Cis/Etop chemotherapy as a ray of hope in mixed adeno-neuroendocrine carcinoma of colon

Cis/Etop chemotherapy as a ray of hope in mixed adeno-neuroendocrine carcinoma of colon | 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 Cis/Etop chemotherapy as a ray of hope in mixed adeno-neuroendocrine carcinoma of colon Sara Rasta, Maryam Rashidian, Fatemeh Bastan, Mohsen Rajabnia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3970095/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: Mixed adeno-neuroendocrine carcinoma (MANEC) is a rare pathological diagnosis reported by the World Health Organization in 2010 for the first time. Neuroendocrine tumors are characterized by rapid progression. Case Presentation: A 70-year-old man who complained about anemia, diarrhea and significant weight loss did colonoscopy. Biopsy showed a poorly differentiated carcinoma. Biopsy upon surgical rectosigmoid resection revealed a mixed neuroendocrine-adenocarcinoma. Chemotherapy with fofox6 regimen was started but after eight months, tumor relapsed in anastomosis site of surgery involving para aortic lymph nodes and growth of tumor had led to gastrointestinal obstruction symptom. We did relieving surgery and changed chemotherapy regimen to cisplatin/etoposide regimen. He responded to the treatment well, and the mass almost disappeared. Conclusions: The optimal strategy for management of mixed endocrine tumor is variable as they present rare and atypical. Adjuvant chemotherapy play a critical role in the treatment and survival due to MANEC aggressive progression and recurrence. Our data derived from this case may be essential for the diagnosis, treatment, and management of MANEC patients’ symptoms. Neuroendocrine Tumor Mucosal Resection Mixed Adenoneuroendocrine Carcinoma MANEC Case Report Figures Figure 1 Figure 2 Figure 3 Background Colorectal cancer (CRC) is a highly prevalent cancer globally, accounting for one to two million new cases diagnosed annually. This makes CRC the third most common cancer overall and the fourth leading cause of cancer-related mortality, accounting for 700,000 deaths annually, with only stomach, liver, and lung cancers accounting for more deaths from CRC ( 1 – 3 ). More than 90% of CRCs are adenocarcinomas, with the other, less common types being adenosquamous, spindle, squamous, and undifferentiated carcinomas making up the remainder. It is possible to further differentiate CRC adenocarcinoma into medullary, micropapillary, serrated, mucinous, and signet-ring cell types( 4 ). In general, neuroendocrine tumors (NETs) are uncommon and show little virulence. Colon neuroendocrine carcinoma (NEC) represents 1% of colorectal malignancies among NETs. A lump in the abdomen, hunger, unintentional weight loss, vague abdominal pain, and obstructive symptoms are common signs of colon non-functional epithelial cells (NECs). Since most colonic NECs are exophytic rather than ulcerative, hematochezia is an uncommon presentation; nevertheless, rectal NECs frequently appear similarly( 5 – 7 ). Adenocarcinomatous and neuroendocrine differentiation comprise at least thirty percent of the rare gastrointestinal tract tumor known as mixed adenoneuroendocrine carcinoma (MANEC) ( 8 – 10 ). Considering the extremely low prevalence of colorectal neuroendocrine cancer and the prolonged lack of response to adenocarcinoma treatment in our case, the existence of colorectal neuroendocrine cancer is demonstrated in this uncommon instance. Case presentation A 70-year-old man following symptoms of anemia, diarrhea and significant weight loss underwent colonoscopy and abdominopelvic spiral CT scan with contrast. CT showed edematous wall thickening with surrounding mesenteric inflammation in a long segment of the proximal - mid sigmoid colon, more suspicious of focal colitis. Colonoscopy showed ulcerative mass in sigmoid 35 cm from anal verge. Biopsy reported a poorly differentiated carcinoma. Following the biopsy, he underwent surgery of rectosigmoid resection and appendectomy. Gross examination of surgical specimen revealed an infiltrative and ulcerative lesion measuring about 8.5 × 3×1 cm, leading to narrowing of lumen. Pathology obtained from lesion reported a mixed neuroendocrine-nonneuroendocrine (adenocarcinoma) neoplasm (Fig. 1 ). Radial margin and other surgical resected margins were free from tumors. Fourteen lymph nodes dissected measuring 0.2 to 0.8 cm. 13 out of 14 dissected