Endometrial Carcinomas with a "Serous" Component in Young Women Are Enriched for DNA Mismatch Repair Deficiency, Lynch Syndrome, and POLE Exonuclease Domain Mutations

Am J Surg Pathol. 2020 May;44(5):641-648. doi: 10.1097/PAS.0000000000001461.

Abstract

Endometrial carcinoma (EC), as described by Bokhman, has historically been classified as Type I (low-grade, hormone-dependant, young patients, good prognosis) or Type II (high-grade, hormone-independent, older patients, poor prognosis). This classification is no longer pragmatic, however, as EC is a much more heterogeneous disease. Four molecular subtypes of EC were identified by The Cancer Genome Atlas (TCGA), and subsequent studies have demonstrated its utility in predicting prognosis. While endometrial serous carcinoma (ESC), the prototypical Type II EC, largely occurs in older women, younger women with ESC were not accounted for in the Bokhman model and were underrepresented in the TCGA study. We hypothesized that a subset of ESCs in young patients do not represent bona fide serous carcinomas but rather high-grade endometrioid carcinomas mimicking a serous phenotype. We identified ESCs and mixed endometrioid/serous carcinomas in women <60 years (n=37), and analyzed their clinical, morphologic, immunohistochemical, and molecular characteristics. Sixteen percent showed mismatch repair deficiency (MMR-D) and 11% were diagnosed with Lynch syndrome. Additionally, 16% of cases tested harbored a hotspot POLE exonuclease domain mutation (POLE-EDM). Morphologically, 47% of tumors showed confirmatory endometrioid features, including atypical hyperplasia, a low-grade endometrioid carcinoma component, or squamous differentiation. Clinically, the overall survival in patients with MMR-D and POLE-EDM was significantly better than that of patients without these features (P=0.0329). In conclusion, ESCs in young patients comprise a heterogeneous group of tumors, demonstrating diverse clinical, immunohistochemical, morphologic, and molecular features which have implications for prognosis and adjuvant therapy.

MeSH terms

  • Adult
  • Age Factors
  • Biomarkers, Tumor / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / enzymology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / therapy
  • DNA Mismatch Repair*
  • DNA Polymerase II / genetics*
  • DNA Repair Enzymes / deficiency*
  • Endometrial Neoplasms / enzymology
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Endometrial Neoplasms / therapy
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasms, Complex and Mixed / enzymology
  • Neoplasms, Complex and Mixed / genetics*
  • Neoplasms, Complex and Mixed / pathology
  • Neoplasms, Complex and Mixed / therapy
  • Neoplasms, Cystic, Mucinous, and Serous / enzymology
  • Neoplasms, Cystic, Mucinous, and Serous / genetics*
  • Neoplasms, Cystic, Mucinous, and Serous / pathology
  • Neoplasms, Cystic, Mucinous, and Serous / therapy
  • Phenotype
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Risk Factors
  • Time Factors

Substances

  • Biomarkers, Tumor
  • Poly-ADP-Ribose Binding Proteins
  • DNA Polymerase II
  • POLE protein, human
  • DNA Repair Enzymes