Delayed Diagnosis and Rapid Progression of Colorectal Small-Cell Neuroendocrine Carcinoma

Delayed Diagnosis and Rapid Progression of Colorectal Small-Cell Neuroendocrine Carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Delayed Diagnosis and Rapid Progression of Colorectal Small-Cell Neuroendocrine Carcinoma Alessandro Verbo, Mattia Angelo Bez, Danilo Di Giorgio, Iacopo Verbo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7850693/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Colorectal small-cell neuroendocrine carcinoma (NEC) is an uncommon, highly aggressive malignancy that can mimic benign adenomatous lesions, leading to diagnostic delay and poor prognosis. Case Presentation: A 67-year-old patient underwent colonoscopy after a positive faecal occult blood test, which revealed a large ulcerated yellowish sigmoid lesion with raised margins. Endoscopic biopsies showed only a tubulovillous adenoma with low-grade dysplasia. Because of benign histology and scheduling constraints, surgery was postponed for 40 days. Laparoscopic sigmoid colectomy with lymphadenectomy ultimately revealed a poorly differentiated small-cell NEC (pT2) with five of twelve lymph nodes positive. Immunohistochemistry showed strong CD56 and NSE positivity, CK20 negativity in tumour cells, and a Ki-67 index > 90%. Forty days post-operatively, PET-CT demonstrated new liver and lung metastases, indicating rapid systemic dissemination. Conclusion: This case underscores the diagnostic challenges of colorectal NEC and the potential impact of treatment delay. When endoscopic findings appear malignant despite benign histology, deep biopsies, expedited resection, and early staging are essential to prevent disease progression. This case emphasizes the need for timely management in lesions with discordant clinical and histopathologic features. Colorectal neuroendocrine carcinoma Delayed surgery Diagnostic discordance Rapid metastasis Small-cell carcinoma Figures Figure 1 Figure 2 Highlights • Colorectal small-cell neuroendocrine carcinoma (NEC) is an extremely rare and highly aggressive malignancy that may mimic benign adenomatous lesions. • Diagnostic discordance between endoscopic appearance and superficial biopsy can delay surgery and allow rapid systemic progression. • Early recognition, deep biopsies, and expedited resection are essential to prevent disease upstaging and improve outcomes. Introduction Colorectal NEC accounts for less than 1% of colorectal cancers and represents one of the most aggressive gastrointestinal malignancies. Histologically, NECs are high-grade tumours (mitotic count > 20/10 HPF; Ki-67 > 20%) and are commonly associated with TP53 and RB1 mutations rather than MEN1, DAXX, or ATRX alterations seen in well-differentiated NETs [ 1 – 3 ]. These tumours typically present with early vascular invasion and distant metastases, leading to a poor overall prognosis. We report a case of sigmoid small-cell NEC initially misdiagnosed as a benign adenoma, in which metastatic dissemination occurred following a 40-day delay in surgical management. Recent studies [ 6 , 7 ] have highlighted the importance of rapid intervention and the role of multidisciplinary assessment in managing aggressive neuroendocrine neoplasms. Case Presentation A 67-year-old man, otherwise healthy, underwent colonoscopy following a positive faecal occult blood test. Endoscopy revealed a large sessile, ulcerated, yellowish mass in the sigmoid colon with raised margins, suggestive of a submucosal lesion. Biopsies showed a tubulovillous adenoma with low-grade dysplasia. Routine laboratory tests, including CEA and liver function, were within normal limits. Given the lesion’s morphology and size, endoscopic resection was unfeasible. Laparoscopic sigmoid colectomy with lymphadenectomy was scheduled but postponed for 40 days due to benign biopsy findings and institutional scheduling constraints. Table 1 summarises the clinical timeline. Table 1. Clinical timeline Event | Approx. day | Findings Positive faecal occult blood test | 0 | Indication for colonoscopy Colonoscopy + biopsy | 7 | Tubulovillous adenoma, low-grade dysplasia CT scan | 14 | Sigmoid wall thickening, no metastasis Planned surgery | 15 | Deferred due to benign biopsy Actual surgery | 55 | Laparoscopic colectomy + lymphadenectomy Histopathology | 65 | Poorly differentiated NEC (pT2), 5/12 LN positive PET-CT | 95 | New hepatic and pulmonary metastases Histopathology and Immunohistochemistry Microscopic examination revealed a solid, undifferentiated small-cell carcinoma infiltrating the submucosa beneath the adenomatous component, with vascular invasion. Immunohistochemistry showed strong positivity for CD56 and NSE, and negativity for CK20 in tumour cells (positive in the adenomatous epithelium). Ki-67 exceeded 90%. Chromogranin A was unavailable due to sample limitation; synaptophysin was positive when tested. A postoperative