The High-grade (WHO G3) Pancreatic Neuroendocrine Tumor Category Is Morphologically and Biologically Heterogenous and Includes Both Well Differentiated and Poorly Differentiated Neoplasms

Abstract

Background The 2010 WHO classification recommends that pancreatic neuroendocrine tumors should be graded based on mitotic rate and Ki67 index, with grade 2 (G2) pancreatic neuroendocrine tumor (PanNET) defined as having a mitotic rate of 2–20 mitotic figures/10 high power fields (HPF) or a Ki67 index of 3–20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 HPF or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well characterized mitotic G2 PanNETs. Design Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67 >20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67 positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of “hot spots”. Results The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3–20), 40% (range, 24–80%) and 70% (range, 40–98), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared to the patients with poorly differentiated NEC (median survival of 54.1 months vs 11 months and 5-year survival of 29.1% vs 16.1%; p=0.002). Also, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 months and 5-year survival of 62.4%); however, the difference was not statistically significant (p=0.2). Conclusion Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogeneous, contains two distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.

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

“…Prints were coded and randomly used for manual counting of Ki67 LI. Counting was performed by manual marking of tumoral cells with and without Ki67 expression with color pens [21,38]. Of note, this approach is a reference technique of Ki67 LI assessment in pancreatic NEN [21].…”

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas

“…Recent studies have shown a significantly longer survival for these patients in comparison with patients with true poorly differentiated NEC, although their clinical outcome is slightly worse than those with grade 2 NET. 210,211 These data thus suggest that grade 3 neuroendocrine neoplasms are heterogeneous. Tumors with well-differentiated morphology but with grade 3 Ki-67 proliferation index should be separated from true poorly differentiated NECs, and they may be more appropriately designated as ''well-differentiated NET with an elevated proliferation rate.''…”

“…Tumors with well-differentiated morphology but with grade 3 Ki-67 proliferation index should be separated from true poorly differentiated NECs, and they may be more appropriately designated as ''well-differentiated NET with an elevated proliferation rate.'' 210 Nevertheless, Ki-67 proliferation index has important therapeutic and prognostic implications. Data from a study on a large number of patients with GI NEC (grade 3) have shown less responsiveness to platinumbased chemotherapy but longer survival in patients with Ki-67 index less than 55%.…”

Reassessing the grade of gastroenteropancreatic neuroendocrine neoplasms

“…Although the most recent WHO classification implied that all G3 neuroendocrine neoplasms are poorly differentiated neuroendocrine carcinomas, emerging data indicate instead that some G3 cases remain well differentiated [11]. 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.…”