5%) 0 (0.0%) 4 (13.3%) 11 (26.8%) 9 (18.7%) 0 (0.0%) Hemoptysis 7 (1.7%) 0 (0.0%) 4 (10.8%) 3 (9.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Nasopharyngeal congestion 18 (4.3%) 0 (0.0%) 0 (0.0%) 18 (54.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Pneumothorax 3 (0.7%) 1 (1%) 1 (2.7%) 1 (3.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Nervous system Vertigo 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (3.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Headache 55 (13.1%) 9 (9.4%) 4 (10.8%) 5 (15.1%) 7 (12.2%) 0 (0.0%) 2 (6.6%) 10 (24.3%) 18 (37.5%) 0 (0.0%) Cognitive disturbance 5 (1.2%) 4 (4.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.0%) 0 (0.0%) Seizure 2 (0.4%) 0 (0.0%) 0 (0.0%) 2 (6.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Dysguisia 22 (5.3%) 0 (0.0%) 10 (27%) 0 (0.0%) 12 (21.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Cardiac-related Chest pain 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0 (0.0%) Left ventricular dysfunction 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0 (0.0%) Pericarditis 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0 (0.0%) Cardiac arrest 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.75%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Vascular-related Hypertension 46 (11.0%) 3 (3.1%) 0 (0.0%) 16 (48.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 27 (56%) 0 (0.0%) Thromboembolic event 7 (1.7%) 4 (4.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 3 (6.2%) 0 (0.0%) Dermatological Skin rash 15 (3.6%) 0 (0.0%) 6 (16.2%) 9 (27.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Maculopapular rash 40 (9.5%) 4 (4.2%) 4 (2.7%) 0 (0.0%) 12 (21.0%) 0 (0.0%) 9 (30%) 0 (0.0%) 11 (23%) 0 (0.0%) Dry skin 2 (0.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Pruritus 37 (8.8%) 6 (6.2%) 9 (24.3%) 9 (27.2%) 6 (10.5%) 4 (20%) 1 (3.3%) 0 (0.0%) 0 (0.0%) 2 (3.5%) Alopecia 28 (6.7%) 0 (0.0%) 14 (42.4%) 0 (0.0%) 14 (24.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Palmar-Plantar-erythrodysthesia syndrome 10 (2.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 10 (21%) 0 (0.0%) Metabolic and nutritional Hypoalbuminemia 36 (8.6%) 21 (21.8%) 0 (0.0%) 0 (0.0%) 9 (0.0%) 0 (0.0%) 0 (0.0%) 6 (14.6%) 0 (0.0%) 0 (0.0%) Hypokalemia 24 (5.7%) 11 (11.4%) 0 (0.0%) 0 (0.0%) 7 (0.0%) 0 (0.0%) 0 (0.0%) 6 (14.6%) 0 (0.0%) 0 (0.0%) Hypomagnesmia 22 (5.2%) 0 (0.0%) 6 (16.2%) 0 (0.0%) 13 (0.0%) 0 (0.0%) 3 (10%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Hypophosphatemia 24 (5.7%) 3 (3.1%) 0 (0.0%) 0 (0.0%) 11 (0.0%) 0 (0.0%) 2 (6.6%) 8 (19.5%) 0 (0.0%) 0 (0.0%) Hypertriglyceridemia 3 (0.7%) 0 (0.0%) 0 (0.0%) 3 (9.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Investigations Decreased WBC count 48 (11.4%) 0 (0.0%) 3 (8.1%) 0 (0.0%) 31(54.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 14 (29.1%) 0 (0.0%) Decreased neutrophil count 47 (11.2%) 0 (0.0%) 9 (24%) 0 (0.0%) 32(56.1%) 0 (0.0%) 0 (0.0%) 6 (14.6%) 0 (0.0%) 0 (0.0%) Elevated hemoglobin 5 (1.2%) 0 (0.0%) 0 (0.0%) 5 (15.0%) 0(0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Increased creatinine or BUN 10 (2.4%) 0 (0.0%) 0 (0.0%) 6 (18.1%) 4(7.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Decreased ejection fraction 2 (0.4%) 0 (0.0%) 2 (5.4%) 0 (0.0%) 0(0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) MSK-Connective tissue-related Myalgia 25 (6.0%) 6 (6.2%) 0 (0.0%) 0 (0.0%) 7 (12.2%) 0 (0.0%) 4 (13.3%) 5 (12.1%) 0 (0.0%) 3 (5.2%) Arthralgia 49 (11.6%) 7 (7.3%) 0 (0.0%) 15 (45.4%) 9 (15.7%) 0 (0.0%) 6 (20%) 7 (17.1%) 0 (0.0%) 5 (8.7%) General Fatigue 217 (51.8%) 34 (35.4%) 21 (56.7%) 26 (78.7%) 41 (72.0%) 16 (80%) 10 (33.3%) 15 (36.5%) 25 (52%) 29(50.8%) Weight loss 55 (13.1%) 18 (18.7%) 6 (16.2%) 12 (36.3%) 17 (29.8%) 0 (0.0%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Fever 34 (8.1%) 0 (0.0%) 7 (19%) 0 (0.0%) 14 (24.5%) 0 (0.0%) 9 (30%) 2 (4.8%) 0 (0.0%) 2 (3.5%) Insomnia 13 (3.1%) 7 (7.3%) 0 (0.0%) 0 (0.0%) 3 (5.2%) 1 (5%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Tumor pain 52 (12.4%) 1 (1.0%) 0 (0.0%) 15 (45.4%) 6 (10.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 30(52.6%) Ocular Dry eye 8 (2.0%) 0 (0.0%) 8 (21.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Optic neuritis/uveitis 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (3.3%) 0 (0.0%) 0 (0.0%) 0(0.0%) Infection Oral mucositis 52 (12.4%) 0 (0.0%) 13 (35.1%) 23 (69.6%) 11 (19.2%) 0 (0.0%) 1 (3.3%) 0 (0.0%) 0 (0.0%) 4(7.0%) Pericarditis 1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0(0.0%) Rectal or vaginal mucositis 7 (1.7%) 0 (0.0%) 1 (2.7 %) 6 (18.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) URTI 4 (1.0%) 0 (0.0%) 4 (10.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Immune-related Hyperglycemia 34 (8.1%) 17 (17.7%) 0 (0.0%) 9 (27.2%) 8 (14.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Autoimmune colitis 1 (0.2%) 0 (0.0%) 0 (0.0%) 1 (3.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Autoimmune hepatitis 2 (0.4%) 0 (0.0%) 0 (0.0%) 1 (3.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.4%) 0 (0.0%) 0(0.0%) Autoimmune arthritis 3 (0.7%) 0 (0.0%) 0 (0.0%) 2 (6.0%) 0 (0.0%) 0 (0.0%) 1 (3.3%) 0 (0.0%) 0 (0.0%) 0(0.0%) Pulmonary embolism 1 (0.2%) 1 (1.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Adrenal insufficiency 1 (0.2%) 1 (1.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Pneumonitis 10 (2.4%) 2 (2.1%) 0 (0.0%) 0 (0.0%) 2 (3.5%) 4 (20%) 2 (6.6%) 0 (0.0%) 0 (0.0%) 0(0.0%) Interstitial nephritis 1 (0.2%) 1 (1.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) * The percentages were calculated by dividing by the total number of enrolled patients (419), **The numbers between the parentheses represent the number of enrolled patients, URTI: Upper respiratory tract infection, Pemb: Pembrolizumab. Compared to pembrolizumab monotherapy, combination therapy was associated with significantly better tumor responses, including higher rates of partial and stable disease and a lower incidence of progressive disease (p < 0.001). Hematological toxicities differed significantly: thrombocytopenia was more frequent with combination therapy (p = 0.010), while lymphopenia and anemia were more common with monotherapy (p < 0.001 and p = 0.001, respectively). Gastrointestinal events such as nausea (p = 0.019), xerostomia (p = 0.001), and abdominal pain (p = 0.003) were also more common in combination therapy. Combination therapy was linked to higher rates of hypothyroidism (p < 0.001), hepatobiliary abnormalities, including elevated liver enzymes (p < 0.001), lipase (p = 0.001), and amylase (p = 0.029). Respiratory (cough: p = 0.006; rhinorrhea: p = 0.018), neurological (dysgeusia: p = 0.004), vascular (hypertension: p = 0.005), and dermatological toxicities (skin rash: p = 0.028; maculopapular rash: p = 0.047; alopecia: p = 0.001) were also significantly higher in combination therapy. Metabolic disturbances such as hypoalbuminemia (p < 0.001), hypokalemia (p = 0.011), and hypomagnesemia (p = 0.004) varied between groups. Additionally, adverse events such as decreased WBC and neutrophil counts, fatigue, tumor pain, and oral mucositis were more common in the combination group (p < 0.001), whereas insomnia (p = 0.014) and hyperglycemia (p < 0.001) were more frequent with monotherapy (Table 6). Table 6. Comparisons of clinical outcomes and adverse events between pembrolizumab monotherapy and combination therapy Parameters Type of therapy P-value Pembrolizumab Alone Combination Therapy Progression-free survival, Days (Median, IQR) 56.0 (75.0) 103.5 (112.0) 0.303 Overall survival, Days (Median, IQR) 343 (201.0) 417 (263.5) 0.559 Outcome (N, %) * Complete response Partial response Stable disease Progressive disease 1 (1.1) 8 (8.7) 24 (26.1) 59 (64.1) 1 (0.4) 48 (17.6) 120 (44.1) 103 (37.9) <0.001 Hematological adverse events Thrombocytopenia Lymphopenia Febrile Neutropenia Anemia 0 (0.0) 26 (27.1) 4 (4.2) 43 (44.8) 19 (5.9) 10 (3.1) 9 (2.8) 83 (25.7) 0.010 <0.001 0.506 0.001 Gastrointestinal adverse events Nausea Vomiting Anorexia Constipation Diarrhea Decreased Appetite Xerostomia Abdominal Pain Colitis 22 (22.9) 11 (11.5) 14 (14.6) 17 (17.7) 15 (15.6) 0 (0.0) 0 (0.0) 13 (13.5) 0 (0.0) 116 (35.9) 45 (13.9) 58 (18.0) 38 (11.8) 81 (25.1) 7 (2.2) 26 (8.0) 14 (4.3) 5 (1.5) 0.019 0.611 0.538 0.167 0.054 0.359 0.001 0.003 0.593 Endocrine adverse events Hypothyroidism Hyperthyroidism 2 (2.1) 7 (7.3) 59 (18.3) 11 (3.4) <0.001 0.146 Hepatobiliary adverse events Elevated ALP, AST, ALT Elevated Bilirubin Elevated Lipase Elevated Serum Amylase 57 (59.4) 3 (3.1) 0 (0.0) 0 (0.0) 105 (32.5) 12 (3.7) 28 (8.7) 16 (5.0) <0.001 0.999 0.001 0.029 Respiratory adverse events Cough Dyspnea Hemoptysis Rhinorrhea Pneumothorax 24 (25.0) 19 (19.8) 0 (0.0) 0 (0.0) 1 (1.0) 41 (12.7) 38 (11.8) 7 (2.2) 18 (5.6) 2 (0.6) 0.006 0.061 0.359 0.018 0.543 Neurological adverse events Headache Dysgeusia 9 (9.4) 0 (0.0) 46 (14.2) 22 (6.8) 0.301 0.004 Vascular adverse events Hypertension 3 (3.1) 43 (13.3) 0.005 Dermatological adverse events Skin Rash Maculopapular Rash Dry Skin Pruritus Alopecia 0 (0.0) 4 (4.2) 0 (0.0) 6 (6.3) 0 (0.0) 15 (4.6) 36 (11.1) 2 (0.6) 31 (9.6) 28 (8.7) 0.028 0.047 0.999 0.413 0.001 Metabolic and nutritional adverse events Hypoalbuminemia Hypokalemia Hypomagnesemia Hypophosphatemia 21 (21.9) 11 (11.5) 0 (0.0) 3 (3.1) 15 (4.6) 13 (4.0) 22 (6.8) 21 (6.5) <0.001 0.011 0.004 0.316 Musculoskeletal and connective tissue adverse events Myalgia Arthralgia 6 (6.3) 7 (7.3) 19 (5.9) 42 (13.0) 0.811 0.149 Others Decreased WBC count Elevated HBG Decreased Neutrophil count Elevated Creatinine or BUN Fatigue Weight Loss Fever Insomnia Tumor pain Oral mucositis Rectal or Vaginal mucositis Hyperglycemia Pneumonitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 34 (35.4) 18 (18.8) 0 (0.0) 7 (7.3) 1 (1.0) 0 (0.0) 0 (0.0) 17 (17.7) 1 (1.0) 48 (14.9) 5 (1.5) 47 (14.6) 10 (3.1) 183 (56.7) 37 (11.5) 34 (10.6) 6 (1.9) 51 (15.8) 52 (16.1) 6 (1.9) 17 (5.3) 8 (2.5) <0.001 0.593 <0.001 0.126 <0.001 0.084 <0.001 0.014 <0.001 <0.001 0.344 <0.001 0.69 * Analyses were done for evaluable cases, IQR: Interquartile range, ALP: Alkaline phosphatase, AST: Aspartate aminotransferase, ALT: Alanine Aminotransferase, WBC: White blood cells, HBG: Hemoglobin, BUN: Blood Urea Nitrogen Discussion The current meta-analysis results demonstrate a stark contrast between pembrolizumab monotherapy and combination approaches in sarcoma treatment. With pembrolizumab monotherapy showing an 83% progressive disease rate compared to 36% with combination therapy, these findings suggest that immune checkpoint inhibitors alone might have limited efficacy in most sarcoma subtypes. However, there is considerable heterogeneity between the studies (I² = 93.3% for monotherapy and I² = 82.7% for combination therapy), reflecting significant differences in histologic subtypes, patient selection, treatment regimens, and tumor biology. The wide prediction interval (0.00–1.00) indicates uncertainty regarding the reproducibility of these results in future studies. Although this introduces variability, it reflects inherent differences across study populations or methodologies rather than undermining the overall consistency and reliability of the core findings. The SARC028 trial, evaluating pembrolizumab monotherapy in sarcomas, reported an ORR of 18% in soft tissue sarcomas, with responses primarily observed in undifferentiated pleomorphic sarcoma and liposarcoma [9]. This contrasts with Boye et al’s finding of 0% ORR in a cohort of 12 patients treated with pembrolizumab alone, highlighting the variability in treatment responses across different sarcoma subtypes and patient populations [7]. The limited efficacy of pembrolizumab monotherapy is further supported by the AcSé trial, which reported an ORR of only 6.2% across various rare sarcoma subtypes [18]. The significant variability in treatment outcomes across different histological subtypes underscores the importance of histology-specific approaches in sarcoma management. The current analysis revealed that leiomyosarcoma was the most common histological subtype, yet previous studies have shown this subtype to be relatively resistant to immune checkpoint inhibition. The SARC028 trial reported no responses in leiomyosarcoma patients treated with pembrolizumab monotherapy. In contrast, certain histological subtypes have demonstrated greater sensitivity to immunotherapy. For instance, undifferentiated pleomorphic sarcoma has shown a 40% ORR [9]. Similarly, alveolar soft part sarcoma has emerged as a particularly responsive subtype, with studies reporting response rates of up to 50% with PD-1 inhibition. These findings highlight the critical importance of histology-specific patient selection for immunotherapy trials in sarcoma [19]. The current meta-analysis demonstrated that combination approaches significantly improve treatment outcomes compared to pembrolizumab monotherapy, with combination therapy showing a 64% lower rate of progressive disease. This substantial improvement suggests that combining immune checkpoint inhibitors with other therapeutic modalities may overcome some of the inherent resistance mechanisms in sarcomas. The combination of pembrolizumab with doxorubicin showed an ORR of 19% [10]. This combination demonstrated manageable toxicity and promising activity. The synergistic effect may be attributed to chemotherapy-induced immunogenic cell death, which can enhance T-cell priming and activation, potentially converting "cold" tumors into "hot" immunogenic ones [20]. The combinations of pembrolizumab with axitinib and lenvatinib showed ORRs of 25% and 15.2%, respectively [11,12]. Wilky et al. reported that axitinib plus pembrolizumab demonstrated manageable toxicity and preliminary activity in advanced sarcomas, particularly in alveolar soft part sarcoma, with a 3-month progression-free survival rate of 65.6% [11]. Similarly, a trial of lenvatinib plus pembrolizumab showed promising activity in certain sarcoma subtypes, including undifferentiated pleomorphic sarcoma and liposarcoma, and malignant peripheral nerve sheath tumors [12]. The enhanced efficacy of these combinations may be attributed to the immunomodulatory effects of tyrosine kinase inhibitors, particularly those targeting VEGF pathways [11]. Novel combination approaches, such as pembrolizumab with talimogene laherparepvec, showed the highest ORR at 35%. Talimogene laherparepvec is an oncolytic virus that can induce immunogenic cell death and enhance systemic anti-tumor immunity, potentially synergizing with immune checkpoint inhibition [13]. In contrast, the combination of pembrolizumab with epacadostat showed an ORR of 3.3%. Epacadostat is an Indoleamine 2,3-dioxygenase 1 inhibitor that was initially thought to complement immune checkpoint inhibition by targeting a different immunosuppressive pathway. However, this combination has shown limited efficacy across multiple tumor types, suggesting that IDO1 inhibition may not be a viable strategy for enhancing immunotherapy responses in sarcomas [14]. The current analysis revealed significant differences in the toxicity profiles between pembrolizumab monotherapy and combination therapy. While combination therapy was associated with better tumor responses, it also resulted in a higher incidence of certain adverse events, particularly thrombocytopenia, hypothyroidism, and hepatobiliary abnormalities. This is consistent with previous studies showing that combining immune checkpoint inhibitors with other therapeutic agents often increases toxicity. A meta-analysis of 18 studies with 2,767 patients found that the risk of severe (grade 3 or higher) adverse events was more than double for combination therapy (risk ratio 2.21, 95% CI 1.57–3.10) [21]. The significant heterogeneity in treatment responses observed in the current analysis and previous studies underscores the need for a personalized approach to sarcoma management. For example, the recent UK guidelines for soft tissue sarcoma management emphasize that certain sarcoma subtypes, such as Ewing sarcoma and rhabdomyosarcoma, require distinct treatment approaches [22]. While the current analysis showed improved outcomes with combination therapy compared to pembrolizumab monotherapy, there is still significant room for improvement. Novel combination strategies targeting multiple aspects of tumor biology and the immune microenvironment may further enhance treatment outcomes [19]. Combinations of immune checkpoint inhibitors with radiation therapy have shown promise in preclinical studies and early clinical trials. Radiation can induce immunogenic cell death, increase neoantigen presentation, and enhance T-cell infiltration, potentially synergizing with immune checkpoint inhibition [19]. Despite initial responses, many patients eventually develop resistance to immunotherapy. Understanding the mechanisms of primary and acquired resistance is crucial for developing effective strategies to overcome resistance. Potential mechanisms include loss of tumor antigens, upregulation of alternative immune checkpoints, and recruitment of immunosuppressive cells to the tumor microenvironment [23]. Conclusion Pembrolizumab-based combination therapies have the potential to enhance treatment efficacy in sarcoma, although they may be associated with an increased risk of adverse events. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: RMA, SSO, SHA, SRH and MMA: major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. FHF, HMH, AMM, SOQ, YMM and ADA: Literature review, design of the study, critical revision of the manuscript, and processing of the tables. AGH, DOQ, and MMA: Literature review, processing of the figures, data analysis and interpretation. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Multiple Concurrent Pilonidal Sinuses: Case report and Literature review
Abstract Introduction: Concurrent pilonidal sinuses (PNSs) at distinct locations are extremely rare. This report highlights an exceptional case of a young female presenting with three PNSs in distinct locations. Case presentation: A 19-year-old female with a family history of PNS presented with a chronic, discharging sinus tract in the intermammary region that had persisted for two years. Physical examination revealed an erythematous lesion with intermittent purulent and bloody discharge, leading to a diagnosis of intermammary PNS (IMPNS). Surgical excision was performed, and histopathology confirmed the diagnosis. Six weeks postoperatively, the patient’s wound had completely healed; however, she mentioned symptoms in the umbilical and sacrococcyx regions that had been intermittent for the past year. Further evaluation led to diagnoses of natal cleft PNS (NCPNS) and umbilical PNS (UPNS). NCPNS was scheduled for surgical treatment, while UPNS was managed conservatively. Histopathology confirmed chronic sinus tract formation in both cases. Literatue review: Nine cases of PNS were reviewed, six of which were males. Two of them had recurrent discharging sinuses, and no family history of PNS was reported. Locations included gluteal, auricular, mammary, cheeks, and umbilical regions. Discharge was present in all of the cases, accompanied by pain in two. Sinus excision was performed for all the cases, accompanied by laser epilation in one. Healing modalities included secondary intention and various dressings. Conclusion: It is extremely rare for NCPNS, UPNS, and IMPNS to occur concurrently. Surgical management for NCPNS and IMPNS, combined with conservative treatment for UPNS, may lead to favorable outcomes. Introduction The term "pilonidal sinus" (PNS) was first introduced by Hodges in 1880. However, the condition was initially described by Anderson in 1847 as "hair extracted from an ulcer" [1]. PNS is an inflammatory disorder that occurs when hair penetrates the epidermis, leading to the formation of a blind tract lined with granulation tissue. The condition primarily affects males, with a male-to-female ratio of 4:1 [2]. It typically manifests in individuals in their late teens to early 20s and decreases in frequency after the age of 25. The risk factors for PNS are male gender, a deep natal cleft, hair in the natal cleft, a family history of the condition, jobs that require prolonged sitting, obesity, and excessive sweating. It is frequently observed in drivers, which is why it is also referred to as "Jeep disease." [2]. A large prospective case-control study found that individuals with hirsutism who sit for more than six hours a day and bathe less than twice a week have a 219-fold increased risk of developing sacrococcygeal PNS compared to those without these risk factors [3]. The incidence of PNS has significantly increased over the past 50 years for unknown reasons. It is estimated to affect 26 per 100,000 individuals [4]. PNS was initially considered a congenital condition. However, increasing reports of cases in various anatomical regions suggest it may be an acquired disorder. It most commonly develops in the sacrococcyx region, located near the base of the spine, where the skin is prone to hair accumulation and irritation. It is rarely found in the breast, intermammary region, umbilical region, endoanal area, preauricular region, neck, hand, face, penis, and clitoris [4]. The occurrence of concurrent PNSs in a single individual is an exceptionally rare condition. This report highlights a case of three concurrent PNSs located in three different cites. This report was written following the CaReL guidelines, and credible, peer reviewed sources were used, while unreliable sources were excluded [5,6]. Case presentation Patient information A 19-year-old female with a family history of PNS and a normal body weight presented with a chronic, discharging sinus tract in the intermammary region. The lesion had persisted for approximately two years before seeking medical consultation. Clinical findings On clinical examination, a small, erythematous lesion was initially observed, which had been painless at first but had progressed to form a single opening, accompanied by intermittent purulent and bloody discharge. The patient reported localized pruritus, and the surrounding skin demonstrated persistent erythema. Diagnostic approach The diagnosis of PNS in the intermammary region (IMPNS) was established through clinical evaluation, which included palpation of the cyst and tract, as well as assessment of drainage. Given the clear clinical presentation, no additional investigations were considered necessary. Therapeutic intervention The patient was scheduled for surgical excision of the sinus tract and associated abscess cavity under general anesthesia. An elliptical skin incision was made over the sinus tract to ensure complete excision while preserving surrounding healthy tissue. Sharp and blunt dissection was used to carefully remove the tract and abscess cavity down to the underlying fascia. Hemostasis was achieved using bipolar cautery. The wound was then thoroughly irrigated with povidone-iodine and normal saline. Considering the patient’s young age and cosmetic concerns, the wound was closed by primary intention using subcuticular absorbable sutures to minimize scarring and optimize the aesthetic outcome. Histopathological examination of the excised skin ellipse revealed focal surface ulceration. Within the underlying dermis, a sinus tract was identified, surrounded by a diffuse mixed inflammatory infiltrate, predominantly composed of plasma cells and neutrophils, along with granulation tissue formation. These histopathological findings, in correlation with the clinical presentation, confirmed the diagnosis of an IMPNS (Figure 1). <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-4062711711750669751257.png" alt="Figure 1. Histopathological examination of the intermammary pilonidal sinus shows fragments of a skin ellipse with focal surface ulceration. The underlying dermis contained a sinus tract surrounded by a dense mixed inflammatory infiltrate, predominantly composed of plasma cells and neutrophils. Granulation tissue formation was also noted around the tract." width="960" height="904" /> Follow-up Six weeks postoperatively, the patient returned for follow-up with complete wound healing and no symptoms in the intermammary region. However, she reported new-onset pain, itching, and discharge from the umbilical and sacrococcyx areas. She disclosed a one-year history of intermittent symptoms in these regions but had previously refrained from mentioning them due to embarrassment. On examination, she was diagnosed with natal cleft PNS (NCPNS) and umbilical PNS (UPNS). The management included the Lord’s procedure for NCPNS, which involves minimal excision of the sinus openings and deroofing of the sinus tracts without removing large amounts of tissue, while UPNS was treated conservatively with hair removal and daily povidone-iodine dressing. The decision was based on the absence of secondary openings and minimal inflammation (Figure 2). Histopathology revealed focal surface ulceration and a sinus tract within the dermis, surrounded by a mixed inflammatory infiltrate predominantly composed of lymphocytes, plasma cells, foamy macrophages, and granulation tissue. These findings confirmed a chronic inflammatory lesion with sinus tract formation, characteristic of NCPNS (Figure 3). <img id="image_2" src="https://www.judijournal.com/public/site/images/journaleditor/mceu-76478417621750669783868.jpg" alt="Figure 2. Three clinical images illustrating different postoperative and clinical examination findings. A) Displays a postoperative intermammary incision with sutures, mild erythema, and crusting along the incision line, indicative of early healing. B) Depicts palpation of the sacrococcygeal area with gloved hands, focusing on a marked region, possibly assessing localized tenderness, a cyst, or fluid collection. C) Shows palpation of the sacrococcygeal region, evaluating a suspected PNS with visible skin indentation, potentially indicating an underlying sinus tract." width="12072" height="4152" /> Discussion Typically, PNS is considered a surgical-dermatological disorder. It is a condition that contributes to the growing number of operations, particularly among young individuals. It is also part of the follicular occlusion tetrad, a group of hair follicle disorders that includes severe acne vulgaris, hidradenitis suppurativa, and dissecting cellulitis of the scalp. It affects approximately 0.07% of the general population and represents around 15% of all perianal diseases [4]. The exact cause of PNS remains uncertain, with two primary theories suggesting either an acquired or congenital origin. Generally, three factors are considered necessary for its development. The first is the presence of hair within the skin, the second is an area of wrinkled or folded skin, such as the natal cleft or a scar, and the third involves a combination of hormonal influences and hygiene-related factors [7]. The hallmark symptoms of PNS include swelling, discomfort, and discharge. Among nine cases that were reviewed, all patients exhibited discharge, while only two (22.2%) experienced pain (Table 1) [2-4,7-12]. The current patient experienced pain, itching, and discharge, which were among the common symptoms. Table 1. Baseline characteristics of pilonidal sinus cases. Author /year [reference] Age (Y) Sex Medical history Family history of PNS Location Symptoms Symptoms Duration (Y) Treatment Wound healing modality Outcome Follow-up (Y) Savant/2025 [9] 26 M Unremarkable N/A Umbilical region Discharge 0.5 Punch excision Secondary intention No recurrence 2 Dhalani et al./ 2025 [2] 35 M Recurrent PNS & polycythemia vera N/A Natal cleft Pain & discharge 0.16 Excision of sinus tract Secondary intention, Leech therapy & turmeric powder No recurrence 2 Anand et al./2022 [10] 10 M Unremarkable Unremarkable Left preauricular region Discharge 10 Excision of sinus tract Sterile dressing No recurrence N/A Salih et al./ 2022 [4] 27 M Unremarkable Unremarkable Posterior aspect of the auricle Discharge 13 Excision of sinus tract Kurdish gum No recurrence N/A Othman et al./2022 [8] 62 M Unremarkable Unremarkable Umbilical region Pain & discharge N/A Excision of sinus tract Not mentioned No recurrence N/A Mirande et al./2022 [3] 13 F Obesity Unremarkable Intermammary region Discharge 1 Wide local excision sinus tract Not mentioned No recurrence 0.2 Adhikari et al/ 2021[7] 37 M Recurrent discharging sinus N/A Bulge of the cheek Discharge 2 Wide excision of the sinuses Not mentioned No recurrence 1.5 Salih et al./2020 [11] 25 F Unremarkable N/A Bilateral Inframammary region Discharge and induration 2 Excision of sinus tract Not mentioned No recurrence 0.5 Deshpande et al./ 2020[12] 22 F Unremarkable Unremarkable Intermammary region Discharge 1 Excision of sinus tract & laser epilation Silicone dressing No recurrence 0.5 M: male, F: female, N/A: non-applicable, PNS: Pilonidal sinus, Y: Years Most cases of IMPNS present with induration in the intermammary region, an abscess, or a sinus opening with spontaneous discharge. Although the current patient was not obese, some studies suggest a higher incidence of IMPNS in obese individuals [1]. Mirande et al. reported a case of a young girl with a history of obesity (BMI: 33.13) who developed recurrent IMPNS, further supporting a possible link between obesity and this condition [3]. While obesity has not been explicitly identified as a risk factor in the literature, its potential contribution warrants further investigation. Although there is no standardized management strategy for IMPNS, definitive treatment, similar to NCPNS, typically involves excision and primary closure to achieve an optimal cosmetic outcome. Incomplete excision of all sinus tracts in IMPNS is associated with a high recurrence rate [1]. In the current case, the patient was successfully treated with sinus tract extraction, resulting in complete resolution. Umbilical discharge is uncommon in adults, especially in the absence of prior surgical history. The primary differential diagnoses include UPNS, urachal remnants, and omphalomesenteric duct remnants [8]. In the current case, the latter two were considered unlikely, as the patient did not exhibit typical signs such as urine leakage from the umbilicus, persistent moisture or irritation, or feculent discharge. The primary risk factors for UPNS are similar to other types of PNS, including male gender and hirsutism, particularly when hair growth directs loose hairs toward the umbilicus. Additional contributing factors include a deep navel and, to a lesser extent, obesity, neither of which was present in the current patient [9]. Hassan et al. stated that conservative treatment of UPNS can be effective, as demonstrated in the current patient, who was treated with hair removal and daily povidone-iodine dressing [13]. According to Savant, the recurrence rate of UPNS is minimal, and the procedure can be easily repeated if needed. Combining it with laser hair removal may further lower recurrence rates and help prevent new lesions [9]. Non-operative management plays a limited role in NCPNS, as surgical excision is typically required. Treatment options include excision with primary closure or excision with secondary healing, where the wound is left open to heal naturally [4]. Lord’s procedure was deemed appropriate as there were no signs of extensive inflammation or abscess formation, making it suitable for a tissue-sparing approach. Conclusion In conclusion, the simultaneous presentation of NCPNS, UPNS, and IMPNS is extremely rare. A surgical approach for NCPNS and IMPNS, combined with a conservative approach for UPNS, may lead to favorable outcomes. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the patient. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: ESS, SHH, and MMA: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. AAQ, IHQ, and KZH: Literature review, critical revision of the manuscript, and processing of the tables and figures. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Provocative Tests in Diagnosis of Thoracic Outlet Syndrome: A Narrative Review