PET-CT at 40 days revealed new liver and lung metastases. The multidisciplinary tumour board recommended adjuvant platinum-based chemotherapy. Discussion This case highlights two key issues in colorectal NEC: diagnostic ambiguity and the impact of delayed treatment. NECs may endoscopically resemble adenomas or adenocarcinomas; superficial biopsies often miss the submucosal component where the NEC predominates [ 4 , 5 ]. Recognition of endoscopic warning signs—yellowish ulceration, raised borders, and firm consistency—should prompt deeper sampling or early surgical excision even if histology appears benign. While a causal link cannot be proven, the temporal association between surgical delay and metastatic spread suggests aggressive disease biology. Reported median survival for metastatic colorectal NEC is less than 12 months, emphasising the importance of rapid diagnosis and multidisciplinary management. Recent studies reinforce that early radical resection followed by systemic therapy offers the best outcome in localized disease [ 6 , 7 ]. This case underscores that clinical suspicion should override benign biopsy results when morphologic features suggest malignancy. Conclusion Colorectal small-cell NEC is a rare but highly aggressive malignancy. Discordance between benign biopsy and suspicious endoscopic features must raise suspicion for sampling error. Prompt surgical resection and early systemic staging are vital to improve outcomes. Declarations Ethical Approval Written informed consent for publication of this anonymised case and accompanying images was obtained from the patient. The study complies with the Declaration of Helsinki (2013 revision). Conflict of Interest The authors declare no conflicts of interest and no external funding. Author Contribution A.V. conceived the study, collected data, and drafted the manuscript.M.B. and I.V. contributed to data analysis and interpretation.D. DG. supervised the research and critically revised the manuscript.All authors read and approved the final version of the manuscript. References Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: the WHO 2019 update. Mod Pathol. 2018;31:1770–1786. Warsinggih G, et al. Colorectal neuroendocrine carcinoma: a case report and literature review. Int J Surg Case Rep. 2020;72:411–417. Yoshida T, et al. Colorectal neuroendocrine carcinoma: clinicopathological features and treatment outcomes. World J Clin Cases. 2019;7:1865–1875. Shafqat H, et al. High-grade neuroendocrine carcinomas of the colon and rectum: clinicopathologic features and outcomes. Dis Colon Rectum. 2015;58:294–303. Jiang M, et al. Prognostic factors and treatment outcomes of colorectal neuroendocrine carcinoma. Gastroenterol Res Pract. 2017;2017:4206172. Dasari A, et al. Clinical, molecular, and therapeutic advances in neuroendocrine carcinomas. Neuroendocrinology. 2023;113(1):10–25. van der Zwan WA, et al. Colorectal neuroendocrine carcinomas: diagnostic pitfalls and treatment challenges. Cancers (Basel). 2022;14(8):1947. Sorbye H, et al. High-grade gastroenteropancreatic neuroendocrine carcinoma: recent progress and future directions. Nat Rev Clin Oncol. 2023;20(2):117–134. Milione M, et al. Colorectal poorly differentiated neuroendocrine carcinomas: molecular profile and clinical implications. Eur J Cancer. 2022;163:138–150. McNamara MG, et al. Systemic therapy in advanced neuroendocrine carcinoma: current evidence and future strategies. J Clin Oncol. 2023;41(12):2145–2156. Esposito I, et al. Colorectal small-cell carcinoma: pathologic spectrum and diagnostic challenges. Histopathology. 2024;84(3):305–316. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7850693","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":528943962,"identity":"eb31fbac-eb99-4b3e-8167-d66214175534","order_by":0,"name":"Alessandro Verbo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIie3RsUoDMRjA8RyB3JKSNUfp+QqRwD1PuzhVn6DIycF1qZ0z+BCCoItDwgd16QPccINSuMnBQygZSvF6Zx30oqtD/kOy5MeXEIR8vv9Y2G1B2u0asXY9hB0EfydR2hLBEXaYH0R0IxriGMMyDLWdlaOHeUp4/VjGsjg32s52lyhkuo9wIGdDuqrkzVqTSFWVTIqLsVmsfrkY0AQjAhPFx1hSDZP7YioAETc5AfZe2/0n2TXkTh3I3k0EUMQHeUuCDWrILW9IkLvJKZBkOFiCVNRcvSx0Jfn6VZjrpYxyjEUfiZ+yTW23MFJhprXVZczmU/lmtzFjzDz3v/+r49ccI3+c9/l8Pp+7D1LEYwk/IC/CAAAAAElFTkSuQmCC","orcid":"","institution":"Catholic University of the Sacred Heart","correspondingAuthor":true,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Verbo","suffix":""},{"id":528943964,"identity":"1f3952c8-b954-43c6-a794-e77943922ea5","order_by":1,"name":"Mattia Angelo Bez","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mattia","middleName":"Angelo","lastName":"Bez","suffix":""},{"id":528943966,"identity":"6921e691-73fd-444e-b8c8-9ddd40b4228e","order_by":2,"name":"Danilo Di Giorgio","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Danilo","middleName":"Di","lastName":"Giorgio","suffix":""},{"id":528943968,"identity":"47f950cc-2d30-4371-839d-6dba34360949","order_by":3,"name":"Iacopo