Neuroendocrine carcinoma of the minor papilla with pancreas divisum: A review of the literature and report of a case

Neuroendocrine carcinoma of the minor papilla with pancreas divisum: A review of the literature and report of a case | 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 Neuroendocrine carcinoma of the minor papilla with pancreas divisum: A review of the literature and report of a case Kenta Saito, Yoichi Matsuo, Yuki Denda, Keisuke Nonoyama, Hiromichi Murase, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1976910/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 Neuroendocrine tumors of the minor papilla are very rare, and only 20 cases have been reported in the literature. Neuroendocrine carcinoma of the minor papilla with pancreas divisum has not been reported; thus, this report describes the first case. Neuroendocrine tumors of the minor papilla have been reported in association with pancreas divisum in about 50% of cases reported in the literature. We herein present our case of neuroendocrine carcinoma of the minor papilla with pancreas divisum in a 75-year-old male with a systematic literature review of the previous 20 reports of neuroendocrine tumors of the minor papilla. Case presentation A 75-year-old man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed a dilated dorsal pancreatic duct, which was not connected to the ventral pancreatic duct; however, it opened to the minor papilla, indicating pancreas divisum. The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. A contrast-enhanced computed tomography scan showed a 12-mm hypervascular mass near the ampulla of Vater. Endoscopic ultrasonography showed a defined hypoechoic mass in the minor papilla with no invasion. The biopsies performed at the previous hospital found adenocarcinoma. The patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. The pathological diagnosis was neuroendocrine carcinoma. At the 15-year follow-up visit, the patient was doing well with no evidence of tumor recurrence. Conclusion In our case, because the tumor was discovered during a medical check-up relatively early in the course of disease, the patient was doing well at the 15-year follow-up visit with no evidence of tumor recurrence. Diagnosing a tumor of the minor papilla is very difficult because of the relatively small size and submucosal location. Carcinoids and endocrine cell micronests in the minor papilla occur more frequently than generally thought. It is very important to include neuroendocrine tumors of the minor papilla in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum. neuroendocrine carcinoma neuroendocrine tumor minor papilla pancreas divisum pancreatitis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Background Tumors of the minor papilla are very rare. Neuroendocrine tumors (NETs), which include tumors such as somatostatinomas and carcinoid tumors, are the majority of tumors of the minor papilla [ 1 – 9 ]. NETs are usually located in the appendix, ileum and rectum [ 10 , 11 ]. NETs of the minor papilla are extremely rare, and about 20 cases have been reported in the literature. However, neuroendocrine carcinoma (NEC) of the minor papilla has not been reported previously. Pancreas divisum is the most common congenital variant of the pancreas; it occurs when the embryological ventral and dorsal parts of the pancreas fail to fuse [ 11 , 12 ]. Thus, pancreatic drainage occurs mainly through the dorsal pancreatic duct and the minor papilla in patients with pancreas divisum. Previous reports have described the association of tumors of the minor papilla with pancreas divisum, but only 9 cases of NETs of the minor papilla with pancreas divisum have been reported in the literature [ 1 – 9 ]. We report a very rare case of NEC of the minor papilla with pancreas divisum and summarize the clinical features of NETs of the minor papilla reported in the medical literature. Case Presentation A 75-year-old man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. The patient’s clinical history included only hypertension. Laboratory data were within normal limits. Carbohydrate antigen (CA) 19 − 9 and carcinoembryonic antigen (CEA) were 1.0 U/mL and 1.6 ng/mL, respectively. Magnetic resonance cholangiopancreatography (MRCP) showed a dilated dorsal pancreatic duct, which was not connected with the ventral pancreatic duct and opened to the minor papilla, indicating pancreas divisum (Fig. 1 ). The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. Contrast-enhanced computed tomography (CT) scan showed a 12-mm hypervascular mass near the ampulla of Vater and