Pancreatic Neuroendocrine Neoplasm Associated with a Familial MAX Deletion

Abstract

Most pancreatic neuroendocrine neoplasms (pNEN) occur sporadically but they can also occur as part of multiple endocrine neoplasia type 1 (MEN1). MAX was originally described as an inherited pheochromocytoma-paraganglioma risk gene, but also has recently been implicated in pituitary tumorigenesis. Here we describe the first case of a pNEN associated with an inherited MAX gene deletion in a family with endocrine tumors. The patient was a male carrier of an intragenic exon 3 deletion inherited from his father who had recurrent pheochromocytomas and a macroprolactinoma. The patient underwent screening and hormonal studies but no pheochromocytoma-paraganglioma, pituitary or renal tumors were identified. However, abdominal magnetic resonance imaging (MRI) identified a 1 cm lesion in body of the pancreas. The lesion was hyperintense on T2-weighted signal, and there was hyperfixation of the tumor on 68Ga-DOTANOC PET-CT images. No biochemical evidence of pancreatic hormone excess was identified. Following a guided biopsy, a pathological diagnosis of a low grade pNEN was made and immunohistochemistry showed loss of MAX nuclear staining. Genetic analysis of the tumor tissue indicated copy number neutral loss of heterozygosity consistent with uniparental disomy. This is the first reported case of a MAX deletion associated pNEN and strengthens the argument that MAX may represent an inheritable multiple endocrine neoplasia risk gene. Further analysis of germline and somatic MAX mutations/deletions in large cohorts of unexplained NEN cases could help clarify the potential role of MAX in NEN etiology.

Key words

familial - MAX - pancreatic neuroendocrine neoplasm - pituitary - pheochromocytoma

Publication History

Received: 09 March 2020

Accepted after revision: 18 May 2020

Article published online:
10 June 2020

• References

• 1 Dasari A, Shen C, Halperin D. et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017; 3: 1335-1342
• 2 Thakker RV, Newey PJ, Walls GV. et al. Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012; 97: 2990-3011
• 3 Di Domenico A, Wiedmer T, Marinoni I. et al. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer 2017; 24: R315-R334
• 4 Hammel PR, Vilgrain V, Terris B. et al. Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d′Etude de la Maladie de von Hippel-Lindau. Gastroenterology 2000; 119: 1087-1095
• 5 Agaimy A, Vassos N, Croner RS. Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen's disease): Clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol 2012; 5: 852-862
• 6 Barrera AS, Serra Pla S, Blázquez Maña CM. et al. Pancreatic non-functioning neuroendocrine tumor: A new entity genetically related to Lynch syndrome. J Gastrointest Oncol 2017; 8: E73-E79
• 7 Neychev V, Sadowski SM, Zhu J. et al. Neuroendocrine tumor of the pancreas as a manifestation of cowden syndrome: A case report. J Clin Endocrinol Metab 2016; 101: 353-358
• 8 Mortaji P, Morris KT, Samedi V. et al. Pancreatic neuroendocrine tumor in a patient with a TSC1 variant: Case report and review of the literature. Fam Cancer 2018; 17: 275-280
• 9 Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and CDKN1B mutations: The latest of the MEN syndromes. Endocr Relat Cancer 2017; 24: T195-T208
• 10 Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F. et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011; 43: 663-667
• 11 Burnichon N, Cascon A, Schiavi F. et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 2012; 18: 2828-2837
• 12 Korpershoek E, Koffy D, Eussen BH. et al. Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis. J Clin Endocrinol Metab 2016; 101: 453-460
• 13 Casey RT, Warren AY, Martin JE. et al. Clinical and molecular features of renal and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS): Case series and literature review. J Clin Endocrinol Metab 2017; 102: 4013-4022
• 14 Romero OA, Torres-Diz M, Pros E. et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov 2014; 4: 292-303
• 15 Pantaleo MA, Urbini M, Indio V. et al. Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in quadruple WT GIST. Mol Cancer Res 2017; 15: 553-562
• 16 Roszko KL, Blouch E, Blake M. et al. Case report of a prolactinoma in a patient with a novel MAX mutation and bilateral pheochromocytomas.. J Endocr Soc 2017; 1: 1401-1407
• 17 Daly AF, Castermans E, Oudijk L. et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr Relat Cancer 2018; 25: L37-L42
• 18 Falconi M, Eriksson B, Kaltsas G. et al. ENETS Consensus Guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016; 103: 153-171
• 19 Bausch B, Schiavi F, Ni Y. et al. Clinical characterization of the pheochromocytoma and paraganglioma susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention. JAMA Oncol 2017; 3: 1204-1212
• 20 Schaefer IM, Wang Y, Liang CW. et al. MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun 2017; 8: 14674
• 21 Mafficini A, Scarpa A. Genetics and epigenetics of gastroenteropancreatic neuroendocrine neoplasms. Endocr Rev 2019; 40: 506-536
• 22 Scarpa A, Chang DK, Nones K. et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017; 543: 65-71
• 23 Jiao Y, Shi C, Edil BH. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331: 1199-1203
• 24 Albattal S, Alswailem M, Moria Y. et al. Mutational profile and genotype/phenotype correlation of non-familial pheochromocytoma and paraganglioma. Oncotarget 2019; 10: 5919-5931