Laparoscopic Surgery for Gallbladder Neuroendocrine Carcinoma: A Case Series and Literature Review

Laparoscopic Surgery for Gallbladder Neuroendocrine Carcinoma: A Case Series and Literature Review | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Case report Laparoscopic Surgery for Gallbladder Neuroendocrine Carcinoma: A Case Series and Literature Review Hongwu Chu, Ying Shi, Changwei Dou, Fangqiang Wei, Chengwu Zhang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-127441/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 May, 2021 Read the published version in Indian Journal of Surgery → Version 1 posted You are reading this latest preprint version Abstract Background: Gallbladder neuroendocrine carcinomas (GB-NECs) are a group of rare and heterogeneous neoplasms. There are few reports regarding laparoscopic surgery for GB-NEC cases diagnosed at advanced stage. Case presentation: Three patients, two females and one male, were admitted to our hospital. Two patients had the chief complaint of upper quadrant pain and one patient was found to have gallbladder occupation during a routine health checkup. No patient complained jaundice, weight loss, or carcinoid syndrome-related symptoms including diarrhea, edema, flushing and wheezing. Contrast-enhanced computed tomography (CT) examination showed local wall thickening of the gallbladder. In addition, one patient showed focal liver parenchymal invasion, and none of the three patients' preoperative imaging examination revealed lymph nodes (LNs) metastases. All three patients underwent laparoscopic radical cholecystectomy according to intraoperative frozen pathological examination, and they were diagnosed as GB-NEC based on postoperative pathology and immunohistochemistry. TNM stages of these patients were ⅢA (T3N0M0), ⅢB (T3N1M0) and ⅣB (T3N2M0), respectively. Chromogranin A (CgA) and synaptophysin (Syn) were positive in all cases. No patient encountered postoperative bleeding, bile leakage, abdominal abscess, gastrointestinal fistulas or pulmonary complication. Two patients underwent postoperative chemotherapy with two cycles and seven cycles of etoposide plus cisplatin, respectively. Another patient did not receive postoperative chemotherapy due to his poor general condition. The overall survival time of three patients was 4.6 months, 16.8 months and 8.5 months, respectively. All three patients presented with liver and/or bile duct recurrence after surgery with the tumor-free survival time of 2.3 months, 3.3 months and 3.0 months, respectively. Conclusion: Laparoscopic surgery may be considered as a potential treatment for advanced GB-NEC in selected patients. However, further studies are needed to investigate the tumor-free survival benefit of laparoscopic surgery, and whether expanding the resection scope could reduce postoperative recurrence. Surgical Obstetrics & Gynecology laparoscopy surgery gallbladder neuroendocrine carcinoma Figures Figure 1 Figure 1 Background Neuroendocrine neoplasms (NENs) are a type of rare and heterogeneous tumors with the incidence of about 6.98 per 100,000 [ 1 ]. They are originated from disseminated neuroendocrine cells and had been found in different organs including lungs, stomach, thyroid, jejunum and ileum. According to the Surveillance, Epidemiology and End result database, the incidence of gallbladder neuroendocrine neoplasms (GB-NENs) was < 0.74/100,000 [ 2 ]. Based on the 2019 World Health Organization (WHO) classification of tumors of the digestive system, gallbladder neuroendocrine carcinomas (GB-NECs) are defined as a kind of poorly-differentiated NENs with mitotic rate > 20 mitoses/2mm 2 and/or Ki-67 index > 20% [ 3 ]. GB-NECs are extremely rare in clinical practice with few reports, and associated with worse prognosis than gallbladder adenocarcinomas. There is no consensus of surgical strategies and guidelines of the GB-NEC, and in clinical practice, the treatment of GB-NEC refers to gallbladder adenocarcinoma. With the improvement of surgical techniques, the clinical application of laparoscopic resection for gallbladder carcinomas is increasing. GB-NEC has high grade malignancy and rapid progress, and is usually diagnosed at advanced stage [ 4 ]. There are few reports regarding laparoscopic surgery for GB-NEC, especially for those at advanced stages. We accidently found three patients who underwent laparoscopic gallbladder surgery with postoperative pathology suggesting GB-NEC and report as follows. Case Presentation Three GB-NEC patients, with two female cases and one male case, were admitted into our hospital (Table 1 ). Two patients complained upper quadrant pain, and one of them showed right upper quadrant tenderness during physical examination. Another one was admitted to our hospital due to an incidental finding of gallbladder occupation during a routine health checkup. No patient complained jaundice, weight loss, or carcinoid syndrome-related symptoms including diarrhea, edema, flushing and wheezing. The preoperative levels of cancer antigen 199 (CA-199) and carcinoembryonic antigen (CEA) for all patients were normal. All patients underwent ultrasonography, and showed space-occupying lesions of gallbladder wall. Contrast-enhanced computed tomography (CT) examination was performed for three patients, and demonstrated local wall thickening of the gallbladder (Fig. 1 ). In addition, two patients had gallbladder stones and one patient showed focal liver parenchymal invasion. None of the three patients' preoperative imaging examination revealed lymph nodes (LNs) metastases. Based on these findings, all three patients were diagnosed as gallbladder tumor preoperatively and failed to define the pathological type, and they were scheduled to undergo laparoscopic treatment. Wedge resection of gallbladder bed (≥ 2 cm) was performed for two patients without liver parenchymal invasion or vascular inflow involvement. For another patient with liver parenchymal invasion, the