BACKGROUND: Mixed neuroendocrine-non-neuroendocrine tumors (MINEN) of the gallbladder are extremely rare; indeed, the English expert literature reports a mere handful of case reports and case series on this topic. According to the WHO classification of 2010, MINEN are considered to be tumors consisting of two major components, neuroendocrine and non-neuroendocrine, each of which hosts at least 30% of the total cellular population. To date, the etiology and pathogenesis of MINEN have not been precisely determined and the non-specific symptoms generally result in late diagnosis (mainly in the terminal stages of the condition) and contribute to the generally poor prognosis. As far as the management of the disease is concerned, radical surgery plays a crucial role; however, the significance of surgical debulking and biological therapy applying somatostatin analogues has not yet been determined. CASE PRESENTATION: A 56-year-old female was referred to our department for a rapidly progressing tumor in the subhepatic area along with the infiltration of S5 and S6 liver segments. With regard to preoperative findings, the tumor appeared as operable, although, during the surgery, an extensive involvement of the hepatoduodenal ligament by the tumor through the lymph nodes was revealed. Due to acute perioperative bleeding from the necrotic tumor, we decided to perform modified resection. Histologically, the tumor was confirmed as MINEN of gallbladder, where the neuroendocrine component was dominant over the non-neuroendocrine component. Six weeks after the discharge, the patient underwent a follow-up CT revealing large recurrence of the disease. Thereafter, the patient was started on systemic therapy with etoposide and carboplatin in combination with somatostatin analogues. Thirteen months after the surgery, the patient is in good clinical condition, and while a recently performed PET/MRI scan revealed a hepatic lesion and hilar lymphadenopathy in full regression, there was a spread of small peritoneal and pleural metastases. The patient remains in the follow-up care. CONCLUSIONS: The occurrence of mixed neuroendocrine-non-neuroendocrine neoplasms is extremely rare. Radical surgery remains the only potentially effective approach to the cure of this disease. The role of biological therapy and debulking in the management of the disease has not yet been precisely defined. In our experience, both of these methods have the potential to positively influence overall survival rates and the postoperational quality of life of patients.

Biomedical Center Faculty of Medicine in Pilsen Charles University 304 60 Pilsen Czech Republic

Department of Imaging Methods University Hospital in Pilsen 304 60 Pilsen Czech Republic

Department of Surgery and Biomedical Center Faculty of Medicine and University Hospital in Pilsen Charles University Prague 304 60 Pilsen Czech Republic

Faculty of Medicine in Pilsen Charles University 301 00 Pilsen Czech Republic

Šikl's Department of Pathology Faculty of Medicine and University Hospital in Pilsen Charles University 305 99 Pilsen Czech Republic

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Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al., editors. WHO classification of tumors of the digestive system. Lyon: IARC; 2010. pp. 13–14.

Kloppel G, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification. Neuroendocrinology. 2009. PMID: 19060454. PubMed

Sobin LH, Gosporadowicz MK, Wittenkind C. TNM classification of malignant tumours. 7. London: Wiley; 2010.

La Rosa S, Marando A, Sessa F, Capella C. Mixed adenoneuronedocrine carcinomas (MANECs) of the gastrointestinal tract: an update. Cancers. 2012;4:11–30. doi: 10.3390/cancers4010011. PubMed DOI PMC

Gurzu S, Karad Z, Bara T, et al. Mixed anedoneuroendocrine carcinoma of the gasrointestinal tract: report of two cases. World J Gastroenterol. 2015;21:1329–1333. doi: 10.3748/wjg.v21.i4.1329. PubMed DOI PMC

Acosta AM, Hamedani FS, Kajdacsy-Balla A, Wiley EL. Primary mixed adenoneuroendocrine carcinoma of the gallbladder in a 55-year-old female patient: a case report and review of the literature. Int J Surg Pathol. 2015;23:414–418. doi: 10.1177/1066896915580433. PubMed DOI

