Second-Generation Neuroendocrine Immunohistochemical Markers: Reflections from Clinical Implementation

Abstract

When analyzing tumors by histopathology, endocrine pathologists have traditionally been restricted to a few key immunohistochemical markers related to secretory vesicles in order to pinpoint neuroendocrine differentiation—most notably Chromogranin A (CGA) and Synaptophysin (SYP). Although proven of great clinical utility, these markers sometimes exhibit tissue-specific patterns depending on tumor origin, and non-neuroendocrine tumors might sometimes display focal expression. Moreover, CGA and SYP might be partially or totally absent in highly proliferative neuroendocrine carcinomas, making the diagnosis particularly challenging on small biopsies of metastatic lesions with unknown location of the primary tumor. The advent of second-generation neuroendocrine markers ISL LIM Homeobox 1 (ISL1), INSM Transcriptional Repressor 1 (INSM1) and Secretagogin (SECG) have expanded the pathology toolbox considerably, constituting markers that often retain expression even in poorly differentiated neuroendocrine carcinomas. As non-neuroendocrine tumors seldom express these antigens, the specificity of ISL1, INSM1 and SECG make them welcome additions to clinical practice. In this commentary, recent advances of this field as well as initial clinical experiences from a tertiary neuroendocrine center are discussed.