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

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.

New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines

“…Indeed, the favorable prognostic value of the POLEmut group appears not to significantly change when normalized for possible confounding factors [ 13 ]. The excellent prognosis of the POLEmut group is maintained across the several histotypes, justifying the guidance of the ESGO/ESTRO/ESP guidelines [ 12 , 23 , 33 , 34 , 35 , 43 , 44 , 52 , 63 , 64 ]. On the other hand, the prognosis of the NSMP group appears heavily affected by tumor grade and histotype.…”

“…Therefore, even in the presence of morphologically unequivocal SC, applying the TCGA classification appears crucial to avoid severe overtreatment of patients. POLEmut and MMRd cases with serous features indeed show a prognosis comparable to that of their EEC counterpart, supporting the need for a similar management [ 34 , 35 ].…”

“…Furthermore, mixed EEC and SEC not rarely show POLEmut or MMRd signature, especially women <60 years. In these cases, a p53 abnormal expression pattern (reflecting TP53 mutations) may occur as a consequence of the high mutational rate, but it does not affect prognosis [ 35 ]. Therefore, even in the presence of morphologically unequivocal SC, applying the TCGA classification appears crucial to avoid severe overtreatment of patients.…”

“…However, the prognosis of mixed carcinomas may be highly heterogeneous and appears strongly affected by the TCGA group. Previous studies showed a significant proportion of MMRd and POLEmut signatures in mixed carcinomas containing an EEC component, especially in younger women; such signatures are associated with good prognosis [ 35 , 42 , 45 ]. On this account, it might be appropriate to consider MMRd mixed carcinomas as analogous to MMRd EEC in terms of risk stratification.…”

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

“…Atypical hyperplasia is associated with unopposed estrogenic stimulation of the endometrium and acquisition of mutations in PTEN , KRAS , PIK3CA , CTNNB1 , and/or ARID1A [57]. EAH/EIN is the precursor lesion of almost all endometrioid carcinomas and a subset of serous carcinomas [58]. The mutational profile of EAH/EIN and the concurrent EC is highly concordant [18,59–62] in the majority of cases; however, Li et al showed that, in 5 out of 30 EAH/EIC cases with concurrent EEC, the EAH/EIC and EC shared less than 5% of the mutations identified, indicating clonality but with a high degree of divergence [62].…”