Verbo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Iacopo","middleName":"","lastName":"Verbo","suffix":""}],"badges":[],"createdAt":"2025-10-13 15:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7850693/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7850693/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93571873,"identity":"e1ba5968-4b8b-4095-ac65-82bbaafd0f09","added_by":"auto","created_at":"2025-10-15 09:06:04","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3128868,"visible":true,"origin":"","legend":"","description":"","filename":"NEC.docx","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/0c06d2fefc6641cd24ec39b9.docx"},{"id":93571866,"identity":"7ccac8cf-975f-465b-9093-9bebe3ff9181","added_by":"auto","created_at":"2025-10-15 09:06:04","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4616,"visible":true,"origin":"","legend":"","description":"","filename":"5eaeceb7ee0c43a2bdab54dfb53e7307.json","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/7ec6f0ec8f1a3194f40c7510.json"},{"id":93574009,"identity":"236048d0-26a8-4cdd-937f-818a0b5c63f0","added_by":"auto","created_at":"2025-10-15 09:14:04","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":23481,"visible":true,"origin":"","legend":"","description":"","filename":"5eaeceb7ee0c43a2bdab54dfb53e73071enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/b2d24204c9ce463da2298570.xml"},{"id":93571871,"identity":"e90365a0-a026-4a2f-ba7a-618fa7c9bf88","added_by":"auto","created_at":"2025-10-15 09:06:04","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":901219,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/d4fb8ee8d3d625e2d336e4d5.png"},{"id":93575096,"identity":"cd429265-7b3f-40b4-9577-806d217ff155","added_by":"auto","created_at":"2025-10-15 09:22:04","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21199,"visible":true,"origin":"","legend":"","description":"","filename":"5eaeceb7ee0c43a2bdab54dfb53e73071structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/2c1f988f906d1f04b761bf04.xml"},{"id":93571868,"identity":"3eacb597-d4ac-4819-8944-9b81d97a65c1","added_by":"auto","created_at":"2025-10-15 09:06:04","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":26749,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/7a563eac511234892bcf902a.html"},{"id":93571867,"identity":"fb35d1ea-0df6-4e02-af08-dd77be8ae10d","added_by":"auto","created_at":"2025-10-15 09:06:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1180884,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic appearance of the sigmoid lesion. A large ulcerated, yellowish mass with raised margins is visible in the sigmoid colon. The lesion appeared submucosal with irregular edges and firm consistency, features suggestive of malignancy despite benign biopsy findings.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/c19f6f25de7de466fc985c6a.png"},{"id":93574010,"identity":"f4896588-a7ae-49ef-9dec-0ec1dc04d28f","added_by":"auto","created_at":"2025-10-15 09:14:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1344510,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological and immunohistochemical findings. (A) Hematoxylin–eosin staining showing sheets of small round blue cells infiltrating the submucosa beneath the adenomatous epithelium (×200). (B) Immunohistochemistry reveals strong CD56 and NSE positivity and high proliferative index (Ki-67 \u0026gt; 90%), consistent with poorly differentiated small-cell neuroendocrine carcinoma.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/b1524bcc61a13b25116a13d1.png"},{"id":94098245,"identity":"6782d32a-4b69-4056-926e-1e264cc77cc9","added_by":"auto","created_at":"2025-10-22 10:32:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3741070,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7850693/v1/0bb6f561-d8dc-47da-aa7e-4e6f3fd04d91.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Delayed Diagnosis and Rapid Progression of Colorectal Small-Cell Neuroendocrine Carcinoma","fulltext":[{"header":"Highlights","content":"\u003cp\u003e• Colorectal small-cell neuroendocrine carcinoma (NEC) is an extremely rare and highly aggressive malignancy that may mimic benign adenomatous lesions.\u003c/p\u003e\n\u003cp\u003e• Diagnostic discordance between endoscopic appearance and superficial biopsy can delay surgery and allow rapid systemic progression.\u003c/p\u003e\n\u003cp\u003e• Early recognition, deep biopsies, and expedited resection are essential to prevent disease upstaging and improve outcomes.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eColorectal NEC accounts for less than 1% of colorectal cancers and represents one of the most aggressive gastrointestinal malignancies. Histologically, NECs are high-grade tumours (mitotic count\u0026thinsp;\u0026gt;\u0026thinsp;20/10 HPF; Ki-67\u0026thinsp;\u0026gt;\u0026thinsp;20%) and are commonly associated with TP53 and RB1 mutations rather than MEN1, DAXX, or ATRX alterations seen in well-differentiated NETs [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These tumours typically present with early vascular invasion and distant metastases, leading to a poor overall prognosis.