The ENETS/WHO grading system for neuroendocrine neoplasms of the gastroenteropancreatic system: a review of the current state, limitations and proposals for modifications

Abstract

The understanding of neuroendocrine neoplasms has evolved significantly since their initial descriptions in the 1800s to early 1900s. In the gastroenteropancreatic system, this group of malignant tumors is subdivided into well and poorly differentiated neuroendocrine neoplasms based on morphologic, proliferative and biologic differences. However, it has become increasingly apparent that well-differentiated neuroendocrine tumors are not a homogeneous group. Attempting to better predict outcome of these tumors has been the motivation behind numerous proposed classification systems, the evolution of which culminated with the currently used system, the ENETS/WHO classification. Herein, we review the genesis of this classification system and some of its shortcomings. In addition, we discuss some of the most recent proposals that suggest modifications to the current system.

Figure 1. Well-differentiated neuroendocrine tumors

They are characterized by a wide array of architectural patterns, such as gyriform (A), nested/organoid, cribriform (B), trabecular and tubular/glandular. Cytologically, they typically display ‘salt and pepper’ chromatin and finely granular cytoplasm. Mitotic index is low in these examples of low-grade NETs. (H&E, 200× magnification).

Figure 2. Poorly differentiated neuroendocrine carcinoma

(A) Small-cell type is characterized by solid/trabecular pattern of growth and cells with scant cytoplasm, inconspicuous nucleoli and nuclear molding. Note the mitoses and apoptotic bodies. An area of necrosis is partially represented in the upper left corner. (B) Large-cell type showing solid/trabecular architecture and cells with abundant basophilic cytoplasm and open chromatin with large nucleoli. Numerous mitotic figures and apoptotic bodies are again easily identified. (H&E, 200× magnification).

Figure 3. Well-differentiated neuroendocrine tumor with a high-grade component, one of the presentations of G3 WDNET

(A) The tumor has areas with typical morphology of a WDNET exhibiting gyriform architecture (center). However, distinctly separate areas display a solid pattern of growth (remainder of tumor lobules) with extensive areas of necrosis (not shown). (B) Corresponding Ki-67 highlights the difference of Ki-67 labeling in the well-differentiated component (within the G2 range) and the solid areas (Ki-67 >90%). (H&E and Ki-67 immunohistochemistry, 40× magnification). (C) Higher magnification of the well-differentiated area in (A), with typical architecture and a paucity of mitoses, and of the (D) high-grade component displaying a solid pattern, greater degree of cytologic atypia, numerous mitoses, and areas of necrosis. (H&E, 200× magnification).