segment Ⅳb/V resection was performed. The surgically removed specimen of all patients were diagnosed as poorly differentiated gallbladder malignancy based on intraoperative histological examination. Thus, they all underwent laparoscopic radical cholecystectomy, and D2 lymph nodes dissection, including the LNs around gallbladder, extrahepatic bile duct, hepatoduodenal ligament plus peri-pancreatic head area, inter-aortocaval area and celiac axis area, was performed for all three patients (Fig. 2 ). The margin of cystic duct was sent to frozen section as well and all cases showed negative margin of cystic duct. According to postoperative pathological report, all patients were diagnosed as poorly differentiated GB-NEC with clear resection margins, and TNM stage were ⅢA (T3N0M0), ⅢB (T3N1M0) and ⅣB (T3N2M0), respectively. Chromogranin A (CgA) and synaptophysin (Syn) were positive in all cases. Ki-67 index ranged from 50–80%, and mitotic count ranged from 4 to 40. Table 1 Clinical features of three gallbladder neuroendocrine carcinoma cases. No. 1 2 3 Sex Female Female Male Age (years) 37 44 84 BMI 26.57 19.53 17.70 Clinical manifestation Right upper quadrant pain Yes Yes No Weight loss No No No Jaundice No No No Diarrhea No No No Flushing No No No Gallbladder stone Yes Yes No Pathological results Tumor size (cm) 4.3 × 3.5 × 2.1 5.5 × 3.0 × 2.0 5.0 × 4.0 × 4.0 TNM grade ⅣB (T3N2M0) ⅢA (T3N0M0) ⅢB (T3N1M0) Ki-67 (%) 80 50 65 Mitotic rate (mitoses/2 mm 2 ) 40 40 4 Cystic duct margin Negative Negative Negative Immunohistochemistry CgA Positive Positive Positive Syn Positive Positive Positive No. number, BMI body mass index, CgA chromogranin A, Syn synaptophysin. No patient encountered postoperative bleeding, bile leakage, abdominal abscess, gastrointestinal fistulas or pulmonary complication (Table 2 ). No patients underwent re-operation during postoperative stay. The average days of oral diet recovery, drainage tubes removal and postoperative hospital stay were 2.0 days, 9.3 days and 11.7 days, respectively. One patient underwent chemotherapies with two cycles of etoposide plus cisplatin, and presented with liver and bile duct recurrence at 2.3 months after surgery, with the overall survival of 4.6 months. One patient underwent chemotherapies with seven cycles of etoposide plus cisplatin, and presented with liver, LNs, and bile duct recurrence at 3.3 months after surgery with the overall survival of 16.8 months. Another patient did not receive postoperative chemotherapy due to his poor general condition and presented with liver metastasis at 3.0 months after surgery. As of the last follow-up, he is still alive with the overall survival of 8.5 months. Table 2 Postoperative outcomes of three gallbladder neuroendocrine carcinoma cases. No. Postoperative complications Oral diet recovery (days) Drainage tubes removal (days) Postoperative hospital stays (days) Chemotherapy Recurrent sites Tumor-free survival time (months) Overall survival time (months) 1 No 3 15 16 Yes Liver, Bile duct 3.3 4.6 2 No 2 7 8 Yes Liver, Bile duct, LNs 2.3 16.8 3 No 1 6 11 No Liver 3.0 8.5 No. number, LNs lymph nodes. Discussion Due to the malignant potential of GB-NEC, surgical resection remains as the most important treatment [ 5 ]. However, because of some reasons, including the rarity, little knowledge on the pathogenesis, biological features and clinicopathological characteristics of this disease, there is no consensus of surgical strategies and guidelines of the GB-NEC. In clinical practice, the treatment of GB-NEC refers to gallbladder adenocarcinoma. With the improvement of surgical techniques, laparoscopic surgery for gallbladder carcinomas is increasing. Compared with conventional laparotomy, our department found that laparoscopic surgery for gallbladder carcinomas may provide comparable perioperative outcomes and it is helpful for less intraoperative bleeding, shorter postoperative days of oral diet recovery and hospital stays [ 6 ]. In the study performed by Liu et al., all three patients with GB-NEC at T1bN0M0 stage underwent laparoscopic cholecystectomy with gallbladder bed cautery, and no recurrences were found during the at least 26.0 months’ follow-up without any postoperative chemotherapy or radiotherapy (Table 3 ) [ 7 ]. However, there are few reports discussing laparoscopic surgery for GB-NECs at advanced stages. Kim et al. reported a 77-year-old female at TNM ⅢB stage (T3N1M0) underwent laparoscopic radical cholecystectomy and combined chemoradiation therapy, and no evidence of recurrence was found over the follow-up period of 14.0 months [ 8 ]. In current study, all three patients were diagnosed at advanced stage and underwent laparoscopic radical cholecystectomy with the median overall survival time of 8.5 months. Compared with laparotomy, laparoscopic surgery provided a comparable overall survival. Liu et al. reported one patient with GB-NEC at TNM ⅢB stage underwent open radical cholecystectomy with the overall survival of 5.0 months [ 9 ]. In the study performed by Chen et al., 4 the overall survival time of one patient at TNM ⅣB stage undergoing open radical cholecystectomy was 5.7 months. In terms of the short-term outcome, in our study, no patient presented severe postoperative complication including bile leakage, abdominal abscess, gastrointestinal fistulas and pulmonary complication. No patient underwent re-operation during postoperative hospitalization. Table 3 Comparison between laparotomy and laparoscopy for gallbladder neuroendocrine carcinoma. Surgical method Laparotomy Laparoscopy Study [Refs.] Liu et al [ 9 ] Chen et al [ 4 ] Liu et al [ 7 ] Kim et al [ 8 ] Present study No. of cases 1 1 3 1 3 TNM stage 1 ⅢB (T3N1M0) 1 ⅣB (T3N2M0) 3 Ⅰ (T1bN0M0) 1 ⅢB (T3N1M0) 1 ⅢA (T3N0M0) 1 ⅢB (T3N1M0) 1 ⅣB (T3N2M0) Surgery Open radical cholecystectomy Open radical cholecystectomy Laparoscopic cholecystectomy Laparoscopic radical cholecystectomy Laparoscopic radical cholecystectomy Metastasis