the dilated main pancreatic duct (Fig. 2 ). Endoscopic retrograde cholangiopancreatography (ERCP) showed an irregular mucosal surface in the minor papilla (Fig. 3 ). Injection of contrast through the ampulla of Vater revealed the common bile duct with no dilation and inferior branches of the pancreatic duct. Injection of contrast through the minor papilla revealed the dilated main pancreatic duct (Fig. 4 ). Endoscopic ultrasonography (EUS) showed a defined hypoechoic mass in the minor papilla with no invasion and flow from the dilated pancreatic duct into the minor papilla (Fig. 5 ). The biopsies performed at the previous hospital showed adenocarcinoma. Because of the diagnosis of adenocarcinoma of the minor papilla with pancreas divisum, the patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. About 10 days after the operation, leakage of the choledochojejunostomy occurred. The patient improved with conservative treatment, and he was discharged. At 15 years of follow-up, the patient was doing well with no evidence of tumor recurrence. Pathological findings On gross examination, the tumor was 25 × 15 mm and was located in the minor papilla (Fig. 6 ). Histologically, there was infiltration of trabecular tumor with abundant granules in the cytoplasm and a low-to-intermediate N/C ratio (Fig. 7 ). The tumor showed invasion of the duodenal mucosa and submucosal layer, and a submuscular lymph node was involved by the tumor. Immunohistochemical staining showed that chromogranin, synaptophysin and CD56 were positive; however, CD10, Alpha fetoprotein, glucagon, gastrin, somatostatin and insulin were negative (Fig. 8 ). The pathological diagnosis was neuroendocrine carcinoma. Discussion And Conclusions NETs located in the minor papilla are very rare, and a thorough review of the literature revealed only 20 cases. The clinical features of these patients are summarized in Table 1. However, NEC of the minor papilla has not been reported previously; therefore, our patient is the first reported case. In our analysis of the 20 previously reported cases of NETs in the minor papilla plus our case of NEC, we found the following. The mean age was 56.6 (range, 35 – 80) years, and patients included 10 men and 11 women. However, in the gender distribution of patients who also had pancreas divisum, a marked female dominance was observed: 8 women, 2 men. The mean largest diameter of the tumors was 13.8 (range, 3 – 27) mm. The most common clinical presentation was abdominal pain in nine cases (43%), and 5 cases were asymptomatic (24%). Lymph node metastases were diagnosed in 7 cases (33%) and liver metastasis in 1 case (5%). Surgical procedures were pancreatoduodenectomy in 12 cases (57%), local resection in 5 cases (24%) and endoscopic papillectomy in 3 cases (14%). Previous reports indicated that tumors of the duodenal papilla have high rates of metastasis [13], so Whipple’s operation is the most appropriate treatment for ampullary tumors [14]. In our case, the cancer diagnosis occurred relatively early because the patient had a medical check-up. The patient underwent pancreaticoduodenectomy, and at 15 years of follow-up, the patient was doing well with no evidence of tumor recurrence. The relationship between NETs of the minor papilla and pancreas divisum has been described previously. Pancreas divisum is a probable cause of pancreatitis because the smaller caliber of the accessory duct and the minor papilla may induce pancreatitis in patients with pancreas divisum [3, 15-17]. There is a possibility that the inflammation of the pancreas with pancreas divisum influences the formation of endocrine cell micronests (ECMs), which are thought to be precursor lesions of NET of the minor papilla. Regardless of the presence of pancreas divisum, carcinoids and ECMs in the minor papilla occur more frequently than generally thought. In a study of single surgical specimens and autopsies, the incidence of carcinoids and neoplastic ECMs of the minor papilla could reach 10%. Furthermore, carcinoids in the minor papilla are twice as common as carcinoids of the major papilla, and neoplastic ECMs of the minor papilla are found five times as often [18]. The number of reported cases of NETs of the major papilla exceeds those of the minor papilla. This discrepancy may be explained by the fact that due to ampullary obstruction, tumors of the major papilla are more likely to cause symptoms, such as jaundice or abdominal pain, whereas patients with minor papillary tumors usually remain asymptomatic because there is no biliary or pancreatic obstruction. NETs of the minor papilla are very