lymph nodes were involved by tumoral tissue. So, pathological stage classification (PTNM, AJCC 8TH Edition) was PT3 PN2B PM. As immunohistochemical (IHC) staining of chromogranin and synaptophysin were positive in some tumor cells, IHC results confirmed neuroendocrine component of tumor tissue. Patient received 12 sessions chemotherapy with fofox6 regimen every two weeks. Eight months later, PET/CT from vertex to mild thigh was done to evaluate treatment response. It showed a hypermetabolic focus adjacent to sigmoid wall and hypermetabolic adenopathy, anterior to aortoiliac bifurcation. So, it seemed that patient didn't respond to chemotherapy. So, tumor had relapsed in anastomosis site of surgery and growth of tumor had led to gastrointestinal obstruction symptoms. Four months later, patient presented to our hospital with complaint of progressive lower abdominal pain radiating to his testis from 2–3 months former. His pain was accompanied by intermittent constipation, diarrhea, and melena as well. He didn't present dyspnea, bone pain and headache. He didn't have any other significant past medical history. On admission, his vital signs were detected normal. Physical examination showed surgical midline scar of previous surgery. He didn't have distention, tenderness, rebound tenderness, or guarding in abdomen. Colonoscopy showed a circumferential mass in anastomosis site (Fig. 2 .A), 12 cm from anal verge. Biopsy revealed an adenocarcinoma with histological changes suggestive of neuroendocrine differentiation. Intravenous contrast enhanced CT scan of the abdomen and pelvis showed an increased circumferential thickness of rectosigmoid (Fig. 2 .B). General surgeons of our hospital performed laparotomy surgery. Surgery showed relapsed tumor in rectum and metastatic paraaortic lymph nodes. Other organs of abdomen were normal grossly. As a result, surgeons made splenic curvature of colon freed and put a loop colostomy. Following surgery, chemotherapy was started with cisplatin 75 mg/m 2 on day 1 and etoposide 100mg/m 2 on day 1 to 3. After three courses of cisplatin/etoposide regimen, he responded well to the treatment, his general condition improved, and the mass almost disappeared (Fig. 3 ). During follow-ups, ELISA detected CEA as 6.12 ng/ml and CA19.9 as 25.01 U/ml. Discussion and Conclusions MANEC a rare tumor that has an aggressive growth pattern, invades the gastrointestinal tract, metastasizes to other organs, and invades adjacent tissues. Less than 100 cases have been reported in the colon, and they are more common in the stomach ( 11 – 13 ). Although surgical resection seems to be a successful treatment strategy, the creation of a dependable standard chemotherapy regimen and care methods are crucial due to the aggressive growth pattern of NEC and the difficulty in precisely diagnosing it in its early stages ( 12 , 14 , 15 ). In previous studies, it was reported after internal colonic stenosis was stented, a patient with NEC was shown to exhibit an aggressive growth pattern, which ultimately led to the tumor's rupture outside the colon. Additionally, the tumor spread to the duodenum, causing duodenal stenosis which required another duodenal stent to be placed ( 12 , 16 , 17 ). In a different investigation, two cases of NET of the colon and sigmoid colon were described, with the main complaints being dyspepsia and abdominal distention. The descending colon's specimen histology revealed characteristics of neuroendocrine carcinoma, which was diagnosed and treated ( 18 ). Two patients were described in earlier investigations to have been diagnosed with a tumor consisting of neuroendocrine carcinoma mixed with a tubular adenocarcinoma that was moderately differentiated. MANECs appear to be highly aggressive tumors with a high chance of distant metastases, regardless of the tumor's location or stage. Irrespective its proportion, the endocrine component appears to be the determinant of aggressiveness ( 8 ). Tumors of the colorectal MANEC type are rare. Only case reports and short case series have been reported in research, making it difficult to determine the true prevalence of MANEC. Due to its dual histological profile, the clinical behavior and management of MANEC differed significantly from adenocarcinoma and were mostly determined by the type of cells in the neuroendocrine component and the contribution of each component. In contrast to NEC, MANEC requires more