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.