sites LNs LNs No LNs, Liver Liver 1, LNs 2 Recurrent sites NA NA No No LNs 1 Liver 3 Bile duct 2 Median tumor-free survival time (month) NA NA 29.0 (26.0–42.0) 14.0 3.0 (2.3–3.3) Median overall survival time (month) 5.0 5.7 29.0 (26.0–42.0) 14.0 8.5 (4.6–16.8) No. number, LNs lymph nodes, NA not available. Port sites recurrence or peritoneal dissemination caused by inadequate manipulation to handle gallbladder, intraoperative gallbladder perforation, and CO2 pneumoperitoneum are the reasons for restricting the use of laparoscopic approach for gallbladder carcinoma [ 10 – 12 ]. However, gallbladder rupture can be avoided through the surgeon's clinical experience and careful operation. For gallbladder carcinomas in situ and T1N0M0 phase, pure cholecystectomy could be enough. For those in advanced stage, en-bloc resection of the gallbladder and liver parenchyma should be performed during the operation. Moreover, compared with laparotomy, laparoscopic surgery could provide a comparable number of lymph nodes resected [ 13 ]. Kitagawa et al. reported that the tumor-free survival rates of laparoscopic radical cholecystectomy tended to be superior to those of open radical cholecystectomy for gallbladder carcinomas [ 14 ]. Previous study by Agarwal et al. showed that the tumor-free survival time in laparoscopic group was comparable to those in the laparotomy group [ 15 ]. In our study, en-bloc resection of the gallbladder and liver parenchyma was strictly performed during the operation with negative microscopic margins and a protective plastic bag was routinely employed for specimen removal to prevent port sites recurrence or peritoneal dissemination. No gallbladder rupture occurred during the operation. In addition, D2 lymph nodes dissection was performed for all three patients. However, all three patients presented with liver and/or bile duct recurrence after surgery with the median tumor-free survival time of 3.0 months. One reason may be that GB-NEC at advanced stages is more malignant than gallbladder adenocarcinoma, so the scope of liver resection and lymph nodes dissection may be insufficient in contrast to gallbladder adenocarcinoma. In our study, all three patients were not clearly diagnosed as GB-NEC by preoperative examination and intraoperative frozen pathological examination, but were diagnosed as GB-NEC by postoperative pathology and immunohistochemistry. Therefore, we did not adopt a more aggressive surgical approach during the operation. We can only conjecture that for patients diagnosed as GB-NEC, it may be possible to reduce the postoperative tumor recurrence by expanding the resection scope, but this needs more research to confirm. Because there are no studies on the tumor-free survival time of patients with advanced GB-NEC undergoing open radical cholecystectomy at present, we can’t compare the tumor-free survival time of laparotomy and laparoscopic surgery. The potential tumor-free survival benefit of laparoscopic surgery for patients with advanced GB-NEC remains controversial. Conclusion Laparoscopic surgery may be considered a potential treatment for advanced GB-NEC in selected patients. However, further studies are needed to investigate the tumor-free survival benefit of laparoscopic surgery, and whether expanding the resection scope could reduce postoperative recurrence. The sample size of our report is limited and more research with a larger sample size is needed, our experience will be very helpful for surgeons when they need to decide the surgical options for patients with advanced GB-NEC. Declarations Authors’ contributions Hongwu Chu and Jungang Zhang designed the study; Hongwu Chu drafted the manuscript; Ying Shi collected the clinical data; Changwei Dou, Fangqiang Wei and Chengwu Zhang performed the operation; Jungang Zhang and Dongsheng Huang reviewed the manuscript. Acknowledgements Not applicable. Competing interests The authors declare that they have no competing interests. Availability of data and materials The data sets during and/or analyzed during the current study available from the corresponding author on reasonable request. Consent for publication Written informed consents for publication of patients’ clinical details and clinical images were obtained from patients. Ethics approval and consent to participate The case report was approved and supervised by the Clinical Research Ethics Committee of the Zhejiang Provincial People’s Hospital of Hangzhou, China. Funding Not applicable. Funding statement Not applicable. References Cen D, Liu H, Wan Z, Lin Z, Wang Y, Xu J, et al. Clinicopathological features and survival for gallbladder NEN: a population-based study. Endocr Connect. 2019;8:1273-81. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol l. 2008;26:3063-72. Bosman FT. WHO classification of tumours of the digestive system. 2010. Chen C, Wang L, Liu X, Zhang G, Zhao Y, Geng Z. Gallbladder neuroendocrine carcinoma: report of 10 cases and comparision of clinicopathologic features with gallbladder adenocarcinoma. Int J Clin Exp Pathol. 2015;8:8218-26. Elahi F, Ahmadzadeh A, Yadollahzadeh M, Hassanpour K, Babaei M. Neuroendocrine tumor of the gallbladder. Arch Iran Med. 2013;16:123-5. Dou C, Zhang Y, Liu J, Wei F, Chu H, Han J, et al. Laparoscopy versus laparotomy approach of a radical resection for gallbladder cancer: a retrospective comparative study. Surg Endosc. 2020;34:2926-38. Liu W, Chen W, He X, Qu Q, Hong T, Li B. Cholecystectomy with gallbladder bed cautery might be sufficient for T1bN0M0 neuroendocrine carcinoma of gallbladders: Cases report and literature review. Medicine (Baltimore). 2017;96:e8778. Kim S, Yoon YS, Han HS, Cho JY, Choi Y. Laparoscopic extended cholecystectomy for T3 gallbladder cancer. Surg Endosc. 2018;32:2984-5. Liu W, Chen W, Chen J, Hong T, Li B, Qu Q, et al. Neuroendocrine carcinoma of gallbladder: a case series and literature review. Eur J Med Res. 2019;24:8. Reddy YP, Sheridan WG. Port-site metastasis following laparoscopic cholecystectomy: a review of the literature and a case report. Eur J Surg Oncol. 