Al Brahim N, Albannai R. Combined large cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder. Endocr Pathol. 2013;24:110–113. doi: 10.1007/s12022-012-9229-4. PubMed DOI

Harada K, Yasunori S, Hiroko I, Maylee H, Igarashi S, Okamura A, Masuda S, Yasuni N. Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs. Virchows Arch. 2012;460:281–289. doi: 10.1007/s00428-012-1212-4. PubMed DOI

Iype S, Mirza TA, Propper DJ, Bhattacharya S, Feakins RM, Kocher HM. Neuroendocrine tumours of the gallbladder: three cases and a review of the literature. Postgrad Med J. 2009;85:213–218. doi: 10.1136/pgmj.2008.070649. PubMed DOI

Jung J, Chae YS, Kim CH, Lee Y, Lee JH, Kim DS, Yu YD, Kim JY. Combined adenosquamous and large cell neuroendocrine carcinoma of the gallbladder. J Pathol Transl Med. 2018;52:121–125. doi: 10.4132/jptm.2017.08.20. PubMed DOI PMC

Kamboj M, Gandhi JS, Gupta G, Sharma A, Pasricha S, Mehta A, Chandragouda D, Sinha R. Neuroendocrine carcinoma of gall bladder: a series of 19 cases with review of literature. J Gastrointest Cancer. 2015;46(4):356–364. doi: 10.1007/s12029-015-9745-9. PubMed DOI

Kim J, Lee WJ, Lee SH, et al. Clinical features of 20 patients with curatively resected biliary neuroendocrine tumours. Dig Liver Dis. 2011;43:965–970. doi: 10.1016/j.dld.2011.07.010. PubMed DOI

Lin YX, Jia QB, Fu YY, Cheng NS. Mixed adenoneuroendocrine carcinoma of the gallbladder. J Gastrointest Surg. 2018;22:1452–1454. doi: 10.1007/s11605-017-3664-y. PubMed DOI

Liu W, Wang L, He XD, Feng C, Chang XY, Lu ZH. Mixed large cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder: a case report and brief review of the literature. World J Surg Oncol. 2015;18(13):114. doi: 10.1186/s12957-015-0533-6. PubMed DOI PMC

Meguro Y, Fukushima N, Koiyumi N, et al. A case of mixed adenoneuroendocrine carcinoma of the gallbladder arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. Pathol Int. 2014;64:465–471. doi: 10.1111/pin.12188. PubMed DOI

Paniz Mondolfi AE, Slova D, Fan W, et al. Mixed adenoneuroendocrine carcinoma (MANEC) of the gallbladder: a possible stem cell tumor? Pathol Int. 2011;61:608–614. doi: 10.1111/j.1440-1827.2011.02709.x. PubMed DOI

Noske A, Pahl S. Combined adenosquamous and large-cell neuroendocrine carcinoma of the gallbladder. Virchows Arch. 2016;449:135–136. doi: 10.1007/s00428-006-0171-z. PubMed DOI

Oshiro H, Matsuo K, Mawatari H, et al. Mucin-producing gallbladder adenocarcinoma with focal small cell and large cell neuroendocrine differentiation associated with pancreaticobiliary maljunction. Pathol Int. 2008;58:780–786. doi: 10.1111/j.1440-1827.2008.02311.x. PubMed DOI

Sato K, Imai T, Shirota Y, Ueda Y, Katsuda S. Combined large cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder. Pathol Res Pract. 2010;206:397–400. doi: 10.1016/j.prp.2009.10.008. PubMed DOI

Shimiziu T, Tajiri T, Akimaru K, et al. Combined neuroendocrine cell carcinoma and adenocarcinoma of the gallbladder: report of a case. J Nippon Med Sch. 2006;73:101–105. doi: 10.1272/jnms.73.101. PubMed DOI

Shintaku M, Kataoka K, Kawabata K. Mixed adenoneuroendocrine carcinoma of the gallbladder with squamous cell carcinomatous and osteosarcomatous differentiation: report of a case. Pathol Int. 2013;63:113–119. doi: 10.1111/pin.12029. PubMed DOI

Song W, Chen W, Zhang S, Peng J, He Y. Successful treatment of gallbladder mixed adenoneuroendocrine carcinoma with neo-adjuvant chemotherapy. Diagn Pathol. 2012;7:163. doi: 10.1186/1746-1596-7-163. PubMed DOI PMC

Komminoth P, Arnold R, Capella C. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumors of the digestive system. Lyon: IARC; 2010. pp. 274–276.

