Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Mod Pathol. 2021 Feb;34(2):490-501. doi: 10.1038/s41379-020-00648-y. Epub 2020 Aug 15.
While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naive TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had "LGSC-like" morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these "usual HGSC-like" tumors often showed evidence of p53 dysfunction, including downregulation of expression ('null' or equivocal p53 staining in 9/14, 64%) or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.
虽然 TP53 突变被广泛认为是管状卵巢高级别浆液性癌（HGSC）的定义特征，但也有罕见的 TP53 突变阴性病例报道。为了更深入地了解这一罕见亚群，对 25 例 TP53 野生型管状卵巢 HGSC 进行了回顾性分析，这些病例构成了 MSK-IMPACT 测序平台分析的 987 例 HGSC 的 2.5%。与浆液性分化一致，几乎所有 TP53 野生型 HGSC 均表现出 Pax8 和 WT1 的阳性染色。这些肿瘤还存在 HGSC 的其他特征，如浆液性输卵管上皮内癌，或 CCNE1 和 BRCA1/2 的遗传改变，进一步支持它们作为真正的 HGSC 的分类，尽管缺乏 TP53 突变。总体而言，TP53 野生型 HGSC 的染色体不稳定性水平介于低级别浆液性癌（LGSC）和 TP53 突变型 HGSC 之间。对突变状态不知情的观察者进行形态评估显示，有一组显著的肿瘤具有 2 级核异型性（超过 LGSC 允许的异型性程度，但低于通常遇到的 HGSC），伴有微乳头状特征（6/19，32%，未经化疗的 TP53 野生型 HGSC 与 0/21，0%，TP53 突变型 HGSC 相比；p=0.007）。一些 TP53 野生型 HGSC 存在 KRAS（n=3）、BRAF（n=1）或 NRAS（n=2）的驱动突变。总体而言，10 例（40%）病例具有“LGSC 样”形态（即 2 级核异型性和微乳头状特征）和/或 RAS/RAF 突变，其中大多数通过免疫组化显示野生型 p53 表达模式（7/9，78%）。其余 15 例 TP53 野生型 HGSC（60%）表现出严重的核异型性（3 级），与传统的 TP53 突变型 HGSC 在形态上无法区分。尽管缺乏 TP53 的遗传改变，但这些“通常的 HGSC 样”肿瘤通常显示出 p53 功能障碍的证据，包括表达下调（9/14，64%的“无”或可疑的 p53 染色）或 MDM2 扩增（n=2）。我们的结果支持存在 TP53 野生型 HGSC，它们构成了一组异质性肿瘤，可能通过不同的发病机制产生。