Abstract Thoracic outlet syndrome (TOS) is a group of conditions caused by the compression of the neurovascular bundle within the thoracic outlet. It is classified into three main types based on the affected structure: neurogenic, arterial, and venous TOS. Diagnosis remains challenging due to symptom overlap with other conditions and a lack of universally accepted criteria. Provocative tests are integral to clinical evaluation, aiming to reproduce symptoms by stressing anatomical structures prone to compression. This review evaluates the commonly used provocative tests for TOS, analyzing their diagnostic performance, limitations, and clinical utility. Individual provocative tests vary widely in diagnostic performance. The Roos test demonstrates high sensitivity but poor specificity, while tests like the Cyriax Release and Wright’s hyperabduction offer better specificity at the cost of sensitivity. Most tests show significant overlap in symptom reproduction with other upper limb or cervical pathologies, contributing to high false-positive rates. Combining multiple tests improves diagnostic accuracy but still falls short of a definitive standard. While provocative tests are valuable for screening and clinical assessment of TOS, their standalone diagnostic reliability is limited. A multimodal approach integrating clinical examination, imaging, and electrodiagnostic studies is essential for improving diagnostic confidence and patient outcomes. Future research should aim to standardize testing protocols and validate findings through large-scale, population-based studies. Introduction Thoracic outlet syndrome (TOS) is a group of conditions characterized by the compression of the neurovascular bundle within the thoracic outlet [1]. Based on the affected structure, TOS is categorized into three primary types: neurogenic (nTOS), arterial (aTOS), and venous (vTOS) [2]. The most common subtype is nTOS, representing more than 90% of cases, and is more frequently observed in females [1]. vTOS makes up 3–5% of cases, while aTOS is the least common, accounting for just 1% [3]. The overall incidence of TOS in the general population is estimated at 2.5 to 4 cases per 100,000 individuals per year [3]. Patients with aTOS and vTOS typically display noticeable signs of vascular issues in the upper limbs, such as venous thrombosis, swelling, or arterial emboli affecting the fingers. On the other hand, diagnosing nTOS mainly depends on the patient's clinical history and reported symptoms [4]. These subgroups can be linked to congenital, traumatic, or functionally acquired causes. Congenital etiologies may involve the presence of a cervical rib or an anomalous first rib. Traumatic causes are most commonly associated with whiplash injuries and falls. Functional acquired causes are often related to intense, repetitive activities linked to sports or work [5]. Diagnosing TOS is challenging because its broad spectrum of symptoms often mimics other conditions such as cervical radiculopathy, carpal tunnel syndrome, or rotator cuff disorders, resulting in frequent misdiagnoses. The absence of a universally accepted diagnostic standard adds to its complexity, leading to a heavy reliance on clinical evaluations and inconsistent use of diagnostic tests [6, 7]. Specifically, diagnosing nTOS is difficult due to the wide range of conditions that can cause shoulder and arm pain, weakness, and neuropathy. These conditions include various musculoskeletal and neurological disorders, which may either serve as primary causes or contribute as additional factors to the patient's symptoms [8]. Provocative tests are essential in diagnosing TOS by reproducing symptoms linked to nerve or vascular compression. These tests intentionally stress the thoracic outlet structures to elicit symptoms. Each test targets specific mechanisms of compression, whether neurogenic or vascular compression [9]. This study reviews the provocative tests used in the diagnosis of TOS, with all references evaluated for relevance and eligibility [10]. Provocative tests in diagnosing TOS Adson’s Test Adson's test, also known as Adson's maneuver, is a diagnostic tool primarily used to assess aTOS. During the test, the patient extends their neck, turns their head toward the affected side, and holds their breath. If this position causes a reduction in the radial pulse or reproduces symptoms, it suggests vascular compromise due to muscular compression. The maneuver is named after Alfred Adson, a neurosurgeon at the Mayo Clinic in the early 20th century [11]. Since its initial description, multiple researchers have challenged Adson’s test. In 1945, Wright observed that pulse obliteration could occur when turning the head to either the ipsilateral or contralateral side [12]. In 1965, Woods reported that among TOS patients, Adson's test was positive more frequently when the head was turned to the contralateral side (63%) compared to the ipsilateral side (22%) [13]. A review of various studies on nTOS patients who underwent Adson's test found that the rate of positive responses varied between 22% and 100%, with a median of 31% [14]. In 2001, Gillard et al. reported that Adson’s test was among the better-performing tests commonly studied for TOS, with a positive predictive value of 85%, a sensitivity of 79%, and a specificity of 76% [15]. In an asymptomatic population, Rayan (1998) found that Adson’s test had a false positive rate of 13.5% for diminished or absent pulse but only 2% for neurological symptoms [16]. Similarly, in 1998, Plewa and Delinger reported a similar false positive rate of 11% for pulse loss, a higher rate of 11% for paresthesia, and a notably low rate of 2% for pain reproduction [17]. Although Adson's test is useful, it has notable limitations. A primary concern is its reliance on vascular signs to diagnose nTOS, which can lead to misinterpretation. Many individuals with nTOS may not exhibit vascular compromise, resulting in false negatives [14]. Anatomical variations, such as cases where the brachial plexus roots pass through the anterior scalene muscle, can produce negative results even when TOS symptoms are present [18]. The variability in results across different populations also raises concerns about the test's reliability, with some studies suggesting that a considerable number of healthy individuals may also test positive on provocative tests like Adson’s [19]. Therefore, while Adson's test can offer valuable insights when used alongside a thorough clinical evaluation, it should not be relied upon as the sole diagnostic tool for TOS. Roos Test In 1963, Gilroy and Meyer modified Adson's test by introducing the 90-degree abduction and external rotation maneuver, a provocative test later popularized by David B. Roos in 1966 [20, 21]. The Roos test, or elevated arm stress test, is a key diagnostic tool for nTOS, designed to provoke symptoms by dynamically compressing the thoracic outlet. The patient holds their arms in 90 degrees of abduction and external rotation while continuously opening and closing their hands for three minutes. A positive result is characterized by symptom reproduction, such as neck-to-arm radiating pain, finger paresthesia, or vascular manifestations like pallor or cyanosis [21, 22]. The Roos test has an estimated sensitivity of about 84%, making it effective in detecting individuals with TOS by eliciting symptoms in most cases. However, its specificity is considerably lower, around 30%, meaning that it produces a high number of false positives. As a result, individuals without TOS may still exhibit symptoms during the test due to factors such as muscle fatigue or other conditions like carpal tunnel syndrome [15, 23]. Research has used transcutaneous oxygen pressure measurements to investigate microvascular responses during the Roos test. A transcutaneous oxygen pressure reduction of more than 15 mmHg during the test has been linked to arterial compression, demonstrating 67% sensitivity and 78% specificity compared to ultrasound findings [22]. These findings emphasize that while the Roos test is valuable for screening due to its high sensitivity, its low specificity limits its ability to confirm TOS definitively. Therefore, it should be combined with other diagnostic methods and clinical evaluations for a more accurate diagnosis, such as electrodiagnostic studies and vascular imaging. Wright’s Hyperabduction Test In 1945, Dr. Irving S. Wright introduced the hyperabduction test to reproduce the arterial and neurological symptoms of TOS [12]. The test is conducted with the patient in a seated position. The examiner first palpates the radial pulse before passively abducting (90 degrees) and externally rotating the arm to ensure the elbow remains flexed at no more than 45 degrees. The arm is held in this position for one minute while monitoring the radial pulse and assessing the onset of symptoms. The procedure is then repeated with the arm placed in full hyperabduction (end-range abduction). A positive test is indicated by a diminished radial pulse and/or symptom reproduction, suggesting possible compression within the retropectoralis minor space [24]. The study by Gillard et al. (2001) remains a cornerstone for understanding the diagnostic performance of Wright’s hyperabduction test. The test was evaluated for its diagnostic utility in detecting TOS among 48 patients (31 diagnosed with TOS and 17 without). Their findings revealed critical variations in sensitivity and specificity depending on interpretation criteria. When pulse abolition alone was used as a positive indicator, the test demonstrated moderate sensitivity (52%) but high specificity (90%), with a positive predictive value of 92% and a negative predictive value of 47%. These metrics underscore its utility in confirming arterial compression, particularly when corroborated by imaging evidence of subclavian artery stenosis. Conversely, when symptom reproduction (e.g., paresthesia, weakness) served as the diagnostic criterion, sensitivity improved to 84%, but specificity plummeted to 40%, reflecting the test’s susceptibility to false positives in nTOS due to overlapping symptoms with conditions like cervical radiculopathy or peripheral neuropathy. The authors emphasized that combining Wright’s test with other provocative maneuvers, such as Adson’s and Roos's tests, significantly enhanced specificity to 92%, though sensitivity remained suboptimal for neurogenic cases [15]. This test evaluates positional subclavian artery compression, focusing on the artery rather than the brachial plexus. Consequently, it is only indirectly related to nTOS. Additionally, the test often yields positive results in healthy, asymptomatic individuals, making it nonspecific [25]. Elvey Test (Upper Limb Tension Test) Australian physiotherapist Robert Elvey introduced the Upper Limb Tension Test (ULTT) in 1986 as a diagnostic tool to assess brachial plexus tension [26]. The test involves the patient sequentially abducting the arm to 90 degrees with a straight elbow, extending the wrist, and tilting the head to the opposite side. Each step incrementally stretches the brachial plexus. The test results are categorized as negative, mild positive (symptoms without distress), or strong positive (severe distress or inability to perform). This method is designed to evaluate the brachial plexus by inducing nerve elongation [25]. The ULTT is commonly incorporated into a comprehensive clinical evaluation for TOS. While specific studies detailing its sensitivity and specificity for TOS are limited, the ULTT is considered a valuable screening tool. A negative ULTT can effectively rule out brachial plexus compression, whereas a positive result suggests the need for further assessment. Clinicians often combine the ULTT with other provocative tests, such as the Elevated Arm Stress Test and Adson's test, to enhance diagnostic accuracy. Utilizing multiple tests in conjunction has been shown to improve specificity, aiding in the accurate diagnosis of TOS [9]. Eden’s Test (Military Brace Test or The Costoclavicular Maneuver) The costoclavicular space lies between the clavicle and the first rib, and it contains the subclavian artery, subclavian vein, and the brachial plexus. A reduction in this space, caused by congenital anomalies such as a cervical rib, poor posture, or muscle hypertrophy, can compress these structures, leading to vascular insufficiency or neurogenic symptoms. The costoclavicular maneuver (CCM), also known as the Military Brace Test or Eden’s Test, deliberately decreases this space by approximating the clavicle and first rib, replicating positions that intensify compression [27]. During this test, the patient is instructed to push the chest forward and retract the shoulders, mimicking a military posture, while the therapist assesses the strength of the radial pulse. Expanding the chest moves the first rib forward, while retracting the shoulder girdle pulls the clavicle backward, reducing the space between them. A weakened radial pulse indicates a positive test, suggesting compression of the subclavian artery within the costoclavicular space. Given this arterial compression, it is likely that the brachial plexus is also affected [25]. If the patient reports sensory symptoms such as pain, tingling, or numbness in the upper extremity during the test, these are also considered a positive finding, indicating direct compression of the brachial plexus within the costoclavicular space [27]. Despite the widespread use of CCM, comprehensive studies evaluating its diagnostic accuracy are limited. In a blinded assessment involving 93 patients diagnosed with TOS, the CCM demonstrated a sensitivity of 67.74%. Specificity was not explicitly reported; however, the study emphasized that combining multiple tests could achieve sensitivities exceeding 90% [28]. Overall, while the CCM is a well-established provocative test for TOS, its diagnostic accuracy is limited when used in isolation. Combining multiple clinical tests may improve sensitivity and specificity; however, clinicians should be mindful of the risk of false positives and interpret results within the broader clinical context. Cyriax Release Test The Cyriax Release Test is a methodical procedure designed to detect nTOS. It is based on the differential diagnosis and selective tissue tension testing techniques developed by Dr. James Cyriax [29]. To perform the test, the patient sits while the examiner stands behind, holding the patient's forearms just below the elbows with elbows bent at 80–90 degrees. The examiner then leans the patient's upper body backward by approximately 15 degrees to reduce tension in the shoulder blades and passively lifts the shoulder girdle. This position is maintained for up to three minutes. A positive result is indicated if the patient experiences typical symptoms, such as tingling or pain, during or immediately after the procedure [30]. A study conducted by Brismée et al. (2004) evaluated the specificity of the Cyriax Release Test in an asymptomatic population. They found that specificity was highest at one minute (97.4%) and decreased over time, reaching 77.4% at 15 minutes. This indicates that shorter test durations may reduce the likelihood of false-positive results [30]. Another study by Hixson et al. (2017) highlighted that while the Cyriax Release Test, along with other clinical diagnostic tests, can provoke symptoms in patients with upper extremity pathology, these tests do not exclusively differentiate TOS from other conditions such as cervical radiculopathy, carpal tunnel syndrome, or rotator cuff pathology. Therefore, while the test has high specificity, especially within the first few minutes, it should be used with other diagnostic procedures to accurately identify TOS [31]. Scalenus Tenderness (Supraclavicular Pressure Test) The Supraclavicular Pressure Test (SPT) focuses on the interscalene triangle area by exerting manual pressure on the supraclavicular fossa, compressing the anterior scalene muscle and the nearby brachial plexus. In this test, the patient sits with their arms relaxed while the examiner places their thumb on the anterior scalene muscle near the first rib, applying steady pressure for 30 seconds. A positive result is indicated by the onset of pain or tingling sensations in the same-side upper extremity (Table 1), which suggests neurogenic compression at the scalene triangle [32]. The sensitivity of the SPT has been reported inconsistently across studies due to variations in diagnostic criteria and testing methods. A systematic review that examined data from various provocative maneuvers, including the SPT, found a combined sensitivity of 72% for detecting nTOS [33]. However, this percentage reflects the performance of several maneuvers rather than the SPT alone. Notably, the individual sensitivity of the SPT remains largely unquantified in large-scale studies, as most research evaluates clusters of tests to enhance diagnostic accuracy [31]. In their prospective study, Plewa and Delinger found that the SPT induced symptoms in 21% of healthy participants during controlled testing, indicating a high false-positive rate and raising concerns about its standalone sensitivity. Based on a 10% false-positive rate in asymptomatic individuals, they determined the SPT’s specificity to be 90% [17]. The European Association of Neurosurgical Societies emphasizes that a diagnosis of nTOS requires at least three positive provocative tests, including the SPT. This strategy helps reduce the risk of overdiagnosis, especially considering the SPT’s high false-positive rate in asymptomatic individuals [33]. Table 1. Clinical Summary of Provocative Tests for Thoracic Outlet Syndrome Tests Types of TOS Procedures Duration Results Adson’s Test nTOS, aTOS Extend neck, turn head toward either side, and hold breath. ~1 minute A positive test is indicated by a diminished radial pulse and/or symptom reproduction. Roos Test nTOS Holds arms in 90 degrees of abduction and external rotation while continuously opening and closing hands for three minutes. 3 minutes A positive result is characterized by symptom reproduction. Wright’s Test nTOS, aTOS Abducting (90-degree) and externally rotating the arm for one minute while monitoring the radial pulse and assessing symptom onset. ~1 minute A positive test is indicated by a diminished radial pulse and/or symptom reproduction. Elvey Test nTOS Abducting the arm to 90 degrees with a straight elbow, dorsiflexing the wrist, and tilting the head to the opposite side. ~1 minute A positive result is characterized by symptom reproduction. Eden’s Test aTOS, nTOS Pushing the chest forward and retracting the shoulders. ~30 seconds A positive test is indicated by a diminished radial pulse. Cyriax Release Test nTOS The patient sits while the examiner stands behind, holding the patient's forearms just below the elbows with elbows bent at 80–90 degrees. The examiner passively lifts the shoulder girdle. Up to 3 minutes A positive result is indicated if the patient experiences typical symptoms. Scalenus tenderness nTOS Exerting manual pressure on the supraclavicular fossa, compressing the anterior scalene muscle and the brachial plexus. Immediate A positive result is indicated by the onset of pain or tingling sensations in the same-sided upper extremity. TOS: thoracic outlet syndrome, nTOS: neurogenic thoracic outlet syndrome, aTOS: arterial thoracic outlet syndrome Future perspectives Advancing the diagnosis of TOS requires a shift toward more standardized, objective, and reproducible assessment methods. While provocative tests remain a cornerstone in clinical evaluation, their variability in sensitivity and specificity underscores the need for improved diagnostic accuracy. Future research should focus on refining these tests through large-scale, multicenter studies that validate their sensitivity and specificity across diverse patient populations. Emerging imaging modalities, such as dynamic ultrasound and functional MRI, hold promise in providing real-time visualization of neurovascular compression, potentially reducing reliance on subjective clinical tests. Ultimately, the future of TOS diagnosis and treatment lies in a multidisciplinary approach that combines clinical expertise with technological advancements. Establishing universally accepted diagnostic criteria and evidence-based treatment guidelines will be essential in improving patient care and reducing misdiagnosis. Conclusion TOS remains a complex and often misdiagnosed condition. While provocative tests play a crucial role in reproducing symptoms associated with neurovascular compression, no single test can definitively confirm TOS. Instead, clinical evaluation, imaging, and electrophysiological studies are essential for enhancing diagnostic accuracy. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: FHK, SKA, BAA, and HAN: major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. AKG, HSN, NSS, YNA, ASH, CSO, SOA, AHA, ADS, LJM and OMH: Equal contribution to Literature review, design of the study, critical revision of the manuscript, and processing of the table. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Thyroid Hemiagenesis: A Single-Center Case Series
Abstract Introduction: Thyroid hemiagenesis (TH) is a rare congenital anomaly characterized by the complete absence of one thyroid lobe, with or without absence of the isthmus. Its etiology remains unclear, and epidemiological data are limited. Although TH is often asymptomatic and discovered incidentally, it may pose clinical challenges when accompanied by thyroid dysfunction or structural abnormalities. This study reviews a single-center experience in diagnosing this condition and highlights its clinical significance.. Methods: This single-center case series was conducted from July 2021–July 2024, analyzing TH cases confirmed via ultrasonography. Eligible patients had complete medical records, including demographics, clinical presentation, radiological findings, and thyroid function status. Data were retrieved from electronic records and analyzed using SPSS 27.0, employing descriptive statistics to summarize means, ranges, frequencies, and percentages, ensuring a comprehensive assessment of TH’s clinical and epidemiological characteristics.. Results: This study analyzed 11 patients with TH (mean age: 28.12 ± 18.14 years; range: <1–55 years), seven of whom were females (63.6%). The diagnosis was incidental in six cases (54.5%), while three (27.3%) presented with neck swelling and two (18.2%) with neck pain. Thyroid function was euthyroid in seven (63.6%), hyperthyroid in two (18.2%), and hypothyroid in two (18.2%). Ultrasound examination confirmed left lobe and isthmus agenesis in eight cases (72.7%). Follow-up ranged from 4 to 48 months. Conclusion: This study confirms the female predominance of TH, with left-lobe absence being the most common. Congenital anomalies suggest embryological links. While thyroid function is typically preserved, those with hypo- and hyperthyroidism highlight the need for individualized endocrine assessment and monitoring. Introduction Thyroid hemiagenesis (TH), first described in 1852, is characterized by the absence of one thyroid lobe, with or without the isthmus. It is typically detected incidentally during neck imaging, as most affected individuals remain asymptomatic and undiagnosed. However, epidemiological studies suggest a higher occurrence in regions endemic for hypothyroidism, potentially indicating an underlying environmental or genetic predisposition [1]. Epidemiological analyses reveal distinct anatomical patterns in TH. Approximately 80% of documented cases involve agenesis of the left thyroid lobe, establishing a left-to-right prevalence ratio of 4:1. When the left lobe is absent, the isthmus is missing in nearly half of cases [2]. In contrast, right lobe agenesis is more frequently associated with complete isthmus absence. Additionally, a well-documented female predominance exists, though the mechanisms contributing to this gender disparity remain unclear [3]. The pathogenesis of TH likely results from disruptions in key developmental processes, including defective migration, differentiation, or proliferation of thyroid precursor cells. Normal thyroid development begins in the fourth gestational week as an endodermal outpouching from the pharyngeal floor, which elongates into a bilobed structure and descends to its final position in the neck [3]. Any disturbance in this sequence can lead to congenital thyroid anomalies, with TH being one of the rarer manifestations. TH remains underreported due to its typically asymptomatic nature compared to more commonly recognized thyroid malformations, such as thyroglossal duct cysts or ectopic thyroid tissue. This underscores the need for systematic studies to assess its true prevalence and clinical significance [4]. The precise molecular mechanisms underlying TH remain to be understood completely, though evidence suggests a multifactorial etiology involving genetic and environmental influences. Genetic analyses of thyroid dysgenesis have identified key regulatory genes, FOXE1, PAX8, NKX2-1, NKX2-5, and TSHR, which play crucial roles in thyroid organogenesis [3]. While TH is primarily considered a sporadic anomaly, familial clustering, in some cases, suggests the possibility of heritable genetic influences. However, establishing definitive genotype-phenotype correlations remains challenging, as many cases occur in isolation without clear inheritance patterns. The interplay between genetic susceptibility and developmental signaling pathways continues to be an area of ongoing research [5]. Although numerous case reports exist, large-scale case series on TH remain scarce. The rarity of the condition, coupled with its typically benign and asymptomatic presentation, has contributed to a gap in comprehensive epidemiological and developmental studies. This study aims to review a single-center experience in diagnosing and managing TH cases. Additionally, all referenced sources have undergone verification [6]. Methods Study design and Setting This study was conducted as a single-center case series at the Thyroid Clinic of Smart Health Tower. The study period extended from July 2021 to July 2024, during which all eligible patients diagnosed with TH were identified and analyzed. The clinic serves as a specialized referral center for thyroid disorders, ensuring comprehensive diagnostic evaluation and follow-up of affected individuals. Participant Selection and Eligibility Criteria The study included all patients with a confirmed diagnosis of TH based on ultrasonographic imaging. Patients were eligible for inclusion if they had complete medical records detailing their demographic characteristics, clinical presentation, and radiological findings. Cases with incomplete data, particularly those lacking essential imaging reports or follow-up details, were excluded to ensure consistency and reliability in the analysis. Data Collection and Variables Assessed Patient data were systematically retrieved from the hospital’s electronic medical records, radiology reports, and clinicaldocumentation. The collected variables included demographic characteristics such as age, sex, residency, and clinical presentation, including symptoms at diagnosis and the presence of thyroid dysfunction or associated comorbidities. Medical and surgical history, including prior thyroid conditions and interventions, was also documented. Radiological findings focused on the laterality of TH, the size of the contralateral lobe, and any evidence of compensatory hypertrophy. Additionally, laboratory investigations, including thyroid function tests (thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) levels), were analyzed to assess thyroid function status. Follow-up data were reviewed to evaluate disease progression, changes in thyroid function, and any medical or surgical interventions undertaken. Data Processing and Statistical Analysis All collected data were documented and organized using Microsoft Excel 2021. Statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) version 27.0. Descriptive statistical methods were employed to summarize the findings, with continuous variables presented as mean and range, while categorical variables were expressed as frequencies and percentages. Results This study included 11 patients diagnosed with TH, with a mean age of 28.12 ± 18.14 years (range: <1 to 55 years). The cohort comprised seven females (63.6%) and four males (36.4%). Clinically, six patients (54.5%) were diagnosed incidentally, three (27.3%) presented with neck swelling, and two (18.2%) reported neck pain. Regarding associated congenital conditions, eight patients (72.7%) had no additional anomalies. Among the remaining three, one had a thyroglossal duct cyst, one had a history of prolonged neonatal jaundice, and another presented with both prolonged neonatal jaundice and a periumbilical hernia. Thyroid function assessment revealed that the majority (7 cases ,63.6%) of patients were euthyroid (0.35-4.5µIU/mL), while two patients exhibited hyperthyroidism (<0.35 µIU/mL), and two of them had hypothyroidism (>4.5 µIU/mL). Ultrasound findings demonstrated left lobe and isthmus agenesis in eight cases (72.7%), while two cases (18.2%) exhibited isolated left lobe agenesis, and one patient exhibited isolated right lobe agenesis (9.1%) (Figures 1 and 2). The largest documented normal lobe measured 100 × 43 × 35 mm, whereas the smallest measured 15 × 6.9 × 7.9 mm. The follow-up period ranged from 4 to 48 months (Tables 1-3). <img id="image_1" src="https://www.judijournal.com/public/site/images/journaleditor/figure-1-473d8970931c044f877f209b2abe6fda.jpg" alt="Figure 1. Ultrasound findings of the thyroid gland demonstrate a right lobe of normal size (53 × 16 × 14 mm) with homogeneous parenchymal echotexture and no evidence of focal