Chatterjee D, Wang H. Mixed adenoneuroendocrine carcinoma arising in papillary adenoma of gallblader. Am J Cancer Case Rep. 2014;2:37–42.

Albores-Saavedra J, Henson D. Tumours of the gallbladder and extrahepatic bile ducts. 2nd Series, fascicle 22. Washington, DC: Armed Forces Institute of Pathology; 1986.

Sons HU, Borchard F, Joel BS. Carcinoma of the gallbladder: autopsy findings in 287 cases and review of the literature. J Surg Oncol. 1985;28:199–206. doi: 10.1002/jso.2930280311. PubMed DOI

Machado MC, Penteade S, Montagnini AL, et al. Carcinoid tumor of the gallbladder. Rev Paul Med. 1998;116:1741–1743. PubMed

Roa I, de Aretxabala X, Araya JC, Roa J. Preneoplastic lesions in gallbladder cancer. J Surg Oncol. 2006;93:615–623. doi: 10.1002/jso.20527. PubMed DOI

Volante M, Marci V, Andrejevic-Blant S, Tavaglione V, Sculli MC, Tampellini M, et al. Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas. Virchows Arch Int J Pathol. 2010;457:521–527. doi: 10.1007/s00428-010-0967-8. PubMed DOI

Li Y, Yau A, Schaeffer D, Magliocco A, Gui X, Urbanski S, et al. Colorectal glandular-neuroendocrine mixed tumor: pathologic spectrum and clinical implications. Am J Surg Pathol. 2011;35:413–425. doi: 10.1097/PAS.0b013e3182093657. PubMed DOI

Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB, et al. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am J Surg Pathol. 2008;32:719–731. doi: 10.1097/PAS.0b013e318159371c. PubMed DOI

Cardinale V, Wang Y, Carpino G, et al. Multipotent stem cells in the biliary tree. Ital J Anat Embryol. 2010;115:85–90. PubMed

Vadlamani I, Brunt E. Hepatocellular progenitor cell tumor of the gallbladder: a case report and review of the literature. Mod Pathol. 2005;18:864–870. doi: 10.1038/modpathol.3800367. PubMed DOI

Khan S, Lloyd C, Szyszko T, Win Zm Rubello D, Al-Nahhas A. PET imaging in endocrine tumours. Minerva Encronol. 2008;33:41–52. PubMed

Panagoitidis E, Bomanji J. Role of 18F-fluorodeoxyglucose PET in the study of neuroendocrine tumors. PET Clin. 2014;9:43–55. doi: 10.1016/j.cpet.2013.08.008. PubMed DOI

Koranda P, Mysliveček M, Švébišová H, Fryšák Z, Formánek R, Buriánková E. 18F-FDG PET/CT u pacientů s maligními neuroendokrinními nádory. Čes Radiol. 2011;65:196–201.

Ferdová E, Ferda J, et al. Zobrazovací metody neuroendokrinních nádorů. In: Ferda J, et al., editors. Inovativní zobrazovací metody. Praha: Galén; 2015.

Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 2006;17:1733–1742. doi: 10.1093/annonc/mdl105. PubMed DOI

Mota JM, Sousa LG, Riechelmann RP. Complications from carcinoid syndrome: review of the current evidence. Ecancermedicalscience. 2016;10:662. doi: 10.3332/ecancer.2016.662. PubMed DOI PMC