SUN-331 Clinical Characteristics and Genotype-Phenotype Analysis of MEN1 Patients with Thymic Neuroendocrine Tumors

Abstract

Patients with the multiple endocrine neoplasia 1 (MEN1) syndrome develop various tumors during their lifetime. One of the rare manifestations observed in MEN1 patients is thymic neuroendocrine tumor (Th-NET) or thymic carcinoid, which is a major cause of death due to its aggressive nature, frequent recurrence, and lack of effective treatment. The goal of this study was to analyze the clinical presentation and outcome of Th-NETs in MEN1 patients at our institution and to investigate the correlation between genotype and phenotype. We evaluated the clinical characteristics of MEN1 patients with Th-NETs from a cohort of 350 patients with a MEN1 germline mutation and identified 13 patients (3.7%) with Th-NETs: 11 with thymic carcinoid, 1 with a thymoma demonstrating a neuroendocrine phenotype, and 1 with a non-neuroendocrine thymoma. Thymic carcinoid occurred exclusively in men and was the first tumor identified in 2 of the patients, while the 2 patients with thymoma were both females. Median age of diagnosis for Th-NETs was 43 years (range: 29-65 years). Mean tumor largest diameter was 7.18 cm (range: 2.5-15 cm). ACTH production was not detected in any of the thymic carcinoid cases. Seven patients died, 4 of them are still followed, and 2 of them were lost to follow-up. Th-NETs recurred following surgical resection in 7 patients. Family history of thymic carcinoid was identified in 6 patients. Smoking history was found in 6 patients. MEN1-associated tumors in our cohort included parathyroid adenoma (n=13), pancreatic NET (n=11), pituitary adenoma (n=8), Zollinger-Ellison syndrome (n=7), and lung carcinoid (n=1). In archived tumor samples obtained from 11 patients, chromogranin-A and synaptophysin immunohistochemistry confirmed the neuroendocrine phenotype in thymic carcinoids and showed neuroendocrine differentiation in one of the thymomas. Tumor grade analysis was performed using Ki-67 staining. Genomic DNA was isolated from peripheral blood leukocytes and the following MEN1 germline heterozygous mutations were identified: 8 frameshift, 3 nonsense, 1 in-frame deletion, and 1 missense mutation (found in a thymoma sample). The mutations were scattered throughout the entire MEN1 coding region without specific clustering. Moreover, the only genotype-phenotype correlation observed was a preponderance of protein truncating mutations (frameshift and nonsense) in the Th-NET cohort. Th-NETs are uncommon in MEN1 syndrome. Our Th-NET cohort showed a male predominance. MEN1 mutations in the Th-NET patients did not show any specific clustering, but a preponderance of protein truncating mutations was observed in the MEN1 gene. Further analysis of Th-NET samples for genetic alterations and gene expression profiles will help to uncover the yet to be determined modifying factors in the pathophysiology of Th-NETs.