Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome

Abstract

A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.

FIGURE 1

Menin immunohistochemical staining and LOH-analysis. A, Sporadic parathyroid tumor (patient 24) showing preserved nuclear menin expression by immunohistochemistry. B, MEN1 syndrome-related parathyroid tumor (patient 16) showing absent nuclear menin expression by immunohistochemistry. C, LOH analysis of patient 16, using SNP-array showing MEN1 LOH.

FIGURE 2

Menin immunohistochemistry and LOH-analysis of 2 parathyroid tumor patients with a clinical suspicion of MEN1 syndrome and a MEN1 VUS mutation. One patient (patient 49) showed retained menin expression (A) and LOH analysis using a SNP array showed no copy number variation nor heterozygous loss of MEN1 (B). The second patient (patient 50) showed aberrant nuclear menin staining by immunohistochemistry (C) and a LOH analysis using an SNP array showed monosomy of chromosome 11, including heterozygous loss of MEN1 (D).