difficult to diagnose because these lesions tend to be small and usually located in the submucosal area. NETs of the minor papilla are rarely accompanied by endocrine manifestations [13]. Hence, deep biopsy samples should be obtained in such cases. A high index of suspicion must be maintained for such lesions in the appropriate setting, such as the young patient without common risk factors for pancreatitis [3]. NETs of the minor papilla should be included in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum; furthermore, patients with pancreas divisum require careful follow-up to monitor for the existence or formation of NETs of the minor papilla. Abbreviations NETs Neuroendocrine tumors NEC Neuroendocrine carcinoma MRCP Magnetic resonance cholangiopancreatography CT Contrast-enhanced computed tomography ERCP Endoscopic retrograde cholangiopancreatography EUS Endoscopic ultrasonography ECMs Endocrine cell micronests Declarations Ethics approval and consent to participate: not applicable Consent for publication: Written informed consent was obtained from the patient for publication of this case report and the accompanying images. Availability of data and material: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: not applicable Author’s contributions: All authors read and approved the final manuscript. KS designed and wrote the paper. MM, RO and HT analyzed and interpreted the patient’s data. YD, KN, HM, HI and TK collected the patient’s data. YH and MM treated and followed the patient. YM and ST supervised this case report. References Stommer PE, Stolte M, Seifert E: Somatostatinoma of Vater's papilla and of the minor papilla . Cancer 1987, 60 (2):232-235. Lowes JR, Rode J, Lees WR, Russell RC, Cotton PB: Obstructive pancreatitis: unusual causes of chronic pancreatitis . The British journal of surgery 1988, 75 (11):1129-1133. Singh VV, Bhutani MS, Draganov P: Carcinoid of the minor papilla in incomplete pancreas divisum presenting as acute relapsing pancreatitis . Pancreas 2003, 27 (1):96-97. Outtas O, Barthet M, De Troyer J, Franck F, Garcia S: [Pancreatic panniculitis with intraductal carcinoid tumor of the pancreas divisum] . Annales de dermatologie et de venereologie 2004, 131 (5):466-469. Waisberg J, de Matos LL, Waisberg DR, dos Santos HV, Fernezlian SM, Capelozzi VL: Carcinoid of the minor duodenal papilla associated with pancreas divisum: Case report and review of the literature . Clinics (Sao Paulo, Brazil) 2006, 61 (4):365-368. Kim YG, Kim TN, Kim KO: Carcinoid tumor of the minor papilla in complete pancreas divisum presenting as recurrent abdominal pain . BMC gastroenterology 2010, 10 :17. Barresi L, Tarantino I, Ligresti D, Liotta R, Curcio G, Granata A, Marrone G, Traina M: Endoscopic ultrasound-guided fine-needle aspiration diagnosis of mixed endocrine somatostatinoma of the minor papilla in von Recklinghausen disease . Endoscopy 2014, 46 Suppl 1 UCTN :E664-665. Bhandari R, Riddiough G, Lokan J, Weinberg L, Efthymiou M, Nikfarjam M: Somatostatinoma of the minor papilla treated by local excision in a patient with neurofibromatosis type 1 . JOP : Journal of the pancreas 2015, 16 (1):81-84. Jara Letelier DI, Bonotto ML, Ardengh JC: Somatostatinoma of the minor duodenal papilla associated with pancreas divisum treated by endoscopic papillectomy . Endoscopy 2016, 48 Suppl 1 :E135-137. Godwin JD, 2nd: Carcinoid tumors. An analysis of 2,837 cases . Cancer 1975, 36 (2):560-569. Modlin IM, Lye KD, Kidd M: A 5-decade analysis of 13,715 carcinoid tumors . Cancer 2003, 97 (4):934-959. Quest L, Lombard M: Pancreas divisum: opinio divisa . Gut 2000, 47 (3):317-319. Hatzitheoklitos E, Buchler MW, Friess H, Poch B, Ebert M, Mohr W, Imaizumi T, Beger HG: Carcinoid of the ampulla of Vater. Clinical characteristics and morphologic features . Cancer 1994, 73 (6):1580-1588. Ricci JL: Carcinoid of the ampulla of Vater. Local resection or pancreaticoduodenectomy . Cancer 1993, 71 (3):686-690. Bernard JP, Sahel J, Giovannini M, Sarles H: Pancreas divisum is a probable cause of acute pancreatitis: a report of 137 cases . Pancreas 1990, 5 (3):248-254. Delhaye M, Cremer M: Clinical significance of pancreas divisum . Acta gastro-enterologica Belgica 1992, 55 (3):306-313. Sahel J, Cros RC, Bourry J, Sarles H: Clinico-pathological conditions associated with pancreas divisum . Digestion 1982, 23 (1):1-8. Noda Y, Watanabe H, Iwafuchi M, Furuta K, Ishihara N, Satoh M, Ajioka Y: Carcinoids and endocrine cell micronests of the minor and major duodenal papillae. Their incidence and characteristics . Cancer 1992, 70 (7):1825-1833. Tables Tables 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files NECtable1.pdf Table1 Summary of the cases of NETs of the minor papilla reported in the world literature. 