In the past, neurosecretory granules were identified by electron microscopy and special stains. Currently those methods have been completely replaced by several immunohistochemical markers. These are called neuroendocrine markers, and they include synaptophysin (SYN) , chromogranin A (CHR) , CD56 (neural cell adhesion molecule) , and neuron-specific enolase (NSE) . NSE is widely known to be highly nonspecific and is not generally used in practice. SYN and CHR specifically recognize dense-core granules. An emerging neuroendocrine marker is insulinoma-associated protein 1 (INSM1), which at the time of writing is promising to be more sensitive and specific than the conventional markers.

Morphologically, there is no single feature that defines neuroendocrine neoplasms as a group. Instead, neuroendocrine morphology is defined by a constellation of several cytologic and architectural features. When someone says a tumor “looks neuroendocrine,” they are implying these features :

The appearance may be thought of vaguely recapitulating the normal neuroendocrine structures. Recall that nesting is a feature of normal adrenal medulla, and subtle trabecular/ribbonlike structures are present in the islets of Langerhans. The presence of rosettes is not easily explained by resemblance to normal neural/neuroendocrine structures in the adult, but such structures can be seen in the developing neural tube, and many neuroglial tumors also form rosettes.

One of the challenges with neuroendocrine tumors is that this family includes tumors with quite different morphology and behavior, spanning from well-differentiated tumors (such as lung carcinoids) to highly aggressive, poorly differentiated carcinomas (such as small cell carcinoma). Whereas the defining neuroendocrine features are usually very obvious in well-differentiated neoplasms, they may be quite subtle to barely detectable in poorly differentiated carcinomas. Nevertheless, even in the latter tumors, the overall uniformity and dispersed finely granular chromatin should be preserved, and at least a hint of neuroendocrine architecture (in the form of nesting, rosettes, or ribbons) is usually present. Therefore, diagnosis frequently hinges on recognition of subtle morphologic clues and confirmation with immunostains. Below is the brief summary of prototypical neuroendocrine neoplasms.