Pancreatic neuroendocrine carcinomas (NECs) are rare and very aggressive neoplasms with dismal prognosis, especially when metastatic or with negative prognostic factors, such as vascular invasion. To the best of our knowledge, no case of pancreatic NEC with mismatch repair deficiency has been reported to date. We describe a 62-year-old patient who underwent pancreaticoduodenectomy for a NEC located in the pancreatic head, with peripancreatic lymph node metastases. Tumor necrosis was prominent and the Ki67 proliferative index was 60%. One year after the diagnosis, the patient experienced recurrence with a left supraclavicular lymph node metastasis, which was surgically removed, followed by standard cisplatin-etoposide chemotherapy. Neoplastic cells showed combined loss of expression of MLH1 and PMS2 in both primary tumor and lymph node metastasis. Microsatellite instability (MSI) test using a mononucleotide repeats pentaplex PCR (BAT-25, BAT-26, NR-21, NR-22, and NR-24) revealed minimal mononucleotide shifts showing deletion of less than 3 bp at NR-21, BAT-26, NR-24, and NR-22 loci. MLH1 methylation analysis revealed absence of the gene promoter methylation. BRAF and KRAS mutations were not detected. In gut, NECs’ mismatch repair deficiency phenotype has been reported in about 10% of cases, and it represents an independent factor of more favorable outcome. Likewise, our patient is currently alive with a follow-up of more than 12 years after pancreaticoduodenectomy, by itself an unexpected finding for such an aggressive neoplasm.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
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
Adsay NV, Perren A, Singhi AD (2019) Pancreatic neuroendocrine carcinoma. In: WHO Classification of Tumours Editorial Board (ed). Digestive system tumours. WHO classification of tumours, 5th edn. IARC, Lyon, pp 367-369
Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, Sigel C, Klimstra DS (2015) The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 39:683-790
Tang LH, Basturk O, Sue JJ, Klimstra DS. A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas (2016) Am J Surg Pathol 40:1192-1202
Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, Pisa E, Barberis M, Vanoli A, Buzzoni R, Pusceddu S, Concas L, Sessa F, Solcia E, Capella C, Fazio N, La Rosa S (2017) The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories. Neuroendocrinology 104:85-93
Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E, Solcia E, Capella C, Sessa F, La Rosa S (2015) Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer 22:35-45
Adsay NV, Klimstra DS, Kloppel G, Oberg K, Papotti M, Rindi G, Scarpa A (2017) Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). In: Lloyd R, Osamura RY, Kloppel G, Rosai J (ed) WHO Classification of Tumours of Endocrine Organs, 4th edn. IARC, Lyon, pp 235-237
Mafficini A, Scarpa A (2019) Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Rev 40:506-536
Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, de Wilde RF, Maitra A, Hicks J, Demarzo AM, Shi C, Sharma R, Laheru D, Edil BH, Wolfgang CL, Schulick RD, Hruban RH, Tang LH, Klimstra DS, Iacobuzio-Donahue CA (2012) Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol 36:173-184
Arnason T, Sapp HL, Rayson D, Barnes PJ, Drewniak M, Nassar BA, Huang WY (2011) Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors. Arch Pathol Lab Med 135:1539-1544
Liu W, Shia J, Gönen M, Lowery MA, O'Reilly EM, Klimstra DS (2014) DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas 43:1264-1270
La Rosa S, Sessa F, Capella C (2015) Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology. Front Med (Lausanne) 2:41
