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.

IRB 00006477.

Background In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. Design One hundred and seven pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the WHO in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well differentiated neuroendocrine tumor or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. Results The mean patient age was 59 years (range, 21–82) and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body and 11 in the tail. The median tumor size was 4 cm (range, 2–18). Twenty-seven tumors were large cell neuroendocrine carcinomas and 17 were small cell carcinomas (mean mitotic rate, 37/10 HPF and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well differentiated neuroendocrine tumor. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease with a median survival of 11 months (range, 0–104); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0–71). The 2-year and 5-year survival rates were 22.5% and 16.1%, respectively. Conclusion Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well differentiated neuroendocrine tumor and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.