lesions. Notably, there is agenesis of the isthmus and absence of the left thyroid lobe (indicated by white arrow), consistent with thyroid hemiagenesis." width="1122" height="874" /> <img id="image_2" src="https://www.judijournal.com/public/site/images/journaleditor/figure-2-b2a5b6116f3465e363aa67c91c488b29.jpg" alt="Figure 2. Ultrasound findings of the thyroid gland reveal a mildly enlarged left lobe measuring 57 × 20 × 19 mm, exhibiting heterogeneous parenchymal echogenicity. Multiple solid isoechoic nodules are present, the largest measuring 20 × 16 × 14 mm and classified as TIRADS 3. The right lobe and isthmus are absent (indicated by white arrow), consistent with right thyroid hemiagenesis." width="1134" height="663" /> Table 1. Demographic, clinical, and surgical characteristics of patients. Cases Age (Y) Gender History Clinical Thyroid Examinations Presentation Duration (W) Other Congenital Conditions PMH PSH Drug Hx Case 1 20 M Neck Swelling 4 None Hyperthyroidism Negative Methimazole G2 Case 2 21 F Neck Pain 3 None Negative Lymph Node Biopsy None G2 Case 3 16 F Incidental 8 Jaundice, Periumbilical Hernia Iron Deficiency Anaemia Hernia Surgery None G0 Case 4 <1 M Incidental N/A Jaundice Hypothyroidism Negative Thyroxine G1 Case 5 31 M Incidental N/A None Negative Negative None G0 Case 6 55 F Neck Pain 8 None Negative Bilateral Total Knee Replacement None G0 Case 7 26 F Neck Swelling 1 None Negative Tonsillectomy None G2 Case 8 6 F Neck Swelling 1 Thyroglossal Duct Cyst Negative Tonsillectomy None G2 Case 9 55 F Incidental N/A None Negative C-section None G0 Case 10 53 F Incidental 1 None Negative C-section None G0 Case 11 27 M Incidental 3 None Negative Negative None G0 M: Male, F: Female, PMH: Past Medical History, PSH: Past Surgical History, Drug Hx: Drug History, G: grades of thyroid enlargement, Y: Years, W: Weeks. Table 2. Laboratory, imaging, and follow-up profiles of included cases. Cases Blood Investigations Ultrasound Reports Follow up (Months) First TSH (µIU/mL) First Free T4 (pmol/L) First Total T4 (nmol/mL) ATPO (IU/mL) First TRAB (IU/mL) Agenesis Side Normal Lobe Size (mm) Case 1 0.005 55.53 N/A N/A 12.55 Left Lobe, Isthmus 70 × 26 × 24 48 Case 2 2.45 19.9 N/A 9 N/A Left Lobe, Isthmus 56 × 19 × 19 12 Case 3 1.8 N/A 165.6 N/A N/A Left Lobe, Isthmus 53 × 16 × 14 12 Case 4 100 2.34 N/A N/A N/A Left Lobe 15 × 6.9 × 7.9 8 Case 5 2.61 18.00 N/A 68.3 N/A Left Lobe, Isthmus 100 × 43 × 35 12 Case 6 1.83 15.86 N/A 109.2 N/A Left Lobe, Isthmus 64 × 31 × 27 4 Case 7 1.27 16.3 N/A 80.9 N/A Left Lobe, Isthmus 55 × 19 × 19 6 Case 8 1.33 21.71 N/A N/A N/A Left Lobe, Isthmus 34 × 10 × 13 36 Case 9 2.27 17.02 N/A 11.45 N/A Left Lobe 48 × 16 × 15 48 Case 10 5.66 9.75 N/A 17.6 N/A Left Lobe, Isthmus 48 × 18 × 20 4 Case 11 0.005 41.6 9.75 N/A 0.8 Right Lobe 58 × 26 × 25 24 TSH: Thyroid-Stimulating Hormone, T4: Thyroxine, ATPO: Anti-Thyroid Peroxidase Antibodies, TRAB: Thyrotropin Receptor Antibodies, N/A: Not Applicable Table 3. Summary of clinical and demographic findings. Variables Frequency (percentage) Gender Male Female 4 (36.4%) 7 (63.6%) Age, Years (Mean ± SD) 28.12 ± 18.14 Clinical presentations Incidental Neck Pain Neck Swelling 6 (54.5%) 2 (18.2%) 3 (27.3%) Past medical history Iron Deficiency Anemia Negative 1 (9.1%) 10 (90.9%) Clinical thyroid examination G0 G1 G2 6 (54.5%) 1 (9.1%) 4 (36.4%) Thyroid function status Euthyroid Hyperthyroidism Hypothyroidism 7 (63.6%) 2 (18.2%) 2 (18.2%) Agenesis Side Right Left 1 (9.1%) 10 (90.9%) Discussion The clinical presentation of TH is predominantly asymptomatic, with most cases identified incidentally during imaging studies performed for unrelated thyroid conditions or neck abnormalities. When symptomatic, manifestations typically arise from concurrent thyroid disorders rather than the hemiagenesis itself. These may include neck swelling due to compensatory hypertrophy of the remaining lobe, thyroid dysfunction, or palpable nodules. The prevalence of thyroid abnormalities in individuals with TH appears to increase with age, likely due to chronic overstimulation of the remaining lobe by TSH, a factor contributing to the ongoing debate regarding the benign nature of the condition [7]. In a study in which 40 patients newly diagnosed with TH, aged between 12 and 79, were enrolled, it was found that 90% of their cohort were clinically asymptomatic regarding hemiagenesis itself, with associated conditions including euthyroid nodular goiters, multinodular goiters, Graves’ disease, and Hashimoto’s thyroiditis [8]. Another study emphasized that even symptomatic cases typically arise from coexisting thyroid pathologies rather than the anatomical defect itself [3]. Rare presentations such as hypothyroidism with prolonged neonatal jaundice and umbilical hernia have been documented in pediatric cases [3]. In the present study, 54.5% of patients were diagnosed incidentally, a lower rate than previously reported in the literature. A notable proportion exhibited clinical symptoms, with neck swelling in 27.3% and neck pain in 18.2% of cases, suggesting potential variations in clinical presentation, particularly among younger populations. Furthermore, congenital anomalies, including thyroglossal duct cyst, prolonged neonatal jaundice, and periumbilical hernia, were observed in 27.3% of cases, findings not prominently reported in earlier studies. These variations highlight the need for further investigation into potential demographic and pathophysiological factors influencing the clinical spectrum of TH. The diagnosis of TH is mainly based on imaging modalities, with ultrasonography as the first-line investigation and thyroid scintigraphy as a complementary confirmatory tool. Ultrasound imaging is particularly valuable as the initial screening method due to its wide availability, lack of radiation exposure, and sensitivity in detecting the absence of a thyroid lobe and any structural changes in the remaining thyroid tissue [3]. Thyroid scintigraphy using technetium or iodine provides functional anatomical assessment with the advantage of detecting ectopic thyroid tissue and diagnosing concurrent thyroid pathologies in the remaining lobe. Combining these two imaging modalities remains essential for accurate diagnosis and differentiation from other conditions that might mimic hemiagenesis [3]. A large cohort case-control study by Ruchala et al. emphasizes the need for both ultrasonography and scintigraphy to distinguish true hemiagenesis from pseudoagenesis, which can occur in cases of severe atrophy or destruction of thyroid tissue [8]. In a study focused on pediatric cases with suspected thyroid dysgenesis, researchers utilized both thyroid scanning and ultrasonography to establish definitive diagnoses, with hemiagenesis identified in one of their subjects [9]. Another case report of a rare male pediatric patient with TH demonstrated how ultrasonography revealed the absence of the left lobe while the right lobe showed minimal hyperplasia without nodules; scintigraphy confirmed these findings and ruled out ectopic thyroid tissue. This case emphasized that when only one thyroid lobe is detected initially, physicians should consider TH and employ both imaging modalities before invasive procedures [10]. A retrospective evaluation of imaging for congenital hypothyroidism revealed that compared to 99mTc-pertechnetate scanning, ultrasound examination demonstrated 100% specificity but only 44% sensitivity for detecting thyroid abnormalities. This finding highlights the value of scintigraphy as a complementary method to ultrasound examination, particularly when ectopic thyroid tissue is suspected. The limitations of relying solely on ultrasonography were further illustrated in cases where thyroid agenesis was diagnosed with ultrasonography, but follow-up scintigraphy revealed sublingual thyroid tissue in a significant proportion of patients [11]. In the current study, ultrasonography was the primary diagnostic tool, revealing left lobe and isthmus agenesis in eight (72.7%) cases, while two cases (18.2%) exhibited isolated left lobe agenesis with preservation of the isthmus, and one case showed isolated right lobe agenesis with preserved isthmus (9.1%). The ultrasound findings documented normal lobe dimensions ranging from the smallest at 15 × 6.9 × 7.9 mm to the largest at 100 × 43 × 35 mm, providing valuable reference values for assessing potential compensatory hypertrophy. Typically, TH is associated with normal thyroid function, as the remaining lobe compensates for the absent tissue. Most patients remain euthyroid, though biochemical patterns may reveal elevated TSH levels despite normal peripheral hormone concentrations, suggesting mild subclinical hypothyroidism or compensatory stimulation of the intact lobe. Functional thyroid disorders such as hyperthyroidism or hypothyroidism may coexist, often linked to concurrent pathologies like autoimmune thyroiditis or nodular goiter [3,12]. Recent studies highlight these trends. Ruchała et al. noted that while TSH and free T3 levels were elevated in TH patients compared to controls, most maintained euthyroidism [8]. Maiorana et al. documented subclinical hypothyroidism in pediatric cases [13]. Genetic factors, including potential PAX8 or FOXE1 gene involvement, may influence thyroid development but do not directly correlate with hormonal status [14]. Management focuses on addressing associated thyroid disorders rather than the anatomical defect itself. For asymptomatic patients, periodic monitoring with ultrasonography and thyroid function tests suffices [3,12]. Surgical intervention is indicated for malignancies or symptomatic nodules in the remaining lobe, necessitating lifelong thyroxine supplementation post-resection [14]. The current study aligns with these findings since 63.6% of patients were euthyroid, and only two cases of hyperthyroidism and two of hypothyroidism were identified, each requiring specific targeted therapy. While compensatory hypertrophy was observed, no evidence of progressive dysfunction emerged during follow-up, reinforcing the conservative approach for uncomplicated TH [3]. The follow-up and outcome of TH primarily focus on monitoring for potential thyroid pathologies and ensuring optimal thyroid function. Since TH itself is generally asymptomatic, the clinical significance lies in its association with other thyroid disorders. Therefore, regular follow-ups with thyroid function tests and ultrasonography are crucial to detect emerging thyroid conditions early. Recent studies emphasize the importance of long-term monitoring. For instance, a study by Peteiro-Gonzalez et al. highlighted that patients with TH are more prone to autoimmune thyroid disease and nodular goiter due to sustained compensatory stimulation of the remaining lobe, necessitating regular surveillance to manage these conditions effectively [12]. Another study suggested that patients with TH might benefit from thyroxine therapy to normalize TSH levels and potentially prevent associated thyroid pathologies. However, further research is needed to confirm this approach. In cases where TH coexists with malignancies like medullary thyroid cancer, follow-up involves regular biochemical monitoring (calcitonin and carcinoembryonic antigen levels) and ultrasonography to detect recurrence early [15]. The current study's follow-up period ranged from 4 to 48 months, with no significant thyroid dysfunction or complications reported during this time. The study's findings align with previous literature in emphasizing the need for ongoing surveillance to manage potential thyroid-related issues in patients with TH. Despite the absence of severe complications during the study period, the importance of continued monitoring cannot be overstated, given the potential for future development of thyroid pathologies in these patients. One of the primary limitations of this study is the unavailability of advanced diagnostic tools such as thyroid scintigraphy and molecular genetic testing. Scintigraphy, which is considered the complementary tool for confirming thyroid hemiagenesis, was not performed in any of the cases due to lack of access to nuclear medicine facilities. However, all cases were assessed using high-resolution ultrasonography performed by experienced clinicians in a high-volume, thyroid-specialized center, supporting the reliability of the diagnoses. Similarly, molecular or genetic analyses that could provide insights into potential hereditary or developmental mechanisms were not feasible, primarily due to financial constraints and limited infrastructure in the setting of a developing country. Conclusion This study confirms the female predominance of TH, with a higher prevalence of left-lobe absence and frequent symptomatic presentations. The association with congenital anomalies suggests embryological links requiring further exploration. While thyroid function is generally preserved, cases of hypo- and hyperthyroidism underscore the need for individualized endocrine evaluation. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Ethical approval for this study was obtained from the Ethics Committee of the Kscien Organization (Approval No. 2025-37) Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the patients or, in the case of minors, from their parents. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: AMS, HOB, ShFA, and AMM: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. KMS, AQQ, SHH, HAA, AJQ and ROM: Literature review, design of the study, critical revision of the manuscript, and processing of the tables. ANQ, AHA, DHH, and RRR: Literature review, processing of the figures, data analysis and interpretation. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Hyalinizing Trabecular Tumor: A Case Series with Literature Review
Abstract Introduction: Hyalinizing trabecular tumor (HTT) is a rare thyroid neoplasm originating from follicular cells and poses diagnostic challenges due to its cytologic and histologic overlap with other thyroid malignancies. This study aims to present the clinical features and management of HTT cases treated at a single center. Methods: This was a single-center retrospective case series. The patients were included from January 2019 to November 2024. Data collection took place over one month, from November 15, 2024, to December 15, 2024. The study included patients with HTT whose diagnoses were confirmed histopathologically. Results: The case series included 11 patients, predominantly female, 10 (90.9%), with a mean age of 50.7±19.01 years. The most common presenting symptom was anterior neck swelling, recorded in 5 (45.5%), while one case (9.1%) was discovered incidentally. Hyperthyroidism was present in 6 (54.5%). The tumors were distributed within the thyroid gland as follows: left lobe in 5 (45.5%) cases, right lobe in 4 (36.4%) cases, and isthmus in 2 (18.1%) cases. Total thyroidectomy was performed in 7 patients (63.6%), with tumor sizes ranging from 0.5 to 5.5 cm and a mean diameter of 2.6 ± 2.05 cm. All diagnoses were confirmed postoperatively through histopathological examination. Conclusion: A rare benign tumor, HTT remains challenging to diagnose accurately. Both total thyroidectomy and lobectomy may result in good outcomes. Introduction Thyroid neoplasms include a wide range of lesions with varying behavior and prognosis [1]. They are generally classified as benign, low-grade malignant, or malignant. Benign tumors, such as adenomas, are common and usually do not cause symptoms. Low-grade malignant neoplasms, like follicular thyroid carcinoma, tend to be more aggressive but often have a good prognosis [2]. Hyalinizing trabecular tumor (HTT) of the thyroid was first identified in 1987. It accounts for approximately 1% of all thyroid tumors, occurs six times more often in men than women, and is most frequently diagnosed in individuals in their 50s [3]. HTT was originally classified as a variant of follicular adenoma but is frequently misdiagnosed due to overlapping morphological features with several thyroid neoplasms. These include papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma. Diagnostic challenges also extend to rare tumors with trabecular architecture, such as fetal-type follicular adenoma, poorly differentiated carcinoma, intrathyroid parathyroid neoplasms, and metastatic lesions to the thyroid [4,5]. This poses a challenge in the clinical management of these lesions, as an accurate presurgical diagnosis of HTT is essential to prevent unnecessary overtreatment of this tumor. A literature review reveals that an accurate preoperative cytological diagnosis of HTT was made in only 8% of reported cases. More worrisome, however, is that the remaining 92% were misdiagnosed with false-positive results [6]. The classification of HTT as benign or malignant remains controversial. While it is generally regarded as benign, it is considered a borderline tumor with the potential for malignancy [7]. This diagnostic complexity has led to confusion in terminology, with HTT also being referred to by various other names, including hyalinizing trabecular adenoma, paraganglioma-like adenoma, hyalinizing trabecular neoplasm, and hyalinizing trabecular carcinoma [8]. This study aims to provide a comprehensive overview of HTT by retrospectively analyzing 11 cases, focusing on clinical presentations, diagnostic challenges, and treatment outcomes. Methods Study design This study was a retrospective single-center case series. The patients were managed over five years, from January 2019 to November 2024. Data collection took place over one month, from November 15, 2024, to December 15, 2024. This study was approved by the Ethics Committee of Kscien organization (Approval No. 2025-33). Participants The study included all patients diagnosed with hyalinizing trabecular tumor. Diagnoses were confirmed through histopathological examination of resected thyroid tissue. Clinical and sociodemographic data were collected from patients, medical records, and healthcare providers. Pre-intervention assessment Assessments included vital signs monitoring, ultrasonography (U/S), thyroid function tests, serum calcium levels, vocal cord evaluation, viral screening (HBV, HCV, and HIV), and complete blood count. Intervention All patients underwent surgery under general anesthesia and were positioned supine with the neck extended and elevated using a roller placed beneath the shoulders. If visible, a 4 cm transverse collar incision was made in a natural skin crease of the lower neck for cosmetic purposes. Subplatysmal flaps were elevated superiorly and inferiorly to allow adequate thyroid gland exposure. A circular skin flap was then raised, with dissection carried laterally, medially, and toward the upper and lower cervical regions. The midline between the strap muscles was divided, and the muscles were retracted laterally to expose the thyroid gland. Dissection commenced with ligation of the middle thyroid vein, followed by the superior and inferior pedicles. The superior and inferior thyroid vessels were ligated and divided close to the thyroid capsule to preserve the recurrent laryngeal nerves and avoid compromising the parathyroid gland vasculature. To minimize thermal injury, electrocautery use was limited; instead, multiple suture ligatures were applied to control oozing. Both sharp and blunt dissection techniques were employed to identify and preserve the recurrent laryngeal nerves, with all dissections maintained close to the thyroid capsule. The parathyroid glands were preserved in all cases, and surrounding adipose tissue was retained to maintain vascular integrity. In cases where devascularization was suspected, parathyroid autotransplantation into the sternocleidomastoid muscle was performed. Of the 11 patients, 7 underwent total thyroidectomy. One of these patients underwent additional lateral and central neck dissection, with identification and preservation of the internal jugular vein, spinal accessory nerve, and phrenic nerve. The remaining 4 patients underwent lobectomy, performed using the same surgical technique but limited to the involved thyroid lobe. After each procedure, hemostasis was confirmed. Closed suction drains (RediVac®) were placed in the patients. The strap muscles were reapproximated in the midline, and the skin was closed with absorbable subcuticular sutures and Steri-Strips. All patients tolerated the procedure without intraoperative complications. Post-intervention Considerations Postoperatively, all patients received intravenous paracetamol, and those who underwent total thyroidectomy were prescribed thyroid hormone replacement therapy (Levothyroxine) adjusted to their body weights. The diagnosis was confirmed through histopathological examination of the surgical specimens. Results Participants The case series included 11 patients, of whom ten (90.9%) were female. Patient ages ranged from 32 to 85 years, with a mean age of 50.7±19.01 years. Seven patients (63.6%) had no significant past medical history, while three (27.3%) had hypertension, including one with concurrent type 2 diabetes and another with a history of renal stones. Surgical history was positive in six patients (55.5%). The most common presenting symptom was anterior neck swelling, observed in six patients (54.5%), followed by weight loss in three patients (27.3%). In one case (9.1%), the finding was incidental. Preoperative thyroid function assessment revealed hyperthyroidism in six patients (54.5%), and the remaining five (45.5%) were euthyroid (Table 1). The left thyroid lobe was involved in five cases (45.5%), the right lobe in four cases (36.4%), and the isthmus in two cases (18.1%). The primary surgical approach was total thyroidectomy in seven cases (63.6%), including one patient who underwent concurrent neck dissection (Table 2). Tumor size ranged from 0.5 to 5.5 cm, with a mean size of 2.6 cm (Table 3). All the diagnoses were made post-operatively through histopathological examination (Figure 1). <img id="image_4" src="https://www.judijournal.com/public/site/images/journaleditor/figure-1.jpg" alt="Figure 1. Multiple sections from the thyroid mass reveal a well-demarcated thyroid nodule capsulated by a thin fibrous capsule. The capsule is composed of small-sized follicles with a mainly trabecular pattern arrangement. The cells are polygonal with pleomorphism and lightly eosinophilic cytoplasm with hyaline material. A) The surrounding thyroid tissue shows evidence of colloid goiter (case 1). B) The surrounding thyroid tissue shows evidence of Hashimoto’s thyroiditis with a focal area of chondroid metaplasia (case 10). C) The surrounding thyroid tissue shows evidence of colloid goiter (case 11)." width="945" height="672" /> Outcomes and follow-up The follow-up period ranged from one month to five years, with a mean duration of 2.3±1.27 years. During this period, no cases of recurrence were reported, and all patients achieved complete recovery. No significant complications were observed during or after the surgical procedures. Table 1. Clinical and sociodemographic data of the patients. Case no. Age Sex Medical history Surgical history Drug history Chief complaint Duration Examination Thyroid function test 1 39 F Unremarkable Unremarkable Unremarkable Incidental 1 week Not palpable Hyperthyroid 2 78 F Hypertension Cataract surgery & cholecystectomy Statin, Anticoagulant & Anti-Hypertension Shortness of breath 8 years Hard Hyperthyroid 3 74 M Unremarkable Kidney transplant Corticosteroids Weight-loss 5 months Not palpable Hyperthyroid 4 85 F Hypertension & renal stone Thyroid lobectomy & lithotripsy Anti-Hypertension Anterior neck swelling 6 years Hard Euthyroid 5 32 F Unremarkable Unremarkable Unremarkable Anterior neck swelling 3 months Hard Euthyroid 6 34 F Hodgkin’s lymphoma C-section & cervical cerclage Antibiotics Weight-loss 8 months Not palpable Euthyroid 7 38 F Unremarkable Cholecystectomy Unremarkable Anterior neck swelling 1.5 years Hard Hyperthyroid 8 42 F Unremarkable Unremarkable Unremarkable Anterior neck swelling 1 year Hard Euthyroid 9 51 F Hypertension & Type 2 Diabetes Mellitus Unremarkable Anti-Hypertension & Anti-diabetics Anterior neck swelling 2 months Hard Hyperthyroid 10 40 F Unremarkable Unremarkable Unremarkable Weight-loss 6 months Not palpable Euthyroid 11 45 F Unremarkable Unremarkable Unremarkable Anterior neck swelling 1 year Hard Hyperthyroid M:Male, F:Female, S.Ca:Serum calcium, TG:Thyroglobulin, N/A:Not applicable Table 2. Diagnostics and management. Case no. S. Ca (mg/dL) US US consistency US echogenicity Side FNA Bethesda Vocal cord assessment Type of operation Post Op complications HPE Tumor Size (cm) Follow-up (years) 1 N/A N/A N/A N/A Left lobe V Normal Lobectomy None HTT 1.4 5 2 9.6 TR3 Mixed Heterogenous Left lobe IV Normal Total thyroidectomy None HTT 3.8 2 3 7.9 GD No nodule No nodule Isthmus NP Normal Total thyroidectomy None HTT 1 2 4 9.8 GD No nodule No nodule Right lobe NP Normal Total thyroidectomy None HTT 6 0.08 5 9.2 TR4 Solid Hyperechoic Left lobe V Normal Total thyroidectomy None HTT 4.5 3 6 9.5 TR4 Solid Hyperechoic Left lobe V Normal Total thyroidectomy None HTT 0.5 3 7 9.1 TR3 Solid Heterogenous Left lobe NP Normal Lobectomy None HTT 1.4 1 8 9.5 TR4 Solid Hypoechoic Right lobe IV Normal Lobectomy None HTT 3 2 9 9 TR3 N/A N/A Isthmus NP Normal Total thyroidectomy None HTT 0.8 2 10 9.2 TR3 N/A N/A Right lobe III Normal Total thyroidectomy None HTT 0.7 3 11 8.9 TR3 N/A N/A Right lobe NP Normal Lobectomy None HTT 5.5 3 N/A: Not Applicable, S.Ca: Serum Calcium, US: Ultrasound, FNA: Fine Needle Aspiration, OP: Operation, HPE: Histopathology, TR: TI-RADS, GD: Graves' Disease, NP: Non-Productive, HTT: Hyalinizing trabecular tumor Table 3. Patient demographics and clinical data. Variables Frequency Sex Male 1 (9.1%) Female 10 (90.9) Age groups (years) 30-39 4 (36.3%) 40-49 3 (27.3%) 50-59 1 (9.1%) >60 3 (27.3%) Mean ± SD 50.7 ± 19.0 Medical history Unremarkable 7 (63.6%) Hypertension 1 (9.1%) Hypertension & renal stones 1 (9.1%) Hodgkin’s lymphoma 1 (9.1%) Hypertension & Type 2 Diabetes Mellitus 1 (9.1%) Surgical history Unremarkable 6 (54.5%) Cholecystectomy 1 (9.1%) C-section & cervical cerclage 1 (9.1%) Cholecystectomy & cataract surgery 1 (9.1%) Kidney transplant 1 (9.1%) Thyroid lobectomy & lithotripsy 1 (9.1%) Drug history Negative 6 (54.5%) Corticosteroids 1 (9.1%) Antibiotics 1 (9.1%) Antihypertensive 1 (9.1%) Antihypertensive & Antidiabetic 1 (9.1%) Chief complaint Anterior neck swelling 6 (54.5%) Shortness of breath 1 (9.1%) Weight loss 3 (27.3%) Incidental 1 (9.1%) Thyroid examination Not palpable 7 (63.6%) Hard 4 (36.4%) Thyroid function Hyperthyroid 6 (54.5%) Euthyroid 5 (45.5%) Affected side Right lobe 4 (36.3%) Left lobe 5 (45.5%) Isthmus 2 (18.2%) Operation Total thyroidectomy 7 (63.6%) Lobectomy 4 (36.4%) Tumor size (cm) Mean ± SD 2.6 ± 1.95 Follow-up (years) 0.0 - 1.0 2 (18.18%) 1.1 - 2.0 4 (36.36%) 2.1 - 3.0 4 (36.36%) 3.1 - 4.0 0 (0.0%) 4.1 - 5.0 1 (9.09 %) Mean ± SD 2.3 ± 1.27 Discussion The diagnosis of HTT is challenging due to its resemblance to other thyroid neoplasms. While most cases are asymptomatic, Rossi et al. stated that symptom presentation may depend on tumor size and location [5]. Among the 11 cases, only one was asymptomatic, while the remaining ten exhibited clinical symptoms, including anterior neck swelling, weight loss, and shortness of breath. However, in the six reviewed cases, three were asymptomatic, two exhibited neck swelling, and one experienced both dyspnea and dysphagia (Table 4) [2,3,7-10]. Table 4. Summary of the cases of hyalinizing trabecular tumor in the literature. Author/year Age Sex Medical history Drug history Surgical history Chief complaint Examination Duration (years) Side Size (cm)* Distant metastasis TI-RADS FNA findings Therapeutic approach IHC findings Diagnosis Outcome Follow-up (years) Zhang et al./2025 [7] 31 F Unremarkable Unremarkable Unremarkable Incidental Palpable mass 1.5 R 2.2 No TR3 N/A Lobectomy TG +ve, CK19 +ve, TTF-1 +ve & Ki-67 5% HTT Resolved 0.6 Hayashi et al./2025 [2] 93 F Diabetes mellitus, hyperlipidemia, hypertension & myocardial infarction N/A N/A Loss of appetite, dyspnea & dysphagia Enlarged, firm, non-tender, without palpable nodules >12 B >10 No N/A N/A Conservative management & rehabilitation N/A HTT Improved N/A Alsogair et al./2023 [3] 60 M Unremarkable Unremarkable Hemorrhoidectomy Mass on the neck Palpable, firm & non-tender N/A R 3.8 No N/A 60%-75% likelihood of malignancy Total thyroidectomy followed by thyroxine TG +ve & Ki-67 +ve HTT Resolved 0.06 Katano et al./ 2021 [10] 54 F Panic disorder & chronic thyroiditis Unremarkable Unremarkable Left cervical mass Growing, painless & elastic N/A L 4.5 No N/A Chronic thyroiditis with possible malignancy Lobectomy Ki-67 +ve for cytoplasm & ColIV +ve HTT Resolved 1.5 Rhee et al./2018 [9] 63 F Breast cancer N/A N/A Incidental N/A N/A L 0.6 No N/A Features of PTC Lobectomy Ki-67 +ve, CD56 +ve & Galectin-3 +ve HTT Resolved N/A Jones et al./2017 [8] 70 F N/A N/A N/A Incidental N/A N/A R 1.94 N/A N/A 60-75% likelihood of malignancy Total thyroidectomy TG +ve, vimentin +ve & CK19 +ve HTT Resolved 0.08 M: Male, F: Female, N/A: Not applicable, FNA: Fine needle aspiration, IHC: Immunohistochemistry, HTT: Hyalinizing trabecular tumor, L: Left, R: Right, B: Both The diagnostic evaluation of most thyroid nodules typically begins with U/S, followed by fine needle aspiration (FNA). The U/S findings suggestive of HTT are well-defined, solitary, oval or round, solid hypoechoic nodules, usually without microcalcifications and displaying peri or intra-nodular vascularity. However, these features are not specific to HTT and may also occur in other thyroid lesions [7]. Recognizing the variability in U/S findings is crucial, as some studies reported an absence of malignant features. In contrast, Choi et al. found that 29% of HTT cases displayed malignant features on U/S [5,11]. In the present study, five cases were classified as mildly suspicious for malignancy, and three were considered moderately suspicious for malignancy according to the thyroid imaging reporting and data system (TI-RADS). Among the reviewed cases, malignancy was also suspected in four patients based on the U/S findings [2,3,7-10]. The primary diagnostic tool for thyroid nodules is FNA, which often leads to the misclassification of HTT as PTC or medullary thyroid carcinoma [9]. Ito et al. suggested that this diagnostic confusion arises from shared cytological features, including intranuclear cytoplasmic inclusions and nuclear grooves, which represent hallmark characteristics of PTC [4]. The cytological appearance of HTT on liquid-based preparations reveals cohesive aggregates or syncytial fragments of tumor cells surrounding hyaline material. Although tumor cells in HTT show enlarged nuclei with hyperchromasia and occasional intranuclear pseudo-inclusions similar to papillary carcinoma, HTT cells typically display dispersed fine chromatin rather than the pale and clear chromatin pattern observed in PTC [9]. Additionally, HTT cells demonstrate less frequent nuclear membrane irregularity and exhibit a more stratified trabecular arrangement compared to papillary carcinoma. These subtle distinctions prove crucial for accurate cytological interpretation, though they remain challenging to discern consistently in clinical practice [9]. Dell’Aquila et al. reported that up to 75% of HTTs are classified within Bethesda categories IV to VI [12]. Among the cases included, two were diagnosed as Bethesda category IV, while three were classified as category V, emphasizing their frequent misinterpretation by cytopathologists. Equivocal cytomorphologic diagnoses, such as atypia of undetermined significance or follicular lesion of undetermined significance, require repeat FNA, as the malignancy risk for nodules in these categories ranges from 1% to 15% [8]. On gross examination, HTT typically presents as a solid, well-circumscribed mass, or less commonly, as an encapsulated tumor, with colors ranging from yellow to tan, opposite to PTC, which is usually white and does not have a capsule. HTT generally lacks invasion into the capsule, vasculature, or thyroid parenchyma [5,7]. However, Gowrishankar reported a case in which invasion and malignant behavior were observed in HTT [13]. Immunohistochemistry can aid in diagnosing HTT, although some biomarkers used may lack significant specificity. HBME-1 and galectin-3 are well-established markers for malignant thyroid lesions, particularly PTC and its variants. However, their expression in HTT remains a subject of debate. In their series, Dell’Aquila et al. found that the majority of HTT cases exhibited a distinct immune profile, with negative immunoreactivity observed in 16 out of 18 (89%) lesions. This finding further supports the classification of HTT as a benign tumor [12]. Recent genetic studies have demonstrated that GLIS rearrangements, particularly the PAX8-GLIS3 gene fusion, are critical for diagnosing HTT. Research indicates this fusion was present in 93% of HTT cases (13 out of 14), with the remaining 7% involving a PAX8-GLIS1 rearrangement. These findings highlight the diagnostic utility of detecting GLIS-related fusions to distinguish HTT from morphologically similar thyroid neoplasms [4]. In 2012, Smith et al. suggested that HTT could potentially acquire mutations leading to RET/PTC expression and undergo malignant transformation into PTC [14]. Given the uncertainty regarding the malignant potential of HTT, treatment approaches typically involve complete resection, near-total thyroidectomy, or lobectomy [8]. However, evidence suggests that up to three-quarters of patients may be subjected to overtreatment, opting for total or subtotal thyroidectomy rather than the less invasive lobectomy. In contrast, some experts argue for a more conservative management strategy, advocating for close monitoring or lobectomy as a first-line approach, rather than resorting to total thyroidectomy immediately [8]. Among the cases included in the current series, seven patients underwent total thyroidectomy, accounting for 63.6% of the surgeries performed. Utilizing total thyroidectomy as the surgical method mainly resulted from uncertainty in diagnosis, as imaging and other pre-operative examinations don’t usually provide a solid diagnosis. Conclusion In conclusion, HTT is a rare tumor that is challenging to diagnose accurately. Both total thyroidectomy and lobectomy may result in good outcomes. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Ethical approval for this study was obtained from the Ethics Committee of the Kscien Organization (Approval No. 2025-33) Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from all patients. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: AMS, ROM, FHK, and MMA: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. HOB, SHH, MBA, IJH, ISS, and DQH: Literature review, design of the study, critical revision of the manuscript, and processing of the tables. KKM, MNH, AAQ, HAA, and HKM: Literature review and processing of the figure. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Blunt Chest Trauma and Chylothorax: A Systematic Review
