Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas

Abstract

Purpose: Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized.

Experimental design: We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed.

Results: The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1-G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively-significantly better than that of a comparison group of true PD-NEC (DSS 11 months).

Conclusions: Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs.

Figure 1

Well-differentiated neuroendocrine tumor with HG component is characterized (in the direction from upper to lower) by subtle architectural alterations (A) and a markedly increased Ki67 proliferative index (B). In comparison with the lower grade component (C), areas with HG component within the same tumor reveal increased nuclear to cytoplasmic ratio and brisk mitotic activity (D).

Figure 2

Compared to the lower grade regions (A), a WD-NET with HG component shows a more solid and confluent growth pattern with loss of stroma and vasculature (B), and tumor necrosis can be present as either geographic (C) or punctuate patterns or as single cell necrosis (D).

Figure 3

Disease Specific Survival of stage-matched pancreatic WD-NET with or without HG component and pancreatic PD-NEC^,.