Endocrine Abstracts (2018) 56 OC11.3 | DOI: 10.1530/endoabs.56.OC11.3

Clinical and histopathological differences between MEN1 carriers and MEN1 phenocopy patients

Tatjana Isailovic1, Djuro Macut1, Ivana Milicevic2, Milan Petakov1, Sanja Ognjanovic1, Valentina Elezovic Kovacevic2, Bojana Popovic1, Ivana Bozic Antic1, Tamara Bogavac2, Dusan Ilic2, Mirjana Sumarac Dumanovic1, Mirjana Stojkovic1 & Svetozar Damjanovic1

1Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia; 2Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia.

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a rare multitumour syndrome, characterized by the occurrence of parathyroid (PHPT), pituitary adenoma (PA) and pancreatic neuroendocrine tumors (pNETs). The gene responsible is MEN1 gene, however 10 to 20% of patients are not carriers of MEN1 mutation. Recently, a study has shown that these patients have less aggressive course of the disease, and more favorable life expectancy than their mutation-positive counterparts. Nevertheless, their clinical and histopathological features are still unknown.

Study design: Genetic, clinical and histopathological features were analyzed in a retrospective, single-center study of 102 consecutive patients with MEN1. Direct sequencing and MLPA of MEN1 gene were performed in all patients, and CDKN1b gene in MEN1 mutation-negative patients.

Results: We found 34% of mutation-negative cases among all patients, or 47% among index cases. None of these patients had gene alterations in CDKN1b gene. Women were more prevalent among all patients, but this was especially pronounced in mutation-negative patients (86% vs 59% in mutation-positive, P<0.01). All major MEN1 tumors appeared earlier in mutation carriers, and none of mutation-negative patients had more than two major MEN1-tumors. The most frequent phenotype was PA/PHPT in mutation-negative, and PA/PHPT/pNET in mutation-positive patients. PAs were more frequent in mutation-negative than in mutation-positive patients (83% vs 57% respectively, P<0.01). Acromegaly appeared almost exclusively in mutation-negative patients (41% vs 3% in mutation positive, P<0.001). Conversely, pNETs predominantly appeared in mutation-positive (45% vs 9% in mutation-negative, P<0.01), and majority of them were multiple (58%). PHPT was equally distributed, but the presence of polyglandular disease was a major feature of mutation carriers (77% vs none in mutation-negative). Bronchial NETs were more prevalent among mutation-negative patients (P<0.05), and adrenal tumors were equally distributed (P>0.05). There was no difference in age of death and OS between mutation-positive and mutation-negative patients (P>0.05).

Conclusion: MEN1 phenocopy differs from genetically confirmed MEN1 syndrome in several aspects: the presence of only two, solitary, coexisting major MEN1-tumors that develop later in life, marked female predominance, frequently occurring acromegaly, and rare pNETs. It appears that other, non-hereditary factors are involved in initiation and development of multiple-organ NETs in MEN1 phenocopy patients. However, the contribution of low-penetrant mutations in other genes cannot be entirely excluded.