Pancreatic neuroendocrine neoplasms: current state and ongoing controversies on terminology, classification and prognostication

Abstract

Significant improvements have taken place in our understanding of classification neuroendocrine neoplasms of the pancreas in the past decade. These are now regarded in three entirely separate categories: (I) neuroendocrine tumors (PanNETs) are by definition well differentiated, the pancreatic counterpart of carcinoids; (II) neuroendocrine carcinomas, which are poorly differentiated (PDNEC), the pancreatic examples of small cell carcinomas or large cell neuroendocrine carcinomas; (III) other neoplasms that have neuroendocrine differentiation or a distinct neuroendocrine component. PanNETs are by far the most common. They are now regarded as malignancies (albeit often curable when low grade and low stage) with the exception of minute incidental proliferations (tumorlets, or dysplastic-like changes) seen in the setting of some syndromes like MEN. PanNETs are staged based on their size, and for small T1 tumors, watchful waiting is now being considered, although these tumors are also known to show about 10% metastatic rate and/or progression, creating concerns about this approach. PanNETs are graded into 3, based on the proliferative activity, mostly based on the Ki-67 index, and also partly mitotic activity, although the latter seldom if ever is the determinant of the final grade. Neuroendocrine neoplasms with well differentiated morphology but Ki-67 >20% are now regarded as PanNET Grade 3 (G3); they have been shown to have a prognosis significantly worse than lesser grade PanNETs but still incomparably better than frank PDNECs, the latter typically has Ki-67 >50% (often much higher) and require platinum-based chemotherapy. There are also cases that are ambiguous between PanNET-G3 and PDNEC, and very rarely transformation of the former to the latter appears to occur. For low grade (G1/G2) PanNETs, more refined criteria to further prognosticate this group are needed. Morphologic variants being recognized may bring new perspectives to this group.

Keywords: Pancreas; WHO 2019; carcinoma; classification; neuroendocrine neoplasm; pathology; prognosis; terminology; tumor.

Figure 1

Unlike pancreatic ductal adenocarcinomas which are scirrhous ill-defined lesions, the pancreatic neuroendocrine tumors typically form a well-demarcated, relatively homogenous and fleshy tumors (A). This is because they are fairly cellular neoplasia in which there is minimal or no stromal desmoplastic component but rather a delicate fibro-vascular stroma rich in capillaries (which are also often appreciated at the radiologic level), intervening in between the nests of cells (Hematoxylin & eosin, 40× magnification) (B).

Figure 2

At the high power microscopic examination, typical PanNETs form nested pattern (distinct, demarcated clusters) composed of uniform monotonous cells with fair amount of cytoplasm and the distinctive “salt and pepper” chromatin pattern characteristic of this tumor type (Hematoxylin & eosin, 100× magnification) (A). Although mitotic activity is generally low, they can be readily evident in some cases (B) which, if >2 per 10 high power fields, places the tumor in higher grade categories (Hematoxylin & eosin, 100× magnification).

Figure 3

Neuroendocrine markers of synaptophysin, chromogranin and CD56 are expressed in the vast majority of PanNETs, detectable by immunohistochemical analysis. Among these, chromogranin is the most specific, while others can be seen in other tumor types. Chromogranin immunostain typically shows a granular pattern (A) because it highlights the neurosecretory granules that are abundant in the tumor cells (Chromogranin immunostain, 100× magnification). Ki-67 immunostain is performed to assess the proliferative index of the tumor. In this case, the index was found to be >20% in the “hot spot” (B) placing the tumor into the “NET G3” category (previously called “grade discordant”) (Ki-67 immunostain, 40× magnification).

Figure 4

PDNECs are high-grade carcinomas that often show more diffuse growth pattern and necrosis (A) and displaying overt signs of cytologic malignancy along with mitotic figures and apoptotic bodies (B) [Hematoxylin & eosin, 40× (A) and 100× (B) magnification].