\u003c/p\u003e\u003cp\u003eWe report a case of sigmoid small-cell NEC initially misdiagnosed as a benign adenoma, in which metastatic dissemination occurred following a 40-day delay in surgical management. Recent studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] have highlighted the importance of rapid intervention and the role of multidisciplinary assessment in managing aggressive neuroendocrine neoplasms.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 67-year-old man, otherwise healthy, underwent colonoscopy following a positive faecal occult blood test. Endoscopy revealed a large sessile, ulcerated, yellowish mass in the sigmoid colon with raised margins, suggestive of a submucosal lesion. Biopsies showed a tubulovillous adenoma with low-grade dysplasia. Routine laboratory tests, including CEA and liver function, were within normal limits.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;Given the lesion\u0026rsquo;s morphology and size, endoscopic resection was unfeasible. Laparoscopic sigmoid colectomy with lymphadenectomy was scheduled but postponed for 40 days due to benign biopsy findings and institutional scheduling constraints.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;Table 1 summarises the clinical timeline.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;Table 1. Clinical timeline\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;Event | Approx. day | Findings\u003cbr\u003e\u0026nbsp;Positive faecal occult blood test | 0 | Indication for colonoscopy\u003cbr\u003e\u0026nbsp;Colonoscopy + biopsy | 7 | Tubulovillous adenoma, low-grade dysplasia\u003cbr\u003e\u0026nbsp;CT scan | 14 | Sigmoid wall thickening, no metastasis\u003cbr\u003e\u0026nbsp;Planned surgery | 15 | Deferred due to benign biopsy\u003cbr\u003e\u0026nbsp;Actual surgery | 55 | Laparoscopic colectomy + lymphadenectomy\u003cbr\u003e\u0026nbsp;Histopathology | 65 | Poorly differentiated NEC (pT2), 5/12 LN positive\u003cbr\u003e\u0026nbsp;PET-CT | 95 | New hepatic and pulmonary metastases\u003c/p\u003e\n\u003ch2\u003eHistopathology and Immunohistochemistry\u003c/h2\u003e\n\u003cp\u003eMicroscopic examination revealed a solid, undifferentiated small-cell carcinoma infiltrating the submucosa beneath the adenomatous component, with vascular invasion. Immunohistochemistry showed strong positivity for CD56 and NSE, and negativity for CK20 in tumour cells (positive in the adenomatous epithelium). Ki-67 exceeded 90%. Chromogranin A was unavailable due to sample limitation; synaptophysin was positive when tested.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;A postoperative PET-CT at 40 days revealed new liver and lung metastases. The multidisciplinary tumour board recommended adjuvant platinum-based chemotherapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case highlights two key issues in colorectal NEC: diagnostic ambiguity and the impact of delayed treatment. NECs may endoscopically resemble adenomas or adenocarcinomas; superficial biopsies often miss the submucosal component where the NEC predominates [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Recognition of endoscopic warning signs\u0026mdash;yellowish ulceration, raised borders, and firm consistency\u0026mdash;should prompt deeper sampling or early surgical excision even if histology appears benign.\u003c/p\u003e\u003cp\u003eWhile a causal link cannot be proven, the temporal association between surgical delay and metastatic spread suggests aggressive disease biology. Reported median survival for metastatic colorectal NEC is less than 12 months, emphasising the importance of rapid diagnosis and multidisciplinary management.\u003c/p\u003e\u003cp\u003eRecent studies reinforce that early radical resection followed by systemic therapy offers the best outcome in localized disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This case underscores that clinical suspicion should override benign biopsy results when morphologic features suggest malignancy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eColorectal small-cell NEC is a rare but highly aggressive malignancy. Discordance between benign biopsy and suspicious endoscopic features must raise suspicion for sampling error. Prompt surgical resection and early systemic staging are vital to improve outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical Approval\u003c/h2\u003e\n\u003cp\u003eWritten informed consent for publication of this anonymised case and accompanying images was obtained from the patient. The study complies with the Declaration of Helsinki (2013 revision).