Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations

Abstract

The Cancer Genome Atlas described four major genomic groups of endometrial carcinomas, including a POLE ultramutated subtype comprising B10% of endometrioid adenocarcinoma, characterized by POLE exonuclease domain mutations, ultrahigh somatic mutation rates, and favorable outcome. Our aim was to examine the morphological and clinicopathological features of ultramutated endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Hematoxylin and eosin slides and pathology reports for 8/17 POLEmutated endometrial carcinomas described in the Cancer Genome Atlas study were studied; for the remaining cases, virtual whole slide images publicly available at cBioPortal (www.cbioportal.org) were examined. A second cohort of eight POLE mutated endometrial carcinomas from University of Calgary was also studied. Median age was 55 years (range 33-87 years). Nineteen patients presented as stage I, 1 stage II, and 5 stage III. The majority of cases (24 of the 25) demonstrated defining morphological features of endometrioid differentiation. The studied cases were frequently high grade (60%) and rich in tumor-infiltrating lymphocytes and/or peri-tumoral lymphocytes (84%); many tumors showed morphological heterogeneity (52%) and ambiguity (16%). Foci demonstrating severe nuclear atypia led to concern for serous carcinoma in 28% of cases. At the molecular level, the majority of the Cancer Genome Atlas POLE-mutated tumors were microsatellite stable (65%), and TP53 mutations were present in 35% of cases. They also harbored mutations in PTEN (94%), FBXW7 (82%), ARID1A (76%), and PIK3CA (71%). All patients from both cohorts were alive without disease, and none of the patients developed recurrence at the time of follow-up (median 33 months; range 2-102 months). In conclusion, the recognition of ultramutated endometrial carcinomas with POLE exonuclease domain mutation is important given their favorable outcome. Our histopathological review revealed that these tumors are commonly high grade, have obvious lymphocytic infiltrates, and can show ambiguous morphology. As they frequently harbor TP53 mutations, it is important not to misclassify them as serous carcinoma.

Association of Polymerase e–Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1

“…3,12,13 Besides PD-1 and PD-L1, other immune checkpoints 14 such as CTLA-4, LAG-3, and IDO may also be upregulated in POLE and MSI ECs. …”

“…1 The ultramutated POLE group exhibited an extremely high mutation rate (232 × 10 −6 mutations/Mb) with a unique nucleotide change spectrum of increased C→A transversion frequency, whereas the hypermutated MSI group exhibited mutation rates of 18 × 10 −6 mutations/Mb with variable length of DNA microsatellites due to an underlying deficiency in mismatch DNA repair. [1][2][3] Mismatch DNA repair deficiency induces singlebase mismatches that lead to point mutations in coding regions of genes, as well as insertions or deletions that lead to frame-shift mutations.…”

Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

“…Clinical Laboratory Improvement Amendments-certified (CLIA-certified) targeted genomic profiling of a pretreatment biopsy specimen revealed that this tumor had a mutation in the DNA polymerase epsilon (POLE) gene. This POLE mutation is associated with disruption of the exonuclease activity required for proofreading function and results in a high mutational burden or "ultramutator" phenotype (15,16). POLE mutations are seen in approximately 10% of endometrial cancers and are associated with increased expression of PD-1 and PD-L1, additional T cell markers (16)(17)(18)(19)(20), and robust lymphocytic infiltration.…”

Practical issues in the diagnosis of serous carcinoma of the endometrium

“…Coexistence with complex endometrial hyperplasia/endometrioid intraepithelial neoplasia favors an EEC, whereas the presence of EIC would support the diagnosis of SC. [34][35][36][37] There are reports suggesting that high-grade EEC with mutations in POLE may be particularly prone to exhibit features mimicking SC, [38][39][40] including predominant solid growth, marked pleomorphism.…”