2000;26:95-8. Berger-Richardson D, Chesney TR, Englesakis M, Govindarajan A, Cleary SP, Swallow CJ. Trends in port-site metastasis after laparoscopic resection of incidental gallbladder cancer: A systematic review. Surgery. 2017;161:618-27. Evrard S, Falkenrodt A, Park A, Tassetti V, Mutter D, Marescaux J. Influence of CO2 pneumoperitoneum on systemic and peritoneal cell-mediated immunity. World J Surg. 1997;21:353-6. Feng JW, Yang XH, Liu CW, Wu BQ, Sun DL, Chen XM, et al. Comparison of Laparoscopic and Open Approach in Treating Gallbladder Cancer. J Surg Res. 2019;234:269-76. Itano O, Oshima G, Minagawa T, Shinoda M, Kitago M, Abe Y, et al. Novel strategy for laparoscopic treatment of pT2 gallbladder carcinoma. Surg Endosc. 2015;29:3600-7. Agarwal AK, Javed A, Kalayarasan R, Sakhuja P. Minimally invasive versus the conventional open surgical approach of a radical cholecystectomy for gallbladder cancer: a retrospective comparative study. HPB (Oxford). 2015;17:536-41. Cite Share Download PDF Status: Published Journal Publication published 21 May, 2021 Read the published version in Indian Journal of Surgery → 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. 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Also discoverable on Platform About In Review Editorial Policies 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-127441","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case report","associatedPublications":[],"authors":[{"id":6349801,"identity":"4087b043-a735-44a8-a595-3d650c883d77","order_by":0,"name":"Hongwu Chu","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hongwu","middleName":"","lastName":"Chu","suffix":""},{"id":6349802,"identity":"eaca7e2b-9223-404f-b4d4-b471fbd109f4","order_by":1,"name":"Ying Shi","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Shi","suffix":""},{"id":6349803,"identity":"2b899671-f570-43bf-b83c-98ee0c0a1c4a","order_by":2,"name":"Changwei Dou","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Changwei","middleName":"","lastName":"Dou","suffix":""},{"id":6349804,"identity":"ddefc7a5-f7f8-4c0b-890e-6f5b35275875","order_by":3,"name":"Fangqiang Wei","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fangqiang","middleName":"","lastName":"Wei","suffix":""},{"id":6349805,"identity":"1cae2214-dc8a-4a0c-9f7a-3e785791df20","order_by":4,"name":"Chengwu Zhang","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chengwu","middleName":"","lastName":"Zhang","suffix":""},{"id":6349806,"identity":"7958778f-7ac9-440f-92b8-7cc490b03cb3","order_by":5,"name":"Jungang Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIie2QIQ7CQBBF/2aTxRSwQyD0CiU1SI6yBIEiQZEqUsyu4QAojoHeqpoNwWPquEKbIGjDATqShH1qxH+ZPwMEAj+JExVAczWwjq3IBFimo8hr9hpFQLa+0irh5eNT+Zg0hraGoFFnt35F5H6fDg3tzPTkxNk/+xUJrzeiU2ZOS2EYimqVoiumSCc8JUJZ5G0xzVcIXsroTgvTPrlg3RJfyldTH45xbG1R1RlDAfkEQn1nx8i3jG0FvHnZQCAQ+FM+I5E9BiCyHIAAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-1642-7554","institution":"Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China. ","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jungang","middleName":"","lastName":"Zhang","suffix":""},{"id":6349807,"identity":"a2b4dde5-35b3-4d1a-a537-28da3968a599","order_by":6,"name":"Dongsheng Huang","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dongsheng","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2020-12-12 19:34:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-127441/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-127441/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12262-021-02923-x","type":"published","date":"2021-05-21T22:12:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":4344429,"identity":"e6887e5e-4144-4472-a40c-f4b265f7178c","added_by":"auto","created_at":"2020-12-17 19:03:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":368546,"visible":true,"origin":"","legend":"Key procedures of laparoscopic radical cholecystectomy for gallbladder neuroendocrine carcinomas (GB-NECs). a The tumor (arrow) was located at the bottom of the gallbladder; b Margin of cystic duct (arrow) was sent to frozen biopsy; c The view of liver cross resection after liver resection; d The extent of lymphadenectomy for GB-NEC cases.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-127441/v1/ee6843e6a11e6079abd043e3.jpg"},{"id":4344428,"identity":"d0a4ad7e-98cc-47ae-97fd-708cafac1545","added_by":"auto","created_at":"2020-12-17 19:03:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":215652,"visible":true,"origin":"","legend":"Typical contrast-enhanced computed tomography (CT) images for gallbladder neuroendocrine carcinomas (GB-NECs). a Arterial phases; b Venous phases. The arrow shows local wall thickening of the gallbladder.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-127441/v1/084a57bd8cdfef0057a54695.jpg"},{"id":17755564,"identity":"9bae0583-1be8-43f2-ab77-609951620324","added_by":"auto","created_at":"2022-01-28 22:12:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":607492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-127441/v1/f8fecc7f-9458-42ff-9b0e-6c9b707e3eab.