Abstract Introduction: Although traumatic chylothorax is predominantly associated with penetrating injuries, instances following blunt trauma, as a rare and challenging condition, are being increasingly documented. This study aims to systematically review the reported cases of blunt chest traumatic chylothorax (BCTC) and provide comprehensive insights into the condition. Methods: Related studies published until December 11, 2024, were identified through Google Scholar. All studies documenting instances of BCTC, without restriction on cause or patient demographics, were included. Studies were excluded if they focused on chylothorax caused by penetrating injuries, their content was unretrievable, they were review articles, or they were published in blacklisted journals. Results: Sixty-five eligible studies, encompassing 69 cases of BCTC, were included in the review. It predominantly affected males (73.91%), with patient ages ranging from 11 months to 84 years old. The most common clinical findings were dyspnea (47.83%) and abnormal auscultation or percussion (34.78%), with road traffic accidents as the primary cause (59.42%). Unilateral chylothorax was found in 72.46% of cases, bilateral chylothorax occurred in 27.54%, and pleural effusion was the most frequent radiological finding (55.07% in X-ray and 33.33% in computed tomography). Treatment typically included drainage (94.20%), parenteral nutrition (50.72%), and thoracic duct closure (39.13%). Most patients achieved complete recovery (89.85%), and six cases (8.70%) died. Conclusion: The condition is rare and complex, underscored by the wide variability in patient demographics, clinical presentations, chylothorax onset, and management approaches. Given the challenges posed by limited evidence, the findings emphasize the need for early recognition and individualized management strategies. Introduction Chylothorax is a rare condition characterized by the accumulation of chyle in the pleural cavity caused by a disruption of the thoracic duct [1]. Chyle is an opalescent fluid that consists of triglycerides, chylomicrons, proteins, electrolytes, immunoglobulins, and fat-soluble vitamins, transported from the gastrointestinal system into the bloodstream by the thoracic duct. It makes up about 1-3% of total body weight in adults. Chylothorax was initially described by Bartolet in 1633 and later reported in the literature by Quinke in 1875 [1,2]. It is categorized into congenital, neoplastic, traumatic, and miscellaneous forms. The most common cause is malignancy, which leads to obstruction of the thoracic duct, while traumatic chylothorax is typically iatrogenic, resulting from surgical procedures or catheter placement. Penetrating trauma is the usual cause of traumatic chylothorax, while blunt trauma is considered an infrequent cause [1,2]. It may also develop due to chest compression or changes in intrathoracic pressure, such as during coughing or persistent vomiting [2]. The incidence of chylothorax is about 0.2% following blunt thoracic trauma and 0.9% after penetrating trauma. Bilateral chylothorax resulting from blunt trauma, mainly when no other injuries are evident, is an infrequent but severe complication [3]. Without prompt treatment, chylothorax can lead to serious complications, such as cardiopulmonary distress and significant nutritional deficiencies, with a high mortality rate of up to 15.5% [2-4]. Although traumatic chylothorax is predominantly associated with penetrating injuries, instances following blunt trauma have been increasingly documented, highlighting the need for awareness among healthcare providers regarding this potential complication [5,6]. This study aims to systematically review the reported cases of blunt chest traumatic chylothorax (BCTC) and provide comprehensive insights into the condition. Methods Literature search The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Related studies published until December 11, 2024, were identified through Google Scholar using a search strategy that combined the following keywords with the “allintitle” and “including citation” features: (blunt trauma chylothorax), (blunt thoracic trauma chylothorax), (blunt thoracic injury chylothorax), (blunt chest injury chylothorax), (blunt torso trauma chylothorax), (blunt thoracic duct trauma), (blunt thoracic duct injury) and (traumatic chylothorax). The search was limited to English-language publications. Eligibility criteria All studies or reports documenting instances of BCTC, without restriction on cause or patient demographics, were eligible for inclusion. Studies were excluded if they focused on chylothorax caused by factors other than blunt chest trauma, if their content was unretrievable, if they were review articles, or if they were published in blacklisted journals. The legitimacy of the studies was verified by cross-referencing with widely recognized predatory journal checklists [7]. Study selection First, an author conducted a literature search using the specified keywords and collected the relevant results. The titles and abstracts of the identified studies were then screened to exclude duplicates, non-English studies, and those unrelated to the study objective. Full-text screening was conducted for studies that passed the initial filtration, excluding those with unretrievable content or irrelevant study designs, such as reviews. This step was supervised by two authors, who independently reviewed each study. Finally, the remaining studies underwent legitimacy filtering. Data extraction The collected data encompassed various parameters, including the first author's name, year of publication, patient demographics, clinical manifestations, causes of chylothorax, chyle volume and content, the onset of chyle production, diagnostic methods, ICU admission status, treatment modalities, outcomes, and follow-up. Statistical Analysis The extracted data were organized in an Excel sheet (2019) and analyzed descriptively using the Statistical Package for the Social Sciences (SPSS, v. 27, IBM Co.). The results were presented in frequencies with percentages, means with standard deviation, and ranges. Results Study identification A systematic search yielded 201 studies, all of which were case reports. After removing duplicates (16) and non-English articles (17), 168 titles and abstracts were screened. Fifty-five case reports were excluded due to irrelevance, and full-text evaluation of the remaining 113 case reports led to the exclusion of an additional 42. Furthermore, six articles were excluded for being published in warning-listed journals. Consequently, 65 eligible case reports, encompassing 69 cases of BCTC, were included in the review [1-6,8-66] (Tables 1 and 2). The identification process is outlined in a PRISMA flowchart (Figure 1). Table 1. Demographic, Cause and Chyle Characteristics First author, year [Reference] Country Age (year) Gender CFP Cause SOC Amount of chyle (ml)/day* COAP (day) Biochemical content of chyle Harvey, 2024 [5] USA 60 F Chest pain, multiple rib fractures RTA Left <500 2 Triglycerides Burduniuc, 2023 [2] Czech Republic 70 F Blunt injury Fall on stairs Right >1000-2000 3 Protein, cholesterol, triglycerides Dung, 2023 [14] Vietnam 32 M Thoracic spine injury, paraplegia RTA Right >1000-2000 At once Cholesterol, triglycerides Kim, 2023 [4] South Korea 45 M Hemodynamically unstable, chest discomfort, multiple fractures, hemopneumothorax Crushed by a 2-ton metal frame Left >1000-2000 1.66 Triglycerides Boateng 2023 [33] USA 75 F Respiratory distress Fall from bed Right <500 At once Triglycerides Ruest 2023 [34] USA 15 months M Tenderness over right paraspinal thoracolumbar back, abnormal auscultation Child abuse Right N/A At once N/A Mohanakrishnan 2022 [35] USA 70 F Dyspnea, back pain, abnormal auscultation Violent coughing episode Right >1000-2000 At once Chylomicrons, triglycerides Mazhar, 2021[23] UK 42 F Dyspnea, abnormal auscultation Fall from horse 1 week before presentation Right >1000-2000 7 Triglycerides Waseem, 2021[32] Pakistan 50 M Dyspnea RTA 2 days before presentation Bilateral >1000-2000 2 Triglycerides, cholesterol, fat-rich fluid with few inflammatory cells Din Dar 2021 [36] India 50 M Blunt injury RTA Right >1000-2000 25 Triglyceride, chylomicrons Bacon, 2020 [9] USA 53 M Hemopneumothorax RTA Left <500 5 N/A Champion, 2020 [12] Canada 29 M Dyspnea, flushing, diaphoresis, vomiting, abnormal auscultation RTA Bilateral >1000-2000 At once Cholesterol, triglycerides Jindal 2019 [37] India 35 M Dyspnea, respiratory distress RTA Bilateral >1000-2000 4 Triglyceride, WBC, albumin, glucose, protein, LDH Ahmed, 2018 [1] Iraq 42 M Severe back pain RTA Right 500-1000 2 Triglycerides and lymphocyte Brown, 2018 [10] USA 53 M Thoracoabdominal injuries, subcutaneous emphysema, unstable pelvis RTA Left >1000-2000 N/A Triglycerides and lymphocyte Litzau, 2018 [22] USA 66 F Dyspnea, multiple fractures, abnormal auscultation RTA 7 days before presentation Right >1000-2000 7 Triglycerides Kozul, 2017 [19] Australia 18 M Multiple injuries RTA Bilateral 500-1000 0.46 N/A Lee, 2017 [21] South Korea 70 M Hemothorax, flail chest RTA Right >2000 5 Triglycerides, cholesterol Mohamed, 2017 [3] USA 51 M Dyspnea, chest pain, abnormal auscultation Fall on stairs Bilateral >1000-2000 5 Triglycerides, Leukocytes, RBCs, LDH, protein Spasić, 2017 [6] Serbia 55 F Multiple injuries RTA Right >2000 5 N/A Sriprasit, 2017 [31] Thailand 27 F Hemothorax, neurogenic shock, multiple fractures RTA Left <500 5 Triglycerides, protein, glucose, LDH Hara 2017 [38] Japan 17 F Breathing difficulty, abnormal percussion Recurrent chylothorax, physical punishment Left 500-1000 At once N/A Jahn 2017 [39] Germany 8 F Respiratory distress, abnormal percussion, and auscultation Pedestrian hit by a motor vehicle Left <500 5 Protein, albumin, LDH, triglycerides, cholesterol Ghodrati 2016 [40] Iran 12 F Dyspnea, respiratory distress Chest trauma during play at school Bilateral N/A N/A N/A Lee 2016 [41] South Korea 50 M Paraplegia Fall from height during construction work Right >1000-2000 3 Triglycerides Sendama 2015 [42] UK 84 F Dyspnea, abnormal auscultation Fall Right 500-1000 4 Protein, LDH, cholesterol, triglycerides Snow 2015 [43] USA 22 months M Cough, dyspnea, respiratory distress, altered mental status, abnormal auscultation Fall from a chair Right <500 2 Triglycerides Adams 2013 [44] USA 73 M Paraplegia, rib fractures, hemothorax RTA Right N/A 9 Triglycerides, lymphocytes, glucose, LDH, lipemia Kumar 2013 [45] India 32 M Blunt injury, fracture of right femur RTA Right >1000-2000 2 Triglycerides, chylomicrons 23 M Hemopneumothorax, multiple rib fractures, subcutaneous emphysema RTA Right 500-1000 1 Triglycerides 40 M Hemothorax RTA Right 500-1000 2 Triglycerides Sharkey 2012 [46] UK 50 M Multiple fractures, hematoma, hemothorax, pneumothorax RTA Right 500-1000 N/A Triglyceride, cholesterol Sokouti, 2011[30] Iran 15 M Respiratory distress, dyspnea, back pain, abnormal auscultation Fall 11 years ago Bilateral >2000 40 Triglycerides, protein, cholesterol, fat Kurklinsky 2011 [47] USA 26 F Pleuritic chest pain Water-skiing fall Bilateral >1000-2000 2 Triglycerides Apostolakis, 2009 [8] USA 75 F Dyspnea, back pain RTA Bilateral 500-1000 At once Protein, LDH, glucose, amylase, triglycerides, cholesterol, albumin, globulin, K, Na, lymphocytes, erythrocytes 22 M Back pain, hematoma of left thigh, chest pain RTA Bilateral <500 0.25 Protein, LDH, glucose, amylase, triglycerides, cholesterol, albumin, globulin, K, Na, lymphocytes, erythrocytes Huber, 2009 [16] USA 47 M Dyspnea, chest pain Crushed by multiple metal gates Bilateral 500-1000 3 Triglycerides Schurz, 2009 [28] Austria 39 M Dyspnea, thoracodorsal pain RTA Left >1000-2000 14 N/A Serin-Ezer, 2009 [29] Turkey 4 M Dyspnea, somnolence, abnormal auscultation Hit by a manufacturing pipe falling from a truck Bilateral <500 At once Triglycerides, cholesterol, protein, LDH, glucose Kamiyoshihara, 2008 [18] Japan 51 M Dyspnea, dullness in percussion RTA 20 years before presentation Bilateral >1000-2000 At once (but the trauma dated back to 20 years prior) Triglycerides Pandey 2008 [48] Australia 36 M Chest pain, flail chest, hypotension Fall from balcony Right >1000-2000 2 N/A Lee, 2006 [20] South Korea 11 M Dyspnea, nausea, vomiting, abdominal discomfort, abnormal auscultation RTA 3 days before presentation Bilateral N/A 3 Triglycerides, cholesterol, protein Ozcelik, 2004 [26] Turkey 15 F Respiratory distress, subcutaneous emphysema, pneumothorax Trapping under rubble during a 7.8 magnitude earthquake Right N/A 45 Cholesterol, triglycerides Robbins 2004 [49] USA 41 M Chest injury, refractory hiccups, nausea RTA Bilateral N/A N/A N/A Buchan 2001 [50] UK 18 M Dyspnea RTA Right >1000-2000 4 N/A Chamberlain, 2000 [11] UK 29 M Pneumothorax, abdominal and paraspinal pain, loss of motor power, and sensation below T12/L1 RTA Right >1000-2000 0.88 N/A Glyn-Jones 2000 [51] UK 28 M Dyspnea, polytrauma, tachypnea RTA Left >2000 N/A Triglyceride, cholesterol, WBC Golden, 1999 [15] USA 53 F Chest pain, multiple fractures, hemopneumothorax, abnormal auscultation RTA Left >2000 6 Triglycerides McCormick, 1999 [24] USA 46 M Chest pain, dyspnea, abnormal auscultation, dullness to percussion Hit-and-run motor vehicle accident Bilateral >1000-2000 14 Protein, cholesterol, triglycerides Ikonomidis, 1997 [17] Canada 17 M Closed head injury, multiple fractures, respiratory distress, tracheal hematoma RTA Bilateral <500 At once Triglycerides 24 M Closed head injury, rib fractures, hemothorax Snowboarding accident Left <500 At once Triglycerides Guleserian, 1996 [52] USA 11 months M Dyspnea, coughing, cold symptoms, grunting, abnormal percussion Child abuse Right 500-1000 N/A Triglycerides, cholesterol, WBC Milano, 1994 [25] Italy 26 F Dyspnea Fall while skiing 4 months prior Left >1000-2000 50 Triglycerides Fogli, 1993 [53] Italy 31 M Suspected traumatic hemothorax, dyspnea, cough RTA Right 500-1000 N/A N/A Grant, 1991 [54] New Zealand 32 M Dyspnea, chest and back pain RTA Right >1000-2000 N/A N/A Dulchavsky, 1988 [13] USA 48 M Dyspnea, chest pain, abnormal auscultation Fistfight Right >1000-2000 At once Cholesterol, HDL, triglycerides, pre-beta lipoprotein, chylomicrons Brook 1988 [55] USA 27 M Respiratory distress, abnormal percussion, tachycardia RTA Bilateral >2000 3 Triglycerides Pai, 1984 [27] USA 19 M Neck, back, and chest pain RTA Right >1000-2000 N/A N/A Krishnan 1982 [56] Malaysia 29 M Dyspnea, abnormal percussion RTA Right >2000 2 N/A Azambuja 1981 [57] Brazil 42 M Paraplegia, hemopneumothorax RTA Right N/A 3 N/A Rea 1960 [58] UK 28 M Dyspnea, apex beat displaced to the left Crush injury from falling planks Right 500-1000 4 Lipid, protein, RBC, lymphocytes Guest 1955 [59] Canada 19 M Dyspnea, dry cough, tachypnea, dull percussion RTA Right >1000-2000 26 N/A Elliot 1948 [60] Canada 56 M Fall injury, paraplegia, respiratory distress Fall from a tree Right 500-1000 3 Fat Dorsey 1942 [61] USA 60 M Alcoholic stupor, dyspnea, chest pain, abnormal percussion Fall down a flight of stairs Right >2000 0.5 Protein, albumin, globulin, fat Cellan-Jones 1940 [62] UK 32 M Dyspnea, chest tightness A stone hitting the chest and dorsal spine striking a block of coal Right >1000-2000 3 Fat Brown 1937 [63] USA N/A F Respiratory distress, abdominal distention RTA Bilateral >1000-2000 At once N/A Bauersfeld 1937 [64] USA 22 M Breathing difficulty, laceration of the scalp, pain in lower abdomen and lumbar region, cyanosis, cold extremities RTA Right >2000 8 Fat globules Lillie 1935 [65] USA 45 M Blunt injury Fall from a scaffold 20 feet high Right >2000 N/A N/A Macnab 1932 [66] Canada 46 M Chest and back pain, dullness percussion, dyspnea, anorexia, weakness, intermittent fever, hypotension Fall from a height of 11 feet Right 500-1000 6 N/A F: female, M: male, CFP: clinical findings & presentation, SOC: Side of chylothorax, hr: hour, N/A: non-available, COAP: Chyle onset after presentation, RTA: road traffic accident, RBC: red blood cell, LDH: lactate dehydrogenase, HDL: high density lipoprotein, WBC: white blood cell. * The amount of chyle has been grouped rather than the actual amount. Table 2. Imaging findings, treatment and outcomes. First author, year [Reference] Chest X-ray CT MRI ICU admission Treatment Thoracic duct ligation approach Mode of drainage Duration of chest tube placement (day) Follow-up (weeks) Outcome Harvey, 2024 [5] Pleural effusion Hemopneumothorax, pneumomediastinum, retrosternal hematoma, multiple rib fracture, lung contusions, and manubrium fractures N/A Yes Drainage, medium chain fatty acid diet N/A Chest tube 7 8 Recovered Burduniuc, 2023 [2] Pleural effusion, multiple rip fracture Pleural effusion, multiple rib fracture Th12 vertebral fracture Yes Drainage, thoracic duct ligation Thoracotomy Chest tube N/A N/A Recovered Dung, 2023 [14] Pleural effusion T9 and T10 vertebral fracture N/A No Drainage, octreotide, TPN, thoracic duct embolization 2.7 Fr microcatheter, fluoroscopic guidance Chest tube 7 N/A Recovered Kim, 2023 [4] Pleural effusion Lipiodol leakage near T10–11 level N/A Yes Drainage, TPN, intranodal lymphangiography, therapeutic lipiodol injection N/A Chest tube 39 N/A Recovered Boateng 2023 [33] N/A Pleural effusion, lung collapse N/A No Drainage, medium-chain triglyceride N/A Chest tube N/A N/A Died Ruest 2023 [34] Pleural effusion T12 vertebral body fracture, rib fractures N/A Yes Drainage N/A Chest tube N/A N/A Recovered Mohanakrishnan 2022 [35] N/A Pleural effusion, minimal ascites N/A No Drainage, octreotide, low-fat diet, NPO, TPN, pleurodesis, thoracic duct embolization Coiling and glue embolization Chest tube N/A N/A Recovered Mazhar, 2021[23] Pleural effusion Pleural effusion, T10 spinous process fracture N/A No Drainage, octreotide, medium-chain triglyceride diet N/A Chest tube 3 N/A Recovered Waseem, 2021[32] Pleural effusion Pleural effusion N/A No Only drainage N/A Chest tube 5 N/A Recovered Din Dar 2021 [36] N/A Multiple rib fractures, hemothorax N/A No Drainage, NPO, TPN, octreotide, thoracic duct embolization Thoracotomy Chest tube 25 48 Recovered Bacon, 2020 [9] Multiple rib fracture Multiple rib fracture N/A Yes Drainage, free-fat diet N/A Chest tube N/A 12 Recovered Champion, 2020 [12] Pleural effusion Pleural effusion N/A No Drainage, octreotide, TPN, thoracic duct ligation Thoracotomy Chest tube N/A 6 Recovered Jindal 2019 [37] Pleural effusion Multiple rib fractures, lung contusions, fracture of L1 and L2 vertebrae N/A Yes Drainage, thoracic duct ligation, TPN, octreotide, fat-free and medium chain triglyceride Thoracotomy Chest tube 8 8 Recovered Ahmed, 2018 [1] Opacification of hemithorax D10 vertebral fracture, multiple rib fracture N/A Yes Drainage, low-fat diet, albumin vial, octreotide N/A Chest tube Brown, 2018 [10] N/A Left temporal epidural hematoma, pulmonary contusions, multiple skeletal fractures, pneumomediastinum compressing the right atrium Not mentioned the findings No Drainage, NPO, TPN, octreotide, thoracic duct embolization, and ligation Thoracotomy, decortication Chest tube Litzau, 2018 [22] Pleural effusion Pleural effusion N/A No Drainage, low-fat diet N/A Chest tube Kozul, 2017 [19] N/A Hemopneumothorax, mediastinal shift to the right, pleural effusion N/A No Drainage, No fat/low-fat diet N/A Chest tube Lee, 2017 [21] Pleural effusion Multiple rib fracture, hemopneumothorax (left), subcutaneous emphysema (left), and atelectasis (right). N/A Yes Drainage, TPN, NPO, fat-free diet, medium-chain lipid diet, thoracic duct ligation, pleurectomy Thoracotomy Chest tube Mohamed, 2017 [3] Obliteration of left costophrenic angle (pleural effusion) Bilateral effusion N/A No Drainage, fat-free diet with medium-chain triglycerides, octreotide N/A Thoracentesis Spasić, 2017 [6] Lung contusion Rib and thoracic vertebral fracture, hydropneumothorax, lung contusion, pneumomediastinum N/A No Drainage, TPN, thoracic duct suturing Thoracotomy Chest tube Sriprasit, 2017 [31] N/A N/A N/A Yes Drainage, NPO, TPN N/A Chest tube Hara 2017 [38] Pleural effusion N/A N/A No Drainage, low-fat diet with medium-chain triglycerides, intranodal lymphangiography with lipiodol N/A Chest tube Jahn 2017 [39] Pulmonary opacification Lung contusions N/A No Drainage, fat-free diet N/A Chest tube Ghodrati 2016 [40] Pleural effusion N/A N/A Yes Drainage, thoracic duct embolization Unknown Chest tube Lee 2016 [41] N/A Incomplete cord injury at the thoracic spinal vertebrae (T10 and T11) N/A No Drainage, TPN, NPO, thoracic duct ligation VATS Chest tube Sendama 2015 [42] Pleural effusion Multisegment fracture of L1 vertebra N/A No Drainage, medium chain fatty acid diet, octreotide N/A Chest tube Snow 2015 [43] Opacification of right chest, mediastinal shift to left N/A N/A Yes Drainage, NPO, TPN, octreotide, low-fat diet N/A Chest tube Adams 2013 [44] Pleural effusion, atelectasis Pleural effusion, atelectasis N/A Yes Drainage, NPO, TPN, octreotide N/A Thoracentesis, chest tube Kumar 2013 [45] N/A Pleural effusion, multiple rib fractures N/A No Drainage, NPO, TPN, octreotide, chest physiotherapy N/A Chest tube N/A Hemopneumothorax, multiple rib fractures N/A No Drainage, NPO, TPN, octreotide, chest physiotherapy N/A Chest tube N/A Bilateral hemothorax, lung contusion N/A Yes Drainage, NPO, TPN, octreotide, exploratory laparotomy for biliary leak N/A Chest tube Sharkey 2012 [46] N/A N/A N/A Yes Drainage, NPO, TPN, octreotide, medium fatty acid diet N/A Chest tube Sokouti, 2011[30] Large cystic mass in left posterior mediastinum Large low-density cystic mass in the left posterior mediastinum, left pleural effusion N/A No Drainage, thoracic duct ligation, TPN Laparotomy, Thoracotomy Chest tube Kurklinsky 2011 [47] N/A Pleural effusion, dilated cisterna chyli, middle mediastinum fluid collection N/A No Drainage, TPN, thoracic duct embolization 3 Fr microcatheter with ultrasound guidance Thoracentesis Apostolakis, 2009 [8] Pleural effusion Pleural effusion N/A No Drainage, starvation diet, TPN N/A Chest tube Pleural effusion, rib fractures, ipsilateral sternoclavicular joint dislocation Lung contusion N/A No Drainage, starvation diet, TPN N/A Chest tube Huber, 2009 [16] Pleural effusion Pleural effusion, right pneumothorax, multiple rib fracture, aortic pseudoaneurysm, retrocrural hemorrhage N/A Yes Drainage, thoracic duct ligation, medium chain fatty acid diet, mechanical pleurodesis Thoracotomy Chest tube Schurz, 2009 [28] Multiple rib fracture, pleural effusion Pleural effusion Osseous lesions and pleural effusion Yes Drainage, TPN, fat-free diet, plain tea, apple puree N/A Pleural puncture, chest tube Serin-Ezer, 2009 [29] Multiple rib fracture, pleural effusion Pleural effusion N/A No Drainage, NPO, TPN N/A Chest tube Kamiyoshihara, 2008 [18] Pleural effusion Pleural effusion N/A No Drainage, low-fat diet, TPN, thoracic duct ligation, pleurodesis Thoracotomy Thoracentesis, Chest tube Pandey 2008 [48] N/A Hemopneumothorax, pulmonary contusion, multiple rib fractures, pneumomediastinum N/A Yes Drainage, octreotide, thoracic duct ligation Laparoscopic ligation Chest tube Lee, 2006 [20] Elevation of diaphragms, cardiomegaly Pleural effusion, massive ascites around liver and spleen N/A No Drainage, medium-chain lipid solution, NPO N/A Thoracentesis, chest tube Ozcelik, 2004 [26] Pneumothorax, consolidated right lung, pleural effusion Right lung consolidation, pleural effusion N/A No Drainage, thoracic duct mass ligation, TPN Thoracotomy Chest tube Robbins 2004 [49] N/A Pleural effusion, focal fluid collection N/A No EUS-guided aspiration, injection of sodium morrhuate N/A Aspiration Buchan 2001 [50] Pleural effusion N/A N/A No Drainage, low-fat diet, medium-chain triglycerides, thoracic duct ligation Thoracotomy Chest tube Chamberlain, 2000 [11] Pneumothorax, hemithorax opacification Free abdominal gas Fractures of T4 and T10 with spinal cord contusion and hematoma No Drainage, TPN, NPO, Supradiaphragmatic duct ligation Thoracotomy Chest tube Glyn-Jones 2000 [51] Mediastinal shift Minor anterior wedge fractures at T5 and T10 Cord injury at T10 No Drainage, thoracic duct ligation, pleurodesis, fat-free diet Thoracotomy Chest tube Golden, 1999 [15] N/A N/A N/A Yes Drainage, TPN, NPO, thoracic duct ligation Thoracotomy Chest tube McCormick, 1999 [24] Pleural effusion Disruption of the thoracic duct at the T5 level N/A No Only drainage N/A Chest tube Ikonomidis, 1997 [17] Pneumomediastinum, pulmonary contusions N/A N/A No Drainage, TPN, bowel rest N/A Chest tube Left hemothorax Left mediastinal hematoma, T3 vertebral fracture N/A No Drainage, TPN, bowel rest N/A Chest tube Guleserian, 1996 [52] Right lung opacification and mediastinal shift to left N/A N/A No Drainage, nasogastric feeding with medium-chain triglycerides, low-fat diet N/A Chest tube Milano, 1994 [25] Pleural effusion Dense lymphatic opacification at L1-L2, chyloma at D11, pleural leakage from left duct N/A No Drainage, low-fat diet, medium-chain triglycerides, TPN, pleuroperitoneal shunt N/A Thoracentesis Fogli, 1993 [53] Pleural effusion, mediastinal shift N/A N/A No Drainage, TPN N/A Chest tube Grant, 1991 [54] Pleural effusion N/A N/A No Drainage, thoracic duct ligation, TPN, low-fat diet Thoracotomy Thoracocentesis, chest tube Dulchavsky, 1988 [13] Pleural effusion N/A N/A No Drainage, TPN, NPO, thoracic duct ligation Thoracotomy Chest tube N/A 144 Recovered Brook 1988 [55] Pleural effusion N/A N/A Yes Drainage, NPO, TPN, low-fat/ high-protein diet N/A Chest tube 10 32 Recovered Pai, 1984 [27] Fracture dislocations of C6-C7 and T11-T12, right hemothorax N/A N/A No Drainage, fat-free diet, TPN, thoracic duct ligation, parietal pleurectomy Thoracotomy Chest tube N/A N/A Recovered Krishnan 1982 [56] Pleural effusion, obliteration of left costophrenic angle, multiple rib fractures N/A N/A No Drainage, thoracic duct ligation Thoracotomy Chest tube 19 5 Recovered Azambuja 1981 [57] Hemopneumothorax N/A N/A No Drainage, thoracic duct ligation, pleural flap to address fistula, pleural abrasion Thoracotomy Chest tube 6 N/A Recovered Rea 1960 [58] Opaque hemithorax N/A N/A No Drainage, thoracic duct ligation Thoracotomy Chest tube N/A N/A Recovered Guest 1955 [59] N/A N/A N/A No Aspiration, high-protein, low-fat diet N/A Thoracentesis N/A 4 Recovered Elliot 1948 [60] Pleural effusion N/A N/A No Aspiration, thoracic duct ligation Thoracotomy Aspiration N/A N/A Recovered Dorsey 1942 [61] Rib fracture, pleural effusion N/A N/A No Drainage, low-fat diet, high-carb, high-protein diet, NPO N/A Thoracentesis N/A N/A Died due to uncontrolled leakage Cellan-Jones 1940 [62] Pleural effusion N/A N/A No Aspiration, low-fat diet, intravenous glucose-saline N/A Aspiration N/A N/A Died due to uncontrolled leakage Brown 1937 [63] Pleural effusion N/A N/A No Drainage, dietary management N/A Thoracentesis, paracentesis N/A N/A Died Bauersfeld 1937 [64] Pleural