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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-1976910","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":130524967,"identity":"fcd4757a-c3ad-4505-b20c-c882f6bb38b0","order_by":0,"name":"Kenta Saito","email":"","orcid":"","institution":"Nagoya City University","correspondingAuthor":false,"prefix":"","firstName":"Kenta","middleName":"","lastName":"Saito","suffix":""},{"id":130524969,"identity":"bfe79384-4bc0-4fdc-b430-456d39bf6dce","order_by":1,"name":"Yoichi 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05:14:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1976910/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1976910/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":25665261,"identity":"c9bb9f3a-81f4-477e-a0e3-35e0a025c4a1","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":512630,"visible":true,"origin":"","legend":"\u003cp\u003eMagnetic resonance cholangiopancreatography showed a dilated dorsal pancreatic duct that was not connected with the ventral pancreatic duct and opened to the minor papilla. The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/ed27cc6da900f8ff67857833.png"},{"id":25665259,"identity":"cef6efb3-0b47-428d-a09b-985da680c514","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":596118,"visible":true,"origin":"","legend":"\u003cp\u003eContrast-enhanced computed tomography scan showed a 12-mm hypervascular mass near the ampulla of Vater and the dilated main pancreatic duct.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/0106ee2f02882773446d7243.png"},{"id":25665262,"identity":"2f2f87ee-b60b-4bb1-ac27-50d0b6cd1516","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1346150,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic retrograde cholangiopancreatography showed an irregular mucosal surface in the minor papilla.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/a5accbbb45c0f2edf6c49da8.png"},{"id":25665267,"identity":"ab930e99-46d5-4340-86ae-67bed7042767","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":504393,"visible":true,"origin":"","legend":"\u003cp\u003eInjection of contrast through the minor papilla revealed the dilated dorsal pancreatic duct.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/f4f2b7a53fc152115a0611af.png"},{"id":25665263,"identity":"4d67c96c-656b-490a-9e03-a95104cb0750","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":579630,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic ultrasonography showed a defined hypoechoic mass in the minor papilla with no invasion.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/1badc1e8a9d716349a615711.png"},{"id":25665851,"identity":"637bd432-9bfd-4835-a67a-68d8e9f899aa","added_by":"auto","created_at":"2022-08-25 16:27:48","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1682962,"visible":true,"origin":"","legend":"\u003cp\u003eThe largest tumor diameter was 25 × 15 mm in the cross-sectioned specimen, and the tumor was located in the minor papilla.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/ebcab96455e41315ac7efdbe.png"},{"id":25665266,"identity":"f56a2705-c94e-44f8-89f1-629c4bbe0619","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1253320,"visible":true,"origin":"","legend":"\u003cp\u003eHistologically, there was infiltration of trabecular tumor with central round nuclei, coarse-clustered chromatin, abundant granules in the cytoplasm, and a low-to-intermediate N/C ratio (×200).\u0026nbsp;\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/a4973522ea886912dfbe2c0c.png"},{"id":25665265,"identity":"cb58f905-8405-487c-bda0-424965f289e7","added_by":"auto","created_at":"2022-08-25 16:22:48","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":2014606,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical staining showed that chromogranin and synaptophysin were positive.\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/657e00dbae0d0c11fd0e9014.png"},{"id":25665852,"identity":"49e255a3-ebb4-4833-89c1-28834678cdbe","added_by":"auto","created_at":"2022-08-25 16:27:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8943045,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/f17f6f5e-b3ce-4ca2-8968-4f689d98195f.pdf"},{"id":25665850,"identity":"42cd46f6-17c7-4cb4-9560-54829ef4e487","added_by":"auto","created_at":"2022-08-25 16:27:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25306,"visible":true,"origin":"","legend":"\u003cp\u003eTable1 Summary of the cases of NETs of the minor papilla reported in the world literature.