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eLaparoscopic Surgery for Gallbladder Neuroendocrine Carcinoma: A Case Series and Literature Review\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eNeuroendocrine neoplasms (NENs) are a type of rare and heterogeneous tumors with the incidence of about 6.98 per 100,000 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. They are originated from disseminated neuroendocrine cells and had been found in different organs including lungs, stomach, thyroid, jejunum and ileum. According to the Surveillance, Epidemiology and End result database, the incidence of gallbladder neuroendocrine neoplasms (GB-NENs) was \u0026lt;\u0026thinsp;0.74/100,000 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Based on the 2019 World Health Organization (WHO) classification of tumors of the digestive system, gallbladder neuroendocrine carcinomas (GB-NECs) are defined as a kind of poorly-differentiated NENs with mitotic rate\u0026thinsp;\u0026gt;\u0026thinsp;20 mitoses/2mm\u003csup\u003e2\u003c/sup\u003e and/or Ki-67 index\u0026thinsp;\u0026gt;\u0026thinsp;20% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. GB-NECs are extremely rare in clinical practice with few reports, and associated with worse prognosis than gallbladder adenocarcinomas. There is no consensus of surgical strategies and guidelines of the GB-NEC, and in clinical practice, the treatment of GB-NEC refers to gallbladder adenocarcinoma. With the improvement of surgical techniques, the clinical application of laparoscopic resection for gallbladder carcinomas is increasing. GB-NEC has high grade malignancy and rapid progress, and is usually diagnosed at advanced stage [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There are few reports regarding laparoscopic surgery for GB-NEC, especially for those at advanced stages. We accidently found three patients who underwent laparoscopic gallbladder surgery with postoperative pathology suggesting GB-NEC and report as follows.\u003c/p\u003e "},{"header":"Case Presentation","content":" \u003cp\u003eThree GB-NEC patients, with two female cases and one male case, were admitted into our hospital (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Two patients complained upper quadrant pain, and one of them showed right upper quadrant tenderness during physical examination. Another one was admitted to our hospital due to an incidental finding of gallbladder occupation during a routine health checkup. No patient complained jaundice, weight loss, or carcinoid syndrome-related symptoms including diarrhea, edema, flushing and wheezing. The preoperative levels of cancer antigen 199 (CA-199) and carcinoembryonic antigen (CEA) for all patients were normal. All patients underwent ultrasonography, and showed space-occupying lesions of gallbladder wall. Contrast-enhanced computed tomography (CT) examination was performed for three patients, and demonstrated local wall thickening of the gallbladder (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, two patients had gallbladder stones and one patient showed focal liver parenchymal invasion. None of the three patients' preoperative imaging examination revealed lymph nodes (LNs) metastases. Based on these findings, all three patients were diagnosed as gallbladder tumor preoperatively and failed to define the pathological type, and they were scheduled to undergo laparoscopic treatment. Wedge resection of gallbladder bed (\u0026ge;\u0026thinsp;2\u0026nbsp;cm) was performed for two patients without liver parenchymal invasion or vascular inflow involvement. For another patient with liver parenchymal invasion, the segment Ⅳb/V resection was performed. The surgically removed specimen of all patients were diagnosed as poorly differentiated gallbladder malignancy based on intraoperative histological examination. Thus, they all underwent laparoscopic radical cholecystectomy, and D2 lymph nodes dissection, including the LNs around gallbladder, extrahepatic bile duct, hepatoduodenal ligament plus peri-pancreatic head area, inter-aortocaval area and celiac axis area, was performed for all three patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The margin of cystic duct was sent to frozen section as well and all cases showed negative margin of cystic duct. According to postoperative pathological report, all patients were diagnosed as poorly differentiated GB-NEC with clear resection margins, and TNM stage were ⅢA (T3N0M0), ⅢB (T3N1M0) and ⅣB (T3N2M0), respectively. Chromogranin A (CgA) and synaptophysin (Syn) were positive in all cases. Ki-67 index ranged from 50\u0026ndash;80%, and mitotic count ranged from 4 to 40.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of three gallbladder neuroendocrine carcinoma cases.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical manifestation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight upper quadrant pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFlushing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGallbladder stone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological results\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3\u0026thinsp;\u0026times;\u0026thinsp;3.5\u0026thinsp;\u0026times;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026times;\u0026thinsp;3.0\u0026thinsp;\u0026times;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.0\u0026thinsp;\u0026times;\u0026thinsp;4.0\u0026thinsp;\u0026times;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNM grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eⅣB (T3N2M0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eⅢA (T3N0M0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eⅢB (T3N1M0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMitotic rate (mitoses/2 mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCystic duct margin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunohistochemistry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCgA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSyn\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNo. number, BMI body mass index, CgA chromogranin A, Syn synaptophysin.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNo patient encountered postoperative bleeding, bile leakage, abdominal abscess, gastrointestinal fistulas or pulmonary complication (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No patients underwent re-operation during postoperative stay. The average days of oral diet recovery, drainage tubes removal and postoperative hospital stay were 2.0 days, 9.3 days and 11.7 days, respectively. One patient underwent chemotherapies with two cycles of etoposide plus cisplatin, and presented with liver and bile duct recurrence at 2.3 months after surgery, with the overall survival of 4.6 months. One patient underwent chemotherapies with seven cycles of etoposide plus cisplatin, and presented with liver, LNs, and bile duct recurrence at 3.3 months after surgery with the overall survival of 16.8 months. Another patient did not receive postoperative chemotherapy due to his poor general condition and presented with liver metastasis at 3.0 months after surgery. As of the last follow-up, he is still alive with the overall survival of 8.5 months.