effusion, mediastinal shift N/A N/A No Drainage, intravenous dextrose, high-calorie diet N/A Thoracentesis 16 N/A Recovered Lillie 1935 [65] Pleural effusion, mediastinal displacement N/A N/A No Drainage, fat-free diet N/A Thoracentesis N/A N/A Recovered Macnab 1932 [66] Displacement of the heart, pleural effusion N/A N/A No Drainage, carbohydrates, protein N/A Aspiration 48 2 Died due to extreme asthenia CT: computed tomography, MRI: magnetic resonance imaging, ICU: intensive care unit, NPO: Nulla Per Os, TPN: total parenteral nutrition, N/A: non-available, EUS: endoscopic ultrasound Presentation and etiology The patients ranged in age from 11 months to 84 years, with a mean of 37.4 ± 19.9 years. Most cases were male (73.91%), while females accounted for 26.09%. The most common presenting symptom or clinical findings were dyspnea, observed in 47.83% of cases, followed by abnormal findings on auscultation or percussion (34.78%) and multiple fractures or injuries (27.54%). Other frequent symptoms included chest pain (21.74%) and pneumothorax, hemothorax, or hemopneumothorax (20.29%). Road traffic accidents (RTA) were the most prevalent cause of BCTC, accounting for 59.42% of cases, followed by falls (23.19%), trauma caused by heavy objects (8.70%), physical punishment or child abuse (4.34%), and fistfights (1.45%). Bilateral chylothorax was observed in 27.54% of cases, while 55.07% had right-sided involvement and 17.39% had left-sided involvement. The chyle leakage ranged widely, which was >1000–2000 mL/day in 40.58% of cases. Smaller volumes (<500 mL/day) were noted in 14.50% and 500 – 1000 mL/day in 20.28%. In 14.50% of cases, >2000 mL/day was drained. Chyle onset occurred within two days of presentation in 40.58% of cases and within three days to a week in 31.88%. Delayed onset (beyond one week) was reported in 13.04% of cases. The chyle predominantly contained only lipids (40.57%). Other compositions included lipid-protein mixtures (11.59%) and lipid-inflammatory cells (7.24%). Complex mixtures of lipids, proteins, sugars, inflammatory cells, and ions were seen in smaller proportions (5.80%) (Table 3). Table 3. Summary of findings of the reviewed cases Variables Frequency / Percentage Patient demography Age range (mean ± SD), years 11 months – 84 (37.4 ± 19.9) Gender Male Female 51 (73.91%) 18 (26.09%) Common presentation and clinical findings* Dyspnea Abnormal auscultation or percussion Multiple fractures or injuries Chest pain Pneumothorax/ hemothorax/ hemopneumothorax Back pain Respiratory distress 33 (47.83%) 24 (34.78%) 19 (27.54%) 15 (21.74%) 14 (20.29%) 11 (15.94%) 11 (15.94%) Cause of blunt trauma Road traffic accident Fall Hit or crushed by heavy objects Physical punishment & child abuse Fistfight Others 41 (59.42%) 16 (23.19%) 6 (8.70%) 3 (4.34%) 1 (1.45%) 2 (2.90%) Side of chylothorax Right Left Bilateral 38 (55.07%) 12 (17.39%) 19 (27.54%) Amount of chyle (ml/day) <500 500 - 1000 >1000-2000 >2000 N/A 10 (14.50%) 14 (20.28%) 28 (40.58%) 10 (14.50%) 7 (10.14%) Chyle onset after presentation (day) At once – 2 days 3 days – one week > one week – one month > one month N/A 28 (40.58%) 22 (31.88%) 6 (8.70%) 3 (4.34%) 10 (14.50%) Biochemical content of chyle Lipid Lipid + Protein Lipid + Inflammatory cells Lipid + Protein + Sugar + Inflammatory cells + Ions Lipid + Protein + Sugar Lipid + Inflammatory cells + Protein N/A 28 (40.57%) 8 (11.59%) 5 (7.24%) 4 (5.80%) 2 (2.90%) 2 (2.90%) 20 (29.00%) Imaging findings Chest X-rays* Pleural effusion Rib Fracture Lung/ mediastinal/ heart shift Opacification of lung Pneumothorax/ hemothorax Lung contusion Pneumomediastinum Vertebral fracture Lung consolidation Others N/A 38 (55.07%) 7 (10.14%) 7 (10.14%) 6 (8.70%) 5 (7.24%) 2 (2.90%) 1 (1.45%) 1 (1.45%) 1 (1.45%) 5 (7.24%) 15 (21.74%) CT scan findings* Pleural effusion Rib fracture Vertebral fracture Pneumothorax/ hemothorax/ hemopneumothorax Lung contusion Pneumomediastinum Hematoma Thoracic duct leakage Others N/A 23 (33.33%) 14 (20.29%) 10 (14.50%) 9 (13.04%) 8 (11.59%) 4 (5.80%) 3 (4.34%) 2 (2.90%) 17 (24.64%) 25 (36.23%) ICU admission Yes No 19 (27.54%) 50 (72.46%) Common treatment approach* Drainage Parenteral nutrition Thoracic duct ligation/embolization/suturing Medium-chain fatty acid or low-fat diet Nulla per Os Free fat diet/starvation diet Octreotide Pleurectomy/Pleurodesis 65 (94.20%) 35 (50.72%) 27 (39.13%) 24 (34.78%) 19 (27.54%) 12 (17.39%) 17 (24.64%) 6 (8.70%) Thoracic duct closure approach Thoracotomy Fr microcatheter with fluoroscopic/ ultrasound guidance VATS/ laparoscopy Coiling and glue embolization Unknown Not performed 22 (31.88%) 2 (2.90%) 2 (2.90%) 1 (1.45%) 1 (1.45%) 41 (59.42%) Mode of drainage Chest tube Thoracentesis Aspiration Chest tube + Thoracentesis 53 (76.81%) 9 (13.04%) 4 (5.80%) 3 (4.34%) Duration of chest tube placement ≤ One week > One week – two weeks > Two weeks – one month > One month N/A 12 (17.39%) 11 (15.94%) 13 (18.84%) 4 (5.80%) 29 (42.03%) Outcome Recovered Partially recovered Died 62 (89.85%) 1 (1.45%) 6 (8.70%) SD: standard deviation, CT: computed tomography, ICU: intensive care unit, VATS: video-assisted thoracoscopic surgery, N/A: non-available. *Each data in the variable might be found in more than one case Imaging characteristics and management Chest X-rays revealed pleural effusion in 55.07% of cases, rib fractures, and lung or mediastinal or heart shift, each in 10.14%, lung opacification in 8.70%, and pneumothorax or hemothorax in 7.24%. Computed tomography (CT) scans confirmed pleural effusion in 33.33% and rib fractures in 20.29%. The vertebral fracture was found in 14.50%, and pneumothorax, hemothorax, or hemopneumothorax in 13.04%. Drainage was performed in 94.20%, predominantly via chest tubes (76.81%). In 17.39% of patients, the chest tube was in place for one week or less, while 15.94% required chest tube placement for more than one week until two weeks. Another 18.84% needed chest tube placement for over two weeks to one month, and 5.80% had chest tube placement exceeding one month. Additional treatments included parenteral nutrition (50.72%), thoracic duct closure (39.13%), and dietary modifications such as a medium-chain fatty acid or low-fat diet (34.78%). Pharmacological treatments included octreotide in 24.64% of cases. Thoracic duct closure was performed through thoracotomy in 31.88%. Other less-used techniques included Fr microcatheter under radiological guidance in 2.90%, video-assisted thoracoscopy or laparoscopy in 2.90%, and coiling and glue embolization in 1.45%. In 59.42% of cases, thoracic duct closure was not performed. The majority of patients (89.85%) achieved complete recovery, with one case showing partial recovery (1.45%), and six cases died (8.70%) (Table 3). Discussion Chylothorax is a pathological condition; if left untreated, it can result in respiratory distress and various complications. The etiology is multifaceted, including traumatic causes, while non-traumatic factors may involve conditions that elevate lymphatic pressure or cause obstruction, such as lymphoma or heart failure [1,67]. Chylothorax was first documented in the medical literature during the 19th century but has since garnered increasing recognition with advancements in diagnostic and surgical techniques. Improved imaging modalities and surgical innovations have significantly enhanced the understanding of its pathophysiology, facilitating more effective identification and management of its underlying causes [1,2]. The demographic data in the present review revealed an age range of 11 months to 84 years, with a mean age of 37.4 ± 19.9 years. This aligns with the literature, as Elsaied et al. reported an approximate mean age of 42.67 years within an age range of 18 to 76 years [68]. Case reports have identified young adults as particularly susceptible to chylothorax following blunt chest trauma, who are commonly involved in motor vehicle collisions or sports injuries [12,31]. Conversely, another study found that individuals aged 50 years or older represented the most common age group among blunt chest trauma patients, comprising 28.9% of the sample [69]. This reflects the increased risk of falls and accidents among older populations [70]. The slightly lower mean age in the present study may be attributable to the inclusion of pediatric cases, broadening the demographic scope. A significant male predominance was observed in the current review, with 73.91% of cases involving males. This finding concurs with the literature, where male representation ranged from 72.3% in a literature review [71] to 85.4% in a cohort study on blunt chest trauma cases [69]. This gender disparity is often linked to higher exposure to high-risk activities and occupations among males [12,31]. The clinical presentation of chylothorax is variable, with dyspnea being the most common symptom, reported by approximately 66.7% of patients. Dyspnea arises from fluid accumulation in the pleural space, which restricts lung expansion and impairs gas exchange. Patients may also experience a dry cough, often exacerbated by pleural fluid [72]. Pleuritic chest pain is another potential symptom, likely caused by pleural irritation from chyle [3,5]. On physical examination, percussion of the thorax often reveals dullness over the affected area due to fluid accumulation, contrasting with the typical resonance of healthy lung tissue [3,12,22]. Auscultation typically shows diminished or absent breath sounds over regions where fluid has accumulated, reflecting impaired air movement [72]. In this review, consistent with the literature, dyspnea was the most common presenting symptom (47.83%). This was followed by abnormal findings on auscultation or percussion in 34.78% of cases. Other frequently reported symptoms included chest pain (21.74%) and complications such as pneumothorax, hemothorax, or hemopneumothorax (20.29%). The thoracic duct, the primary conduit for lymphatic fluid, can be ruptured or injured by blunt trauma, leading to chyle leakage into the pleural space [71,73]. Damage to adjacent structures, such as vertebral fractures or mediastinal injuries, can also contribute to chylothorax. For example, thoracic spine injuries have been associated with chylothorax due to their anatomical proximity to the thoracic duct [4,14]. Chylothorax is predominantly unilateral. In a study of 74 cases, 78% involved one hemithorax, with the right side being affected in 67% and the left in 33%. Bilateral pleural effusion was observed in 22% of cases [74]. The volume of chyle leakage varies based on the severity of the injury and the extent of thoracic duct damage. Low-output chylothorax (<1000 mL/day) is typically managed conservatively, whereas high-output cases (>1–1.5 L/day) often require surgical or radiological intervention [4,37,75]. In extreme cases, chyle output exceeding 2000 mL/day has been reported [6,15,21,30]. Blunt chest trauma frequently results from RTA, underscoring the risks of high-speed collisions [5,22,32]. Falls are another common cause, accounting for approximately 45% of cases in a study of patients with multiple traumas [76]. In this review, RTA was found to be the leading cause of injury in 41 cases (59.42%), followed by falls in 16 cases (23.19%), trauma by heavy objects in 6 cases (8.70%), physical punishment or child abuse in three cases (4.34%) and fistfights in one case (1.45%). Bilateral chylothorax occurred in 27.54% of cases, higher than previously reported. Consistent with the literature, right-sided involvement (55.07%) was more common than left-sided involvement (17.39%). This finding contrasts with the observation of Kakamad et al., who reported no laterality difference, but is similar to the findings of Maldonado et al., who reported right-sided involvement in 67% of cases and left-sided involvement in 33% [71,74]. Chyle volume varied significantly, with 40.58% of cases producing >1000–2000 mL/day, while 10 cases (14.50%) exceeded 2000 mL/day. The timing of chyle onset in this review varied, with symptoms developing within two days in 40.58% of cases and within three days to a week in 31.88%. These align with the finding that chylothorax most commonly manifests within 2 to 7 days following blunt chest trauma due to gradual pleural accumulation from duct leakage [71]. However, delayed onset beyond one month, as observed in 4.34% of reviewed cases, is rare but documented in the literature, with an extreme case reported up to 20 years post-trauma [18]. The biochemical composition of chyle among the reviewed cases primarily consisted of lipids (40.57%), with smaller proportions of lipid-protein mixtures (11.59%) and lipid-inflammatory cell mixtures (7.24%). Complex mixtures, including lipids, proteins, sugars, inflammatory cells, and ions, were identified in 5.80% of cases. These findings are consistent with the established biochemical profile of chyle, which is rich in triglycerides (≥110 mg/dL) and lymphocytes [71]. As reported in the literature, immunoglobulins and protein levels ranging from 2.2 to 6 g/dL underscore the nutritional and immunological impact of chyle loss [1,8,32]. In the present review, chest X-rays revealed pleural effusion in 55.07% of cases, consistent with its status as the most common radiographic finding in chylothorax, typically presenting as a homogeneous opacity [2,4,32,71]. Rib fractures and lung or mediastinal or heart shift each were observed in 10.14% of cases, with lung opacification in 8.70% and pneumothorax, or hemothorax in 7.24%, aligning with literature that highlights the utility of chest X-rays in detecting associated traumatic injuries, such as rib fractures and pulmonary contusions [2,6,77]. CT scans in the reviewed cases showed pleural effusion in 33.33% of cases and rib fractures in 20.29%. The detection of pneumothorax, hemothorax, or hemopneumothorax in 13.04% of cases further emphasizes the role of CT in visualizing coexisting traumatic injuries with greater detail than X-rays [4,77]. The initial approach to managing chylothorax primarily involves conservative measures, including nil per os (nothing by mouth), total parenteral nutrition, and adherence to a low-fat diet. Pharmacological interventions, such as octreotide, may decrease lymphatic flow and facilitate the closure of the leak [10,14,21,23]. In chylothorax management, chest tube placement is commonly maintained until chyle drainage significantly decreases or resolves. The duration varies from a few days to several weeks, influenced by the effectiveness of conservative approaches [78]. In this review, the chest tube was in place for one week or less in 17.39% of patients, while 15.94% required chest tube placement for more than one week until two weeks. Another 18.84% needed chest tube placement for over two weeks to one month, and 5.80% had chest tube placement exceeding one month. In cases where conservative management proves ineffective, surgical intervention becomes imperative. Thoracic duct ligation remains the definitive surgical option and can be performed via open thoracotomy or minimally invasive approaches [79]. Based on the findings of this review, besides drainage, treatments for chylothorax included parenteral nutrition (50.72%), thoracic duct closure (39.13%), and dietary modifications, such as a medium-chain fatty acid or low-fat diet (34.78%). Octreotide was administered in 24.64% of cases. Thoracic duct closure was performed via thoracotomy in 31.88% of cases, Fr microcatheter with fluoroscopic/ ultrasound guidance in 2.90%, VATS or laparoscopy in 2.90%, and coiling and glue embolization in 1.45%. In 59.42% of cases, thoracic duct closure was not performed or was unnecessary. The limitations of this study include the inherent nature of the reviewed studies, which were exclusively case reports due to the rarity of the condition. Consequently, drawing conclusions based on statistical analyses was not feasible. Additionally, the small sample size and the non-standardized data reporting across the included reports may have introduced potential bias into the findings of this review. While every effort was made to include all relevant studies identified through the search using predefined keywords, there remains the possibility that some studies were inadvertently overlooked. Conclusion BCTC is rare and complex, underscored by the wide variability in patient demographics, clinical presentations, chylothorax onset, and management approaches. Given the challenges posed by limited evidence, the findings emphasize the need for early recognition and individualized management strategies. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: FHK and HOA: major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. HKA, BJHA, and HMA: Literature review, critical revision of the manuscript, and processing of the tables. SHM, BeAA, SMA, MNH, SSA, YMM, KAN, SHK and BaAA: Data extraction, data organization, and critical revision. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Pediatric Adrenal Hydatid Cyst: A Case Report and Literature Review
Abstract Introduction: Echinococcosis is a zoonotic disease that can affect various organs and tissues in the human body. However, primary adrenal hydatid cyst (AHC) is rare and may be overlooked, making its early detection crucial. This report presents a case of an incidentally diagnosed primary AHC. Methods: A 5-year-old female with an unremarkable medical history underwent abdominal ultrasonography for assessment of an inguinal hernia, and a right adrenal lesion was incidentally discovered. Intraoperatively, the lesion was suspected to be AHC, which was later confirmed by histopathology. Results: The 10 cases of AHC that were reviewed had a mean age of 46.2 ± 12.2 years; six patients were male. Three cases had a history of contact with animals. No laterality differences were observed, and the mean cyst size was 7.45 ± 2.7 cm. Flank pain was the most common symptom (3 of 10), and surgery was performed for all the cases, accompanied by antiparasitic drugs in five cases. No cases of recurrence were reported. Conclusion: Primary AHC can be easily overlooked or misdiagnosed as an adrenal mass, often being identified incidentally during investigations for unrelated health concerns. Surgical excision of the cyst without rupture may yield favorable results. Introduction Echinococcosis is a widely recognized zoonotic disease caused by the larval form of the tapeworm Echinococcus granulosus [1]. Although the disease can occur globally, it is considered endemic in several regions, including the Middle East, the Mediterranean basin, parts of South America, South Africa, and Australia [1]. Humans serve as accidental intermediate hosts for the parasite, acquiring the infection through direct contact with definitive hosts (such as dogs) or via ingestion of food or water contaminated with feces that contain parasitic eggs, often originating from livestock environments involving sheep, goats, or cattle [2]. Major risk factors include close contact with dogs, involvement in livestock activities, and living in endemic areas [2]. The prevalence of hydatid cysts in children differs by region, with a reported incidence of 2-6 cases per 100,000 children affecting individuals as young as six months old. Human infections typically occur incidentally through the ingestion of parasite eggs in contaminated food or water or by direct contact with infected hosts [3,4]. Hydatid cysts (HCs) are typically found in the liver and lungs, while the adrenal gland is a rare and unusual site of involvement [5]. This report presents a case of a primary adrenal HC (AHC) that was incidentally diagnosed in a child. The references cited in this report have been reviewed to ensure the exclusion of any non-peer-reviewed data, and the study has been structured following the CaReL guidelines [6,7]. Case presentation Patient information and clinical findings A 5-year-old girl presented with a two-month history of reducible inguinal swelling on the left side. She had undergone a left inguinal herniotomy nine months earlier. The swelling, consistent with a recurrent inguinal hernia, increased in size during episodes of coughing or crying. Otherwise, her past medical history was unremarkable. She belonged to a socioeconomically poor family with limited education and resided in an urban area. Notably, her grandfather, who lived in a rural area and had direct contact with animals, had a history of HC. Diagnostic approach Ultrasonography was performed to rule out a right-sided inguinal hernia. Incidentally, it revealed a well-defined 30 × 20 mm lesion with a central cystic area between the right kidney's upper pole and the liver's right lobe, suggesting an adrenal lesion. Five days later, a follow-up ultrasound conducted by another radiologist identified a similar well-defined lesion measuring 31 × 19 mm. Subsequently, the patient was referred to a pediatric hematologist for further evaluation. Laboratory investigations revealed a normal complete blood count. Urinalysis indicated the presence of mucus, while aspartate aminotransferase (38 IU/L, Normal range: 15–40 IU/L) was borderline elevated, lactate dehydrogenase (370 IU/L, Normal range: 100–250 IU/L ), and erythrocyte sedimentation rate (28 mm/hr, Normal range: 0–10 mm/hr) were elevated. Computed tomography (CT) of the chest and abdomen demonstrated a well-defined, irregular, heterogeneous mass in contact with the right adrenal gland, with evidence of invasion into segment VII of the liver and involvement of the posterior right hemidiaphragm (Figure 1). <img id="image_3" src="https://www.judijournal.com/public/site/images/journaleditor/figure1.jpg" alt="Figure 1. Contrast-enhanced CT scan of the abdomen in axial (A) and coronal (B) views demonstrates a well-defined heterogeneous mass with cystic components (yellow arrow) adjacent to the right adrenal gland (blue arrow), exhibiting focal invasion of hepatic segment VII (red arrow). The mass is in contact with the right hemidiaphragm without definitive evidence of diaphragmatic invasion." width="1451" height="596" /> Therapeutic intervention Following a multidisciplinary discussion, the patient underwent surgery under general anesthesia. The procedure involved complete resection of the mass through a 10cm right subcostal incision, along with the excision of several ipsilateral lymph nodes for histopathological analysis (Figure 2). Subsequently, a left-sided herniotomy for the recurrent hernia was performed. Albendazole was administered postoperatively. Follow-up On the eighth postoperative day, the surgical wound was clean and dry. Histopathological examination revealed an infected wall of HC, accompanied by a granulomatous reaction, with adherent and compressed adrenal and liver tissue (Figure 3). Additionally, the ipsilateral lymph nodes exhibited reactive follicular hyperplasia. The patient's recovery was uneventful, and she remains under ongoing follow-up care. <img id="image_5" src="https://www.judijournal.com/public/site/images/journaleditor/figure3-01.jpg" alt="Figure 3. A) The upper part shows a lamellated wall of hydatid cyst (blue arrow) with cellular debris, and the lower part shows the adrenal cortex (H&E x100). B) Section shows lamellated wall of hydatid cyst (blue arrow) with chronic inflammation and foreign body giant cell reaction (black arrows) (H&E x100)." width="1920" height="725" /> Discussion Four distinct types of Echinococcus have been recognized as responsible for hydatid disease in humans, with E. granulosus being the most commonly encountered type (95%) [8]. The disease can affect all organs and tissues in the human body [9]. The mechanism behind adrenal involvement remains unclear. The most plausible theory suggests that once the larvae exit the digestive system, they pass through the hepatic filter to reach the lungs. If they evade destruction by the immune system or are not trapped in the filtration system, they can spread out to the unusual sites of the body, such as the spleen, kidneys, brain, bones, heart, muscle tissue, pancreas, retroperitoneum, thyroid, and adrenal glands via the arterial circulation [5]. Larvae can also disseminate through systemic circulation via lymphatic vessels or direct adjacent contact [5]. AHC is a rare entity, accounting for only 0.073% of all hydatid cyst cases [9]. While individuals of all ages can be affected, this condition is more frequently seen in those aged 50 to 60, with a slightly higher prevalence in women [10]. However, the 10 reviewed cases had a mean age of 46.2 ± 12.2 years; six patients were male. The youngest case was an 18-year-old male, and the oldest was a 64-year-old male [5, 8-16]. The present case was only a 5-year-old female, which seems to be an infrequent age for this disease. Children can contract the infection through several pathways, such as direct contact with infected animals or consuming contaminated food or water. Furthermore, the higher prevalence of HCs in endemic areas accounts for the increased incidence in younger age groups. The disease typically presents as unilateral in 92% of cases and does not exhibit a preference for either side [11]. This is supported by the fact that the disease was unilateral in all 10 cases reviewed in this report, with no differences in laterality observed (Table 1) [5, 8-16]. HCs are typically asymptomatic and often found incidentally during imaging studies for other reasons. They seldom lead to complications and usually become symptomatic primarily due to pressure-related effects [8]. Table 1. Summary of 10 reported cases of adrenal hydatid cysts Author /year [reference] Age (Y) Sex Country Contact with animals Tumor size (cm) Side Symptoms Medical history Therapeutic approach Recurrence Follow-up (M) Zouari et al./ 2020 [5] 55 N/A Tunisia N/A 12 Left Left hypochondrium pain None Surgery N/A N/A Tajmalzai et al./ 2025 [8] 18 M Afghanistan Yes 5.2 Right Right side flank pain None Albendazole & Surgery No N/A Agarwal et al./2024 [9] 38 M India N/A 6.8 Right Vague abdominal pain None Surgery & Albendazole No 12 Staouni et al./ 2022 [10] 46 F Morocco N/A 6 Left Left hypochondrial pain None Surgery No 12 Salih et al./ 2018 [11] 48 F United Arab Emirates Yes 7.2 Left Large palpable mass, moderate left loin pain None Laparoscopic surgery N/A N/A Tazi et al./ 2012 [12] 64 M Morocco No 11.3 Left Left flank pain nausea & vomiting Arterial hypertension Surgery No 24 Elzein et al./ 2016 [13] 44 M Saudi Arabia Yes 7.1 Right Flank pain N/A Surgery & Albendazole N/A N/A Abdulmajed et al./ 2010[14] 48 F Turkey No 5.2 Right Vague right loin pain Systolic hypertension Surgery & Albendazole N/A N/A Bouchaala et al./ 2021[15] 46 M Tunisia No 9.7 Right Non-specific abdominal pain Abdominal pain & weight loss Surgery & Albendazole No N/A Nardi et al./ 2015 [16] 55 M Argentina N/A 4 Left Back pain None Laparoscopic surgery N/A N/A M: male, F: female, N/A: non-applicable,Y: Years, M: months The most common symptoms are pain (hypochondriac or flank pain), nausea and vomiting, and palpable mass, usually due to inflammation of adjacent tissues caused by the cyst. Systemic symptoms may also occur, such as hypertension resulting from renal artery occlusion or symptoms that mimic pheochromocytoma due to compression of the adrenal medulla by cysts [9]. The most severe complication of HCs is cyst rupture, leading to anaphylaxis and bleeding [5,10]. Flank pain was the most common presenting symptom among the reviewed cases (3 of 10), with no systemic or severe complications reported [5,8-16]. Consistent with the literature, the present case was asymptomatic, and the HC was incidentally detected as an adrenal lesion on ultrasonography performed for an inguinal hernia. The imaging characteristics of hydatid disease vary depending on the stage of progression. Early lesions present as purely cystic, and as the germinal layer undergoes changes and intraluminal pressure decreases, the capsule becomes fibrotic and may occasionally calcify. Meanwhile, daughter cysts can detach from the wall and float within the lumen [12]. Based on the histopathological findings, which revealed a lamellated wall with cellular debris, accompanied by chronic inflammation and a foreign body giant cell reaction, the features may suggest that the cyst was in a relatively advanced or degenerative stage. The differential diagnosis of an adrenal cyst includes an endothelial cyst, a pseudocyst caused by infarction or hemorrhage in the adrenal gland, cystic neoplasm, cystic lymphangioma, calcified hemorrhagic cyst, extra-adrenal cystic masses, and post-traumatic cysts [9]. The identification of HCs in the adrenal gland primarily relies on ultrasonography and CT scans. Ultrasound has a sensitivity of 93% to 98% for diagnosis, while CT scans achieve around 97% sensitivity [10]. Ultrasound is typically the initial examination. However, the depth of the adrenal glands and occasional peripheral calcifications can make this assessment challenging. A CT scan provides a clearer view of the location and its relationship with nearby organs [5]. Hydatid serology (such as hemagglutination and ELISA) can offer diagnostic confirmation when results are positive. However, false negative results are possible [13]. Recognizing rare presentations like adrenal involvement is clinically important to avoid misdiagnosis and utilize an appropriate therapeutic approach. The treatment for the AHCs is primarily surgery. The two preferred options are pericystectomy and complete adrenal gland resection. However, the cyst resection while preserving the gland is considered the optimal approach [14,15]. Some authors reported that the laparoscopic approach represents a viable option due to its association with low morbidity and complication rates when performed by experienced surgeons [16]. In the present case, a CT scan was conducted following the incidental finding on ultrasonography. The scan revealed a well-defined, irregular, heterogeneous mass in contact with the right adrenal gland, with evidence of invasion into segment VII of the liver. Subsequently, the patient underwent surgery, during which the mass was completely resected. Histopathological examination confirmed the diagnosis of AHC. Conclusion Primary AHC can be easily overlooked or misdiagnosed as an adrenal mass, often being identified incidentally during investigations for unrelated health concerns. Surgical excision of the cyst without rupture may yield favorable results. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Written informed consent for publication was obtained from the parents. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: WNS, HAY, SFA, FHK, and MMA: Major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. SFA, HOA, BAA, and KAN: Literature review, critical revision of the manuscript, and processing of the table. PAN, SMA, and SSA: Literature review, and processing of the figures. All authors have read and approved the final version of the manuscript. Use of AI: ChatGPT-3.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Not applicable.
