Insulinoma‐associated 1: A sensitive marker of neuroendocrine differentiation in cutaneous and metastatic neuroendocrine tumors

Abstract

Insulinoma-associated 1 (INSM1) is a nuclear zinc finger transcription factor, which is a sensitive and specific marker of neuroendocrine differentiation. INSM1 binds to DNA and is involved in the expression of multiple neuroendocrine-related genes, including those encoding for chromogranin and synaptophysin; it also regulates other proteins such as cyclin D1 involved in the cell cycle. 1-3 INSM1 was first discovered in human glucagonoma and insulinoma tumor tissues, and has been shown to be expressed in normal development of endocrine and neural tissues, benign neuroendocrine cells, and neuroendocrine tumors in many organ systems, including the lung, pancreas, thyroid, adrenal gland, pituitary gland, central nervous system, and gastrointestinal tract. 1-3 It is typically expressed in carcinoid tumors, pheochromocytomas, insulinomas, medulloblastomas, neuroblastomas, pituitary adenomas and carcinomas, small cell carcinomas, and large-cell neuroendocrine carcinomas, among others. 1-6 Although this marker has been shown to be expressed in neuroendocrine cells and tumors in many other organ systems, in the skin, INSM1 has been mostly studied in Merkel cell carcinoma (MCC). Strong staining has been reported in the majority of cases, in which it can be useful to confirm neuroendocrine differentiation. 1,4-6 It is also helpful to exclude other tumors which may be considered in the differential diagnosis, such as basal cell carcinoma, poorly differentiated primary and metastatic carcinomas (other than neuroendocrine carcinomas), melanoma, and lymphomas, most of which are negative for this marker (although the numbers of cases of these other tumors analyzed so far is quite small). 4-6 It is a more sensitive and specific neuroendocrine marker than traditional neuroendocrine stains such as CD56, chromogranin, and synaptophysin, which are cytoplasmic markers. In addition, CK20 staining can be very focal and difficult to identify in some cases of MCC. In contrast, INSM1 has been reported to show stronger and more diffuse staining than these other markers in most MCC cases. 4-6 In addition, the nuclear staining is easier to detect in small, often crushed biopsies, and does not show as much non-specific background staining as the cytoplasmic markers. To date, including all of the studies on INSM1 in MCC, it has been reported positive in 100 (99%) out of 101 cases published. 1,4-6 No cases of

Cutaneous Neuroendocrine Mucinous Carcinomas Are Low-grade But May Be Associated With Other Cancers

“…In a prior study, 2 we identified insulinoma-associated protein 1 (INSM1) and MUC2 as sensitive markers for the identification of EMPSGC and confirmed the ability of INSM1 to increase recognition of neuroendocrine differentiation in these low-grade mucinous tumors when compared with the conventional markers synaptophysin and chromogranin. While reviewing the literature, we noted that the vast majority of primary cutaneous mucinous and nonmucinous adnexal carcinoma reported have not been subjected to this sensitive neuroendocrine marker INSM1, 3 and most cases of reportedly non-neuroendocrine mucinous primary cutaneous sweat gland carcinoma are solitary and/or from historical series, thus the true prevalence of neuroendocrine differentiation in these higher grade tumors is unknown, potentially weakening the conclusions of Agni et al 1 …”

“…In a prior study, 2 we identified insulinoma-associated protein 1 (INSM1) and MUC2 as sensitive markers for the identification of EMPSGC and confirmed the ability of INSM1 to increase recognition of neuroendocrine differentiation in these low-grade mucinous tumors when compared with the conventional markers synaptophysin and chromogranin. While reviewing the literature, we noted that the vast majority of primary cutaneous mucinous and nonmucinous adnexal carcinoma reported have not been subjected to this sensitive neuroendocrine marker INSM1, 3 and most cases of reportedly non-neuroendocrine mucinous primary cutaneous sweat gland carcinoma are solitary and/ or from historical series, thus the true prevalence of neuroendocrine differentiation in these higher grade tumors is unknown, potentially weakening the conclusions of Agni et al 1 For this study, we therefore proposed to evaluate INSM1 labeling in a cohort of mucinous and nonmucinous primary cutaneous adenocarcinoma from our single cancer center and to correlate the characterized neuroendocrine phenotypes with patients' disease-related outcomes, pathologic features, and other clinical data. A secondary aim was to further validate the utility of INSM1 in distinguishing periocular neoplasms, including sebaceous carcinoma, basal cell carcinoma (BCC), and benign apocrine neoplasms.…”

Hiding in Plain Sight: An Atypical Presentation of the Uncommon Merkel Cell Carcinoma

“…Immunohistochemical staining for MCC commonly involves several markers, including cytokeratin 20 (CK20), neuron-specific enolase (NSE), and insulinoma-associated protein 1 (INSM1) [12]. INSM1 has emerged as a valuable marker for neuroendocrine differentiation and is increasingly used in the diagnosis of MCC due to its high specificity and sensitivity for MCC [12,13].…”