The High-grade (WHO G3) Pancreatic Neuroendocrine Tumor Category Is Morphologically and Biologically Heterogenous and Includes Both Well Differentiated and Poorly Differentiated Neoplasms. Am J Surg Pathol. 2015, [Epub ahead of print]

Abstract  The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields 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. 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." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, 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 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). 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 heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.

2010版世界卫生组织（WHO）分类推荐胰腺神经内分泌肿瘤（PanNETs）的分级建立在核分裂像和Ki67指数基础上，2级（G2）PanNETs界定为核分裂像2-20个/10HPF或Ki67指数在3%-20%之间，3级（G3）胰腺神经内分泌癌（NEC）界定为核分裂像>20个/10HPF或Ki67指数>20%。然而一些PanNETs在核分裂像和Ki67指数上存在不一致性，通常Ki67指数在G3范围，而核分裂像属于G2范围，这就促使我们在一个大系列的核分裂像属于G2 PanNETs中检测Ki67指数的临床意义。作者复习了本单位经外科切除的核分裂像G2、分化好的PanNETs。其中19例PanNETs Ki67 >20%，被选定为级别-不一致性研究组（核分裂像计数G2/Ki67指数G3）。另选53例级别-一致性的PanNETs（核分裂像计数和Ki67指数均属G2），和43例形态学分化差的(小细胞或大细胞型)胰腺NECs作对照。在几个核分裂像“热点区域”通过人工计数至少500个细胞来量化Ki67阳性肿瘤细胞的百分比。级别-一致性和级别-不一致性PanNETs及差分化NECs的平均Ki67指数分别为8.1% (范围3% -20%)，40% (24%-80%)，70% (40%-98%)。总的来说，级别-不一致性PanNETs患者比差分化NEC的患者有显著长的生存时间（中位生存期54.1 vs. 11月，5年生存率29.1% vs. 16.1%; P=0.002）。另外，级别-不一致性PanNETs患者的生存时间比级别-一致性PanNETs患者的短（中位生存期67.8月，5年生存率62.4%），然而差异不具有统计学意义（P=0.2）。本研究发现以核分裂像和Ki67指数为基础的PanNETs分级可能不一致，当Ki67指数指示G3时，临床预后相对较差。更重要的是，通过Ki67分级的G3期中分化好的PanNETs与分化差的NECs相比，其侵袭性较弱，表明目前的WHO G3分类存在异质性，包含两种不同的肿瘤，应该进一步分类为伴高增殖指数的分化好的PanNETs和分化差的NEC。