\u003c/p\u003e","description":"","filename":"NECtable1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1976910/v1/69a1f23aa88b6dea6cc70fde.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neuroendocrine carcinoma of the minor papilla with pancreas divisum: A review of the literature and report of a case","fulltext":[{"header":"Background","content":"\u003cp\u003eTumors of the minor papilla are very rare. Neuroendocrine tumors (NETs), which include tumors such as somatostatinomas and carcinoid tumors, are the majority of tumors of the minor papilla [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. NETs are usually located in the appendix, ileum and rectum [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. NETs of the minor papilla are extremely rare, and about 20 cases have been reported in the literature. However, neuroendocrine carcinoma (NEC) of the minor papilla has not been reported previously.\u003c/p\u003e \u003cp\u003ePancreas divisum is the most common congenital variant of the pancreas; it occurs when the embryological ventral and dorsal parts of the pancreas fail to fuse [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Thus, pancreatic drainage occurs mainly through the dorsal pancreatic duct and the minor papilla in patients with pancreas divisum. Previous reports have described the association of tumors of the minor papilla with pancreas divisum, but only 9 cases of NETs of the minor papilla with pancreas divisum have been reported in the literature [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe report a very rare case of NEC of the minor papilla with pancreas divisum and summarize the clinical features of NETs of the minor papilla reported in the medical literature.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 75-year-old man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. The patient\u0026rsquo;s clinical history included only hypertension. Laboratory data were within normal limits. Carbohydrate antigen (CA) 19\u0026thinsp;\u0026minus;\u0026thinsp;9 and carcinoembryonic antigen (CEA) were 1.0 U/mL and 1.6 ng/mL, respectively. Magnetic resonance cholangiopancreatography (MRCP) showed a dilated dorsal pancreatic duct, which was not connected with the ventral pancreatic duct and opened to the minor papilla, indicating pancreas divisum (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. Contrast-enhanced computed tomography (CT) scan showed a 12-mm hypervascular mass near the ampulla of Vater and the dilated main pancreatic duct (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Endoscopic retrograde cholangiopancreatography (ERCP) showed an irregular mucosal surface in the minor papilla (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Injection of contrast through the ampulla of Vater revealed the common bile duct with no dilation and inferior branches of the pancreatic duct. Injection of contrast through the minor papilla revealed the dilated main pancreatic duct (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Endoscopic ultrasonography (EUS) showed a defined hypoechoic mass in the minor papilla with no invasion and flow from the dilated pancreatic duct into the minor papilla (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The biopsies performed at the previous hospital showed adenocarcinoma.\u003c/p\u003e \u003cp\u003eBecause of the diagnosis of adenocarcinoma of the minor papilla with pancreas divisum, the patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. About 10 days after the operation, leakage of the choledochojejunostomy occurred. The patient improved with conservative treatment, and he was discharged. At 15 years of follow-up, the patient was doing well with no evidence of tumor recurrence.\u003c/p\u003e \u003ch2\u003ePathological findings\u003c/h2\u003e \u003cp\u003eOn gross examination, the tumor was 25 \u0026times; 15 mm and was located in the minor papilla (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Histologically, there was infiltration of trabecular tumor with abundant granules in the cytoplasm and a low-to-intermediate N/C ratio (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The tumor showed invasion of the duodenal mucosa and submucosal layer, and a submuscular lymph node was involved by the tumor. Immunohistochemical staining showed that chromogranin, synaptophysin and CD56 were positive; however, CD10, Alpha fetoprotein, glucagon, gastrin, somatostatin and insulin were negative (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). The pathological diagnosis was neuroendocrine carcinoma.