Current Perspectives on Cystic Echinococcosis: A Systematic Review
Abstract Introduction: Hydatidosis, a zoonotic disease caused by the larval stage of Echinococcus granulosus, is a significant public health concern with notable economic impact. It leads to morbidity and mortality worldwide, particularly in endemic regions. This study systematically reviews recent literature on cystic echinococcosis (CE) to provide updated insights into its prevalence, impact, and management. Methods: A systematic review was conducted using PubMed to find original articles on hydatid cysts published between September 1, 2019, and September 1, 2024. Data extracted included the first author's name, country, publication year, study type, number of cases, clinical presentation, diagnostic methods, cyst location and quantity, cyst status, treatment type and medications, follow-up details, recurrence, and mortality rates. Data were organized and qualitatively analyzed. Results: A total of 398 articles were identified, of which 229 articles with 1,002 patients met the inclusion criteria. Spain reported the highest number of CE cases at 362 (36.13%). Asia accounted for 487 cases (48.60%), and Europe contributed 460 cases (45.91%). The liver was the most frequently affected organ, accounting for 731 cases (72.95%), followed by the lungs with 110 cases (10.98%), and the kidney with 43 cases (4.29%). The age distribution of the cases showed that 63 (6.29%) were aged between 3 and 18 years. Conclusion: Hydatidosis remains a significant global public health concern, impacting developing and developed countries. The liver and lungs remain the primary sites of infection. Preventive strategies, including regular animal screening and enhanced public health education, are essential for controlling the spread of the disease. Introduction Cystic echinococcosis (CE), also known as hydatid disease (HD) or hydatidosis, is a well-known zoonotic disease caused by the larval stage of the tapeworm Echinococcus granulosus. Humans usually act as intermediate hosts, contracting the infection through direct contact with primary hosts like sheep, goats, cattle, dogs, and other canines or consuming food and water contaminated with the parasite's eggs [1, 2]. To date, HD is a serious public health problem that carries considerable economic implications. It leads to morbidity and mortality in various regions, notably in Mediterranean countries, the Middle East, New Zealand, Australia, India, and South America, mainly due to the close connections between sheep, dogs, and humans. It remains a neglected disease in many regions, necessitating concerted efforts for prevention and control, especially in rural areas where it is more prevalent [3, 4]. Hydatidosis can affect nearly any part of the body, but the liver is the organ most frequently impacted (75%), followed by the lungs (15%) and other organs like the brain (2%) and spine (1%) [3]. Hydatidosis is marked by a prolonged asymptomatic incubation period, often lasting several years. Clinical symptoms appear when the cysts grow large enough to compress nearby tissues. Additionally, cyst rupture into the peritoneal cavity can result in secondary cyst formation and the development of daughter cysts within them [3, 4]. This study systematically reviews recent literature on CE to provide updated insights into its prevalence, impact, and management. Methods Study design This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data sources and search strategy A systematic review was performed using PubMed to identify original articles on hydatid cysts. The search strategy targeted recent, peer-reviewed clinical studies on echinococcosis in human populations, published from September 1, 2019, to September 1, 2024, and restricted to English-language research. The search was limited to the literature of the last five years to shed light on the current disease situation. Eligibility criteria This systematic review included only original studies and case reports. Exclusion criteria were as follows: 1) articles not in English, 2) abstract only, 3) studies on alveolar echinococcosis, 4) studies unrelated to humans, 5) inadequately peer-reviewed articles, and 6) any study types that did not meet the inclusion criteria. All references in this study were evaluated for eligibility [5]. Study selection and data extraction The titles and abstracts of the selected studies were initially screened, followed by an in-depth full-text review to assess eligibility. Data extracted from each included study encompassed the first author’s name, country of origin, publication year, study type, number of cases, clinical presentation, diagnostic approaches, hydatid cyst location, cyst quantity, cyst status (intact or ruptured), treatment type, medications used, follow-up details, recurrence rate, and mortality rate. Statistical analyses Data were organized in an Excel spreadsheet (Microsoft Excel, 2021) and qualitatively analyzed using the Statistical Package for the Social Sciences (SPSS, version 27.0). Key findings were summarized as median, range, frequencies, and percentages. Results A total of 398 articles were identified through the search. After an initial review, 11 articles were excluded due to duplication and non-English language. The remaining 387 articles underwent title and abstract screening, during which 64 articles were excluded for not meeting the inclusion criteria. Consequently, 323 articles proceeded to full-text screening, and 93 were excluded due to unretrievable data, editorials, letters, or incomplete information. The remaining articles were then assessed for eligibility, resulting in 229 articles [1, 3, 4, 6-231] with 1,002 patients meeting the inclusion criteria and included in the study [Fig. 1]. Among the included studies, 217 (94.76%) were case reports, seven (3.06%) were cohort studies, three (1.31%) were case series, one (0.44%) was a cross-sectional study, and one (0.44%) was a randomized controlled trial (Table 1). Among the countries, Spain recorded the highest number of cases with 362 (36.13%), followed by China with 270 cases (26.95%) and Turkey with 128 cases (12.77%), collectively accounting for approximately 75% of the total reported cases (Table 2). In terms of continental distribution, Asia recorded 487 cases (48.60%), while Europe was not far behind with 460 cases (45.91%) (Table 3). Table 1. The details of the included studies First Author, Year Study design Country No. of cases First Author, Year Study design Country No. of cases First Author, Year Study design Country No. of cases AlRashed, 2024 [1] A Saudi Arabia 1 Mutlu, 2022 [82] A Turkey 1 Gatt, 2020 [157] A Israel 1 Amer, 2024 [6] A Iran 1 Ozgokce, 2022 [83] A Turkey 1 Giri, 2020 [158] A Bhutan 1 Babiker, 2024 [7] A Qatar 1 Passarelli, 2022 [84] A US 1 Gopivallabha, 2020 [159] A India 1 Bazzi, 2024 [8] A Lebanon 1 Pulavarty, 2022 [85] A India 1 Delgado, 2020 [160] A Spain 1 Brezeanu, 2024 [9] A Romania 1 Rodríguez-Laiz, 2022 [86] A Spain 1 Handran, 2020 [161] A US 1 Calu, 2024 [10] A Romania 2 Sezer, 2022 [87] A Turkey 1 İriz, 2020 [162] A Turkey 1 Chen, 2024 [11] A Taiwan 1 Shahid, 2022 [88] A Pakistan 1 İyigün, 2020 [163] A Turkey 1 Darestani, 2024 [12] A Iran 1 Sharma, 2022 [89] A India 1 Jarovsky, 2020 [164] A Brazil 1 Ghaedamini, 2024 [13] A Iran 1 Sozutok, 2022 [90] A Turkey 1 Johny, 2020 [165] A India 1 Gulati, 2024 [14] A US 1 Sun, 2022 [91] B China 2 Kankilic, 2020 [166] B Turkey 6 Hasnaoui, 2024 [15] A Tunisia 1 Ulusoy, 2022 [92] A Turkey 1 Kaskar, 2020 [167] A India 1 Haydar, 2024 [16] A Iran 1 Uzunoğlu, 2022 [93] A Turkey 1 Kiran, 2020 [168] A India 1 Jalayeri, 2024 [17] A Iran 1 Wang, 2022 [94] A China 1 Kırmacı, 2020 [169] A Turkey 1 Jellali, 2024 [18] A Tunisia 1 Agarwal, 2021 [95] A India 1 Kumar, 2020 [170] A India 1 Karahan, 2024 [19] A India 1 Aghajanzadeh, 2021 [4] A Iran 1 Lahdhil, 2020 [171] A Tunisia 1 Koren, 2024 [20] A Israel 1 Aili, 2021 [96] A China 1 Lapierre, 2020 [172] A Canada 1 Mahesan, 2024 [21] A India 1 Akhan, 2021 [97] A Turkey 1 Llanos, 2020 [173] A US 1 Bouhout, 2024 [22] A Morocco 1 Basne, 2021 [98] A Nepal 1 Lodhia, 2020 [174] A Tanzania 2 Manuel, 2024 [23] A Angola 1 Biswas, 2021 [99] A India 3 Lyske, 2020 [175] A Canada 1 Mierzejewski, 2024 [24] A Poland 1 Boumarah, 2021 [100] A Saudi Arabia 1 Ma, 2020 [176] E China 195 Mutlu, 2024 [25] A Turkey 1 Çankaya, 2021 [101] A Turkey 1 Mitrovic, 2020 [177] A Serbia 1 Remmerswaal, 2024 [26] A Netherlands 1 Cathomas, 2021 [102] A Switzerland 2 Mittal, 2020 [178] A India 1 Reyimu, 2024 [27] A China 1 Chatzifotiou, 2021 [103] A Germany 1 Moghtadaie, 2020 [179] A Iran 1 Sączek, 2024 [28] A Poland 1 Christodouli dis, 2021 [3] C Greece 50 Nistor, 2020 [180] A Romania 1 Thakar, 2023 [29] A India 1 Ciftci, 2021 [104] C Turkey 34 Ogul, 2020 [181] A Turkey 1 Voicu, 2024 [30] A Romania 1 Conlon, 2021 [105] A Ireland 1 Pappas, 2020 [182] A Greece 1 Aarif, 2023 [31] A India 1 Elvan-Tuz, 2021 [106] A Turkey 2 Ramia, 2020 [183] C Spain 71 Alsulami, 2023 [32] A Saudi Arabia 1 Gautam, 2021 [107] A India 1 Samadian, 2020 [184] A Iran 1 Ammar, 2023 [33] A Tunisia 1 Ghabisha, 2021 [108] A Yemen 1 Sangal, 2020 [185] A India 1 Borni, 2023 [34] A Tunisia 1 Gonder, 2021 [109] C Turkey 9 Sauteur, 2020 [186] A Switzerland 1 Carrel, 2023 [35] A Uzbekistan 1 Govindaraj, 2021 [110] A India 1 Savu, 2020 [187] A Romania 1 Casulli, 2023 [36] A Italy 1 Guha, 2021 [111] A India 1 Schleenvoigt, 2020 [188] A Germany 1 Caushi, 2023 [37] A Albania 1 Hãlmaciu, 2021 [112] A Romania 1 Singh, 2020 [189] A India 1 Das, 2023 [38] A India 1 Harmouchi, 2021 [113] A Morocco 1 Singh, 2020 [190] A India 1 Galvis, 2023 [39] A Colombia 1 Helvaci, 2021 [114] A Turkey 1 Singla, 2020 [191] A India 1 Göktürk, 2023 [40] A Turkey 1 Hermosa, 2021 [115] A Spain 1 Sonsoz, 2020 [192] A Turkey 1 Hakimi, 2023 [41] A Afghanistan 1 Iken, 2021 [116] A Morocco 1 Tekin, 2020 [193] A Turkey 1 Hasnaoui, 2023 [42] A Tunisia 1 Jaén-Torrejimeno, 2021 [117] C Spain 287 Tlili, 2020 [194] A Tunisia 1 Jia, 2023 [43] A China 1 Jindal, 2021 [118] A India 1 Tonkaz, 2020 [195] A Turkey 1 Kardoun, 2023 [44] A Tunisia 1 Kafadar, 2021 [119] A Turkey 1 Van De, 2020 [196] A Korea 2 Lao, 2023 [45] A China 1 Kankam, 2021 [120] A Iran 1 Vasilescu, 2020 [197] A Romania 1 Lees, 203 [46] A UK 1 Kechiche, 2021 [121] B Tunisia 10 Verma, 2020 [198] A India 1 Li, 2023 [47] A China 1 Khasawneh, 2021 [122] A Jordan 2 Villalobos, 2020 [199] A US 1 Ma, 2023 [48] A China 1 Kumar, 2021 [123] A India 1 Xu, 2020 [200] A China 1 Maggioni, 2023 [49] A Italy 1 Li, 2021 [124] A China 1 Yang, 2020 [201] A China 1 Mahmood, 2023 [50] A Pakistan 1 Maliqari, 2021 [125] A Albania 1 Yimamu, 2020 [202] A China 1 Mayekar, 2023 [51] A India 1 Moshref, 2021 [126] A Saudi Arabia 1 Abbas, 2019 [203] A Morocco 1 Moraes, 2023 [52] A Brazil 1 Mozafar, 2021 [127] A Iran 1 Aydin, 2019 [204] A Turkey 1 Moscatelli, 2023 [53] A Argentina 1 Rabhi, 2021 [128] A Tunisia 1 Banerjee, 2019 [205] A India 1 Ntombela, 2023 [54] A South Africa 2 Rhissassi, 2021 [129] A Morocco 1 Beyhan, 2019 [206] A Turkey 1 Peralta, 2023 [55] A Ecuador 1 Safari, 2021 [130] A Iran 1 Bracha, 2019 [207] A Israel 2 Peulier‐Maitre, 2023 [56] A France 1 Shakerian, 2021 [131] A Iran 1 Chaouch, 2019 [208] A Tunisia 1 Ruíz-Pérez, 2023 [57] A Peru 1 Shariﬁ, 2021 [132] A Iran 1 Demir, 2019 [209] A Turkey 1 Safarpour, 2023 [58] A Iran 2 Sharma, 2021 [133] A India 1 Derbel, 2019 [210] A Tunisia 1 Shah, 2023 [59] A India 1 Shuaibi, 2021 [134] A US 1 Gök, 2019 [211] A Turkey 1 Türkoğlu, 2023 [60] A Turkey 1 Simsek, 2021 [135] A Turkey 3 Kandemirli, 2019 [212] A Turkey 1 Wang, 2023 [61] A China 1 Şimşek, 2021 [136] A Turkey 1 Kang, 2019 [213] A Korea 1 Ahmady‑Nezhad, 2023 [62] A Iran 1 Singh, 2021 [137] A India 1 Kaya, 2019 [214] A Turkey 1 Assefa, 2022 [63] A Ethiopia 1 Ucar, 2021 [138] A Turkey 1 Khullar, 2019 [215] A India 1 Bicer, 2022 [64] A Turkey 1 van Zijl, 2021 [139] A South Africa 1 Kuzmanovska, 2019 [216] A Macedonia 2 Bishnoi, 2022 [65] A India 1 Velho, 2021 [140] A Portugal 1 MadissonBernardo, 2019 [217] A Brazil 1 Castro, 2022 [66] A Brazil 1 Wang, 2021 [141] A China 1 Magistri, 2019 [218] C Italy 15 Dantis, 2022 [67] A India 1 Wu, 2021 [142] A China 1 Milosavljevic, 2019 [219] A Serbia 1 Dere, 2022 [68] A Turkey 1 Yasin, 2021 [143] A Malaysia 1 Ramteke, 2019 [220] A India 2 Fourati, 2022 [69] A Tunisia 1 Zedelj, 2021 [144] A Croatia 1 Sharma, 2019 [221] A India 1 González Arboleda, 2022 [70] A Chile 1 Zhang, 2021 [145] A China 1 Singh, 2019 [222] A India 1 Hammade, 2022 [71] A Syria 1 Zouaghi, 2021 [146] A Tunisia 1 Syllaios, 2019 [223] A Greece 1 Hanalioglu, 2022 [72] A Turkey 1 Aboksari, 2020 [147] A Iran 1 Taşlıçay, 2019 [224] A Turkey 1 Çeviker,2022 [73] A Turkey 1 Acharya, 2020 [148] A Nepal 1 Tonkaz, 2019 [225] A Turkey 1 Huertas, 2022 [74] A Spain 1 Akhan, 2020 [149] D Turkey 38 Trawinski, 2019 [226] A Germany 1 Ijaz, 2022 [75] A Pakistan 1 Akhtar, 2020 [150] A India 1 Wa, 2019 [227] A China 1 Karahan, 2022 [76] A Turkey 1 Arora, 2020 [151] A India 1 Wang, 2019 [228] A China 1 Karami, 2022 [77] A Iran 1 Assimakopoulos, 2020 [152] A Greece 1 Xu, 2019 [229] A China 1 Kartavya, 2022 [78] A India 1 Bakshi, 2020 [153] A India 1 Yacine, 2019 [230] A Tunisia 1 Kumar, 2022 [79] A India 1 Destek, 2020 [154] A Turkey 1 Zhuoli, 2019 [231] A China 1 Li, 2022 [80] C China 53 Dkhissi, 2020 [155] A Morocco 1 Li, 2022 [81] A China 1 Ewnte, 2020 [156] A Ethiopia 1 A: case report, B: case series, C: cohort, D: randomized control trial, E: cross-sectional study, US: United States, UK: United Kingdom Table 2. The distribution of reported cases across countries Country Number of Cases Percentage (%) Spain 362 36.13% China 270 26.95% Turkey 128 12.77% Greece 53 5.29% India 44 4.39% Tunisia 24 2.40% Iran 18 1.80% Italy 17 1.70% Romania 8 0.80% Morocco 6 0.60% United States 6 0.60% Brazil 4 0.40% Israel 4 0.40% Saudi Arabia 4 0.40% Germany 3 0.30% Pakistan 3 0.30% South Africa 3 0.30% South Korea 3 0.30% Switzerland 3 0.30% Albania 2 0.20% Canada 2 0.20% Ethiopia 2 0.20% Jordan 2 0.20% Macedonia 2 0.20% Nepal 2 0.20% Poland 2 0.20% Serbia 2 0.20% Tanzania 2 0.20% Afghanistan 1 0.10% Angola 1 0.10% Argentina 1 0.10% Bhutan 1 0.10% Chile 1 0.10% Colombia 1 0.10% Croatia 1 0.10% Ecuador 1 0.10% France 1 0.10% Ireland 1 0.10% Lebanon 1 0.10% Malaysia 1 0.10% Netherlands 1 0.10% Peru 1 0.10% Portugal 1 0.10% Qatar 1 0.10% Syria 1 0.10% Taiwan 1 0.10% United Kingdom 1 0.10% Uzbekistan 1 0.10% Yemen 1 0.10% Table 3. Distribution of cases across continents Continent Number of cases Percentage (%) Asia 487 48.60% Europe 460 45.91% Africa 38 3.79% South America 9 0.90% North America 8 0.80% The liver was the most frequently affected organ, accounting for 731 cases (72.95%), followed by the lungs with 110 cases (10.98%), the kidney with 43 cases (4.29%), the heart with 37 cases (3.69%), and muscle tissue with 24 cases (2.40%) (Table 4). The gender distribution among the cases was nearly equal, with 505 males (50.40%) and 496 females (49.50%). The age distribution revealed that 63 cases (6.29%) were between 3 and 18 years old, while the age of 740 patients (73.85%) was unspecified. Among the identified cases, the median age was 35 (QR:19-51) years. The most common clinical presentations included pain (18.86%), fever (6.59%), shortness of breath (4.09%), and cough (2.69%), with 51 cases (5.09%) being asymptomatic. Clinical presentation was not documented for 616 cases (61.48%). Regarding cyst characteristics, single cysts were identified in 466 cases (46.51%), and intact cysts were found in 100 patients (9.98%). Treatment predominantly involved surgical intervention, performed in 639 cases (63.77%), and Albendazole was the most commonly prescribed medication, given in 275 cases (27.44%). Follow-up data revealed that 347 patients were monitored for less than six months (34.63%). Recurrence was observed in 26 cases (2.59%), and mortality occurred in 17 patients (1.70%) (Table 5). Table 4. Distribution of organs and body parts affected by hydatid cysts Organ Number of cases* Percentage (%) Liver 731 72.95% Lung 110 10.98% Kidney 43 4.29% Heart 37 3.69% Muscle 24 2.40% Brain 21 2.10% Abdominal cavity 16 1.60% Bone 14 1.40% Vertebral and spinal region 14 1.40% Pelvic region 12 1.20% Pancreas 9 0.90% Spleen 8 0.80% Mediastinum 5 0.50% Breast 4 0.40% Uterus 4 0.40% Intra-orbital 3 0.30% Thyroid gland 2 0.20% Gallbladder 1 0.10% Others 14 1.40% * Some patients had hydatid cysts in more than one organ. Table 5. Clinical and demographic characteristics of patients Variables Frequency (percentage) Gender Male Female Non-Identified 505 (50.40%) 496 (49.50%) 1 (0.10%) Age (year) 3 – 18 19 – 30 31 – 40 41 – 50 51 – 60 61 – 70 > 70 N/A Median (QR) 63 (6.29%) 52 (5.19%) 47 (4.69%) 34 (3.39) 18 (1.80%) 28 (2.79%) 20 (2.00%) 740 (73.85%) 35 (19–51) Clinical presentations* Pain Fever Shortness of breath Cough Asymptomatic Others N/A 189 (18.86%) 66 (6.59%) 41 (4.09%) 27 (2.69%) 51 (5.09%) 42 (4.19%) 616 (61.48%) Diagnostic findings Hydatid serology Positive Negative N/A CT scan Ultrasound MRI X. ray Echocardiogram N/A 139 (13.87%) 31 (3.09%) 832 (83.03%) 806 (80.44%) 475 (47.40%) 168 (16.77%) 69 (6.88%) 23 (2.29%) 105 (10.48%) Quantity of the cyst Single cyst Multiple cysts N/A 466 (46.51%) 203 (20.26%) 333 (33.23%) Cyst status Patients with intact cysts Patients with ruptured cysts Patients with intact and ruptured cysts N/A 100 (9.98%) 97 (9.68%) 6 (0.60%) 799 (79.74%) Type of treatment Surgical intervention Percutaneous treatment Medical treatment None N/A 639 (63.77%) 75 (7.49%) 31 (3.09%) 2 (0.20%) 255 (25.45%) Medication Albendazole Albendazole & Praziquantel Mebendazole None N/A 275 (27.44%) 9 (0.90%) 1 (0.10%) 26 (2.59%) 691 (68.96%) Follow up < 1 month – 6 months > 6 months – 1 year > 1 year – 2 years > 2years – 4 years > 4 years – 7 years > 7 years N/A 347 (34.63%) 25 (2.50%) 27 (2.69%) 13 (1.30%) 5 (0.50%) 2 (0.20%) 583 (58.18%) Recurrence Yes No N/A 26 (2.59%) 566 (56.49%) 410 (40.92%) Death Yes No N/A 17 (1.70%) 666 (66.47%) 319 (31.83%) * Some patients had multiple clinical presentations, CT scan: computed tomography scan, MRI: magnetic resonance imaging, N/A: not available Discussion Hydatidosis is most common in countries with extensive livestock industries but has recently become a significant global health issue due to rising immigration and travel [117, 232]. The disease is prevalent in Peru, Chile, Argentina, Uruguay, southern Brazil, the Mediterranean basin, Central Asia, western China, and East Africa. It remains absent in Antarctica and has been successfully eradicated through comprehensive control measures in Iceland, New Zealand, Tasmania, the Falkland Islands, and Cyprus [233]. In the present study, Spain unexpectedly showed the highest percentage of CE cases, with 36.13%, followed by China (26.95%) and Turkey (12.77%), collectively accounting for nearly 75% of all reported cases. Spain is known to be an endemic country for CE, but this unusually high percentage may be attributed to the fact that Spain has advanced healthcare infrastructure and diagnostic capabilities, which could lead to more accurate identification and reporting of CE cases. In contrast, in many developing countries, where resources and diagnostic tools may be limited, CE cases might be underreported or misdiagnosed [234]. This diversity underscores the importance of diagnostic and reporting capabilities when comparing CE prevalence across countries with differing healthcare systems. Regarding continental distribution, Asia represented 48.60% of cases, with Europe closely following at 45.91%. This distribution demonstrates that CE is not limited to traditionally endemic regions in developing countries but is also present in developed countries. Studies have identified the liver as the most common site for hydatid cysts, accounting for 75% of cases, followed by the lungs (15%) and the brain (2%) [3]. Furthermore, cysts can form in various other organs and structures, including the abdominal and pleural cavities, kidneys, spleen, bones, eyes, ovaries, testes, and pancreas [233]. The current study's findings confirm that the liver remains the most frequently affected organ (73%), with the lungs (11%) being the second most common site, consistent with the literature. However, the current study found that the kidneys, heart, and muscles were more frequently affected than the brain (2%–4% of cases). This contrasts with previous studies identifying the brain as the third most commonly affected organ [3, 235]. The European Centre for Disease Prevention and Control (ECDC) indicates that the occurrence of echinococcosis does not display a notable difference between genders, presenting a nearly balanced male-to-female ratio of 1.1:1 [236]. This finding aligns with the results of the present study, where the gender distribution among the cases was nearly equal, with males comprising 50.39% and females 49.50%, yielding a male-to-female ratio of approximately 1:0.98. However, Otero-Abad et al. reported that women are more susceptible to echinococcosis than men. This increased risk was linked to their more significant participation in household activities, such as food preparation and caring for pets, heightening their exposure to infected dogs, soil, and vegetables [237]. Moro et al. stated that only 10-20% of CE cases are identified in patients under 16 years old [238]. This is likely because CE is slow-growing and often asymptomatic, with most liver and lung cysts becoming symptomatic and diagnosed in adults. In contrast, in the current study, the highest prevalence of CE was observed in the pediatric age group of 3-18 years, with a rate of 24.05% among the 262 patients with available age data. This difference may be attributed to advancements in early CE diagnosis and the fact that most cases in this study were based on case reports. However, it is important to note that age data were unavailable for 73.85% of patients, which could potentially influence the observed distribution, as the missing data might disproportionately affect certain age groups and alter the findings. The next highest prevalence was in the 19-30 years (19.85%) and 31-40 years (17.94%) age groups, indicating that CE is also common among young and middle-aged adults. In contrast, a study in Western Romania found the highest prevalence in individuals aged 50-59 years (21.7%) [239], while the current study showed a much lower prevalence in the 51-60 years age group (1.80%). These differences may be attributed to regional variations in risk factors, such as livestock exposure, environmental conditions, and access to healthcare, all of which can influence the age distribution of CE. The clinical presentation of CE is highly variable, primarily influenced by factors such as the cyst's location, size, and condition. As CE cysts tend to grow slowly over time, they often result in a prolonged asymptomatic phase. Symptoms usually appear when the cysts reach a size that causes pressure effects or functional impairment in the affected organ [238]. Several studies highlight the differences in asymptomatic rates across various organ involvements. Ciftci et al. reported that 52.9% of patients with renal hydatid cysts were asymptomatic, indicating that cysts in the kidneys may remain unnoticed for extended periods until they cause local complications or are incidentally discovered [104]. In contrast, Akhan et al. found a higher rate of asymptomatic cases, 73.68%, among patients with liver hydatid cysts, suggesting that hepatic involvement might often go undetected, potentially due to the liver's capacity to accommodate growth without immediate symptoms [149]. In the present study, clinical presentation for 386 patients was available, and a much lower asymptomatic rate of 13.21% was observed. This discrepancy could be due to differences in cyst locations. It is possible that a higher proportion of patients in this study presented with symptoms due to the cysts being located in more clinically sensitive areas. Additionally, the lower asymptomatic rate might reflect a population with more advanced or larger cysts at the time of diagnosis, thereby increasing the likelihood of symptomatic presentation. Early detection of CE can greatly improve the success of its management and treatment [240]. The definitive diagnosis of CE typically relies on imaging techniques such as radiology, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) [241]. Serological tests like enzyme-linked immunosorbent assay (ELISA) offer high specificity for detecting HD, but a positive result does not accurately reveal the cyst’s location. Conversely, imaging methods provide detailed visualization, identifying cysts at specific sites. This limitation emphasizes combining serological testing with imaging to diagnose and precisely locate the hydatid cyst [242]. In the present study, among the 170 patients with CE who had serological test results available, 18.23% tested negative. Preventing CE relies on disrupting E. granulosus's life cycle. For instance, regular screening and treatment of infected dogs have effectively eradicated the disease in endemic regions. Additional control measures include restricting the feeding of home-slaughtered livestock to dogs and vaccinating intermediate hosts, such as sheep [243]. Community education plays a crucial role in preventing disease spread by raising awareness of the risks associated with infected animals and contaminated environments. Ongoing monitoring and collaboration among healthcare providers, veterinarians, and the community are essential for early detection and prompt intervention [244]. One limitation of this study is the predominance of case reports among the included studies. While these reports offer valuable insights into rare occurrences, they are inherently limited by small sample sizes, and potential selection bias. As a result, the findings may not be easily generalized to broader populations, and the ability to draw strong conclusions. Further research is needed to address the diagnostic challenges of CE in non-endemic regions, with a focus on improving early detection and treatment. Future studies should prioritize increasing healthcare professionals' knowledge, refining diagnostic processes, and evaluating the effectiveness of serological and imaging tools in regions with low disease prevalence. Conclusion Hydatidosis persists as a significant global public health concern, impacting both developing and developed countries. The liver and lungs remain the primary sites of infection. Preventive strategies, including regular animal screening and enhanced public health education, are essential for controlling the spread of the disease. Declarations Conflicts of interest: The author(s) have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgments: None to be declared. Authors' contributions: HAN, BAA, FHK, and HOA: major contributors to the conception of the study, as well as the literature search for related studies, and manuscript writing. SMA, SHM, RQS FA, YMM and DAH: Literature review, design of the study, critical revision of the manuscript, and processing of the tables. TMM, MNH, HAH, SHK, KKM, DAO, SHS and KAN: Literature review, data analysis and interpretation. All authors have read and approved the final version of the manuscript. Use of AI: AI was not used in the drafting of the manuscript, the production of graphical elements, or the collection and analysis of data. Data availability statement: Not applicable.
