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Gallbladder Mixed Neuroendocrine-Non-neuroendocrine Neoplasm (MiNEN) Arising in Intracholecystic Papillary Neoplasm: Clinicopathologic and Molecular Analysis of a Case and Review of the Literature

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Abstract

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.

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References

  1. 1.

    Klimstra D, Klöppel G, La Rosa S, Rindi G (2019) Classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours Editorial Board (ed). Digestive system tumours WHO classification of tumours, 5th edn. IARC, Lyon, pp 16-19

  2. 2.

    La Rosa S, Sessa F, Uccella S (2016) Mixed neuroendocrine-nonneuroendocrine neoplasms (MINENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 27:284–311

  3. 3.

    Adsay N, La Rosa S (2019) Neuroendocrine neoplasms of the gallbladder and bile ducts. In: WHO Classification of Tumours Editorial Board (ed). Digestive system tumours WHO classification of tumours, 5th edn. IARC, Lyon, pp 292-294

  4. 4.

    Harada K, Sato Y, Ikeda H, Maylee H, Igarashi S, Okamura A, Masuda S, Nakanuma Y (2012) Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs. Virchows Arch 460:281–289

  5. 5.

    Chatterjee D, Wang H (2014) Mixed adenoneuroendocrine carcinoma arising in a papillary adenoma of gallbladder. American Journal of Cancer Case Reports 2:37–42

  6. 6.

    Meguro Y, Fukushima N, Koizumi M, et al (2014) A case of mixed adenoneuroendocrine carcinoma of the gallbladder arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. Pathol Int 64:465–471

  7. 7.

    Scardoni M, Vittoria E, Volante M, Rusev B, Bersani S, Mafficini A, Gottardi M, Giandomenico V, Malleo G, Butturini G, Cingarlini S, Fassan M, Scarpa A (2014) Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract: targeted next-generation sequencing suggests a monoclonal origin of the two components. Neuroendocrinology 100:310–316

  8. 8.

    Volante M, Monica V, Birocco N, Brizzi MP, Busso S, Daniele L, la Rosa S, Righi L, Sapino A, Berruti A, Scagliotti GV, Papotti M (2015) Expression analysis of genes involved in DNA repair or synthesis in mixed neuroendocrine/nonneuroendocrine carcinomas. Neuroendocrinology 101:151–160

  9. 9.

    Jesinghaus M, Konukiewitz B, Keller G, Kloor M, Steiger K, Reiche M, Penzel R, Endris V, Arsenic R, Hermann G, Stenzinger A, Weichert W, Pfarr N, Klöppel G (2017) Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas. Mod Pathol 30:610–619

  10. 10.

    Ines F, Anceno A, Salamat R, et al (2019) Targeted sequencing of mixed neuroendocrine- non-neuroendocrine neoplasm of the gallbladder suggests a monoclonal origin: a case report. Philippine Journal of Pathology 4. https://doi.org/10.21141/PJP.2010.16

  11. 11.

    Cavazzana AO, Fassina AS, Tollot M, Ninfo V (1991) Small-cell carcinoma of gallbladder. An immunocytochemical and ultrastructural study. Pathol Res Pract 187:472–476

  12. 12.

    Duan HJ, Ishigame H, Ishii Z, Itoh N, Shigematsu H (1991) Small cell carcinoma of the gallbladder combined with adenocarcinoma. Acta Pathol Jpn 41:841–846

  13. 13.

    Iida Y, Tsutsumi Y (1992) Small cell (endocrine cell) carcinoma of the gallbladder with squamous and adenocarcinomatous components. Acta Pathol Jpn 42:119–125

  14. 14.

    Nishihara K, Nagai E, Tsuneyoshi M, Nagashima M (1994) Small-cell carcinoma combined with adenocarcinoma of the gallbladder. A case report with immunohistochemical and flow cytometric studies. Arch Pathol Lab Med 118:177–181

  15. 15.

    Resnick MB, Jacobs DO, Brodsky GL (1994) Multifocal adenocarcinoma in situ with underlying carcinoid tumor of the gallbladder. Arch Pathol Lab Med 118:933–934

  16. 16.

    Moskal TL, Zhang PJ, Nava HR (1999) Small cell carcinoma of the gallbladder. J Surg Oncol 70:54–59

  17. 17.

    Sakaki M, Hirokawa M, Sano T, Horiguchi H, Wakatsuki S, Ogata S (2000) Gallbladder adenocarcinoma with florid neuroendocrine cell nests and extensive paneth cell metaplasia. Endocr Pathol 11:365–371

  18. 18.

    Eriguchi N, Aoyagi S, Noritomi T, et al (2000) Adeno-endocrine cell carcinoma of the gallbladder. J Hepatobiliary Pancreat Surg 7:97–101

  19. 19.