\u003c/p\u003e\n\u003ch2\u003eConflict of Interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest and no external funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.V. conceived the study, collected data, and drafted the manuscript.M.B. and I.V. contributed to data analysis and interpretation.D. DG. supervised the research and critically revised the manuscript.All authors read and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: the WHO 2019 update. Mod Pathol. 2018;31:1770\u0026ndash;1786.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWarsinggih G, et al. Colorectal neuroendocrine carcinoma: a case report and literature review. Int J Surg Case Rep. 2020;72:411\u0026ndash;417.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshida T, et al. Colorectal neuroendocrine carcinoma: clinicopathological features and treatment outcomes. World J Clin Cases. 2019;7:1865\u0026ndash;1875.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShafqat H, et al. High-grade neuroendocrine carcinomas of the colon and rectum: clinicopathologic features and outcomes. Dis Colon Rectum. 2015;58:294\u0026ndash;303.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJiang M, et al. Prognostic factors and treatment outcomes of colorectal neuroendocrine carcinoma. Gastroenterol Res Pract. 2017;2017:4206172.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDasari A, et al. Clinical, molecular, and therapeutic advances in neuroendocrine carcinomas. Neuroendocrinology. 2023;113(1):10\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan der Zwan WA, et al. Colorectal neuroendocrine carcinomas: diagnostic pitfalls and treatment challenges. Cancers (Basel). 2022;14(8):1947.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSorbye H, et al. High-grade gastroenteropancreatic neuroendocrine carcinoma: recent progress and future directions. Nat Rev Clin Oncol. 2023;20(2):117\u0026ndash;134.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMilione M, et al. Colorectal poorly differentiated neuroendocrine carcinomas: molecular profile and clinical implications. Eur J Cancer. 2022;163:138\u0026ndash;150.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcNamara MG, et al. Systemic therapy in advanced neuroendocrine carcinoma: current evidence and future strategies. J Clin Oncol. 2023;41(12):2145\u0026ndash;2156.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEsposito I, et al. Colorectal small-cell carcinoma: pathologic spectrum and diagnostic challenges. Histopathology. 2024;84(3):305\u0026ndash;316.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Colorectal neuroendocrine carcinoma, Delayed surgery, Diagnostic discordance, Rapid metastasis, Small-cell carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-7850693/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7850693/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Colorectal small-cell neuroendocrine carcinoma (NEC) is an uncommon, highly aggressive malignancy that can mimic benign adenomatous lesions, leading to diagnostic delay and poor prognosis.\u003cbr\u003e\n\u003cstrong\u003eCase Presentation:\u003c/strong\u003e A 67-year-old patient underwent colonoscopy after a positive faecal occult blood test, which revealed a large ulcerated yellowish sigmoid lesion with raised margins. Endoscopic biopsies showed only a tubulovillous adenoma with low-grade dysplasia. Because of benign histology and scheduling constraints, surgery was postponed for 40 days. Laparoscopic sigmoid colectomy with lymphadenectomy ultimately revealed a poorly differentiated small-cell NEC (pT2) with five of twelve lymph nodes positive. Immunohistochemistry showed strong CD56 and NSE positivity, CK20 negativity in tumour cells, and a Ki-67 index \u0026gt; 90%. Forty days post-operatively, PET-CT demonstrated new liver and lung metastases, indicating rapid systemic dissemination.\u003cbr\u003e\n\u003cstrong\u003eConclusion:\u003c/strong\u003e This case underscores the diagnostic challenges of colorectal NEC and the potential impact of treatment delay. When endoscopic findings appear malignant despite benign histology, deep biopsies, expedited resection, and early staging are essential to prevent disease progression. This case emphasizes the need for timely management in lesions with discordant clinical and histopathologic features.\u003c/p\u003e","manuscriptTitle":"Delayed Diagnosis and Rapid Progression of Colorectal Small-Cell Neuroendocrine Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 09:05:59","doi":"10.21203/rs.3.rs-7850693/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"14e45e4e-2963-4320-b4f9-25cb740537de","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-22T10:23:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-15 09:05:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7850693","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7850693","identity":"rs-7850693","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}