Department of Pathology, University of California, San Francisco, San Francisco, California.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Mod Pathol. 2023 Mar;36(3):100065. doi: 10.1016/j.modpat.2022.100065. Epub 2023 Jan 10.
Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Although current recommendations suggest that immunohistochemistry for p53, Rb, ATRX, and DAXX can distinguish most cases, some cases remain difficult to classify using this approach. In this study, we reviewed 47 high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains, we performed capture-based sequencing of approximately 500 cancer genes and immunohistochemistry for p16 and trypsin or chymotrypsin. Using an integrated molecular and clinicopathologic approach, 42 (89%) of 47 cases had a clear final diagnosis of either G3 PanNET (n = 17), PanNEC (n = 17), or mixed acinar-NEC (n = 8). The 17 G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. The 17 PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was coaltered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. The 8 acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Five cases remained difficult to classify, 3 of which exhibited overlapping molecular features with alterations in MEN1 with or without ATRX, and RB1 with or without TP53, making it unclear whether to classify as PanNET or PanNEC. Our data demonstrate that molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC.
鉴别 3 级胰腺神经内分泌肿瘤（G3 PanNET）和神经内分泌癌（PanNEC）是一个已知的诊断挑战，准确分类至关重要，因为它们的临床行为和治疗方法不同。尽管目前的建议表明，p53、Rb、ATRX 和 DAXX 的免疫组织化学可以区分大多数病例，但有些病例使用这种方法仍然难以分类。在这项研究中，我们回顾了最初诊断为胰腺神经内分泌肿瘤的 47 例高级别肿瘤。除了目前推荐的染色外，我们还对大约 500 个癌症基因进行了基于捕获的测序，并进行了 p16 和胰蛋白酶或糜蛋白酶的免疫组织化学检测。使用综合的分子和临床病理方法，47 例中的 42 例（89%）有明确的最终诊断，分别为 G3 PanNET（n=17）、PanNEC（n=17）或混合腺泡-NEC（n=8）。17 例 G3 PanNET 中 MEN1（71%）、DAXX（47%）、ATRX（24%）、TSC2（35%）、SETD2（42%）和 CDKN2A（41%）频繁发生改变。与之前的报告相反，TP53 改变在 G3 PanNET 中也很常见（35%），但在该组中总是与 CDKN2A 改变相互排斥。17 例 PanNEC 中 TP53（88%）、细胞周期基因 RB1（47%）、CCNE1/CCND1（12%）、CDKN2A（29%）和 KRAS（53%）和 SMAD4（41%）频繁发生改变；TP53 与 PanNEC 中 76%的细胞周期基因共突变。与 G3 PanNET 的 0%相比，在 69%的 PanNEC 中观察到弥漫性强 p16 染色。8 例腺泡-NEC 中 ATM（25%）、APC（25%）和 STK11（25%）经常发生改变。有 5 例仍难以分类，其中 3 例具有 MEN1 与 ATRX 共存或缺失，或 RB1 与 TP53 共存或缺失的重叠分子特征，不清楚是否归类为 PanNET 或 PanNEC。我们的数据表明，分子分析和 p16 的免疫组织化学极大地提高了高级别胰腺神经内分泌肿瘤的诊断准确性，并确定了一小部分具有 PanNET 和 PanNEC 特征重叠的罕见病例。
