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Well-differentiated Pancreatic Neuroendocrine Tumor in a Patient With Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)

Noë, Michaël MD*,†; Hackeng, Wenzel M. MD*; de Leng, Wendy W.J. PhD*; Vergeer, Menno MD, PhD; Vleggaar, Frank P. MD, PhD§; Morsink, Folkert H.M. BA*; Wood, Laura D. MD, PhD; Hruban, Ralph H. MD; Offerhaus, G. Johan A. MD, PhD*,†; Brosens, Lodewijk A.A. MD, PhD*

The American Journal of Surgical Pathology: September 2019 - Volume 43 - Issue 9 - p 1297–1302
doi: 10.1097/PAS.0000000000001314
Case Report

Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM), which is associated with an increased risk for pancreatic ductal adenocarcinoma and melanoma. CDKN2A is somatically inactivated in multiple neoplasms, raising the possibility that, although the data are not conclusive, germline CDKN2A mutation may also impose an increased risk for other neoplasms. We present a patient with a CDKN2A germline mutation (p16-Leiden mutation) and mosaicism for neurofibromatosis type 2, who presented with a small asymptomatic pancreatic lesion, detected during endoscopic ultrasound screening of the pancreas. After resection, the lesion was found to be a well-differentiated pancreatic neuroendocrine tumor (PanNET). Molecular analysis of the tumor showed somatic loss of the second allele, supporting a causal relation of the PanNET to the underlying FAMMM syndrome. Recent data, showing the association between certain single-nucleotide polymorphisms in the CDKN2A gene and an increased incidence for PanNET, further support a role for germline CDKN2A alterations in PanNET risk. We conclude that PanNETs can be a phenotypic expression of FAMMM syndrome. This can have implications for screening and for the diagnosis of pancreatic neoplasms in carriers of germline CDKN2A mutations.

Departments of *Pathology

Internal Medicine

§Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Hospital, Baltimore, MD

Conflicts of Interest and Source of Funding: Supported by the Nijbakker-Morra Foundation and the Living With Hope Foundation (M.N.) and The Dutch Digestive Foundation grant MLDS CDG 14-020 (L.A.A.B.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Lodewijk A.A. Brosens, MD, PhD, Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands (e-mail:

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