INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an extremely aggressive skin cancer that must be distinguished from other basaloid cutaneous neoplasms that have different treatments and prognoses. This is sometimes challenging in small shave specimens, crushed samples, lymph nodes, and core needle biopsies. Insulinoma-associated protein 1 (INSM1) immunohistochemistry is a sensitive nuclear marker of neuroendocrine differentiation. INSM1 staining was performed on 56 MCC (47 primary tumors, 9 nodal metastases), 50 skin control cases that included basal cell carcinomas, basaloid squamous cell carcinomas, Bowen disease, sebaceous neoplasms, melanoma, and B-cell lymphomas, and 28 lymph node control cases that included metastatic neuroendocrine neoplasms, melanomas, squamous cell carcinomas, lymphomas, and adenocarcinomas. Percent of staining nuclei (0,<25%, 25% to 50%, 50% to 75%, >75%) and intensity (weak, moderate, strong) were recorded for each sample. All 56 MCC expressed INSM1. By comparison, synaptophysin, CK20, and chromogranin were expressed in 96%, 92%, and 32% of MCC, respectively. While the 3 conventional markers showed significant variability in staining intensity and distribution, INSM1 stained >75% tumor nuclei in 89% of MCC and 50% to 75% of tumor nuclei in 11%. Staining intensity was strong in 85% and moderate in 15%. None of the 50 cutaneous basaloid non-MCC neoplasms in the control group stained with INSM1, and among the lymph node controls 5 of 5 neuroendocrine neoplasms expressed INSM1, confirming that INSM1 staining cannot distinguish MCC from metastatic extracutaneous neuroendocrine carcinoma. INSM1 holds promise as a neuroendocrine marker that can distinguish MCC from its mimickers in the skin and improve detection of sentinel lymph node metastases.

Insulinoma‐associated protein 1 immunostaining for various types of neuroendocrine tumors on FNA smears

“…For example, Rooper et al 7 found that INSM1, CG, and SYN were positive in all 24 cases of medullary thyroid carcinoma; for 15 cases of olfactory neuroblastoma, the positive rates were 100%, 81.8%, and 100%, respectively. For Merkel cell carcinoma, in the current study, INSM1 staining had a higher detection rate (90%) than the rates of CG (50%) and SYN (80%); these rates were comparable to the rates of 100%, 32%, and 96%, respectively, reported in a surgical pathology study using 56 cases of primary and metastatic Merkel cell carcinoma 10 . Studies of other smaller cohorts have also reported superior sensitivity of INSM1 in comparison with SYN and CG in the diagnosis of Merkel cell carcinoma 11,14,24 …”

Syntaxin 1: A Novel Robust Immunophenotypic Marker of Neuroendocrine Tumors

“…INSM1 is a recently described IHC NE marker [36], demonstrating nuclear localization. It has been studied in the NENs of many anatomical regions, including the lung, head and neck, central nervous system, prostate, skin, and pancreas, but, according to the reported series, the INSM1 reveals a lower sensitivity [13,[36][37][38][39][40][41] than STX1 in our series. Although a direct comparison of the two markers is warranted in future studies, based on the literature data and results of the present study, STX1 outperforms INSM1 in terms of its specificity and sensitivity.…”

A Therapeutic and Diagnostic Multidisciplinary Pathway for Merkel Cell Carcinoma Patients

“…Indeed, MCC cells are usually positive for both epithelial markers, such as AE1/AE3, CAM5.2, and CK20 (especially in the dot-like paranuclear pattern), and neuroendocrine markers, such as chromogranin, synaptophysin, CD56, and NSE. Recently, insulinoma-associated protein 1 (INSM1) has been proposed as promising marker to confirm the neuroendocrine nature of MCC (12). Most cases are also positive for neurofilament and for huntingtin-interacting protein 1 (HIP1) (13).…”