intricate care, such as the delivery of a chemotherapy regimen customized for each patient based on the tumor's histology. Complete surgical resection (R0 resection) of the main tumor and any metastases is the only treatment option for metastatic MANEC. Adjuvant chemotherapy is an essential component of treatment due to the aggressive nature of the disease and its high recurrence rate, which also greatly increases survival ( 19 , 20 ). Selecting the appropriate chemotherapy for the original tumor as well as any distant metastases is the most taxing and difficult aspect of managing patients with manic ulcerative colitis (MANEC). The therapy of gastrointestinal poorly differentiated NECs is seen to be successful when using cisplatin and etoposide, according the criteria set forth by the European Neuroendocrine Tumor Society ( 5 ). Furthermore, as the best adjuvant treatment, the National Comprehending Cancer Network recommended cisplatin and irinotecan or carboplatin and etoposide( 19 ). Our case presented with a high-grade MANEC who underwent resection surgery and adjunctive chemotherapy with fofox6. Surprisingly follow-ups during chemotherapy sessions, revealed a relapse in anastomosis site of surgery. The relapsed tumor had led to gastrointestinal obstruction symptoms. After three courses of cisplatin/etoposide regimen, the mass almost disappeared. We believe that the data offered here is essential for the identification, treatment, and control of MANEC patients' symptoms. Abbreviations Colorectal cancer CRC Neuroendocrine tumor NET Neuroendocrine carcinoma NEC Mixed adenoneuroendocrine carcinoma MANEC Immunohistochemical IHC Declarations Ethics approval and consent to participate Ethical approval is not required as this article is a case report. Consent for publication Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Availability of data and materials The data that support the findings of this study are available on request from the corresponding author. Competing interests All authors have no conflict of interest to declare. Funding The authors received no financial support for the research, authorship, and/or publication of this article Sources of funding There are no funding sources. Authors' contributions All authors have same contribution Acknowledgements We acknowledge all medical professionals who collaborated in patient assessment, care, and appropriate interventions. Financial support and sponsorship: none Conflicts of interest: none Presentation: none References Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi MJ. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci. 2017;18(1). Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89–103. Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 2021;14(10):101174. Lotfollahzadeh SR-BA, Cagir B. Colon Cancer. StatPearls: StatPearls; 2023. Jun 3. Masood S, Gupta R, Jaiswal A, Bhardwaj G, Srivastav U. Neuroendocrine Carcinoma of the Colon: Emergency Presentation of a Rare Disease With Poor Biology. Cureus. 2021;13(11):e19582. Daraghmeh L, Shbaita S, Nassef O, Melhem L, Maqboul I. Non-specific Symptoms of Small Bowel Neuroendocrine Tumor and the Diagnostic Challenges: A Case Report. Cureus. 2023;15(6):e41080. Lee S, Jyala A, Ghazanfar H, Shin D, Patel H. Diagnostic Challenge of Small Bowel Neuroendocrine Tumor in a Young Female Patient. Cureus. 2023;15(4):e37925. Gurzu S, Kadar Z, Bara T, Bara T Jr., Tamasi A, Azamfirei L, Jung I. Mixed adenoneuroendocrine carcinoma of gastrointestinal tract: report of two cases. World J Gastroenterol. 2015;21(4):1329–33. La Rosa S, Marando A, Sessa F, Capella C. Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update. Cancers (Basel). 2012;4(1):11–30. Kadhim MM, Jespersen ML, Pilegaard HK, Nordsmark M, Villadsen GE. Mixed Adenoneuroendocrine Carcinoma Is a Rare but Important Tumour Found in the Oesophagus. Case Rep Gastrointest Med. 2016;2016:9542687. Minaya-Bravo AM, Garcia Mahillo JC, Mendoza Moreno F, Noguelares Fraguas F, Granell J. Large cell neuroendocrine - Adenocarcinona mixed tumour of colon: Collision tumour with peculiar behaviour. What do we know about these tumours? Ann Med Surg (Lond). 2015;4(4):399–403. Yoshida T, Kamimura K, Hosaka K, Doumori K, Oka H, Sato A, et al. Colorectal neuroendocrine carcinoma: A case report and review of the literature. World J Clin Cases. 2019;7(14):1865–75. Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–86. Yalamarty SSK, Filipczak N, Li X, Subhan MA, Parveen F, Ataide JA et al. Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM). Cancers (Basel). 2023;15(7). Krasteva N, Georgieva M. Promising Therapeutic Strategies for Colorectal Cancer Treatment Based on Nanomaterials. Pharmaceutics. 2022;14(6). Schwartz MZ, Hayden CK, Richardson CJ, Tyson KR, Lobe TE. A prospective evaluation of intestinal stenosis following necrotizing enterocolitis. J Pediatr Surg. 1982;17(6):764–70. Wei TH, Ye BW, Wu PS, Li CP, Chao Y, Lee PC, et al. Outcomes of patients with malignant duodenal obstruction after receiving self-expandable metallic stents: A single center experience. PLoS ONE. 2022;17(5):e0268920. Warsinggih L, Prihantono, Ariani GDW, Faruk M. Colorectal neuroendocrine tumors: A case series. Int J Surg Case Rep. 2020;72:411–7. Paspala A, Machairas N, Prodromidou A, Spartalis E, Ioannidis A, Kostakis ID, et al. Management of MANEC of the colon and rectum: A comprehensive review of the literature. Mol Clin Oncol. 2018;9(2):219–22. Tanaka T, Kaneko M, Nozawa H, Emoto S, Murono K, Otani K, et al. Diagnosis, Assessment, and Therapeutic Strategy for Colorectal Mixed Adenoneuroendocrine Carcinoma. Neuroendocrinology. 2017;105(4):426–34. Additional Declarations No competing interests reported. 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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-3970095","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":273884955,"identity":"5962fa1d-18a7-4bb0-899c-38f4089325d0","order_by":0,"name":"Sara Rasta","email":"","orcid":"","institution":"Non-Communicable Diseases Research Center, Alborz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Rasta","suffix":""},{"id":273884956,"identity":"ebcdf754-114c-4a93-8374-f840e6d8ec80","order_by":1,"name":"Maryam Rashidian","email":"","orcid":"","institution":"Student Research Committee, School of Medicine, Alborz University of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"","lastName":"Rashidian","suffix":""},{"id":273884957,"identity":"fe5ef660-e169-40cd-afe4-a4199e1a988a","order_by":2,"name":"Fatemeh Bastan","email":"","orcid":"","institution":"Student Research Committee, School of Medicine, Alborz University of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Fatemeh","middleName":"","lastName":"Bastan","suffix":""},{"id":273884958,"identity":"6d8a975b-9e09-4595-ab8c-4a6e35eae1c3","order_by":3,"name":"Mohsen Rajabnia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIie3QsQrCMBCA4QsH7XLqaqH4DBGh4uKzVATdXApScFAQOuUB9C10cY4UdCm6Kl2c3IS6SAcHIzoJrR0F8w8hhPuGC4BO94vJ50HgAgI7qasNYBQnyAE4FSSgiBqtFiLlWBpJarcHTRPP/jW4U8UMXEj9VSaxdi7OBXW91tRwjvOAkyU2kokoziQ8UksQYWcRghOXFOGH/gRZkE/YncaKmDevMEGiUBFy8EV6MpdYEZuiTVuPh+RZs13juYu7ztulHGHILmI04PvtMkmGtZr6sfop9bMJAJsAEx9vMmf+Xfp9RKfT6f64B1SOUMHftIqmAAAAAElFTkSuQmCC","orcid":"","institution":"Non-Communicable Diseases Research Center, Alborz University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Mohsen","middleName":"","lastName":"Rajabnia","suffix":""}],"badges":[],"createdAt":"2024-02-19 13:36:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3970095/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3970095/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51504989,"identity":"d90274db-257e-4578-a0db-5f433264730c","added_by":"auto","created_at":"2024-02-22 18:41:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":692304,"visible":true,"origin":"","legend":"\u003cp\u003eColon biopsy mixed of adenocarcinoma and neuroendocrine tumor\u003c/p\u003e","description":"","filename":"Figure11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3970095/v1/0abb7feb99f01bd7f75347f0.jpg"},{"id":51504990,"identity":"02a2a8c9-9485-48a9-a80c-2d8024fd8586","added_by":"auto","created_at":"2024-02-22 18:41:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2654004,"visible":true,"origin":"","legend":"\u003cp\u003eTumor relapsed in surgical bed after 8 curses of mfolfox6 chemotherapy\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3970095/v1/5165f424ad4b80d6fccfc6e8.jpg"},{"id":51504988,"identity":"6d2f4922-be0c-418f-9bfc-c72000b0b00c","added_by":"auto","created_at":"2024-02-22 18:41:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":273698,"visible":true,"origin":"","legend":"\u003cp\u003eTumor complete response after 3 cycle of cis/etop chemotherapy\u003c/p\u003e","description":"","filename":"Figure31.