    Papotti M, Cassoni P, Sapino A, Passarino G, Krueger JE, Albores-Saavedra J (2000) Large cell neuroendocrine carcinoma of the gallbladder: report of two cases. Am J Surg Pathol 24:1424–1428

  20. 20.

    Yannakou N, Rizos S, Parissi-Mathiou P, Smailis D, Charanioti S, Dervenis C (2001) Mixed (composite) glandular-endocrine cell carcinoma of the gallbladder. HPB 3:7–9

  21. 21.

    Okamoto H, Miura K, Ogawara T, Fujii H, Matsumoto Y (2003) Small-cell carcinoma manifesting systemic lymphadenopathy combined with adenocarcinoma in the gallbladder: aggressiveness and sensitivity to chemotherapy. J Gastroenterol 38:801–805

  22. 22.

    Koea J, MacCormack M, Findlay M, Ramsdorp R (2004) Adeno-endocrine cancer of the gallbladder. ANZ J Surg 74:808–809

  23. 23.

    Shimizu T, Tajiri T, Akimaru K, Arima Y, Yoshida H, Yokomuro S, Mamada Y, Taniai N, Mizuguchi Y, Kawahigashi Y, Naito Z (2006) Combined neuroendocrine cell carcinoma and adenocarcinoma of the gallbladder: report of a case. J Nippon Med Sch 73:101–105

  24. 24.

    Tsuchiya A, Endo Y, Yazawa T, Saito A, Inoue N (2006) Adenoendocrine cell carcinoma of the gallbladder: report of a case. Surg Today 36:849–852

  25. 25.

    Sosnik H, Sosnik K (2006) Double cancer of the gallbladder--a case report. Pol J Pathol 57:213–215

  26. 26.

    Oshiro H, Matsuo K, Mawatari H, Inayama Y, Yamanaka S, Nagahama K, Endo I, Shimada H, Nakajima A, Kubota K (2008) Mucin-producing gallbladder adenocarcinoma with focal small cell and large cell neuroendocrine differentiation associated with pancreaticobiliary maljunction. Pathol Int 58:780–786

  27. 27.

    Iype S, Mirza TA, Propper DJ, Bhattacharya S, Feakins RM, Kocher HM (2009) Neuroendocrine tumours of the gallbladder: three cases and a review of the literature. Postgrad Med J 85:213–218

  28. 28.

    Sato K, Imai T, Shirota Y, Ueda Y, Katsuda S (2010) Combined large cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder. Pathol Res Pract 206:397–400

  29. 29.

    Paniz Mondolfi AE, Slova D, Fan W, et al (2011) Mixed adenoneuroendocrine carcinoma (MANEC) of the gallbladder: a possible stem cell tumor? Pathol Int 61:608–614

  30. 30.

    Kim J, Lee WJ, Lee SH, Lee KB, Ryu JK, Kim YT, Kim SW, Yoon YB, Hwang JH, Han HS, Woo SM, Park SJ (2011) Clinical features of 20 patients with curatively resected biliary neuroendocrine tumours. Dig Liver Dis 43:965–970

  31. 31.

    Song W, Chen W, Zhang S, Peng J, He Y (2012) Successful treatment of gallbladder mixed adenoneuroendocrine carcinoma with neo-adjuvant chemotherapy. Diagn Pathol 7:163

  32. 32.

    Al-Brahim N, Albannai R (2013) Combined large cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder. Endocr Pathol 24:110–113

  33. 33.

    Shintaku M, Kataoka K, Kawabata K (2013) Mixed adenoneuroendocrine carcinoma of the gallbladder with squamous cell carcinomatous and osteosarcomatous differentiation: report of a case. Pathol Int 63:113–119

  34. 34.

    Abe T, Kajiyama K, Harimoto N, Gion T, Shirabe K, Nagaie T (2013) Composite adeno-endocrine carcinoma of the gallbladder with long-term survival. Int J Surg Case Rep 4:504–507

  35. 35.

    Chen H, Shen YY, Ni XZ (2014) Two cases of neuroendocrine carcinoma of the gallbladder. World J Gastroenterol 20:11916–11920

  36. 36.

    Liu W, Wang L, He XD, Feng C, Chang XY, Lu ZH (2015) Mixed large cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder: a case report and brief review of the literature. World J Surg Oncol 13:114

  37. 37.

    Kamboj M, Gandhi JS, Gupta G, Sharma A, Pasricha S, Mehta A, Chandragouda D, Sinha R (2015) Neuroendocrine carcinoma of gall bladder: a series of 19 cases with review of literature. J Gastrointest Cancer 46:356–364

  38. 38.

    Acosta AM, Hamedani FS, Kajdacsy-Balla A, Wiley EL (2015) 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 23:414–418

  39. 39.

