Second-Generation Neuroendocrine Immunohistochemical Markers: Reflections from Clinical Implementation

SIMPLE SUMMARY: Neuroendocrine tumors are a collection of neoplastic lesions arising in cells with traits similar to hormone-producing and nerve cells with the ability to secrete peptide hormones using an intricate vesicle transportation system. From a clinical standpoint, neuroendocrine tumors are unique in terms of therapeutic modalities, and a correct diagnosis is therefore imperative in order for the patient to obtain the most efficient treatment. In this process, the pathologist can analyze if the tumor cells express Chromogranin A and Synaptophysin, two proteins associated with the regulation of secretory vesicles. Unfortunately, these markers are not always present in neuroendocrine tumors, and non-neuroendocrine tumors may also occasionally express Chromogranin A or Synaptophysin—making the diagnosis difficult to make for certain cases. Recently, three proteins termed ISL1, INSM1 and Secretagogin were found to be selectively expressed in neuroendocrine cells, and subsequent studies have identified their potential as markers of neuroendocrine differentiation in the clinical setting. In this commentary, the benefits of these novel “second-generation” markers are briefly discussed from a clinical context. 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.