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3970095/v1/8a75e916db2c0fa00efc1367.jpg"},{"id":53200018,"identity":"3036da6a-527a-4a37-86f7-02ec7621ad10","added_by":"auto","created_at":"2024-03-21 19:15:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":538769,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3970095/v1/86bd65c9-d7ed-4da3-83f3-65e9665a7639.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cis/Etop chemotherapy as a ray of hope in mixed adeno-neuroendocrine carcinoma of colon","fulltext":[{"header":"Background","content":"\u003cp\u003eColorectal cancer (CRC) is a highly prevalent cancer globally, accounting for one to two million new cases diagnosed annually. This makes CRC the third most common cancer overall and the fourth leading cause of cancer-related mortality, accounting for 700,000 deaths annually, with only stomach, liver, and lung cancers accounting for more deaths from CRC (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMore than 90% of CRCs are adenocarcinomas, with the other, less common types being adenosquamous, spindle, squamous, and undifferentiated carcinomas making up the remainder. It is possible to further differentiate CRC adenocarcinoma into medullary, micropapillary, serrated, mucinous, and signet-ring cell types(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn general, neuroendocrine tumors (NETs) are uncommon and show little virulence. Colon neuroendocrine carcinoma (NEC) represents 1% of colorectal malignancies among NETs. A lump in the abdomen, hunger, unintentional weight loss, vague abdominal pain, and obstructive symptoms are common signs of colon non-functional epithelial cells (NECs). Since most colonic NECs are exophytic rather than ulcerative, hematochezia is an uncommon presentation; nevertheless, rectal NECs frequently appear similarly(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Adenocarcinomatous and neuroendocrine differentiation comprise at least thirty percent of the rare gastrointestinal tract tumor known as mixed adenoneuroendocrine carcinoma (MANEC) (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering the extremely low prevalence of colorectal neuroendocrine cancer and the prolonged lack of response to adenocarcinoma treatment in our case, the existence of colorectal neuroendocrine cancer is demonstrated in this uncommon instance.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 70-year-old man following symptoms of anemia, diarrhea and significant weight loss underwent colonoscopy and abdominopelvic spiral CT scan with contrast. CT showed edematous wall thickening with surrounding mesenteric inflammation in a long segment of the proximal - mid sigmoid colon, more suspicious of focal colitis. Colonoscopy showed ulcerative mass in sigmoid 35 cm from anal verge. Biopsy reported a poorly differentiated carcinoma. Following the biopsy, he underwent surgery of rectosigmoid resection and appendectomy. Gross examination of surgical specimen revealed an infiltrative and ulcerative lesion measuring about 8.5 \u0026times; 3\u0026times;1 cm, leading to narrowing of lumen. Pathology obtained from lesion reported a mixed neuroendocrine-nonneuroendocrine (adenocarcinoma) neoplasm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Radial margin and other surgical resected margins were free from tumors. Fourteen lymph nodes dissected measuring 0.2 to 0.8 cm. 13 out of 14 dissected lymph nodes were involved by tumoral tissue. So, pathological stage classification (PTNM, AJCC 8TH Edition) was PT3 PN2B PM. As immunohistochemical (IHC) staining of chromogranin and synaptophysin were positive in some tumor cells, IHC results confirmed neuroendocrine component of tumor tissue.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatient received 12 sessions chemotherapy with fofox6 regimen every two weeks. Eight months later, PET/CT from vertex to mild thigh was done to evaluate treatment response. It showed a hypermetabolic focus adjacent to sigmoid wall and hypermetabolic adenopathy, anterior to aortoiliac bifurcation. So, it seemed that patient didn't respond to chemotherapy. So, tumor had relapsed in anastomosis site of surgery and growth of tumor had led to gastrointestinal obstruction symptoms.