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.