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostoperative outcomes of three gallbladder neuroendocrine carcinoma cases.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative complications\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOral diet recovery (days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDrainage tubes removal (days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePostoperative hospital stays (days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRecurrent sites\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTumor-free survival time (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOverall survival time (months)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiver, Bile duct\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiver, Bile duct, LNs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e16.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNo. number, LNs lymph nodes.\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eDue to the malignant potential of GB-NEC, surgical resection remains as the most important treatment [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, because of some reasons, including the rarity, little knowledge on the pathogenesis, biological features and clinicopathological characteristics of this disease, there is no consensus of surgical strategies and guidelines of the GB-NEC. In clinical practice, the treatment of GB-NEC refers to gallbladder adenocarcinoma. With the improvement of surgical techniques, laparoscopic surgery for gallbladder carcinomas is increasing. Compared with conventional laparotomy, our department found that laparoscopic surgery for gallbladder carcinomas may provide comparable perioperative outcomes and it is helpful for less intraoperative bleeding, shorter postoperative days of oral diet recovery and hospital stays [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the study performed by Liu et al., all three patients with GB-NEC at T1bN0M0 stage underwent laparoscopic cholecystectomy with gallbladder bed cautery, and no recurrences were found during the at least 26.0 months\u0026rsquo; follow-up without any postoperative chemotherapy or radiotherapy (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, there are few reports discussing laparoscopic surgery for GB-NECs at advanced stages. Kim et al. reported a 77-year-old female at TNM ⅢB stage (T3N1M0) underwent laparoscopic radical cholecystectomy and combined chemoradiation therapy, and no evidence of recurrence was found over the follow-up period of 14.0\u0026nbsp;months [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In current study, all three patients were diagnosed at advanced stage and underwent laparoscopic radical cholecystectomy with the median overall survival time of 8.5\u0026nbsp;months. Compared with laparotomy, laparoscopic surgery provided a comparable overall survival. Liu et al. reported one patient with GB-NEC at TNM ⅢB stage underwent open radical cholecystectomy with the overall survival of 5.0\u0026nbsp;months [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the study performed by Chen et al.,\u003csup\u003e4\u003c/sup\u003e the overall survival time of one patient at TNM ⅣB stage undergoing open radical cholecystectomy was 5.7\u0026nbsp;months. In terms of the short-term outcome, in our study, no patient presented severe postoperative complication including bile leakage, abdominal abscess, gastrointestinal fistulas and pulmonary complication. No patient underwent re-operation during postoperative hospitalization.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison between laparotomy and laparoscopy for gallbladder neuroendocrine carcinoma.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eSurgical method\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eLaparotomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c8\" namest=\"c5\"\u003e \u003cp\u003eLaparoscopy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy [Refs.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiu et al [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChen et al [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eLiu et al [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eKim et al [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePresent study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNM stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 ⅢB (T3N1M0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 ⅣB (T3N2M0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e3 Ⅰ (T1bN0M0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 ⅢB (T3N1M0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 ⅢA (T3N0M0)\u003c/p\u003e \u003cp\u003e1 ⅢB (T3N1M0)\u003c/p\u003e \u003cp\u003e1 ⅣB (T3N2M0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOpen radical cholecystectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOpen radical cholecystectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eLaparoscopic cholecystectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLaparoscopic radical cholecystectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLaparoscopic radical cholecystectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis sites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLNs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLNs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLNs, Liver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiver 1, LNs 2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent sites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLNs 1\u003c/p\u003e \u003cp\u003eLiver 3\u003c/p\u003e \u003cp\u003eBile duct 2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian tumor-free survival time (month)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e29.0 (26.0\u0026ndash;42.