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Management and outcomes of mixed adenoneuroendocrine carcinoma of the ampulla of Vater: A systematic review and pooled analysis of 56 patients

  • Ioannis A. Ziogas
    Correspondence
    Corresponding author. Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA.
    Affiliations
    Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA

    Surgery Working Group, Society of Junior Doctors, Athens, Greece
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  • Kathrine S. Rallis
    Affiliations
    Surgery Working Group, Society of Junior Doctors, Athens, Greece

    Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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  • Panagiotis T. Tasoudis
    Affiliations
    Surgery Working Group, Society of Junior Doctors, Athens, Greece

    School of Health Sciences, University of Thessaly, Larissa, Greece
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  • Dimitrios Moris
    Affiliations
    Department of Surgery, Duke University Medical Center, Durham, NC, USA
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  • Richard D. Schulick
    Affiliations
    Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA

    University of Colorado Cancer Center, Aurora, CO, USA
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  • Marco Del Chiaro
    Affiliations
    Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA

    University of Colorado Cancer Center, Aurora, CO, USA
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Published:January 08, 2023DOI:https://doi.org/10.1016/j.ejso.2023.01.005

      Abstract

      Background

      Tumors of mixed neuroendocrine and nonneuroendocrine histology are classified as collision, combined, or amphicrine and can occur in most organs, including the hepato-pancreato-biliary tract. Given the rarity of mixed adenoneuroendocrine carcinoma (MANEC) of the ampulla of Vater, the patient characteristics, management, and outcomes remain unclear. We sought to systematically review the worldwide literature on ampullary MANECs.

      Methods

      Eligible studies were identified through a systematic search of the MEDLINE (via PubMed), Scopus, and Cochrane Library databases (end-of-search-date: January 5th, 2022), according to the PRISMA 2020 statement.

      Results

      A total of 39 studies reporting on 56 patients with ampullary MANEC were included. The median age was 63.0 (interquartile range [IQR]: 51.0–69.0) years and 55.6% were male (n = 25/45). Most had combined tumors (64.4%; n = 29/45), followed by collision (24.4%; n = 11/45), and amphicrine tumors (11.1%; n = 5/45). More than half had lymph node metastasis (56.8%; n = 25/44), yet only 7.9% had distant metastasis (n = 3/38). Tumor resection (i.e., mostly pancreaticoduodenectomy) was performed in 96.3% (n = 52/54), followed by adjuvant chemotherapy in 61.8% (n = 21/34). Nearly half experienced disease recurrence (47.2%; n = 17/36) over a median follow-up of 12.0 (IQR: 3.0–16.0) months, and 42.1% (n = 16/38) died over a median follow-up of 12.0 (IQR: 4.0–18.0) months. The most common cause of death was disease progression/recurrence in 81.3% (n = 13/16).

      Conclusion

      Early diagnosis and management of ampullary MANEC is challenging yet crucial to improve outcomes since many patients are diagnosed at an advanced disease stage and have unfavorable outcomes. Multicenter granular data are warranted to further understand and improve outcomes in these patients.