Complex Collision Tumors: A Systematic Review
Abstract Introduction: A collision tumor consists of two distinct neoplastic components located within the same organ, separated by stromal tissue, without histological intermixing. These rare tumors are usually identified incidentally in surgical specimens. This study systematically reviews complex collision tumors (those with three or more distinct histological types) to explore their features and clinical behavior. Methods: A comprehensive literature search was conducted using Google Scholar, Consensus AI, and Perplexity AI to identify all articles that describe collision tumors comprising more than two distinct pathologies. Studies lacking full texts, reviews, or those from predatory journals were excluded. Data extracted included publication details, patient demographics, clinical and diagnostic findings, tumor characteristics, treatments, outcomes, and follow-up. Findings were analyzed qualitatively and summarized using frequencies, percentages, and means with standard deviations. Results: A total of 2,798 articles were identified, and 26 studies (28 cases) met the inclusion criteria. Female patients accounted for 17 cases (60.72%), with a mean age of 63.46 ± 14.00 years. Surgery was performed in 26 cases (92.86%). Triple collision tumors were reported in 26 cases (92.86%), and quadruple collision tumors in 2 cases (7.14%). The thyroid gland was affected in 7 cases (25.00%), and papillary thyroid carcinoma was identified in 9 cases (32.14%). At the last follow-up, 22 patients (78.57%) were alive. Conclusion: Complex collision tumors represent rare and histologically diverse entities with significant diagnostic and therapeutic implications. They are most frequently found in the thyroid and skin. Accurate diagnosis typically requires comprehensive histopathological and immunohistochemical analysis of the entire lesion. Introduction A collision tumor is defined by the presence of two histologically distinct neoplastic components situated adjacent to each other within the same organ. These components are separated by intervening stromal tissue and lack histological intermingling, thereby classifying the tumor as a type of multiple synchronous neoplasm [1]. The concept of collision tumors was first introduced by Bernet in 1902 and later refined by Meyer in 1919 [2]. They most commonly arise in the liver, stomach, adrenal glands, ovaries, lungs, kidneys, and colon [3]. Collision tumors are exceedingly rare and are typically discovered incidentally during the pathological examination of surgically resected specimens. Due to their rarity, the biological behavior and optimal treatment strategies for collision tumors remain poorly understood, with most available evidence limited to case reports and small case series [4]. From a histopathological viewpoint, collision tumors typically contain both epithelial and mesenchymal components. Therefore, they must be carefully differentiated from other biphasic neoplasms such as carcinosarcomas, which show squamous epithelial and spindle cell elements; composite tumors, which display mixed histologic patterns within one lesion; and tumor-to-tumor metastasis [5]. The exact mechanisms underlying the development of collision tumors remain poorly understood. These neoplasms are thought to originate from a common malignant progenitor cell, which subsequently differentiates into two distinct lineages, each retaining its own malignant characteristics [5]. Collision tumors can consist of different combinations, including two benign neoplasms, a benign and a malignant tumor, or two malignant tumors [6]. A defining feature is that each component preserves its own morphological, immunohistochemical, and sometimes genetic identity, despite its close anatomical proximity [7]. This study aims to systematically review complex collision tumors (defined here as neoplasms composed of three or more distinct histological types within a single anatomical site without any intermixing) and offer comprehensive insights into their characteristics and clinical behavior. Methods Study Design This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data Sources and Search Strategy A comprehensive literature search was conducted using Google Scholar, Consensus AI (Pro), and Perplexity AI to identify all articles that describe collision tumors comprising more than two distinct pathologies. In Google Scholar, the search strategy incorporated the use of the “allintitle” and “excluding citation” features. Each of the following terms: Collision, Triple, Quadruple, Triad, Colliding, Combined, Simultaneous, Coexisting, Coexistence, Multicomponent, and Concurrent was individually paired with pathology-related terms using Boolean operators: Tumor, Tumors, Tumour, Tumours, Malignancy, Malignancies, Neoplasm, Neoplasms, Cancer, Cancers, Histology, Histologies, Carcinoma, and Carcinomas. The search was restricted to English-language publications. In Consensus AI and Perplexity AI, searches were performed using natural language queries formulated in a systematic review format (e.g., “reports of collision tumors involving three or more histologically distinct malignancies”). Retrieved responses were screened for primary literature sources, with cross-verification through direct journal links to ensure inclusion of peer-reviewed articles only. Eligibility Criteria All studies or case reports describing collision tumors involving more than two distinct pathological components were considered eligible for inclusion. Exclusion criteria included inaccessible full texts, review articles, or publications appearing in journals with insufficient peer review standards. The authenticity of the included studies was confirmed by comparing their publishing journals against recognized lists of predatory journals [8]. Study Selection and Data Extraction Titles and abstracts were screened to remove studies of dual-component collision tumors, non-human publications, and irrelevant study designs, such as review articles and studies that did not align with the research objectives. Full-text articles that passed the initial screening were then reviewed in detail, with exclusions made for irrelevant studies. Data extracted from the eligible studies included: the first author’s name, year of publication, patient demographics, clinical presentations, affected organs, initial diagnostic methods, imaging findings, type of surgery performed, histological diagnosis, histopathological features, immunohistochemical markers, lymph node involvement, organ metastasis, adjuvant therapies, postoperative complications, follow-up duration, recurrence, and patient status at the last follow-up. Statistical Analyses The data were compiled using Microsoft Excel (version 2021) and analyzed qualitatively with the Statistical Package for the Social Sciences (SPSS, version 27.0). Results were presented as frequencies with corresponding percentages, and means with standard deviations. Results Study Identification A total of 2,798 articles were identified through the comprehensive search. After the initial screening, 616 articles were excluded for the following reasons: duplication (n = 359), non-English language (n = 104), unretrieved data (n = 77), abstract-only publications (n = 58), non-article formats (n = 10), and preprints (n = 8). The titles and abstracts of the remaining 2,182 articles were screened, and 2,145 were excluded due to irrelevance (n = 1,187), including dual-component collision tumors (n = 892), non-human studies (n = 19), review articles (n = 16), and publications in journals with inadequate peer review standards (n = 31). The remaining 37 articles underwent full-text screening, 11 of which were excluded due to lack of relevance. Consequently, 26 eligible articles, encompassing 28 cases of complex collision tumors, were included in the review [1, 5, 9-32] (Table 1). The steps taken to identify relevant studies are represented in the PRISMA diagram (Figure 1). Table 1. Demographics, Clinical Features, and Imaging Findings of the Included Cases Author (yr) Study design Age (yr)/Sex Country of origin Cause of presentation Duration Medical history Surgical history Family history of cancer History of radiation exposure Site of tumors Initial diagnostic method Imaging findings Luo et al., 2024 [5] Case report 58/M China Progressive dysphagia 2 Months None N/A None N/A Esophagus Barium swallow + gastroscopic biopsy Barium: Irregular filling defect 8.9×5.0 cm mid-esophagus. CT: Emphysema, bullae, mass. Gastroscopy: Mass 28-32 cm from incisors, blocks ⅔ of the lumen. Bahbahani et al., 2023 [9] Case report 57/M Kuwait Routine checkup N/A Hypertension, dyslipidemia, GERD None Thyroid, breast N/A Left kidney Urinalysis, US, Contrast CT, PET/CT US: multiple left renal cysts; CT: multiple complex cystic lesions (Bosniak III & IV); PET/CT: hypermetabolic lesions in the left kidney. Boukhannous et al., 2022 [10] Case report 59/M Morocco Febrile right flank pain Not specified Type 2 diabetes, hypertension N/A N/A N/A Right kidney CT, MRI, ultrasound-guided biopsy CT: Right renal abscess, bilateral septic emboli. MRI: Right renal lesion (8.1×7.8×8.2 cm), possible infection vs. tumor. Rose et al., 2021 [11] Case report 82/M United Kingdom Ulcerated keratotic lesion on the upper right ear 3 months Hypertension, multiple non-melanoma skin cancers N/A N/A N/A Right ear Clinical examination, excisional biopsy CT: no evidence of distant metastasis Rupchandani et al., 2021 [12] Case report 89/M United Kingdom Right forearm lesion N/A Osteoarthritis, glaucoma, Klinefelter syndrome, DVT, paroxysmal atrial fibrillation, SCC, and actinic keratoses Previous excisions for SCCs and actinic keratoses; wide local excisions for the current lesion N/A N/A Right forearm skin Clinical evaluation, excisional biopsy CT: local extension to axilla, right subpectoral and axillary lymphadenopathy, chest wall extension; no distant visceral metastasis Toyoshima et al., 2021 [13] Case report 63/F Brazil Longstanding thyroid nodules, neck pain, and dysphagia 25 years Chronic lymphocytic thyroiditis, Hashimoto’s thyroiditis Total thyroidectomy N/A N/A Thyroid gland US, FNA US: heterogeneous nodules with calcifications in the left thyroid lobe (largest 6.4 cm) Hobbs et al., 2020 [14] Case report 66/M United States Asymptomatic enlarging lesion on the right anterior shoulder 1 year End-stage renal disease (post-kidney transplant), cirrhosis (post-liver transplant), immunosuppression, multiple NMSCs Kidney and liver transplant N/A N/A Right anterior shoulder skin Biopsy CT chest/abdomen/pelvis: no metastatic disease detected Lai et al., 2020 [15] Case report 62/F Taiwan Epigastric pain and dysphagia Not specified N/A N/A N/A N/A Esophagus Upper GI endoscopy with biopsy CT: esophageal mass at mid-third esophagus (T2N0M0); PET: no distant metastasis; endoscopic US: T1N0. Mizoguchi et al., 2020 [16] Case report 63/F Japan Recurrent abnormal uterine bleeding and anemia N/A Diabetes mellitus, hypertension Appendectomy N/A N/A Uterus Hysteroscopy, pelvic exam, MRI, CT MRI: 3.4 cm multiple nodular mass confined to the uterine cavity, no myometrial invasion; CT: confined to the uterus, no lymphadenopathy or metastases. Roshini et al., 2018 [17] Case report 27/F India Right-sided neck swelling 1 year None N/A None None Thyroid gland Ultrasound + FNA US: 3.8×2.4 cm hypoechoic solid nodule with small cystic areas in the right lower thyroid lobe; left lobe and isthmus normal. Liu et al., 2017 [18] Case report 58/F United States Fevers, chills, abdominal fullness, chest/back pain 1 month Invasive ductal carcinoma of left breast Lumpectomy for breast cancer N/A Post-lumpectomy radiation therapy Right adrenal gland CT scan of the abdomen CT: 6.2×4.3 ×5.1 cm heterogeneous right adrenal mass, increased in size compared to prior imaging (3.2 cm in 2005); irregular enhancement. Schizas et al., 2017 [19] Case report 76/M Greece Progressive dysphagia, weight loss (15 kg over 4 months) 4 months GERD N/A N/A N/A Esophagus Upper GI endoscopy, biopsy, CT scan Endoscopy: Barrett’s esophagus, 2 nodules (mid-esophagus and cardia); CT: diffuse esophageal wall thickening; no lymphadenopathy or distant metastasis. Masuyama et al., 2016 [20] Case report 52/F Japan Genital bleeding N/A N/A N/A None N/A Uterus Transvaginal US, MRI, PET-CT, biopsy Transvaginal US: 4.9×4.9×5.7 cm mixed echogenic cervical mass; MRI: 5.5×5.1×5.2 cm hyperintense mass invading lower uterine segment; PET-CT: high FDG uptake in cervical and endometrial masses, no distant metastasis. Bloom et al., 2014 [21] Case report 68/F United States Large, red-brown plaque on left buttock Since childhood Hypertension, hyperlipidemia, non-alcoholic steatohepatitis Cholecystectomy None N/A Left buttock skin Clinical examination, shave biopsy N/A Kim et al., 2014 [22] Case report 67/F South Korea A palpable mass on the anterior neck 2 years None None None None Thyroid gland FNA US: right thyroid 4.4 cm heterogeneous iso-echoic nodule; left thyroid 1.2 cm low-echoic nodule; no cervical lymphadenopathy; no distinct features of papillary carcinoma on imaging. Suzuki et al., 2014 [23] Case report 72/M Japan Routine checkup N/A Lung disease None None N/A Lung Chest CT, PET-CT, transthoracic needle biopsy CT: infiltrative shadow in right lower lobe with air bronchogram; PET-CT: SUV max 2.6; no lymphadenopathy or distant metastasis. Adnan et al., 2013 [24] Case series 43/F Israel Thyroid follicular nodular disease N/A N/A N/A None N/A Thyroid gland FNA N/A 44/F Israel Thyroid nodule N/A N/A N/A None N/A Thyroid gland FNA N/A 77/F Israel Incidental thyroid nodule N/A Osteoporosis N/A None None Thyroid gland FNA CT: right thyroid nodule 1.63 cm; US: solid, hypervascular nodule. Cornejo et al., 2013 [25] Case report 84/M United States Pearly, nonpigmented papule on the chest Not specified Multiple actinic keratoses, basal cell carcinoma N/A N/A N/A Chest skin Shave biopsy N/A Jang et al., 2012 [1] Case report 70/F South Korea Abnormal uterine bleeding and abdominal pain N/A Hypertension N/A None N/A Uterus Transvaginal US, pelvic CT Transvaginal US: 9.2×5.9 cm mixed echogenic mass; CT: Large endometrial mass with myometrial invasion, omental nodules; MRI: Heterogeneous uterine mass with poor enhancement, peritumoral infiltration. Rothschild et al., 2010 [26] Case report 74/F United States Left flank pain Not specified Long history of recurrent UTIs and renal calculi N/A N/A N/A Left kidney US, CT with contrast, MAG3 renal scan US: enlarged left kidney with cystic areas and stones; CT: staghorn calculus, multiple cystic low-attenuation lesions replacing parenchyma, consistent with XGP; MAG3 scan: non-functioning left kidney. Terada, 2010 [27] Case report 66/F Japan Cough; lung shadow detected on chest X-ray N/A N/A N/A N/A N/A Lung Chest X-ray, CT, MRI, lung biopsy Chest X-ray: abnormal shadow; CT/MRI: 3.5 cm mass in the right lower lobe, multiple lung metastases. Broughton et al., 2008 [28] Case report 78/F Belgium Fever, painful left axillary swelling, nausea, loss of appetite, asthenia 2 weeks Hypothyroidism, psoriasis, Diabetes mellitus Hysterectomy, left breast tumor resection N/A N/A Left axillary lymph nodes FNA CT: left axillary lymphadenopathy with surrounding soft tissue inflammation; PET: hot spots in the left axillary region, left breast, spleen, gastric fundus, left infraclavicular region. Wang et al., 2008 [29] Case report 62/M United States Vocal fatigue; nasopharyngeal mass N/A None N/A N/A N/A Nasopharynx Videolaryngoscopy, biopsy, IHC, flow cytometry CT neck, chest, abdomen, pelvis: negative for additional disease. Rekhi et al., 2007 [30] Case report 59/F India Enlarging neck mass with hoarseness of voice, dry cough, and increasing neck pain 5 years None N/A N/A None Thyroid gland FNA US: 3 nodules (left lobe, mid/inferior pole, isthmus) with calcification and cystic areas; CT: heterogeneous left thyroid mass displacing strap muscles and vessels, multiple enlarged cervical nodes. De Giorgi et al., 2005 [31] Case report 38/F Italy Pigmented lesion on the hip 6 months Cutaneous malignant melanoma Previous melanoma excision N/A N/A Hip skin Clinical exam, dermoscopy, surgical excision Dermoscopy: pigment network, regressive white area, punctiform vessels, blue-grey globules, pseudohorn cysts. Badiali et al., 1987 [32] Case report 63/M Italy Shortness of breath; occasional hemoptysis 1 month Chronic bronchitis and emphysema; 48-year smoking history None N/A None Lung Cytologic sputum exam, bronchoscopy Chest X-ray: large lobulated upper lobe mass (6 cm), smaller peripheral lower lobe lesion (3 cm); CT: confirmed lesions; bone/liver scans negative. CT: Computed tomography; FDG: Fluorodeoxyglucose; F: Female; FNA: Fine needle aspiration; GERD: Gastroesophageal reflux disease; GI: Gastrointestinal; IHC: Immunohistochemistry; M: Male; MAG3: Mercaptoacetyltriglycine; MRI: Magnetic resonance imaging; N/A: Not applicable; NMSC: Non-melanoma skin cancers; PET-CT: Positron emission tomography–computed tomography; SCC: Squamous cell carcinoma; SUV: Standardized Uptake Value; US: Ultrasonography; UTIs: Urinary tract infections; XGP: Xanthogranulomatous Pyelonephritis; yr: Year; DVT: Deep vein thrombosis. Demographic and Clinical Characteristics The mean age at diagnosis was 63.46 ± 14.00 years. Of the 28 patients, 17 female cases (60.71%) and 11 male cases (39.29%) were identified. The most commonly affected organs were the thyroid, with 7 cases (25.0%), and the skin, with 5 cases (17.86%). The esophagus, kidney, lung, and uterus were each involved in 3 cases (10.71%). Clinical manifestations varied according to tumor location. In thyroid tumors, thyroid nodules were the most common presenting symptom, observed in 3 cases (42.86%). Among skin tumors, lesions were reported in 3 cases (60.0%). All esophageal tumors presented with dysphagia (Table 1). Diagnostic Modalities and Interventions The most frequently used initial diagnostic method was biopsy, performed in 21 cases (75.0%), followed by CT scan in 9 cases (32.14%) and ultrasound in 7 cases (25.0%) (Table 1). Surgical intervention was performed in 26 cases (92.86%), tailored to tumor type and location (Table 2). Among all cases, 15 cases (53.57%) received adjuvant therapy, most commonly radiotherapy in 9 cases (60.0%), followed by chemotherapy in 5 cases (33.33%) (Table 3). Table 2. Surgical Management and Histopathological Characterization of Reported Complex Collision Tumors Author (yr) Type of surgery performed Collision tumor Short HPE description 1st tumor 2nd tumor 3rd tumor 4th tumor 1st tumor 2nd tumor 3rd tumor 4th tumor Luo et al., 2024 [5] Thoracoscopic-laparoscopic partial esophagectomy with lymphadenectomy Undifferentiated pleomorphic sarcoma Adenoid cystic carcinoma Squamous cell carcinoma None Storiform pattern, pleomorphic cells, myxoid degeneration. IHC: Vimentin+, CD68+, Desmin focal+, CD56+ Cribriform/tubular/solid patterns, glandular and myoepithelial cells. IHC: CK5/6+, p63+, CD117+, EMA+, S100 weak focal+, SMA weak focal+ Confined to mucosa, incomplete keratinization, and intercellular bridges. IHC: CK+, CK5/6+, EMA+, P40+, p63+, BerEP4 focal+ N/A Bahbahani et al., 2023 [9] Radical left nephrectomy Multilocular cystic clear cell renal cell carcinoma Clear cell papillary renal cell carcinoma Renal oncocytoma Renomedullary interstitial cell tumor Multilocular cystic tumor with thin fibrous septa and serous to gelatinous fluid. IHC: Not reported Solid, hemorrhagic, cystic tumor in the medulla. IHC: Not reported Well-demarcated, unencapsulated brown-tan nodule in cortex with pushing border. IHC: Not reported Composed of stellate cells in loose fibrotic basophilic stroma with entrapped tubules. IHC: Not reported Boukhannous et al., 2022 [10] Radical right nephrectomy Papillary Renal Cell Carcinoma Chromophobe Renal Cell Carcinoma Sarcomatoid dedifferentiation None Papillae of carcinomatous cells, moderate to marked nucleocytoplasmic atypia. IHC: CD10+, CK7+, vimentin+, pancytokeratin (weak +) Large nests of cells with abundant cytoplasm and perinuclear halo. IHC: CK7+, CD117+, E-cadherin+ Sheets of atypical spindle/giant cells, high mitotic activity. IHC: Not reported. N/A Rose et al., 2021 [11] Wedge excision, followed by re-excision Squamous cell carcinoma Basal cell carcinoma Invasive nodular melanoma None Moderately differentiated (pT2). IHC: Not reported Infiltrative (pT1). IHC: Not reported Invasive nodular (pT3a), 2.8 mm Breslow thickness. IHC: Melan-A+; others not specified N/A Rupchandani et al., 2021 [12] Excisional biopsy Merkel cell carcinoma Sebaceous carcinoma Bowen’s disease (Squamous cell carcinoma in situ) None Dermal nodules of small, round, blue cells. IHC: Not reported Lobular architecture with sebaceous differentiation. IHC: Not reported Full-thickness epidermal atypia (SCC in situ). IHC: Not reported N/A Toyoshima et al., 2021 [13] Total thyroidectomy; later bilateral neck dissection Widely invasive oncocytic carcinoma Classical variant papillary thyroid carcinoma Hobnail variant of PTC Poorly differentiated thyroid carcinoma Capsular invasion, oncocytic cells. IHC:Thyroglobulin+, TTF-1+, PAX8 focal+, p53+ Classical papillary architecture. IHC: Thyroglobulin+, TTF-1 inconclusive, p53 inconclusive Hobnail features with nuclear atypia and eosinophilic cytoplasm. IHC: Thyroglobulin+, p53+ Solid blocks with atypia, mitoses, and necrosis. IHC: Thyroglobulin+, p53+; Metastases: CK7+, GATA3+, negative for PAX8, TTF-1 Hobbs et al., 2020 [14] Mohs micrographic surgery followed by WLE and sentinel lymph node biopsy Merkel cell carcinoma Squamous cell carcinoma in situ Basal cell carcinoma None Small blue cell tumor, neuroendocrine features, stippled chromatin, molding, high mitotic activity. IHC: TTF-1+, CK20−, synaptophysin+, CAM5.2+, AE1/AE3 (dot-like), neurofilament (rare +), chromogranin− Intraepidermal atypia. IHC: CK5/6+ Peripheral palisading, retraction artifact. IHC: BerEP4+, chromogranin+, synaptophysin+, CK7 (some areas) N/A Lai et al., 2020 [15] Robotic minimally invasive esophagectomy, gastric tube reconstruction, cervical esophagogastrostomy, feeding jejunostomy Small cell carcinoma Squamous cell carcinoma Adenocarcinoma None Major component, poorly differentiated (G3), positive for insulinoma-associated one and CD56. IHC: insulinoma-associated 1+, CD56+, p40− IHC: p40+ Morphology consistent with glandular origin. IHC: Not reported N/A Mizoguchi et al., 2020 [16] Total abdominal hysterectomy with bilateral salpingo-oophorectomy Low-grade endometrial stromal sarcoma Uterine tumor resembling ovarian sex-cord tumor Leiomyoma None CD10+, sex cord-like differentiation, necrosis, MI 20/10 HPF. IHC: CD10+ CD10−, cords of epithelioid/spindle cells, hyalinized stroma. IHC: CD10−; cyclin D1 negative Spindle cells in fascicles, infarct-type necrosis. IHC: Not reported N/A Roshini et al., 2018 [17] Right hemithyroidectomy followed by completion thyroidectomy Not otherwise specified follicular-pattern carcinoma Papillary thyroid carcinoma Medullary thyroid carcinoma None Well-differentiated follicular pattern, capsular invasion. IHC: Not reported Classical nuclear features in Hashimoto’s background. IHC: Not reported Oval-to-spindle cells with salt and pepper chromatin. IHC: Synaptophysin (3+, 90%), CEA (3+, 90%), Chromogranin (2+, 90%) N/A Liu et al., 2017 [18] Laparoscopic right adrenalectomy Adrenal adenoma Myelolipoma Metastatic breast carcinoma None Zona fasciculata-like cells. IHC: Inhibin+, GATA-3− 4 mm focus within adenoma. IHC: Not reported Scattered atypical cells (~2% mass). IHC: GATA-3+, CK7+, ER+, PR+, CKAE1/AE3+, inhibin− N/A Schizas et al., 2017 [19] Transthoracic total esophagectomy with standard lymphadenectomy Small cell carcinoma (neuroendocrine) Moderately differentiated adenocarcinoma Signet ring cell carcinoma None Neuroendocrine appearance, upper lesion. IHC: Not reported Moderately differentiated, enteric type. IHC: Not reported Signet ring cell carcinoma: poorly cohesive adenocarcinoma, lower lesion. IHC: Not reported N/A Masuyama et al., 2016 [20] Radical hysterectomy, bilateral adnexectomy, pelvic lymph node dissection Endometrioid carcinoma Undifferentiated carcinoma Choriocarcinoma None G2, squamous differentiation, confined to the endometrium. IHC: Not reported Invaded half of the myometrium. IHC: Not reported Lymphovascular invasion, no endometrioid component. IHC: Not reported N/A Bloom et al., 2014 [21] Shave biopsy Eccrine poroma Seborrheic keratosis Viral wart None Bulbous aggregates of small squamous cells with eccrine ductal differentiation. IHC: Not reported Horn pseudocysts, hypergranulosis, compact orthokeratosis with parakeratosis. IHC: Not reported Papillated and polypoid lesion with crusting, spongiosis, and inflammatory infiltrate (neutrophils, plasma cells, lymphocytes). IHC: Not reported N/A Kim et al., 2014 [22] Bilateral total thyroidectomy with central neck dissection Follicular carcinoma Papillary microcarcinoma Medullary carcinoma None 4.3 cm with capsular invasion. IHC: Not reported 0.3 cm microcarcinoma, papillary features. IHC: Not reported 0.8 cm, small round nuclei, positive calcitonin staining. IHC: calcitonin+ N/A Suzuki et al., 2014 [23] Right lower lobectomy with mediastinal lymph node dissection Invasive mucinous adenocarcinoma Invasive non-mucinous adenocarcinoma Squamous cell carcinoma None Columnar, mucin-secreting cells with papillary invasion. IHC: Not reported Invasive glandular growth. IHC: Not reported Pseudostratified cells with keratinization and angular nuclei. IHC: Not reported N/A Adnan et al., 2013 [24] Total thyroidectomy + right modified neck dissection Medullary thyroid carcinoma Papillary thyroid microcarcinoma Follicular thyroid adenoma None Nests of oval cells. IHC: calcitonin+, thyroglobulin− IHC: thyroglobulin+ microfollicular pattern. IHC: Not reported N/A Total thyroidectomy + right modified neck dissection Medullary thyroid carcinoma Papillary thyroid microcarcinoma Follicular thyroid adenoma None IHC: calcitonin+, chromogranin+, synaptophysin+, CEA (partial)+ Not reported Not reported N/A Right thyroidectomy and isthmectomy Medullary thyroid carcinoma Papillary thyroid microcarcinoma Follicular thyroid adenoma None IHC: calcitonin+, CEA+, pankeratin+ Not reported Not reported N/A Cornejo et al., 2013 [25] WLE Melanoma Squamous cell carcinoma Basal cell carcinoma None High-grade atypia, pleomorphism, hyperchromasia, multinucleation, prominent nucleoli, brisk mitotic activity, involved hair follicles. IHC: S-100+, MART-1+, HMB-45+ Eosinophilic cytoplasm, marked nuclear atypia. IHC: cytokeratins+, p63+ but negative for Ber-EP4 and CD10 Basaloid cells with peripheral palisading. IHC: cytokeratins+, Ber-EP4+, CD10+ N/A Jang et al., 2012 [1] Total hysterectomy, bilateral salpingo-oophorectomy, lymphadenectomy, omentectomy, appendectomy Malignant mixed müllerian tumor Papillary serous carcinoma Endometrioid adenocarcinoma None Carcinomatous (glandular) and sarcomatous (spindle cell) components. IHC: p53+, CK+ (carcinoma), vimentin+ (sarcoma), MyoD1 focal+ Papillary growth, poorly differentiated, myometrial invasion. IHC: p53+, CK+, PR+, ER- Glandular and solid patterns with squamous differentiation, confined to endometrium. IHC: p53+, CK+, ER-, PR- N/A Rothschild et al., 2010 [26] Radical left nephrectomy Squamous cell carcinoma Osteogenic sarcoma Xanthogranulomatous pyelonephritis None Moderately differentiated, keratinizing, with necrosis and angiolymphatic invasion. IHC: Not reported High-grade spindle/polyhedral cells producing unmineralized osteoid. IHC: CD10+, pancytokeratin–, EMA–, SMA–, S100–, ALK-1– Lipid-laden macrophages, foamy histiocytes, and abscess formation. IHC: Not reported N/A Terada, 2010 [27] None; treated with chemotherapy only; autopsy performed after death Adenocarcinoma Squamous cell carcinoma Small cell carcinoma None Irregular glands with atypical cells and desmoplastic stroma. IHC: CK7+, CK8+, CK18+, CK19+, EMA+, CEA+, PDGFRA+ Keratinizing nests with intercellular bridges; merged with adenocarcinoma. IHC: CK5/6+, CK7+, CK8+, EMA+, CEA+, PDGFRA+ Small hyperchromatic cells with nuclear molding; distinct and separate. IHC: CK18+, chromogranin+, synaptophysin+, CD56+, PDGFRA+ N/A Broughton et al., 2008 [28] Left upper-inner quadrantectomy and axillary lymph node dissection Infiltrating lobular carcinoma (from breast cancer) Scleronodular Hodgkin’s disease Tuberculous lymphadenitis None Cohesive sheets of tumor cells (metastasis in the lymph node). IHC: ER+, Cerb2 (HER2) - Reed-Sternberg cells in hyperplastic cortex/para-cortex. IHC: Not reported Caseous necrosis, granulomas with epithelioid and Langhans giant cells. IHC: Not reported N/A Wang et al., 2008 [29] Biopsy only Mantle cell lymphoma (IgM+ phenotype) Mantle cell lymphoma (IgA+ phenotype) Extramedullary plasmacytoma None Sheets of small- to medium-sized lymphoid cells with slightly irregular nuclear contours and scant cytoplasm. IHC: CD20+, CD5+, cyclin D1+, IgM+ Similar morphology to the IgM+ MCL, but a distinct population based on immunophenotyping. IHC: CD20+, CD5+, cyclin D1+, IgA+ Composed of mature-appearing plasma cells arranged in sheets. IHC: CD138+, CD20−, IgG+, κ+, λ−, cyclin D1− N/A Rekhi et al., 2007 [30] Total thyroidectomy with bilateral cervical lymph node dissection Medullary thyroid carcinoma Papillary thyroid carcinoma Follicular variant of Papillary thyroid carcinoma None Nests of plasmacytoid cells with amyloid stroma. IHC: Calcitonin+, CEA+, Chromogranin+ Clear nuclei, grooves, and intranuclear inclusions. IHC: Thyroglobulin+ Papillary structures with colloid-filled cystic areas. IHC: Thyroglobulin+ N/A De Giorgi et al., 2005 [31] Surgical excision Melanocytic compound naevus Nodular basal cell carcinoma Seborrhoeic keratosis None Nests of pigmented melanocytes without significant atypia. IHC: Not reported Basaloid cells with peripheral palisading, clefts between the tumor and stroma. IHC: Not reported Pigmented basaloid cell proliferation, small keratin-filled cysts. IHC: Not reported N/A Badiali et al., 1987 [32] Right upper lobectomy, atypical resection of RLL, total right pneumonectomy Squamous cell carcinoma Small cell carcinoma Adenocarcinoma None Moderately differentiated; keratinization; intercellular bridges. IHC: Not reported Typical intermediate type; high nuclear-cytoplasmic ratio. IHC: Grimelius stain + Well-differentiated, mucin-secreting cells; glandular formation. IHC: Not reported N/A IHC: Immunohistochemistry; N/A: Not applicable; WLE: Wide local excision; yr: Year; HPE: Histopathological examination; SCC: Squamous cell carcinoma; PTC: Papillary thyroid carcinoma; MCL: Mantle cell lymphoma; RLL: Right lower lobe Table 3. Clinical outcomes and follow-up data Author (yr) Lymph node metastasis Organ metastasis Adjuvant therapies Postoperative complications Follow-up duration Recurrence Status at last follow-up Luo et al., 2024 [5] Yes, the middle esophageal lymph node N/A None N/A 101 months None Alive, no recurrence or metastasis Bahbahani et al., 2023 [9] None None None Elevated creatinine/eGFR drop 1 week None Alive with stable disease Boukhannous et al., 2022 [10] Yes, ipsilateral hilar lymphadenopathy Lungs Sunitinib N/A 1 year None Alive with stable disease Rose et al., 2021 [11] N/A N/A None N/A Ongoing at the time of the report N/A Alive, on regular follow-up Rupchandani et al., 2021 [12] Yes, extensive nodal disease in the right axilla and subpectoral region None Palliative radiotherapy N/A 43 days Local recurrence at the distal forearm wound site before radiotherapy Deceased Toyoshima et al., 2021 [13] Yes, bilateral cervical levels II–V, extracapsular invasion Lungs and liver RAI therapy (206 mCi); external-beam radiotherapy; sorafenib Developed respiratory failure; tracheostomy required 12 months Local, lymph node, and distant (lung and liver) Deceased Hobbs et al., 2020 [14] Yes, positive sentinel lymph node biopsy None N/A N/A N/A N/A Alive, under evaluation. Lai et al., 2020 [15] Yes, pericardial lymph nodes Esophagus Concurrent chemoradiation therapy with etoposide and cisplatin N/A N/A N/A Alive, under treatment Mizoguchi et al., 2020 [16] None None None N/A 6 months None Alive and disease-free Roshini et al., 2018 [17] N/A N/A N/A N/A N/A N/A Alive, on regular follow-up Liu et al., 2017 [18] Yes, axillary lymph nodes Adrenal gland, bone, left supraclavicular region, lung hila Aromatase inhibitor N/A 10 months Progression of metastatic disease Deceased Schizas et al., 2017 [19] Yes, the Gastrohepatic ligament lymph node Liver Cisplatin and etoposide N/A 6 months Multiple liver metastases Alive, undergoing definitive chemotherapy Masuyama et al., 2016 [20] Yes, the left external iliac lymph node None 6 cycles paclitaxel/carboplatin + 5 cycles methotrexate N/A 1 year N/A Alive and disease-free Bloom et al., 2014 [21] None None None N/A N/A N/A N/A Kim et al., 2014 [22] None None RAI (130 mCi) N/A 7 months None Alive and disease-free Suzuki et al., 2014 [23] None N/A None N/A 12 months N/A Alive and disease-free Adnan et al., 2013 [24] None None RAI (I-131, 100 mCi) N/A 1 year None Alive and disease-free None None RAI (I-131, 100 mCi) N/A N/A None Alive and disease-free None None None N/A N/A None Alive and disease-free Cornejo et al., 2013 [25] N/A N/A None N/A 6 months None Alive and disease-free Jang et al., 2012 [1] Yes, pelvic and para-aortic lymph nodes Omentum, serosa of the sigmoid colon Intraperitoneal chemotherapy (paclitaxel); systemic chemotherapy (paclitaxel, epirubicin, carboplatin); radiation therapy N/A 8 years None Alive and disease-free Rothschild et al., 2010 [26] None N/A N/A N/A N/A N/A Alive Terada, 2010 [27] Yes, systemic lymph nodes are positive for all three components Lungs, pleura, brain, bones, liver Chemotherapy N/A 7 months (from diagnosis to death) N/A Deceased Broughton et al., 2008 [28] Yes, nodes positive for breast carcinoma N/A Tamoxifen (for breast cancer), six cycles ABVD chemotherapy (for Hodgkin’s), 9-month anti-TB (isoniazid, rifampicin, ethambutol) Progressive anemia N/A N/A Alive with stable disease Wang et al., 2008 [29] N/A Bone marrow Radiotherapy to the nasopharynx (50 Gy in 25 fractions) N/A 15 months None Alive Rekhi et al., 2007 [30] Yes N/A RAI ablation (195 mCi) N/A Ongoing at the time of the report N/A Alive, on regular follow-up De Giorgi et al., 2005 [31] None None None N/A N/A N/A Alive and disease-free Badiali et al., 1987 [32] None None None Empyema <1 month N/A Deceased ABVD: Adriamycin (doxorubicin), Bleomycin, Vinblastine, and Dacarbazine; eGFR: Estimated glomerular filtration rate; GY: Gray; mCi: Millicuries; RAI: Radioactive iodine; TB: Tuberculosis; yr: Year; N/A: Not available Histopathology and Tumor Components Regarding tumor composition, 26 cases (92.86%) were triple collision tumors, while 2 cases (7.14%) were quadruple collision tumors (Table 2). The most common tumor types identified in collision neoplasms were papillary thyroid carcinoma in 9 cases (32.14%) and squamous cell carcinoma in 8 cases (28.57%), followed by adenocarcinoma in 7 cases (25.0%), medullary thyroid carcinoma in 6 cases (21.43%), small cell carcinoma in 4 cases (14.28%), and both basal cell carcinoma and follicular thyroid adenoma in 3 cases each (10.71%) (Table 4). Table 4. Types of Tumors Constituting the Reported Complex Collision Neoplasms Type of tumors Frequency (%) Papillary thyroid carcinoma (all variants) 9 (32.14%) Squamous cell carcinoma 8 (28.57%) Adenocarcinoma (all subtypes) Endometrioid adenocarcinoma Invasive mucinous adenocarcinoma Invasive non-mucinous adenocarcinoma Others 7 (25.0%) 1 (3.57%) 1 (3.57%) 1 (3.57%) 4 (14.28%) Medullary thyroid carcinoma 6 (21.43%) Small cell carcinoma 4 (14.28%) Basal cell carcinoma 3 (10.71%) Follicular thyroid adenoma 3 (10.71%) Merkel cell carcinoma 2 (7.14%) Seborrheic keratosis 2 (7.14%) Bowen’s disease (Squamous cell carcinoma in situ) 2 (7.14%) Adenoid cystic carcinoma 1 (3.57%) Adrenal adenoma 1 (3.57%) Choriocarcinoma 1 (3.57%) Chromophobe renal cell carcinoma 1 (3.57%) Clear cell papillary renal cell carcinoma 1 (3.57%) Eccrine poroma 1 (3.57%) Endometrioid carcinoma 1 (3.57%) Extramedullary plasmacytoma 1 (3.57%) Follicular carcinoma 1 (3.57%) Infiltrating lobular carcinoma 1 (3.57%) Invasive nodular melanoma 1 (3.57%) Leiomyoma 1 (3.57%) Low-grade endometrial stromal sarcoma 1 (3.57%) Malignant mixed müllerian tumor 1 (3.57%) Mantle cell lymphoma (IgA+ phenotype) 1 (3.57%) Mantle cell lymphoma (IgM+ phenotype) 1 (3.57%) Melanocytic compound naevus 1 (3.57%) Melanoma 1 (3.57%) Metastatic breast carcinoma 1 (3.57%) Multilocular cystic clear cell renal cell carcinoma 1 (3.57%) Myelolipoma 1 (3.57%) Nodular basal cell carcinoma 1 (3.57%) Not otherwise specified follicular-pattern carcinoma 1 (3.57%) Osteogenic sarcoma 1 (3.57%) Papillary Renal Cell Carcinoma 1 (3.57%) Papillary serous carcinoma 1 (3.57%) Renal oncocytoma 1 (3.57%) Poorly differentiated thyroid carcinoma 1 (3.57%) Renomedullary interstitial cell tumor 1 (3.57%) Sarcomatoid dedifferentiation 1 (3.57%) Scleronodular Hodgkin’s disease 1 (3.57%) Sebaceous carcinoma 1 (3.57%) Signet ring cell carcinoma 1 (3.57%) Tuberculous lymphadenitis 1 (3.57%) Undifferentiated carcinoma 1 (3.57%) Undifferentiated pleomorphic sarcoma 1 (3.57%) Uterine tumor resembling ovarian sex-cord tumor 1 (3.57%) Viral wart 1 (3.57%) Widely invasive oncocytic carcinoma 1 (3.57%) Xanthogranulomatous pyelonephritis 1 (3.57%) Metastatic Spread and Patient Outcomes Lymph node metastasis was present in 13 cases (46.43%), and organ metastasis occurred in 8 cases (28.57%), most commonly to the lungs in 4 cases (50.0%) and to the liver in 3 cases (37.50%). Recurrence was reported in 4 cases (14.28%) (Table 5). At the time of last follow-up, 22 cases (78.57%) were alive, 5 cases (17.86%) had died, and 1 case (3.57%) was lost to follow-up. Follow-up durations varied widely, ranging from one week to over 8 years (Table 3). Table 5. Summary of Clinical Features, Diagnosis, Treatment, And Outcomes Parameters Frequency (%) Age (mean ± SD) 63.46 ± 14.00 years Sex Female Male 17 (60.71%) 11 (39.29%) Tumor site/Presentations(a) Thyroid Thyroid nodule Neck mass Neck pain Dry cough Dysphagia Hoarseness Thyroid follicular nodular disease Neck swelling 7 (25.0%) 3 (42.86%) 2 (28.57%) 2 (28.57%) 1 (14.28%) 1 (14.28%) 1 (14.28%) 1 (14.28%) 1 (14.28%) Skin Lesion Nonpigmented papule Red-brown plaque 5 (17.86%) 3 (60.0%) 1 (20.0%) 1 (20.0%) Esophagus Dysphagia Epigastric pain Weight loss 3 (10.71%) 3 (100.0%) 1 (33.33%) 1 (33.33%) Kidney Flank pain Routine checkup 3 (10.71%) 2 (66.66%) 1 (33.33%) Lung Cough Hemoptysis Routine checkup Shortness of breath 3 (10.71%) 1 (33.33%) 1 (33.33%) 1 (33.33%) 1 (33.33%) Uterus Abnormal uterine bleeding Abdominal pain Anemia Genital bleeding 3 (10.71%) 2 (66.66%) 1 (33.33%) 1 (33.33%) 1 (33.33%) Adrenal gland Abdominal fullness Back pain Chest pain Chills Fever 1 (3.57%) 1 (100.0%) 1 (100.0%) 1 (100.0%) 1 (100.0%) 1 (100.0%) Lymph nodes Fever Axillary swelling Nausea Loss of appetite Asthenia 1 (3.57%) 1 (100.0%) 1 (100.0%) 1 (100.0%) 1 (100.0%) 1 (100.0%) Ear Ulcerated keratotic lesion 1 (3.57%) 1 (100.0%) Upper respiratory tract Vocal fatigue Nasopharyngeal mass 1 (3.57%) 1 (100.0%) 1 (100.0%) Initial diagnostic methods(b) Biopsy CT scan Ultrasound Clinical examination MRI PET-CT Others 21 (75.0%) 9 (32.14%) 7 (25.0%) 4 (14.28%) 4 (14.28%) 3 (10.71%) 13 (46.43%) Type of intervention Surgical Non-surgical 26 (92.86%) 2 (7.14%) Types of complex collision tumors Triple collision tumor Quadruple collision tumor 26 (92.86%) 2 (7.14%) Lymph node metastasis Yes No N/A 13 (46.43%) 11 (39.28%) 4 (14.28%) Organ metastasis(c) Yes Lungs Liver Bone Adrenal gland Bone marrow Brain Esophagus Omentum Pleura Sigmoid colon Supraclavicular region No N/A 8 (28.57%) 4 (50.0%) 3 (37.50%) 2 (25.0%) 1 (12.50%) 1 (12.50%) 1 (12.50%) 1 (12.50%) 1 (12.50%) 1 (12.50%) 1 (12.50%) 1 (12.50%) 12 (42.86%) 8 (28.57%) Adjuvant therapies(d) Yes Radiotherapy Chemotherapy Hormonal therapy Targeted therapy Anti-TB therapy Chemoradiotherapy No N/A 15 (53.57%) 9 (60%) 5 (33.33%) 2 (13.33%) 2 (13.33%) 1 (6.66%) 1 (6.66%) 10 (35.71%) 3 (10.71%) Recurrence Yes No N/A 4 (14.28%) 11 (39.29%) 13 (46.43%) Status at last follow-up Alive Deceased N/A 22 (78.57%) 5 (17.86%) 1 (3.57%) (a): Some patients had more than one presenting symptom; (b): Some patients underwent more than one initial diagnostic method; (c): Some patients had metastases involving multiple organs; (d): Some patients received more than one type of adjuvant therapy; TB: Tuberculosis; CT scan: Computed tomography scan; FNA: Fine needle aspiration; MRI: Magnetic resonance imaging; PET-CT: Positron emission tomography–computed tomography; N/A: Not applicable; SD: Standard deviation Discussion Terminological inconsistencies can lead to significant confusion, particularly when the term “double neoplasia” is used interchangeably across various clinical and pathological contexts. To minimize ambiguity, it is crucial to differentiate these entities based on both their anatomical location and the timing of their presentation [33]. Spagnolo and Heenan proposed specific diagnostic criteria for identifying collision tumors, emphasizing their dual origin. According to their definition, the two neoplastic components must arise from anatomically distinct topographic sites. At least partial separation should be evident between the components, enabling recognition of their independent origins, even in areas where the tumors are closely intermingled. Within the collision zone, transitional patterns may occur, ranging from areas of intimate admixture to regions displaying hybrid morphologies [34]. In contrast, synchronous tumors are defined as two or more independent primary malignancies diagnosed within a six-month period, whether they arise within the same organ or across separate anatomical locations. Metachronous tumors, on the other hand, are temporally separated, with the second tumor emerging more than six months after the first diagnosis. Meanwhile, composite, mixed, or heterologous tumors consist of histologically distinct cell populations within a single lesion, usually sharing a common molecular origin, as evidenced by clonal analyses that suggest derivation from a single progenitor mutation [33]. In this study, the term complex collision tumor was adopted to describe tumors composed of three or more histologically distinct neoplasms occurring within the same anatomical region without any intermixing. This subclassification represents a more advanced form of tumor heterogeneity, surpassing the traditional biphasic definition. Recognition of such complex entities holds clinical significance, as they often present diagnostic pitfalls and may necessitate individualized therapeutic strategies [5, 9, 10]. The pathogenesis of collision tumors remains incompletely understood, though multiple theories have been proposed. The most widely accepted explanation involves neoplastic heterogeneity, meaning that two or more different groups of tumor cells develop independently within the same area, resulting in separate but coexisting neoplasms [6]. Within this framework, Cornejo and Deng (2013) proposed several possible mechanisms. One is pure coincidence, as exemplified by the frequent co-occurrence of melanocytic nevus and basal cell carcinoma [25]. The second explanation is the field cancerization theory, which posits that chronically damaged tissue, such as sun-exposed skin or prior burn scars, has a predisposition for developing multiple distinct tumors in proximity. This is supported by the frequent occurrence of collision tumors in sun-damaged areas and in patients with conditions like xeroderma pigmentosum [6]. The third hypothesis, the interaction theory, suggests that one tumor may induce stromal or epithelial alterations in the surrounding tissue, thereby facilitating the emergence of a second tumor via paracrine signaling [6]. Alternative mechanisms not reliant on clonal divergence have also been proposed. Satter et al. described potential pathways such as hybrid tumor cell formation, aberrant immunophenotypic marker expression, stochastic genomic derepression, and dedifferentiation into a common stem-like precursor [35]. Despite these theoretical frameworks, the precise pathogenesis of complex collision tumors remains elusive. In a molecular study by Wang et al. (2008), fluorescence in situ hybridization and immunoglobulin gene rearrangement analyses revealed that two mantle cell lymphomas and a plasmacytoma were clonally unrelated, supporting the notion of a true collision event [29]. In contrast, Terada (2010) identified overlapping immunophenotypic features between adenocarcinoma and squamous cell carcinoma components of a lung scar carcinoma, suggesting divergent differentiation from a shared progenitor [27]. In this review of 28 complex collision tumors, 60.71% of patients were female, with a mean age of approximately 63.5 years. However, as patient age and sex were not stratified by tumor location in this study, these findings should be interpreted with caution. This apparent female predominance contrasts with most reports on dual-component collision tumors. For example, Schizas et al. (2024) reported that gastrointestinal collision tumors (n=53) predominantly affected males (81%) [4]. Conversely, Abdullah et al. (2024), in a systematic review of thyroid collision tumors (n = 122), observed a higher prevalence among females (71%) and a younger mean age of approximately 50 years [3]. Clinically, tumors in the current review presented with site-specific symptoms: thyroid lesions commonly appeared as nodules or neck masses, skin tumors as cutaneous lesions or plaques, esophageal tumors with dysphagia, renal tumors with flank pain, and uterine tumors with abnormal bleeding. These presentations are consistent with previous reports; thyroid collision tumors often present with neck swelling [3], while gastrointestinal collisions, such as those in the esophagus, typically cause obstructive symptoms [4]. All esophageal tripartite collisions in the present review presented as progressive dysphagia, mirroring the symptoms of dual-component gastrointestinal collisions. Collision tumors are frequently diagnosed incidentally, as they often lack distinctive radiological or clinical features. Preoperative biopsies commonly sample only a single histological component, limiting diagnostic accuracy [4]. In this review, 78.57% of cases underwent an initial biopsy, while definitive diagnosis required surgical resection in 92.86% of cases. This highlights a significant diagnostic challenge, as limited tissue sampling may fail to reveal the complex and heterogeneous nature of these tumors. In the case reported by Suzuki et al. (2014), the biopsy initially indicated only chronic inflammation, whereas the final diagnosis following surgery revealed a triple-component lung tumor composed of squamous cell carcinoma, invasive mucinous adenocarcinoma, and invasive non-mucinous adenocarcinoma [23]. Similarly, Thomas et al. (2021) found that in thyroid collision tumors, preoperative imaging failed to detect the smaller component in 60% of cases, and fine-needle aspiration cytology identified only the medullary element in all evaluated patients [36]. Luo et al. (2024) also reported that esophageal tripartite collisions were not suspected prior to surgery, as biopsies detected only one histological type and imaging revealed no distinguishing features [5]. Histopathologically, the most commonly observed components in complex collision tumors were papillary thyroid carcinoma (32.14%), squamous cell carcinoma (28.57%), adenocarcinoma (25.0%), medullary thyroid carcinoma (21.43%), and small cell carcinoma (14.28%). These findings align with reports in the literature. Toyoshima et al. (2021) described an aggressive thyroid tumor comprising widely invasive oncocytic carcinoma, classical and hobnail variants of papillary carcinoma, and poorly differentiated carcinoma [13]. Similarly, Kim et al. (2014) and Rekhi et al. (2007) reported combinations involving medullary, follicular, and papillary components [22, 30]. Tumors incorporating small cell carcinoma tended to exhibit particularly aggressive clinical courses, as noted in cases by Schizas et al. (2017) and Terada (2010), involving small cell carcinoma in conjunction with adenocarcinoma and squamous cell carcinoma in the esophagus and lung, respectively [19, 27]. Anatomically, dual collision tumors are most frequently reported in the liver, stomach, adrenal glands, ovaries, lungs, kidneys, and colon [3]. In contrast, the present study found that complex collision tumors most commonly involved the thyroid gland (25%), followed by the skin (17.86%), with the esophagus, lung, kidney, and uterus each accounting for approximately 10.71% of cases. The marked predominance of thyroid involvement may reflect the gland’s intrinsic predisposition to multiple neoplastic transformations arising from its follicular, parafollicular, and oncocytic cell lineages [3]. Although less frequent, cutaneous complex collision tumors present considerable diagnostic challenges. Rupchandani et al. (2021) and Hobbs et al. (2020) reported triple skin tumors combining Merkel cell carcinoma, basal or sebaceous carcinoma, and Bowen’s disease (in situ squamous cell carcinoma). Such lesions often mimic benign dermatologic conditions, increasing the risk of misdiagnosis unless thoroughly sampled and supported by immunohistochemical evaluation [12, 14]. Adjuvant therapy, including radiation and chemotherapy, was administered in over half of the cases (53.6%), reflecting the heterogeneity of tumor types. Despite these interventions, the recurrence rate was 14.28%, and the mortality rate approached 17.86%, highlighting the clinical severity of these tumors. Schizas et al. (2024) reported that among gastrointestinal collision tumors, several patients experienced early recurrence or metastasis (7.55%), and an equal proportion died within months of surgery, indicating the aggressive nature of certain tumor components [4]. Bladder collision tumors appear particularly concerning; a literature review by Omar et al. (2025) found that approximately 60% of cases were associated with recurrence or mortality [37]. Similarly, Luo et al. (2024) observed that most esophageal tripartite tumors exhibited rapid disease progression, with several patients dying within 1 to 14 months [5]. This study has several limitations, primarily stemming from the nature of the available literature, which consisted solely of case reports due to the rarity of the condition. As a result, quantitative statistical analysis was not possible. Furthermore, the limited number of cases and the variability in data reporting across the included reports may have introduced bias into the review’s findings. Despite a comprehensive search strategy using predefined keywords, it is also possible that some relevant studies were unintentionally missed. Conclusion Complex collision tumors represent rare and histologically diverse entities with significant diagnostic and therapeutic implications. They are most frequently found in the thyroid and skin. Accurate diagnosis typically requires comprehensive histopathological and immunohistochemical analysis of the entire lesion. Recognition of these entities is critical to guide appropriate management and improve patient outcomes. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Consent for participation: Not applicable. Consent for publication: Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: D.A: contribution to the conceptualization of the study, performing the literature search, data extraction, and methodological assessment, and drafting the initial version of the manuscript, including the preparation of the diagram and tables. M.A.A: contribution to the conceptualization and supervision of the study, validating the methodological quality and interpreting the data, critically revising the manuscript for important intellectual content. Both authors approved the final version of the manuscript for submission. Use of AI: ChatGPT-4.5 was used to assist with language refinement and improve the overall clarity of the manuscript. All content was thoroughly reviewed and approved by the authors, who bear full responsibility for the final version. Data availability statement: Data are available from the corresponding author upon reasonable request.