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion And Conclusions","content":"\u003cp\u003eNETs located in the minor papilla are very rare, and a thorough review of the literature revealed only 20 cases. The clinical features of these patients are summarized in Table 1. However, NEC of the minor papilla has not been reported previously; therefore, our patient is the first reported case.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our analysis of the 20 previously reported cases of NETs in the minor papilla plus our case of NEC, we found the following. The mean age was 56.6 (range, 35 \u0026ndash; 80) years, and patients included 10 men and 11 women. However, in the gender distribution of patients who also had pancreas divisum, a marked female dominance was observed: 8 women, 2 men. The mean largest diameter of the tumors was 13.8 (range, 3 \u0026ndash; 27) mm. The most common clinical presentation was abdominal pain in nine cases (43%), and 5 cases were asymptomatic (24%). Lymph node metastases were diagnosed in 7 cases (33%) and liver metastasis in 1 case (5%). Surgical procedures were pancreatoduodenectomy in 12 cases (57%), local resection in 5 cases (24%) and endoscopic papillectomy in 3 cases (14%). Previous reports indicated that tumors of the duodenal papilla have high rates of metastasis [13], so Whipple\u0026rsquo;s operation is the most appropriate treatment for ampullary tumors [14]. In our case, the cancer diagnosis occurred relatively early because the patient had a medical check-up. The patient underwent pancreaticoduodenectomy, and at 15 years of follow-up, the patient was doing well with no evidence of tumor recurrence.\u003c/p\u003e\n\u003cp\u003eThe relationship between NETs of the minor papilla and pancreas divisum has been described previously. Pancreas divisum is a probable cause of pancreatitis because the smaller caliber of the accessory duct and the minor papilla may induce pancreatitis in patients with pancreas divisum [3, 15-17]. There is a possibility that the inflammation of the pancreas with pancreas divisum influences the formation of endocrine cell micronests (ECMs), which are thought to be precursor lesions of NET of the minor papilla. Regardless of the presence of pancreas divisum, carcinoids and ECMs in the minor papilla occur more frequently than generally thought. In a study of single surgical specimens and autopsies, the incidence of carcinoids and neoplastic ECMs of the minor papilla could reach 10%. Furthermore, carcinoids in the minor papilla are twice as common as carcinoids of the major papilla, and neoplastic ECMs of the minor papilla are found five times as often [18]. The number of reported cases of NETs of the major papilla exceeds those of the minor papilla. This discrepancy may be explained by the fact that due to ampullary obstruction, tumors of the major papilla are more likely to cause symptoms, such as jaundice or abdominal pain, whereas patients with minor papillary tumors usually remain asymptomatic because there is no biliary or pancreatic obstruction.\u003c/p\u003e\n\u003cp\u003eNETs of the minor papilla are very difficult to diagnose because these lesions tend to be small and usually located in the submucosal area. NETs of the minor papilla are rarely accompanied by endocrine manifestations [13]. Hence, deep biopsy samples should be obtained in such cases. A high index of suspicion must be maintained for such lesions in the appropriate setting, such as the young patient without common risk factors for pancreatitis [3]. NETs of the minor papilla should be included in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum; furthermore, patients with pancreas divisum require careful follow-up to monitor for the existence or formation of NETs of the minor papilla.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNETs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeuroendocrine tumors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeuroendocrine carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance cholangiopancreatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eContrast-enhanced computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eERCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndoscopic retrograde cholangiopancreatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndoscopic ultrasonography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECMs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndocrine cell micronests\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication: Written informed consent was obtained from the patient for publication of this case report and the accompanying images.