Molecular Alterations of TP53 are a Defining Feature of Ovarian High-Grade Serous Carcinoma: A Rereview of Cases Lacking TP53 Mutations in The Cancer Genome Atlas Ovarian Study

Abstract

The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data are the subject of this report. Only 1 case (Case 5), which contained a homozygous deletion of TP53, had unanimous interobserver agreement for a diagnosis of pure HGSC. In 1 case (Case 3), all 5 observers (100%) rendered a diagnosis of HGSC; however, 3 observers (60%) noted that the histologic features were not classic for HGSC and suggested this case may have arisen from a low-grade serous carcinoma (arisen from an alternate pathway compared with the usual HGSC). In 2 cases (Cases 4 and 12), only 3 observers (60%) in each case, respectively, interpreted it as having a component of HGSC. In the remaining 10 (71%) of tumors (Cases 1, 2, 6-11, 13, and 14), the consensus diagnosis was not HGSC, with individual diagnoses including low-grade serous carcinoma, high-grade endometrioid carcinoma, HGSC, metastatic carcinoma, clear cell carcinoma, atypical proliferative (borderline) serous tumor, and adenocarcinoma, not otherwise specified. Therefore, 13 (93%) of the tumors (Cases 1-4 and 6-14) were either not a pure HGSC or represented a diagnosis other than HGSC, all with molecular results not characteristic of HGSC. Accordingly, our review of the TP53 wild-type HGSCs reported in The Cancer Genome Atlas suggests that 100% of de novo HGSCs contain TP53 somatic mutations or deletions, with the exception of the rare HGSCs that develop from a low-grade serous tumor precursor. We, therefore, propose that lack of molecular alterations of TP53 are essentially inconsistent with the diagnosis of ovarian HGSC and that tumors diagnosed as such should be rigorously reassessed to achieve correct classification.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG. 1

Case 5: all 5 observers classified this case as high-grade serous carcinoma. (A) The architectural features are notable for large papillae lined by stratified epithelium with irregular slit-like spaces. Numerous detached and small epithelial clusters are present. (B) The cytologic features consist of large nuclei, nuclear pleomorphism, hyperchromasia, bizarre nuclear atypia, and mitotic activity (arrow).

FIG. 2

Case 3: all 5 observers classified this case as high-grade serous carcinoma; however, 3 noted features suggestive of evolution from lowgrade serous carcinoma. (A) The tumor is predominantly composed of a micropapillary-rich pattern, commonly seen in invasive low-grade serous carcinoma, in which small micropapillary nests within clear lacunar spaces haphazardly infiltrate through stroma. (B) The nuclei are not as large as frequently seen in high-grade serous carcinoma and more uniform than in most such cases. However, the combined presence of some degree of both chromatin irregularity and variation in nuclear shape and mitotic activity (arrows) favor classification as high-grade serous carcinoma.

FIG. 3

Case 4: this case was classified as high-grade serous carcinoma by 2 observers, serous carcinoma with a mixture of low-grade and high-grade features by 1, and clear cell carcinoma by 2. (A) This tumor featured areas with tubulocystic-like architecture and a vague suggestion of hobnail cell shapes. (B) The papillae in other foci were lined by a single layer of low-cuboidal cells with a slight degree of monotony and without the degree of stratification seen in many high-grade serous carcinomas. A vague suggestion of hobnail cell shapes is also present. (C) Some areas had solid architecture consisting of polygonal cells with abundant clear cytoplasm.

FIG. 4

Case 12: this case was classified as high-grade serous carcinoma by 3 observers, clear cell carcinoma by 1, and adenocarcinoma, not otherwise specified by 1. (A) The tumor shows solid architecture with variably sized nests haphazardly arranged within stroma. (B) Many areas had polygonal cells with round and relatively uniform nuclei and abundant clear cytoplasm. (C) A bizarre atypical cell (upper left) is present. (D) Some foci exhibited cord-like architecture. Note the presence of high-grade nuclei.