Traditionally considered non-functional low proliferative benign neuroendocrine proliferations measuring less than 5 mm, pancreatic (neuro)endocrine microadenomas are now classified as pancreatic neuroendocrine microtumors in the 2022 WHO classification of endocrine and neuroendocrine tumors. This case report discussed the features of an incidentally identified 4.7-mm glucagon-expressing pancreatic neuroendocrine microtumor with MEN1 mutation only, chromosomally stable and an epigenetic alpha-like phenotype. The tumor was associated with an unexplained increased proliferation rate in Ki-67 of 15%. There was no associated DAXX/ATRX deficiency. The presented case challenges the conventional thought of a low proliferative disease of the so-called "pancreatic neuroendocrine microadenomas" and provides additional support to the 2022 WHO classification that also requires grading of these neoplasms. Despite exhibiting molecular features of less aggressive behavior, the case also underscores the biological complexity of pancreatic neuroendocrine microtumors. By recognizing the heterogenous spectrum of neuroendocrine neoplasms, the current case also contributes to ongoing discussions on how to optimize the clinical management of such tumors.

Clinical and Transplant Pathology Centre Institute of Clinical and Experimental Medicine Prague Czech Republic

Department of Pathology Liberec Regional Hospital Liberec Czech Republic

Institute For Tissue Medicine and Pathology University of Bern Bern Switzerland

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Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, Ezzat S, de Herder WW, Klimstra DS, Papotti M, Asa SL. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol. 2022 doi: 10.1007/s12022-022-09708-2. PubMed DOI

Di Domenico A, Pipinikas CP, Maire RS, Bräutigam K, Simillion C, Dettmer MS, Vassella E, Thirlwell C, Perren A, Marinoni I. Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression. Commun Biol. 2020 doi: 10.1038/s42003-020-01479-y. PubMed DOI PMC

Singhi AD, Liu TC, Roncaioli JL, Cao D, Zeh HJ, Zureikat AH, Tsung A, Marsh JW, Lee KK, Hogg ME, Bahary N, Brand RE, McGrath KM, Slivka A, Cressman KL, Fuhrer K, O'Sullivan RJ. Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors. Clin Cancer Res. 2017 PubMed PMC

M. Falconi, B. Eriksson, G. Kaltsas, D.K. Bartsch, J. Capdevila, M. Caplin, B. Kos-Kudla, D. Kwekkeboom, G. Rindi, G. Klöppel, N. Reed, R. Kianmanesh, R.T. Jensen, all other Vienna Consensus Conference participants; ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 1 April 2016 PubMed PMC

Stefano Partelli, Sara Massironi, Alessandro Zerbi, Patricia Niccoli, Wooil Kwon, Luca Landoni, Francesco Panzuto, Ales Tomazic, Alberto Bongiovanni, Gregory Kaltsas, Alain Sauvanet, Emilio Bertani, Vincenzo Mazzaferro, Martyn Caplin, Thomas Armstrong, Martin O Weickert, John Ramage, Eva Segelov, Giovanni Butturini, Stefan Staettner, Mauro Cives, Andrea Frilling, Carol Anne Moulton, Jin He, Florian Boesch, Andreas Selberheer, Orit Twito, Antonio Castaldi, Claudio G De Angelis, Sebastien Gaujoux, Katharina Holzer, Colin H Wilson, Hussein Almeamar, Emanuel Vigia, Francesca Muffatti, Martina Lucà, Andrea Lania, Jacques Ewald, Hongbeom Kim, Roberto Salvia, Maria Rinzivillo, Alojz Smid, Andrea Gardini, Marina Tsoli, Olivia Hentic, Samuele Colombo, Davide Citterio, Christos Toumpanakis, Emma Ramsey, Harpal S Randeva, Ray Srirajaskanthan, Daniel Croagh, Paolo Regi, Silvia Gasteiger, Pietro Invernizzi, Cristina Ridolfi, Marc Giovannini, Jin-Young Jang, Claudio Bassi, Massimo Falconi, Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: interim analysis of prospective ASPEN trial, British Journal of Surgery, Volume 109, Issue 12, December 2022, 10.1093/bjs/znac267 PubMed PMC

Kwon JH, Kim HJ, Park DH, Lee YJ, Heaphy CM, Klöppel G, Hruban RH, Hong SM. Incidentally detected pancreatic neuroendocrine microadenoma with lymph node metastasis. Virchows Arch. 2018 doi: 10.1007/s00428-018-2407-0. PubMed DOI

