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-NETs) 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 Ki67 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. Methods We investigated the 31 cases of WD-NETs with evidence of 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 immunohistochemistry 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). Conclusion Mixed grades can occur in WD-NETs, which are distinguished from PDNECs 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 PDNECs.

Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreascriteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas

“…However, only in 5% (3/60) of cases this resulted in change of grade from G1 to G2 [15]. This value could be underestimated, since higher grade component may form a minor portion of the tumour [9]. Valous et al showed that lacunarity measurement allows categorization of samples of pancreatic NEN to groups with homogenous or with heterogenous spatial Ki-67 LI distribution across whole virtual sections [10].…”

“…Ki67 LI heterogeneity was observed not only within primary tumour tissue [9,10,11,12], but also between primary and metastatic lesions [13,14,15] and within and between metastases [16,17].…”

Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors

“…SSTR positivity is an important finding for demonstrating that a lesion is in fact a NET; therefore, to characterize a finding on CI, SSTR PET can be used to clarify whether a suspected lesion is a NET and represents true progression or recurrence. In addition, it is possible for NETs to dedifferentiate, changing from welldifferentiated to poorly differentiated NETs over time (49). SSTR PET can be an indirect indicator of grade, and therefore reimaging at the time of progression can provide insight into possible underlying dedifferentiation of a tumor.…”

Reassessing the grade of gastroenteropancreatic neuroendocrine neoplasms

“…These cases (G3 well-differentiated GEP-NETs) generally have histologic features in common with other well-differentiated NETs, and in most cases, only the Ki67 index-not the mitotic rate-falls in the G3 range. Available genetic information also suggests that G3 well-differentiated GEPNETs share molecular alterations with their lower grade GEP-NET counterparts, and they lack the mutations commonly found in poorly differentiated neuroendocrine carcinomas (e.g., TP53 and RB1 ) [12]. Although G3 welldifferentiated GEP-NETs are more aggressive than G1 and G2 GEP-NETs, they are not as aggressive as true poorly differentiated neuroendocrine carcinomas.…”

“…Progression of a G1 or G2 GEP-NET to a higher grade (even G3) can occur with metastatic progression [12]. Therefore, reassessment of the grade of a previous specimen such as the primary tumor may not reflect the biology of the active disease.…”