      Keywords

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      References

        • Albores-Saavedra J.
        • Schwartz A.M.
        • Batich K.
        • Henson D.E.
        Cancers of the ampulla of vater: demographics, morphology, and survival based on 5,625 cases from the SEER program.
        J Surg Oncol. 2009; 100: 598-605https://doi.org/10.1002/jso.21374
        • Bosman F.T.
        • Carneiro F.
        • Hruban R.H.
        • Theise N.D.
        WHO classification of tumours of the digestive system.
        World Health Organization, 2010
        • Lewin K.
        Carcinoid tumors and the mixed (composite) glandular-endocrine cell carcinomas.
        Am J Surg Pathol. 1987; 11: 71-86https://doi.org/10.1097/00000478-198700111-00007
        • La Rosa S.
        • Marando A.
        • Sessa F.
        • Capella C.
        Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: an update.
        Cancers. 2012; 4: 11-30https://doi.org/10.3390/cancers4010011
        • Ginori A.
        • Lo Bello G.
        • Vassallo L.
        • Tripodi S.A.
        Amphicrine carcinoma of the ampullary region.
        Tumori. 2015; 101: e70-e72https://doi.org/10.5301/tj.5000254
        • Mahansaria S.S.
        • Agrawal N.
        • Arora A.
        • Bihari C.
        • Appukuttan M.
        • Chattopadhyay T.K.
        Ampullary mixed adenoneuroendocrine carcinoma: surprise histology, familiar management.
        Int J Surg Pathol. 2017; 25: 585-591https://doi.org/10.1177/1066896917712454
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71https://doi.org/10.1136/bmj.n71
        • Wohlin C.
        Guidelines for snowballing in systematic literature studies and a replication in software engineering.
        in: Proc. 18th int. Conf. Eval. Assess. Softw. Eng. ACM, New York, NY, USA2014: 38:1-38:10https://doi.org/10.1145/2601248.2601268
        • Fornelli A.
        • Zanini N.
        • De Biase D.
        • Lega S.
        • Lombardi R.
        • Masetti M.
        • et al.
        Signet ring cell carcinoma of the ampulla of vater with focal neuroendocrine differentiation of the amphicrine type: report of a case with long-term survival.
        Int J Surg Pathol. 2019; 27: 89-93https://doi.org/10.1177/1066896918784666
        • Yoshioka S.
        • Ebisu Y.
        • Ishida M.
        • Uemura Y.
        • Yanagimoto H.
        • Satoi S.
        • et al.
        Cytological features of mixed adenoneuroendocrine carcinoma of the ampulla of Vater: a case report with immunocytochemical analyses.
        Diagn Cytopathol. 2018; 46: 540-546https://doi.org/10.1002/dc.23891
        • Max N.
        • Rothe A.
        • Langner C.
        Mixed adenoneuroendocrine carcinoma of the ampulla of Vater: a case report.
        Mol Clin Oncol. 2016; 5: 95-98https://doi.org/10.3892/mco.2016.858
        • Huang Z.
        • Xiao W.-D.
        • Li Y.
        • Huang S.
        • Cai J.
        • Ao J.
        Mixed adenoneuroendocrine carcinoma of the ampulla: two case reports.
        World J Gastroenterol. 2015; 21: 2254-2259https://doi.org/10.3748/wjg.v21.i7.2254
        • Zhang Q.
        • Lu C.-J.
        • Zhang X.
        • Ma Z.
        • Xin Q.
        • Zhang C.-S.
        Neuroendocrine neoplasms of the major duodenal papilla with focus on histopathological features and prognosis.
        Int J Surg Pathol. 2015; 23: 433-438https://doi.org/10.1177/1066896915586808
        • Serra S.
        • Chetty R.
        Amphicrine (mixed adenoneuroendocrine carcinoma) of the duodenum and coexistent metastatic well differentiated neuroendocrine tumour.
        Diagn Histopathol. 2014; 20: 297-300https://doi.org/10.1016/j.mpdhp.2014.05.005
        • Tewari N.
        • Rollins K.
        • Gandhi N.
        • Kaye P.V.
        • Lobo D.N.
        Mixed periampullary adenocarcinoma and somatostatinoma with small bowel gastrointestinal stromal tumour in neurofibromatosis type 1.
        J Pancreas. 2014; 15: 600-603
        • Zhang L.
        • DeMay R.M.
        Cytological features of mixed adenoneuroendocrine carcinoma of the ampulla: two case reports with review of literature.
        Diagn Cytopathol. 2014; 42: 1075-1084https://doi.org/10.1002/dc.23107
        • Kim H.J.
        • Choi B.G.
        • Kim C.Y.
        • Cho C.K.
        • Kim J.W.