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.0 (2.3\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian overall survival time (month)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e29.0 (26.0\u0026ndash;42.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.5 (4.6\u0026ndash;16.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eNo. number, LNs lymph nodes, NA not available.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePort sites recurrence or peritoneal dissemination caused by inadequate manipulation to handle gallbladder, intraoperative gallbladder perforation, and CO2 pneumoperitoneum are the reasons for restricting the use of laparoscopic approach for gallbladder carcinoma [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, gallbladder rupture can be avoided through the surgeon's clinical experience and careful operation. For gallbladder carcinomas in situ and T1N0M0 phase, pure cholecystectomy could be enough. For those in advanced stage, en-bloc resection of the gallbladder and liver parenchyma should be performed during the operation. Moreover, compared with laparotomy, laparoscopic surgery could provide a comparable number of lymph nodes resected [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Kitagawa et al. reported that the tumor-free survival rates of laparoscopic radical cholecystectomy tended to be superior to those of open radical cholecystectomy for gallbladder carcinomas [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Previous study by Agarwal et al. showed that the tumor-free survival time in laparoscopic group was comparable to those in the laparotomy group [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our study, en-bloc resection of the gallbladder and liver parenchyma was strictly performed during the operation with negative microscopic margins and a protective plastic bag was routinely employed for specimen removal to prevent port sites recurrence or peritoneal dissemination. No gallbladder rupture occurred during the operation. In addition, D2 lymph nodes dissection was performed for all three patients. However, all three patients presented with liver and/or bile duct recurrence after surgery with the median tumor-free survival time of 3.0 months. One reason may be that GB-NEC at advanced stages is more malignant than gallbladder adenocarcinoma, so the scope of liver resection and lymph nodes dissection may be insufficient in contrast to gallbladder adenocarcinoma. In our study, all three patients were not clearly diagnosed as GB-NEC by preoperative examination and intraoperative frozen pathological examination, but were diagnosed as GB-NEC by postoperative pathology and immunohistochemistry. Therefore, we did not adopt a more aggressive surgical approach during the operation. We can only conjecture that for patients diagnosed as GB-NEC, it may be possible to reduce the postoperative tumor recurrence by expanding the resection scope, but this needs more research to confirm. Because there are no studies on the tumor-free survival time of patients with advanced GB-NEC undergoing open radical cholecystectomy at present, we can\u0026rsquo;t compare the tumor-free survival time of laparotomy and laparoscopic surgery. The potential tumor-free survival benefit of laparoscopic surgery for patients with advanced GB-NEC remains controversial.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eLaparoscopic surgery may be considered a potential treatment for advanced GB-NEC in selected patients. However, further studies are needed to investigate the tumor-free survival benefit of laparoscopic surgery, and whether expanding the resection scope could reduce postoperative recurrence. The sample size of our report is limited and more research with a larger sample size is needed, our experience will be very helpful for surgeons when they need to decide the surgical options for patients with advanced GB-NEC.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHongwu Chu and Jungang Zhang designed the study; Hongwu Chu drafted the manuscript; Ying Shi collected the clinical data; Changwei Dou, Fangqiang Wei and Chengwu Zhang performed the operation; Jungang Zhang and Dongsheng Huang reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets during and/or analyzed during the current study available from\u003c/p\u003e\n\u003cp\u003ethe corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consents for publication of patients\u0026rsquo; clinical details and clinical images were obtained from patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe case report was approved and supervised by the Clinical Research Ethics Committee of the Zhejiang Provincial People\u0026rsquo;s Hospital of Hangzhou, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCen D, Liu H, Wan Z, Lin Z, Wang Y, Xu J, et al. Clinicopathological features and survival for gallbladder NEN: a population-based study. Endocr Connect. 2019;8:1273-81.\u003c/li\u003e\n\u003cli\u003eYao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after \"carcinoid\": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol l. 2008;26:3063-72.\u003c/li\u003e\n\u003cli\u003eBosman FT. WHO classification of tumours of the digestive system. 2010.\u003c/li\u003e\n\u003cli\u003eChen C, Wang L, Liu X, Zhang G, Zhao Y, Geng Z. Gallbladder neuroendocrine carcinoma: report of 10 cases and comparision of clinicopathologic features with gallbladder adenocarcinoma. Int J Clin Exp Pathol. 2015;8:8218-26.