Hu ZI, Shia J, Stadler ZK, Varghese AM, Capanu M, Salo-Mullen E, Lowery MA, Diaz LA Jr, Mandelker D, Yu KH, Zervoudakis A, Kelsen DP, Iacobuzio-Donahue CA, Klimstra DS, Saltz LB, Sahin IH, O'Reilly EM (2018) Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res 24:1326-1336
Karamurzin Y, Zeng Z, Stadler ZK, Zhang L, Ouansafi I, Al-Ahmadie HA, Sempoux C, Saltz LB, Soslow RA, O'Reilly EM, Paty PB, Coit DG, Shia J, Klimstra D (2012) Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Hum Pathol 43:1677-1687
Serracant Barrera A, Serra Pla S, Blázquez Maña CM, Salas RC, García Monforte N, Bejarano González N, Romaguera Monzonis A, Andreu Navarro FJ, Bella Cueto MR, Borobia FG (2017) Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome. J Gastrointest Oncol 8:E73-E79
Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, Middha S, Hechtman J, Zehir A, Dubard-Gault M, Tran C, Stewart C, Sheehan M, Penson A, DeLair D, Yaeger R, Vijai J, Mukherjee S, Galle J, Dickson MA, Janjigian Y, O'Reilly EM, Segal N, Saltz LB, Reidy-Lagunes D, Varghese AM, Bajorin D, Carlo MI, Cadoo K, Walsh MF, Weiser M, Aguilar JG, Klimstra DS, Diaz LA Jr, Baselga J, Zhang L, Ladanyi M, Hyman DM, Solit DB, Robson ME, Taylor BS, Offit K, Berger MF, Stadler ZK (2019) Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol 37:286-295
Laghi L, Beghelli S, Spinelli A, Bianchi P, Basso G, Di Caro G, Brecht A, Celesti G, Turri G, Bersani S, Schumacher G, Röcken C, Gräntzdörffer I, Roncalli M, Zerbi A, Neuhaus P, Bassi C, Montorsi M, Scarpa A, Malesci A (2012) Irrelevance of microsatellite instability in the epidemiology of sporadic pancreatic ductal adenocarcinoma. PLoS One 7:e46002
Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH (1998) Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 152:1501-1507
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000) Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol 156:1641-1651
Wang Y, Shi C, Eisenberg R, Vnencak-Jones CL. Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers: A Potential Cause for False-Negative Results? (2017) J Mol Diagn 19:57-64
Wu X, Snir O, Rottmann D, Wong S, Buza N, Hui P (2019) Minimal microsatellite shift in microsatellite instability high endometrial cancer: a significant pitfall in diagnostic interpretation. Mod Pathol 32:650-658
Libera L, Sahnane N, Carnevali IW, Cimetti L, Cerutti R, Chiaravalli AM, Riva C, Tibiletti MG, Sessa F, Furlan D (2017) Microsatellite analysis of sporadic and hereditary gynaecological cancer in routine diagnostics. J Clin Pathol 70:792-797
Fraune C, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kluth M, Büscheck F, Amin T, Viol F, Fehrle W, Dum D, Höflmayer D, Burandt E, Clauditz TS, Perez D, Izbicki J, Wilczak W, Sauter G, Steurer S, Schrader J (2020) Homogeneous MMR Deficiency Throughout the Entire Tumor Mass Occurs in a Subset of Colorectal Neuroendocrine Carcinomas. Endocr Pathol [Epub ahead of print]
La Rosa S, Marando A, Furlan D, Sahnane N, Capella C (2012) Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol 36:601-611
Cavalcanti MS, Lee LH, Vakiani E, Hechtman JF, Klimstra D, Shia J (2016) Mismatch Repair-Deficient Neuroendocrine Carcinomas of the Lower GI Tract. Modern Pathology 29:198 (Abstract)
Conflict of Interest
The authors declare that they have no conflict of interest.
Informed consent was obtained from the patient.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Vanoli, A., Perfetti, V., Furlan, D. et al. Long Survival and Prolonged Remission after Surgery and Chemotherapy in a Metastatic Mismatch Repair Deficient Pancreatic Neuroendocrine Carcinoma with MLH1/PMS2 Immunodeficiency and Minimal Microsatellite Shift. Endocr Pathol 31, 411–417 (2020). https://doi.org/10.1007/s12022-020-09622-5
- Microsatellite instability
- Minimal microsatellite shift
- Neuroendocrine carcinoma