        • Lee J.H.
        • et al.
        Collision tumor of the ampulla of Vater - coexistence of neuroendocrine carcinoma and adenocarcinoma: report of a case.
        Korean J Hepato-Biliary-Pancreatic Surg. 2013; 17: 186-190https://doi.org/10.14701/kjhbps.2013.17.4.186
        • Hirano H.
        • Terada N.
        • Yamada N.
        • Yamanegi Y.
        • Oyama H.
        • Nishigami T.
        • et al.
        A case of mixed ductal-endocrine carcinoma of the pancreas.
        Med Mol Morphol. 2011; 44: 58-62https://doi.org/10.1007/s00795-010-0533-0
        • Yang S.
        • Lu J.
        • Cai Y.
        • Li B.
        • Xiong X.
        Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-intent resection: a single center cases series.
        BMC Gastroenterol. 2021; 21: 329https://doi.org/10.1186/s12876-021-01909-z
        • Khurana A.
        • Sharma A.
        • Gupta G.
        • Gandhi J.S.
        Peri-ampullary collision tumor - high grade neuroendocrine carcinoma and signet ring cell carcinoma: a case report and review of literature.
        Indian J Pathol Microbiol. 2011; 54: 161-163https://doi.org/10.4103/0377-4929.77391
        • Kim J.
        • Lee W.J.
        • Lee S.H.
        • Lee K.B.
        • Ryu J.K.
        • Kim Y.-T.
        • et al.
        Clinical features of 20 patients with curatively resected biliary neuroendocrine tumours.
        Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2011; 43: 965-970https://doi.org/10.1016/j.dld.2011.07.010
        • Soubra A.
        • Faraj W.
        • Saab J.
        • Shamseddine A.
        Peri-ampullary mixed acinar-endocrine carcinoma.
        Rare Tumors. 2011; 3: e15https://doi.org/10.4081/rt.2011.e15
        • Sunose Y.
        • Ogawa T.
        • Itoh H.
        • Andoh T.
        • Tomizawa N.
        • Tanaka T.
        • et al.
        Large cell neuroendocrine carcinoma of the ampulla of vater with adenocarcinoma and squamous cell carcinoma components.
        Jpn J Clin Oncol. 2011; 41: 434-439https://doi.org/10.1093/jjco/hyq186
        • Vilardell F.
        • Velasco A.
        • Cuevas D.
        • Olsina J.J.
        • Matias-Guiu X.
        Composite papillary intestinal-type adenocarcinoma/poorly differentiated neuroendocrine carcinoma of the ampulla of Vater.
        J Clin Pathol. 2011; 64: 174-177https://doi.org/10.1136/jcp.2010.084954
        • Deschamps L.
        • Dokmak S.
        • Guedj N.
        • Ruszniewski P.
        • Sauvanet A.
        • Couvelard A.
        Mixed endocrine somatostatinoma of the ampulla of vater associated with a neurofibromatosis type 1: a case report and review of the literature.
        JOP. 2010; 11: 64-68
        • Musialik J.A.
        • Kohut M.J.
        • Marek T.
        • Wodołazski A.
        • Hartleb M.
        Composite neuroendocrine and adenomatous carcinoma of the papilla of Vater.
        World J Gastroenterol. 2009; 15: 4199-4200https://doi.org/10.3748/wjg.15.4199
        • Liu S.-H.
        • Tsay S.-H.
        Coexistence of large cell neuroendocrine carcinoma and adenocarcinoma of the ampulla of vater.
        J Chin Med Assoc. 2008; 71: 536-540https://doi.org/10.1016/S1726-4901%2808%2970164-3
        • Ferrando Marco J.
        • Pallas Regueira A.
        • Moro Valdezate D.
        • Fernández Martínez C.
        [Collision tumor of the ampulla of Vater: carcinoid and adenocarcinoma].
        Rev Esp enfermedades Dig organo Of la Soc Esp Patol Dig. 2007; 99: 235-238https://doi.org/10.4321/s1130-01082007000400010
        • Nassar H.
        • Albores-Saavedra J.
        • Klimstra D.S.
        High-grade neuroendocrine carcinoma of the ampulla of vater: a clinicopathologic and immunohistochemical analysis of 14 cases.
        Am J Surg Pathol. 2005; 29: 588-594https://doi.org/10.1097/01.pas.0000157974.05397.4f
        • Tachibana M.
        • Kamimura K.
        • Tsukamoto K.
        • Tsutsumi Y.
        A rare collision tumor: adenocarcinoma in the ampulla of vater and neuroendocrine tumor in the lower part of the common bile duct.
        Cureus. 2021; 13e15882https://doi.org/10.7759/cureus.15882
        • Cheng S.-P.
        • Yang T.-L.
        • Chang K.-M.
        • Liu C.-L.
        Large cell neuroendocrine carcinoma of the ampulla of Vater with glandular differentiation.