\u003c/p\u003e\n\u003cp\u003eAvailability of data and material: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: not applicable\u003c/p\u003e\n\u003cp\u003eAuthor\u0026rsquo;s contributions: All authors read and approved the final manuscript. KS designed and wrote the paper. MM, RO and HT analyzed and interpreted the patient\u0026rsquo;s data. YD, KN, HM, HI and TK collected the patient\u0026rsquo;s data. YH and MM treated and followed the patient. YM and ST supervised this case report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStommer PE, Stolte M, Seifert E: \u003cstrong\u003eSomatostatinoma of Vater\u0026apos;s papilla and of the minor papilla\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e1987, \u003cstrong\u003e60\u003c/strong\u003e(2):232-235.\u003c/li\u003e\n\u003cli\u003eLowes JR, Rode J, Lees WR, Russell RC, Cotton PB: \u003cstrong\u003eObstructive pancreatitis: unusual causes of chronic pancreatitis\u003c/strong\u003e. \u003cem\u003eThe British journal of surgery \u003c/em\u003e1988, \u003cstrong\u003e75\u003c/strong\u003e(11):1129-1133.\u003c/li\u003e\n\u003cli\u003eSingh VV, Bhutani MS, Draganov P: \u003cstrong\u003eCarcinoid of the minor papilla in incomplete pancreas divisum presenting as acute relapsing pancreatitis\u003c/strong\u003e. \u003cem\u003ePancreas \u003c/em\u003e2003, \u003cstrong\u003e27\u003c/strong\u003e(1):96-97.\u003c/li\u003e\n\u003cli\u003eOuttas O, Barthet M, De Troyer J, Franck F, Garcia S: \u003cstrong\u003e[Pancreatic panniculitis with intraductal carcinoid tumor of the pancreas divisum]\u003c/strong\u003e. \u003cem\u003eAnnales de dermatologie et de venereologie \u003c/em\u003e2004, \u003cstrong\u003e131\u003c/strong\u003e(5):466-469.\u003c/li\u003e\n\u003cli\u003eWaisberg J, de Matos LL, Waisberg DR, dos Santos HV, Fernezlian SM, Capelozzi VL: \u003cstrong\u003eCarcinoid of the minor duodenal papilla associated with pancreas divisum: Case report and review of the literature\u003c/strong\u003e. \u003cem\u003eClinics (Sao Paulo, Brazil) \u003c/em\u003e2006, \u003cstrong\u003e61\u003c/strong\u003e(4):365-368.\u003c/li\u003e\n\u003cli\u003eKim YG, Kim TN, Kim KO: \u003cstrong\u003eCarcinoid tumor of the minor papilla in complete pancreas divisum presenting as recurrent abdominal pain\u003c/strong\u003e. \u003cem\u003eBMC gastroenterology \u003c/em\u003e2010, \u003cstrong\u003e10\u003c/strong\u003e:17.\u003c/li\u003e\n\u003cli\u003eBarresi L, Tarantino I, Ligresti D, Liotta R, Curcio G, Granata A, Marrone G, Traina M: \u003cstrong\u003eEndoscopic ultrasound-guided fine-needle aspiration diagnosis of mixed endocrine somatostatinoma of the minor papilla in von Recklinghausen disease\u003c/strong\u003e. \u003cem\u003eEndoscopy \u003c/em\u003e2014, \u003cstrong\u003e46 Suppl 1 UCTN\u003c/strong\u003e:E664-665.\u003c/li\u003e\n\u003cli\u003eBhandari R, Riddiough G, Lokan J, Weinberg L, Efthymiou M, Nikfarjam M: \u003cstrong\u003eSomatostatinoma of the minor papilla treated by local excision in a patient with neurofibromatosis type 1\u003c/strong\u003e. \u003cem\u003eJOP : Journal of the pancreas \u003c/em\u003e2015, \u003cstrong\u003e16\u003c/strong\u003e(1):81-84.\u003c/li\u003e\n\u003cli\u003eJara Letelier DI, Bonotto ML, Ardengh JC: \u003cstrong\u003eSomatostatinoma of the minor duodenal papilla associated with pancreas divisum treated by endoscopic papillectomy\u003c/strong\u003e. \u003cem\u003eEndoscopy \u003c/em\u003e2016, \u003cstrong\u003e48 Suppl 1\u003c/strong\u003e:E135-137.\u003c/li\u003e\n\u003cli\u003eGodwin JD, 2nd: \u003cstrong\u003eCarcinoid tumors. An analysis of 2,837 cases\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e1975, \u003cstrong\u003e36\u003c/strong\u003e(2):560-569.\u003c/li\u003e\n\u003cli\u003eModlin IM, Lye KD, Kidd M: \u003cstrong\u003eA 5-decade analysis of 13,715 carcinoid tumors\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e2003, \u003cstrong\u003e97\u003c/strong\u003e(4):934-959.\u003c/li\u003e\n\u003cli\u003eQuest L, Lombard M: \u003cstrong\u003ePancreas divisum: opinio divisa\u003c/strong\u003e. \u003cem\u003eGut \u003c/em\u003e2000, \u003cstrong\u003e47\u003c/strong\u003e(3):317-319.\u003c/li\u003e\n\u003cli\u003eHatzitheoklitos E, Buchler MW, Friess H, Poch B, Ebert M, Mohr W, Imaizumi T, Beger HG: \u003cstrong\u003eCarcinoid of the ampulla of Vater. Clinical characteristics and morphologic features\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e1994, \u003cstrong\u003e73\u003c/strong\u003e(6):1580-1588.