\u003c/p\u003e \u003cp\u003eFour months later, patient presented to our hospital with complaint of progressive lower abdominal pain radiating to his testis from 2\u0026ndash;3 months former. His pain was accompanied by intermittent constipation, diarrhea, and melena as well. He didn't present dyspnea, bone pain and headache. He didn't have any other significant past medical history. On admission, his vital signs were detected normal. Physical examination showed surgical midline scar of previous surgery. He didn't have distention, tenderness, rebound tenderness, or guarding in abdomen. Colonoscopy showed a circumferential mass in anastomosis site (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.A), 12 cm from anal verge. Biopsy revealed an adenocarcinoma with histological changes suggestive of neuroendocrine differentiation. Intravenous contrast enhanced CT scan of the abdomen and pelvis showed an increased circumferential thickness of rectosigmoid (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.B).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGeneral surgeons of our hospital performed laparotomy surgery. Surgery showed relapsed tumor in rectum and metastatic paraaortic lymph nodes. Other organs of abdomen were normal grossly. As a result, surgeons made splenic curvature of colon freed and put a loop colostomy. Following surgery, chemotherapy was started with cisplatin 75 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1 and etoposide 100mg/m\u003csup\u003e2\u003c/sup\u003e on day 1 to 3. After three courses of cisplatin/etoposide regimen, he responded well to the treatment, his general condition improved, and the mass almost disappeared (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). During follow-ups, ELISA detected CEA as 6.12 ng/ml and CA19.9 as 25.01 U/ml.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eMANEC a rare tumor that has an aggressive growth pattern, invades the gastrointestinal tract, metastasizes to other organs, and invades adjacent tissues. Less than 100 cases have been reported in the colon, and they are more common in the stomach (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Although surgical resection seems to be a successful treatment strategy, the creation of a dependable standard chemotherapy regimen and care methods are crucial due to the aggressive growth pattern of NEC and the difficulty in precisely diagnosing it in its early stages (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In previous studies, it was reported after internal colonic stenosis was stented, a patient with NEC was shown to exhibit an aggressive growth pattern, which ultimately led to the tumor's rupture outside the colon. Additionally, the tumor spread to the duodenum, causing duodenal stenosis which required another duodenal stent to be placed (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a different investigation, two cases of NET of the colon and sigmoid colon were described, with the main complaints being dyspepsia and abdominal distention. The descending colon's specimen histology revealed characteristics of neuroendocrine carcinoma, which was diagnosed and treated (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Two patients were described in earlier investigations to have been diagnosed with a tumor consisting of neuroendocrine carcinoma mixed with a tubular adenocarcinoma that was moderately differentiated. MANECs appear to be highly aggressive tumors with a high chance of distant metastases, regardless of the tumor's location or stage. Irrespective its proportion, the endocrine component appears to be the determinant of aggressiveness (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Tumors of the colorectal MANEC type are rare. Only case reports and short case series have been reported in research, making it difficult to determine the true prevalence of MANEC. Due to its dual histological profile, the clinical behavior and management of MANEC differed significantly from adenocarcinoma and were mostly determined by the type of cells in the neuroendocrine component and the contribution of each component. In contrast to NEC, MANEC requires more intricate care, such as the delivery of a chemotherapy regimen customized for each patient based on the tumor's histology. Complete surgical resection (R0 resection) of the main tumor and any metastases is the only treatment option for metastatic MANEC. Adjuvant chemotherapy is an essential component of treatment due to the aggressive nature of the disease and its high recurrence rate, which also greatly increases survival (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSelecting the appropriate chemotherapy for the original tumor as well as any distant metastases is the most taxing and difficult aspect of managing patients with manic ulcerative colitis (MANEC). The therapy of gastrointestinal poorly differentiated NECs is seen to be successful when using cisplatin and etoposide, according the criteria set forth by the European Neuroendocrine Tumor Society (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Furthermore, as the best adjuvant treatment, the National Comprehending Cancer Network recommended cisplatin and irinotecan or carboplatin and etoposide(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Our case presented with a high-grade MANEC who underwent resection surgery and adjunctive chemotherapy with fofox6. Surprisingly follow-ups during chemotherapy sessions, revealed a relapse in anastomosis site of surgery. The relapsed tumor had led to gastrointestinal obstruction symptoms. After three courses of cisplatin/etoposide regimen, the mass almost disappeared.\u003c/p\u003e \u003cp\u003eWe believe that the data offered here is essential for the identification, treatment, and control of MANEC patients' symptoms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eColorectal cancer\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCRC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNeuroendocrine tumor\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNET\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNeuroendocrine carcinoma\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNEC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMixed adenoneuroendocrine carcinoma\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMANEC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eImmunohistochemical\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIHC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval is not required as this article is a case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have no conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship, and/or publication of this article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSources of funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no funding sources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have same contribution\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge all medical professionals who collaborated in patient assessment, care, and appropriate interventions.\u003c/p\u003e\n\u003cp\u003eFinancial support and sponsorship: none\u003c/p\u003e\n\u003cp\u003eConflicts of interest: none\u003c/p\u003e\n\u003cp\u003ePresentation: none\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eM\u0026aacute;rmol I, S\u0026aacute;nchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi MJ. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci. 2017;18(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89\u0026ndash;103.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 2021;14(10):101174.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLotfollahzadeh SR-BA, Cagir B. Colon Cancer. StatPearls: StatPearls; 2023. Jun 3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasood S, Gupta R, Jaiswal A, Bhardwaj G, Srivastav U. Neuroendocrine Carcinoma of the Colon: Emergency Presentation of a Rare Disease With Poor Biology. Cureus. 2021;13(11):e19582.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaraghmeh L, Shbaita S, Nassef O, Melhem L, Maqboul I. Non-specific Symptoms of Small Bowel Neuroendocrine Tumor and the Diagnostic Challenges: A Case Report. Cureus. 2023;15(6):e41080.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee S, Jyala A, Ghazanfar H, Shin D, Patel H. Diagnostic Challenge of Small Bowel Neuroendocrine Tumor in a Young Female Patient. Cureus. 2023;15(4):e37925.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGurzu S, Kadar Z, Bara T, Bara T Jr., Tamasi A, Azamfirei L, Jung I. Mixed adenoneuroendocrine carcinoma of gastrointestinal tract: report of two cases. World J Gastroenterol. 2015;21(4):1329\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLa Rosa S, Marando A, Sessa F, Capella C. Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update. Cancers (Basel). 2012;4(1):11\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKadhim MM, Jespersen ML, Pilegaard HK, Nordsmark M, Villadsen GE. Mixed Adenoneuroendocrine Carcinoma Is a Rare but Important Tumour Found in the Oesophagus. Case Rep Gastrointest Med. 2016;2016:9542687.