        J Clin Pathol. 2004; 57: 1098-1100https://doi.org/10.1136/jcp.2004.019414
        • Moncur J.T.
        • Lacy B.E.
        • Longnecker D.S.
        Mixed acinar-endocrine carcinoma arising in the ampulla of Vater.
        Hum Pathol. 2002; 33: 449-451https://doi.org/10.1053/hupa.2002.124040
        • Alex W.R.
        • Auerbach H.E.
        • Pezzi C.M.
        Adenocarcinoid tumor of the ampulla of Vater.
        Am Surg. 1998; 64: 355-359
        • Williams I.M.
        • Williams N.W.
        • Stock D.
        • Foster M.E.
        Collision tumour of the ampulla of Vater: carcinoid and adenocarcinoma.
        HPB Surg. 1997; 10: 241-244https://doi.org/10.1155/1997/46751
        • Gardner H.A.
        • Matthews J.
        • Ciano P.S.
        A signet-ring cell carcinoma of the ampulla of Vater.
        Arch Pathol Lab Med. 1990; 114: 1071-1072
        • Misonou J.
        • Kanda M.
        • Kitagawa T.
        • Ota T.
        • Muto E.
        • Nenohi M.
        • et al.
        A case of coexisting malignant carcinoid tumor and adenocarcinoma in the papilla of Vater.
        Gastroenterol Jpn. 1990; 25: 630-635https://doi.org/10.1007/BF02779365
        • Shah I.A.
        • Schlageter M.O.
        • Boehm N.
        Composite carcinoid-adenocarcinoma of ampulla of Vater.
        Hum Pathol. 1990; 21: 1188-1190https://doi.org/10.1016/0046-8177(90)90158-2
        • Jones M.A.
        • Griffith L.M.
        • West A.B.
        Adenocarcinoid tumor of the periampullary region: a novel duodenal neoplasm presenting as biliary tract obstruction.
        Hum Pathol. 1989; 20: 198-200https://doi.org/10.1016/0046-8177(89)90187-1
        • Stamm B.
        • Hedinger C.E.
        • Saremaslani P.
        Duodenal and ampullary carcinoid tumors. A report of 12 cases with pathological characteristics, polypeptide content and relation to the MEN I syndrome and von Recklinghausen's disease (neurofibromatosis).
        Virchows Arch A Pathol Anat Histopathol. 1986; 408: 475-489https://doi.org/10.1007/BF00705301
        • Li X.
        • Li D.
        • Sun X.
        • Lv G.
        Mixed adenoneuroendocrine carcinoma (MANEC) of the ampulla of Vater in a Chinese patient: a case report.
        J Int Med Res. 2020; 48300060520947918https://doi.org/10.1177/0300060520947918
        • Kochar T.
        • Dhingra P.
        • Shah H.
        When adenocarcinoma went hand in hand with neuroendocrine tumor: a rare case of adenocarcinoma synchronous with neuroendocrine tumor in ampulla of vater.
        Cureus. 2019; 11: e5168https://doi.org/10.7759/cureus.5168
        • Yoshimachi S.
        • Ohtsuka H.
        • Aoki T.
        • Miura T.
        • Ariake K.
        • Masuda K.
        • et al.
        Mixed adenoneuroendocrine carcinoma of the ampulla of Vater: a case report and literature review.
        Clin J Gastroenterol. 2020; 13: 37-45https://doi.org/10.1007/s12328-019-01009-2
        • Zheng Z.
        • Chen C.
        • Li B.
        • Liu H.
        • Zhou L.
        • Zhang H.
        • et al.
        Biliary neuroendocrine neoplasms: clinical profiles, management, and analysis of prognostic factors.
        Front Oncol. 2019; 9: 38https://doi.org/10.3389/fonc.2019.00038
        • Düzköylü Y.
        • Aras O.
        • Bostancı E.B.
        • Keklik Temuçin T.
        • Ulaş M.
        Mixed adeno-neuroendocrine carcinoma; case series of ten patients with review of the literature.
        Balkan Med J. 2018; 35: 263-267https://doi.org/10.4274/balkanmedj.2017.1471
        • Milanetto A.C.
        • Pasquali C.
        • Da Broi M.
        • Brambilla T.
        • Capretti G.
        • Zerbi A.
        Ampullary neuroendocrine neoplasms: surgical experience of a rare and challenging entity.
        Langenbeck's Arch Surg. 2018; 403: 581-589https://doi.org/10.1007/s00423-018-1695-9
        • Harada K.
        • Sato Y.
        • Ikeda H.
        • Maylee H.
        • Igarashi S.
        • Okamura A.
        • et al.
        Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs.
        Virchows Arch. 2012; 460: 281-289https://doi.org/10.1007/s00428-012-1212-4
        • Kim T.-Y.
        • Chae H.-D.
        Composite neuroendocrine carcinoma with adenocarcinoma of the stomach misdiagnosed as a giant submucosal tumor.