\u003c/li\u003e\n\u003cli\u003eRicci JL: \u003cstrong\u003eCarcinoid of the ampulla of Vater. Local resection or pancreaticoduodenectomy\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e1993, \u003cstrong\u003e71\u003c/strong\u003e(3):686-690.\u003c/li\u003e\n\u003cli\u003eBernard JP, Sahel J, Giovannini M, Sarles H: \u003cstrong\u003ePancreas divisum is a probable cause of acute pancreatitis: a report of 137 cases\u003c/strong\u003e. \u003cem\u003ePancreas \u003c/em\u003e1990, \u003cstrong\u003e5\u003c/strong\u003e(3):248-254.\u003c/li\u003e\n\u003cli\u003eDelhaye M, Cremer M: \u003cstrong\u003eClinical significance of pancreas divisum\u003c/strong\u003e. \u003cem\u003eActa gastro-enterologica Belgica \u003c/em\u003e1992, \u003cstrong\u003e55\u003c/strong\u003e(3):306-313.\u003c/li\u003e\n\u003cli\u003eSahel J, Cros RC, Bourry J, Sarles H: \u003cstrong\u003eClinico-pathological conditions associated with pancreas divisum\u003c/strong\u003e. \u003cem\u003eDigestion \u003c/em\u003e1982, \u003cstrong\u003e23\u003c/strong\u003e(1):1-8.\u003c/li\u003e\n\u003cli\u003eNoda Y, Watanabe H, Iwafuchi M, Furuta K, Ishihara N, Satoh M, Ajioka Y: \u003cstrong\u003eCarcinoids and endocrine cell micronests of the minor and major duodenal papillae. Their incidence and characteristics\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e1992, \u003cstrong\u003e70\u003c/strong\u003e(7):1825-1833.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 is available in the Supplementary Files section.\u003c/p\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 carcinoma, neuroendocrine tumor, minor papilla, pancreas divisum, pancreatitis","lastPublishedDoi":"10.21203/rs.3.rs-1976910/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1976910/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eNeuroendocrine tumors of the minor papilla are very rare, and only 20 cases have been reported in the literature. Neuroendocrine carcinoma of the minor papilla with pancreas divisum has not been reported; thus, this report describes the first case. Neuroendocrine tumors of the minor papilla have been reported in association with pancreas divisum in about 50% of cases reported in the literature. We herein present our case of neuroendocrine carcinoma of the minor papilla with pancreas divisum in a 75-year-old male with a systematic literature review of the previous 20 reports of neuroendocrine tumors of the minor papilla.\u003c/p\u003e\u003cp\u003eCase presentation\u003c/p\u003e\u003cp\u003eA 75-year-old man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed a dilated dorsal pancreatic duct, which was not connected to the ventral pancreatic duct; however, it opened to the minor papilla, indicating pancreas divisum. The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. A contrast-enhanced computed tomography scan showed a 12-mm hypervascular mass near the ampulla of Vater. Endoscopic ultrasonography showed a defined hypoechoic mass in the minor papilla with no invasion. The biopsies performed at the previous hospital found adenocarcinoma. The patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. The pathological diagnosis was neuroendocrine carcinoma. At the 15-year follow-up visit, the patient was doing well with no evidence of tumor recurrence.\u003c/p\u003e\u003cp\u003eConclusion\u003c/p\u003e\u003cp\u003eIn our case, because the tumor was discovered during a medical check-up relatively early in the course of disease, the patient was doing well at the 15-year follow-up visit with no evidence of tumor recurrence. Diagnosing a tumor of the minor papilla is very difficult because of the relatively small size and submucosal location. Carcinoids and endocrine cell micronests in the minor papilla occur more frequently than generally thought. It is very important to include neuroendocrine tumors of the minor papilla in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum.\u003c/p\u003e","manuscriptTitle":"Neuroendocrine carcinoma of the minor papilla with pancreas divisum: A review of the literature and report of a case","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-25 16:22:46","doi":"10.21203/rs.3.rs-1976910/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":"5d10d322-4e16-48cd-ae73-4c001a933da9","owner":[],"postedDate":"August 25th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-08-25T16:22:48+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-25 16:22:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1976910","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1976910","identity":"rs-1976910","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}