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinaya-Bravo AM, Garcia Mahillo JC, Mendoza Moreno F, Noguelares Fraguas F, Granell J. Large cell neuroendocrine - Adenocarcinona mixed tumour of colon: Collision tumour with peculiar behaviour. What do we know about these tumours? Ann Med Surg (Lond). 2015;4(4):399\u0026ndash;403.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida T, Kamimura K, Hosaka K, Doumori K, Oka H, Sato A, et al. Colorectal neuroendocrine carcinoma: A case report and review of the literature. World J Clin Cases. 2019;7(14):1865\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYalamarty SSK, Filipczak N, Li X, Subhan MA, Parveen F, Ataide JA et al. Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM). Cancers (Basel). 2023;15(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrasteva N, Georgieva M. Promising Therapeutic Strategies for Colorectal Cancer Treatment Based on Nanomaterials. Pharmaceutics. 2022;14(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwartz MZ, Hayden CK, Richardson CJ, Tyson KR, Lobe TE. A prospective evaluation of intestinal stenosis following necrotizing enterocolitis. J Pediatr Surg. 1982;17(6):764\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei TH, Ye BW, Wu PS, Li CP, Chao Y, Lee PC, et al. Outcomes of patients with malignant duodenal obstruction after receiving self-expandable metallic stents: A single center experience. PLoS ONE. 2022;17(5):e0268920.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWarsinggih L, Prihantono, Ariani GDW, Faruk M. Colorectal neuroendocrine tumors: A case series. Int J Surg Case Rep. 2020;72:411\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaspala A, Machairas N, Prodromidou A, Spartalis E, Ioannidis A, Kostakis ID, et al. Management of MANEC of the colon and rectum: A comprehensive review of the literature. Mol Clin Oncol. 2018;9(2):219\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka T, Kaneko M, Nozawa H, Emoto S, Murono K, Otani K, et al. Diagnosis, Assessment, and Therapeutic Strategy for Colorectal Mixed Adenoneuroendocrine Carcinoma. Neuroendocrinology. 2017;105(4):426\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Neuroendocrine Tumor, Mucosal Resection, Mixed Adenoneuroendocrine Carcinoma, MANEC, Case Report","lastPublishedDoi":"10.21203/rs.3.rs-3970095/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3970095/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Mixed adeno-neuroendocrine carcinoma (MANEC) is a rare pathological diagnosis reported by the World Health Organization in 2010 for the first time. Neuroendocrine tumors are characterized by rapid progression.\u003c/p\u003e\n\u003cp\u003eCase Presentation: A 70-year-old man who complained about anemia, diarrhea and significant weight loss did colonoscopy. Biopsy showed a poorly differentiated carcinoma. Biopsy upon surgical rectosigmoid resection revealed a mixed neuroendocrine-adenocarcinoma. Chemotherapy with fofox6 regimen was started but after eight months, tumor relapsed in anastomosis site of surgery involving para aortic lymph nodes and growth of tumor had led to gastrointestinal obstruction symptom. We did relieving surgery and changed chemotherapy regimen to cisplatin/etoposide regimen. He responded to the treatment well, and the mass almost disappeared.\u003c/p\u003e\n\u003cp\u003eConclusions: The optimal strategy for management of mixed endocrine tumor is variable as they present rare and atypical. Adjuvant chemotherapy play a critical role in the treatment and survival due to MANEC aggressive progression and recurrence. Our data derived from this case may be essential for the diagnosis, treatment, and management of MANEC patients’ symptoms.\u003c/p\u003e","manuscriptTitle":"Cis/Etop chemotherapy as a ray of hope in mixed adeno-neuroendocrine carcinoma of colon","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-22 18:41:47","doi":"10.21203/rs.3.rs-3970095/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":"3976b8fe-a37e-41b1-a1dd-c1b955646839","owner":[],"postedDate":"February 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-21T19:07:05+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-22 18:41:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3970095","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3970095","identity":"rs-3970095","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}