        J Gastric Cancer. 2011; 11: 126-130https://doi.org/10.5230/jgc.2011.11.2.126
        • Makino A.
        • Serra S.
        • Chetty R.
        Composite adenocarcinoma and large cell neuroendocrine carcinoma of the rectum.
        Virchows Arch. 2006; 448: 644-647https://doi.org/10.1007/s00428-006-0169-6
        • Volante M.
        • Rindi G.
        • Papotti M.
        The grey zone between pure (neuro)endocrine and non-(neuro)endocrine tumours: a comment on concepts and classification of mixed exocrine-endocrine neoplasms.
        Virchows Arch. 2006; 449: 499-506https://doi.org/10.1007/s00428-006-0306-2
        • Rindi G.
        • Petrone G.
        • Inzani F.
        The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction.
        Endocr Pathol. 2014; 25: 186-192https://doi.org/10.1007/s12022-014-9313-z
        • 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: 163https://doi.org/10.1186/1746-1596-7-163
        • Lee H.H.
        • Jung C.K.
        • Jung E.S.
        • Song K.Y.
        • Jeon H.M.
        • Park C.H.
        Mixed exocrine and endocrine carcinoma in the stomach: a case report.
        J Gastric Cancer. 2011; 11: 122-125https://doi.org/10.5230/jgc.2011.11.2.122
        • Stueger A.
        • Winder T.
        • Tinguely M.
        • Petrausch U.
        • Helbling D.
        Metastatic mixed adenoneuroendocrine carcinoma of the colon with response to immunotherapy with pembrolizumab: a case report.
        J Immunother. 2019; 42
        • Tang Q.
        • Zhou Z.
        • Chen J.
        • Di M.
        • Ji J.
        • Yuan W.
        • et al.
        Correlation of metastasis characteristics with prognosis in gastric mixed adenoneuroendocrine carcinoma: two case reports.
        Medicine (Baltim). 2017; 96e9189https://doi.org/10.1097/MD.0000000000009189
        • Klimstra D.S.
        • Modlin I.R.
        • Coppola D.
        • Lloyd R.V.
        • Suster S.
        The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems.
        Pancreas. 2010; 39: 707-712https://doi.org/10.1097/MPA.0b013e3181ec124e
        • Sorbye H.
        • Baudin E.
        • Perren A.
        The problem of high-grade gastroenteropancreatic neuroendocrine neoplasms: well-differentiated neuroendocrine tumors, neuroendocrine carcinomas, and beyond.
        Endocrinol Metab Clin N Am. 2018; 47: 683-698https://doi.org/10.1016/j.ecl.2018.05.001
        • Sorbye H.
        • Welin S.
        • Janson E.T.
        • Langer S.W.
        • Vestermark L.W.
        • Holt N.
        • et al.
        Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.
        Ann Oncol. 2013; 24: 152-160https://doi.org/10.1093/annonc/mds276
        • Basturk O.
        • Tang L.
        • Hruban R.H.
        • Adsay V.
        • Yang Z.
        • Krasinskas A.M.
        • et al.
        Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases.
        Am J Surg Pathol. 2014; 38: 437-447https://doi.org/10.1097/PAS.0000000000000169
        • Choe J.
        • Kim K.W.
        • Kim H.J.
        • Kim D.W.
        • Kim K.P.
        • Hong S.-M.
        • et al.
        What is new in the 2017 World Health organization classification and 8th American joint committee on cancer staging system for pancreatic neuroendocrine neoplasms?.
        Korean J Radiol. 2019; 20: 5-17https://doi.org/10.3348/kjr.2018.0040
        • Nagtegaal I.D.
        • Odze R.D.
        • Klimstra D.
        • Paradis V.
        • Rugge M.
        • Schirmacher P.
        • et al.
        The 2019 WHO classification of tumours of the digestive system.
        Histopathology. 2020; 76: 182-188https://doi.org/10.1111/his.13975
        • Ziogas I.A.
        • Tasoudis P.T.
        • Borbon L.C.
        • Sherman S.K.
        • Breheny P.J.
        • Chandrasekharan C.
        • et al.
        Surgical management of G3 gastroenteropancreatic neuroendocrine neoplasms: a systematic review and meta-analysis.
        Ann Surg Oncol. 2022; https://doi.org/10.1245/s10434-022-12643-5
        • Ziogas I.A.
        • Dillon J.S.
        • Chandrasekharan C.
        • Howe J.R.
        ASO author reflections: surgical resection should be considered in the multidisciplinary care of patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms.
        Ann Surg Oncol. 2022; https://doi.org/10.1245/s10434-022-12644-4