    Azad S, Shukla D, Garg A, Negi SS, Malhotra V (2015) Mixed adenoneuroendocrine carcinoma of the gallbladder, histopathological features. Indian J Pathol Microbiol 58:543–545

  40. 40.

    Noske A, Pahl S (2006) Combined adenosquamous and large-cell neuroendocrine carcinoma of the gallbladder. Virchows Arch 449:135–136

  41. 41.

    Lin YX, Jia QB, Fu YY, Cheng NS (2018) Mixed adenoneuroendocrine carcinoma of the gallbladder. J Gastrointest Surg 22:1452–1454

  42. 42.

    Jung J, Chae YS, Kim CH, Lee Y, Lee JH, Kim DS, Yu YD, Kim JY (2018) Combined adenosquamous and large cell neuroendocrine carcinoma of the gallbladder. J Pathol Transl Med 52:121–125

  43. 43.

    Skalický A, Vištejnová L, Dubová M, Malkus T, Skalický T, Troup O (2019) Mixed neuroendocrine-non-neuroendocrine carcinoma of gallbladder: case report. World J Surg Oncol 17:55

  44. 44.

    Fraga J, Caetano Oliveira R, Alexandrino H, Cipriano MA (2019) Neuroendocrine carcinoma and intracystic papillary neoplasm: a rare association in the gallbladder. GE Port J Gastroenterol 26:356–361

  45. 45.

    Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P (2012) Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are >/=1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol 36:1279–1301

  46. 46.

    Basturk O, Aishima S, Esposito I (2019) Intracholecystic papillary neoplasm. In: WHO Classification of Tumours Editorial Board (ed). Digestive system tumours, WHO classification of tumours, 5th edn. IARC, Lyon, pp 276-278

  47. 47.

    George J, Walter V, Peifer M, et al (2018) Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9:1048

  48. 48.

    Akita M, Fujikura K, Ajiki T, et al (2019) Intracholecystic papillary neoplasms are distinct from papillary gallbladder cancers: a clinicopathologic and exome-sequencing study. Am J Surg Pathol 43:783–791

  49. 49.

    La Rosa S, Simbolo M, Franzi F, et al (2018) Combined adenocarcinoma–atypical carcinoid of the lung. Targeted Next-Generation Sequencing (NGS) suggests a monoclonal origin of the two components. Diagn Histopathol 24:120–123

  50. 50.

    Simbolo M, Mafficini A, Sikora KO, Fassan M, Barbi S, Corbo V, Mastracci L, Rusev B, Grillo F, Vicentini C, Ferrara R, Pilotto S, Davini F, Pelosi G, Lawlor RT, Chilosi M, Tortora G, Bria E, Fontanini G, Volante M, Scarpa A (2017) Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D. J Pathol 241:488–500

  51. 51.

    Liu P, Morrison C, Wang L, Xiong D, Vedell P, Cui P, Hua X, Ding F, Lu Y, James M, Ebben JD, Xu H, Adjei AA, Head K, Andrae JW, Tschannen MR, Jacob H, Pan J, Zhang Q, van den Bergh F, Xiao H, Lo KC, Patel J, Richmond T, Watt MA, Albert T, Selzer R, Anderson M, Wang J, Wang Y, Starnes S, Yang P, You M (2012) Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing. Carcinogenesis 33:1270–1276

  52. 52.

    La Rosa S, Uccella S, Molinari F, et al (2018) Mixed adenoma well-differentiated neuroendocrine tumor (manet) of the digestive system: an indolent subtype of mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN). Am J Surg Pathol 42:1503–1512

  53. 53.

    Fakhri B, Lim KH (2017) Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature. J Gastrointest Oncol 8:379–386

  54. 54.

    Li CC, Xu B, Hirokawa M, Qian Z, Yoshimoto K, Horiguchi H, Tashiro T, Sano T (2002) Alterations of E-cadherin, alpha-catenin and beta-catenin expression in neuroendocrine tumors of the gastrointestinal tract. Virchows Arch 440:145–154

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Author information

AS, SLR study design, data collection, drafting. CS, JPB: data collection. MT, EdM molecular analysis. EmM surgery. All authors approved the manuscript.

Correspondence to Stefano La Rosa.

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Sciarra, A., Missiaglia, E., Trimech, M. et al. Gallbladder Mixed Neuroendocrine-Non-neuroendocrine Neoplasm (MiNEN) Arising in Intracholecystic Papillary Neoplasm: Clinicopathologic and Molecular Analysis of a Case and Review of the Literature. Endocr Pathol (2020). https://doi.org/10.1007/s12022-020-09605-6

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Keywords

  • Gallbladder
  • MiNEN
  • MANEC
  • Mixed neuroendocrine-non-neuroendocrine neoplasm