Sadanandam A, Wullschleger S, Lyssiotis CA, Grötzinger C, Barbi S, Bersani S, Körner J, Wafy I, Mafficini A, Lawlor RT, Simbolo M, Asara JM, Bläker H, Cantley LC, Wiedenmann B, Scarpa A, Hanahan D. A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics. Cancer Discov. 2015;5(12):1296–1313. doi: 10.1158/2159-8290.CD-15-0068. PubMed DOI PMC

Mete O, Pakbaz S, Lerario AM, Giordano TJ, Asa SL. Significance of Alpha-inhibin Expression in Pheochromocytomas and Paragangliomas. Am J Surg Pathol. 2021;45(9):1264–1273. doi: 10.1097/PAS.0000000000001715. PubMed DOI

Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr Pathol. 2022;33(1):90–114. doi: 10.1007/s12022-022-09704-6. PubMed DOI

Couvelard A, O'Toole D, Turley H, Leek R, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K, Pezzella F. Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. Br J Cancer. 2005;92(1):94–101. doi: 10.1038/sj.bjc.6602245. PubMed DOI PMC

Schmitt AM, Schmid S, Rudolph T, Anlauf M, Prinz C, Klöppel G, Moch H, Heitz PU, Komminoth P, Perren A. VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocr Relat Cancer 2009. doi: 10.1677 PubMed

Marinoni I, Kurrer AS, Vassella E, Dettmer M, Rudolph T, Banz V, Hunger F, Pasquinelli S, Speel EJ, Perren A. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 2014 PubMed

Partelli S, Ramage JK, Massironi S, Zerbi A, Kim HB, Niccoli P, Panzuto F, Landoni L, Tomazic A, Ibrahim T, Kaltsas G, Bertani E, Sauvanet A, Segelov E, Caplin M, Coppa J, Armstrong T, Weickert MO, Butturini G, Staettner S, Boesch F, Cives M, Moulton CA, He J, Selberherr A, Twito O, Castaldi A, De Angelis CG, Gaujoux S, Almeamar H, Frilling A, Vigia E, Wilson C, Muffatti F, Srirajaskanthan R, Invernizzi P, Lania A, Kwon W, Ewald J, Rinzivillo M, Nessi C, Smid LM, Gardini A, Tsoli M, Picardi EE, Hentic O, Croagh D, Toumpanakis C, Citterio D, Ramsey E, Mosterman B, Regi P, Gasteiger S, Rossi RE, Smiroldo V, Jang JY, Falconi M. Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study. Front Med (Lausanne). 2020 doi: 10.3389/fmed.2020.598438. PubMed DOI PMC

Aysal A, Agalar C, Egeli T, Unek T, Oztop I, Obuz F, Sagol O. Reconsideration of Clinicopathologic Prognostic Factors in Pancreatic Neuroendocrine Tumors for Better Determination of Adverse Prognosis. Endocr Pathol. 2021;32(4):461–472. doi: 10.1007/s12022-021-09687-w. PubMed DOI

Ozturk Sari S, Taskin OC, Gundogdu G, Yegen G, Onder S, Keskin M, Saglam S, Ozluk Y, Gulluoglu M, Mete O. The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well-Differentiated Pancreatic Neuroendocrine Tumors. Endocr Pathol. 2016;27(2):162–170. doi: 10.1007/s12022-016-9424-9. PubMed DOI

Schiavo Lena M, Partelli S, Andreasi V, Muffatti F, Redegalli M, Brunetto E, Maghini B, Falke M, Cangi MG, Perren A, Falconi M, Doglioni C. Infiltrative Growth Predicts the Risk of Recurrence After Surgery in Well-Differentiated Non-Functioning Pancreatic Neuroendocrine Tumors. Endocr Pathol. 2023;34(1):142–155. doi: 10.1007/s12022-022-09745-x. PubMed DOI

Taskin OC, Reid MD, Bagci P, Balci S, Armutlu A, Demirtas D, Pehlivanoglu B, Saka B, Memis B, Bozkurtlar E, Leblebici CB, Birceanu A, Xue Y, Erkan M, Kapran Y, Baygul A, Sokmensuer C, Scarpa A, Luchini C, Basturk O, Adsay V. Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading. Mod Pathol. 2022;35(6):777–785. doi: 10.1038/s41379-021-00995-4. PubMed DOI