\u003c/li\u003e\n\u003cli\u003eElahi F, Ahmadzadeh A, Yadollahzadeh M, Hassanpour K, Babaei M. Neuroendocrine tumor of the gallbladder. Arch Iran Med. 2013;16:123-5.\u003c/li\u003e\n\u003cli\u003eDou C, Zhang Y, Liu J, Wei F, Chu H, Han J, et al. Laparoscopy versus laparotomy approach of a radical resection for gallbladder cancer: a retrospective comparative study. Surg Endosc. 2020;34:2926-38.\u003c/li\u003e\n\u003cli\u003eLiu W, Chen W, He X, Qu Q, Hong T, Li B. Cholecystectomy with gallbladder bed cautery might be sufficient for T1bN0M0 neuroendocrine carcinoma of gallbladders: Cases report and literature review. Medicine (Baltimore). 2017;96:e8778.\u003c/li\u003e\n\u003cli\u003eKim S, Yoon YS, Han HS, Cho JY, Choi Y. Laparoscopic extended cholecystectomy for T3 gallbladder cancer. Surg Endosc. 2018;32:2984-5.\u003c/li\u003e\n\u003cli\u003eLiu W, Chen W, Chen J, Hong T, Li B, Qu Q, et al. Neuroendocrine carcinoma of gallbladder: a case series and literature review. Eur J Med Res. 2019;24:8.\u003c/li\u003e\n\u003cli\u003eReddy YP, Sheridan WG. Port-site metastasis following laparoscopic cholecystectomy: a review of the literature and a case report. Eur J Surg Oncol. 2000;26:95-8.\u003c/li\u003e\n\u003cli\u003eBerger-Richardson D, Chesney TR, Englesakis M, Govindarajan A, Cleary SP, Swallow CJ. Trends in port-site metastasis after laparoscopic resection of incidental gallbladder cancer: A systematic review. Surgery. 2017;161:618-27.\u003c/li\u003e\n\u003cli\u003eEvrard S, Falkenrodt A, Park A, Tassetti V, Mutter D, Marescaux J. Influence of CO2 pneumoperitoneum on systemic and peritoneal cell-mediated immunity. World J Surg. 1997;21:353-6.\u003c/li\u003e\n\u003cli\u003eFeng JW, Yang XH, Liu CW, Wu BQ, Sun DL, Chen XM, et al. Comparison of Laparoscopic and Open Approach in Treating Gallbladder Cancer. J Surg Res. 2019;234:269-76.\u003c/li\u003e\n\u003cli\u003eItano O, Oshima G, Minagawa T, Shinoda M, Kitago M, Abe Y, et al. Novel strategy for laparoscopic treatment of pT2 gallbladder carcinoma. Surg Endosc. 2015;29:3600-7.\u003c/li\u003e\n\u003cli\u003eAgarwal AK, Javed A, Kalayarasan R, Sakhuja P. Minimally invasive versus the conventional open surgical approach of a radical cholecystectomy for gallbladder cancer: a retrospective comparative study. HPB (Oxford). 2015;17:536-41.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"laparoscopy, surgery, gallbladder, neuroendocrine carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-127441/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-127441/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eGallbladder neuroendocrine carcinomas (GB-NECs) are a group of rare and heterogeneous neoplasms. There are few reports regarding laparoscopic surgery for GB-NEC cases diagnosed at advanced stage.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e Three patients, two females and one male, were admitted to our hospital. Two patients had the chief complaint of upper quadrant pain and one patient was found to have gallbladder occupation during a routine health checkup. No patient complained jaundice, weight loss, or carcinoid syndrome-related symptoms including diarrhea, edema, flushing and wheezing. Contrast-enhanced computed tomography (CT) examination showed local wall thickening of the gallbladder. In addition, one patient showed focal liver parenchymal invasion, and none of the three patients' preoperative imaging examination revealed lymph nodes (LNs) metastases. All three patients underwent laparoscopic radical cholecystectomy according to intraoperative frozen pathological examination, and they were diagnosed as GB-NEC based on postoperative pathology and immunohistochemistry.\u003cstrong\u003e \u003c/strong\u003eTNM stages of these patients were ⅢA (T3N0M0), ⅢB (T3N1M0) and ⅣB (T3N2M0), respectively. Chromogranin A (CgA) and synaptophysin (Syn) were positive in all cases. No patient encountered postoperative bleeding, bile leakage, abdominal abscess, gastrointestinal fistulas or pulmonary complication. Two patients underwent postoperative chemotherapy with two cycles and seven cycles of etoposide plus cisplatin, respectively. Another patient did not receive postoperative chemotherapy due to his poor general condition. The overall survival time of three patients was 4.6 months, 16.8 months and 8.5 months, respectively. All three patients presented with liver and/or bile duct recurrence after surgery with the tumor-free survival time of 2.3 months, 3.3 months and 3.0 months, respectively.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Laparoscopic surgery may be considered as a potential treatment for advanced GB-NEC in selected patients. However, further studies are needed to investigate the tumor-free survival benefit of laparoscopic surgery, and whether expanding the resection scope could reduce postoperative recurrence.\u003c/p\u003e","manuscriptTitle":"Laparoscopic Surgery for Gallbladder Neuroendocrine Carcinoma: A Case Series and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-17 19:03:35","doi":"10.21203/rs.3.rs-127441/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":"fa954299-b27b-41be-be80-3665d3312994","owner":[],"postedDate":"December 17th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1527725,"name":"Surgical Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2022-01-28T22:12:27+00:00","versionOfRecord":{"articleIdentity":"rs-127441","link":"https://doi.org/10.1007/s12262-021-02923-x","journal":{"identity":"indian-journal-of-surgery","isVorOnly":false,"title":"Indian Journal of Surgery"},"publishedOn":"2021-05-21 22:12:27","publishedOnDateReadable":"May 21st, 2021"},"versionCreatedAt":"2020-12-17 19:03:35","video":"","vorDoi":"10.1007/s12262-021-02923-x","vorDoiUrl":"https://doi.org/10.1007/s12262-021-02923-x","workflowStages":[]},"version":"v1","identity":"rs-127441","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-127441","identity":"rs-127441","version":["v1"]},"buildId":"pf3fE39SIOqb-0xH_OWvX","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}