Immunoreactivity to classic neuroendocrine markers such as CgA and synaptophysin is almost always present, and second-generation neuroendocrine markers ISL LIM Homeobox 1 (ISL1) and INSM1 have also been found as reliable markers of an adrenal medullary origin in pheochromocytoma [74,75,76] (Figure 3). This evidence concerns the gene ISL1 and hereditary pheochromocytoma-paraganglioma.