Diagnostic Utility of INSM1 in Medullary Thyroid Carcinoma

Abstract

Insulinoma-associated protein 1 (INSM1) is shown to be an excellent marker for neuroendocrine differentiation. However, the diagnostic utility of INSM1 in medullary thyroid carcinoma (MTC) has not yet been extensively investigated. INSM1 staining was performed on 21 MTCs, 7 MTC mimickers (including 3 papillary carcinomas, 2 poorly differentiated carcinomas, 1 follicular adenoma, and 1 nodular plasma cell hyperplasia), and 3 cases of C-cell hyperplasia. INSM1 staining of these cases was compared with the traditional MTC markers including calcitonin (CT), monoclonal carcinoembryonic antigen (mCEA), chromogranin A (CgA), and synaptophysin (Syn). The H-score was generated using the QuPath program, an open-source image analysis software. All 21 MTC cases and 3 C-cell hyperplasia cases were positive for all markers. The MTC mimickers were entirely negative for INSM1. INSM1 and Syn displayed, more consistently, high expression with minimal variability than CgA that showed a wide range of expression with significant variability. mCEA and CT exhibited mostly a high expression with some variability. Being a nuclear stain, interpretation was easier with INSM1 compared to other cytoplasmic markers. INSM1 is an excellent marker for neuroendocrine differentiation, entirely applicable in the diagnosis of MTC and C-cell hyperplasia with high sensitivity and specificity. In comparison with the traditional MTC markers, INSM1 is unique in the crisp nuclear staining pattern with a consistent, diffuse, and strong expression. INSM1 can be potentially combined with CT or mCEA as a dual stain, especially when the lesional tissue is limited for a panel of immunostains.

Emerging Biomarkers in Thyroid Practice and Research

“…These, along with calcitonin and the carcinoembryonic antigen, are useful for the diagnosis of MTC. The second-generation neuroendocrine markers insulinoma-associated protein 1 (INSM1), ISL1, and secretagogin, have high sensitivity and specificity for neuroendocrine differentiation, expressed even in poorly differentiated neuroendocrine carcinomas [ 148 , 149 , 150 ]. INSM1 has been reported to be a highly sensitive and specific neuroendocrine marker, useful in the diagnosis of MTC and C cell hyperplasia [ 149 ].…”

INSM1, a Novel Biomarker for Detection of Neuroendocrine Neoplasms: Cytopathologists’ View

“…In a multi-institutional series of 49 thyroid medullary carcinomas, cytological specimens (including 29 primary tumors and 20 metastases), and 20 control thyroid gland carcinomas and secondary tumors, 93.75% of medullary carcinomas revealed INSM1 nuclear positivity including all primary tumors showing a sensitivity of 92.3% and a specificity of 100% to discriminate medullary carcinoma from other thyroid malignancies [ 24 ]. In addition to medullary carcinoma and its mimickers, INSM1 was successfully applied as a NE marker in C-cell hyperplasia [ 35 ].…”

“…Pancreatic specimens may pose diagnostic challenges as well, due to nuclear expression of INSM1 in islet cells (pancreatic neuroendocrine cells) [ 25 ]. In addition, normal cortical adrenal cells and also a very small percentage of prostate cells are positive for INSM1 [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ].…”

Immunohistochemical analyses of the expression profiles of INSM1, ATRX, DAXX and DLL3 in solid papillary carcinomas of the breast

“…Incidentally, INSM1 has been recognised as a useful and specific neuroendocrine marker because it is an essential transcription factor for developing normal neuroendocrine cells wherein its expression is highly restricted (3)(4)(5). Previously several reports have concluded that INSM1 expression is specific to various neuroendocrine tumours (7)(8)(9)(10)(11)(12)(13). Furthermore, SPC is a distinct clinicopathological feature of breast carcinoma that frequently shows neuroendocrine differentiation; SPC shows frequent positive immunoreactivity for chromogranin A and synaptophysin (1,2).…”

“…its expression has been reported in various neuroendocrine tumours, such as pituitary adenoma (7), medullary carcinoma of the thyroid (7,8), carcinoid tumour, small and large cell neuroendocrine carcinoma of the lung (9)(10)(11), neuroendocrine carcinoma of the gastrointestinal tract (12), and pancreatic neuroendocrine tumours (12,13). Additionally, excellent sensitivity and specificity of INSM1 for neuroendocrine differentiation in these tumours have also been described (7)(8)(9)(10)(11)(12)(13). To date, the expression of INSM1 in SPC has been analysed only in three reports (14)(15)(16), with the largest case series comprising of 19 patients, which showed that INSM1 is a useful neuroendocrine marker in SPC because 58% (11 of 19 patients) showed positive immunoreactivity (14).…”