Blinded histopathological characterisation of POLE exonuclease domain-mutant endometrial cancers: sheep in wolf's clothing

Abstract

Aims

POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. Implementation of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid the detection of POLE-mutant ECs.

Methods and results

Fifty-one POLE-mutant endometrioid, 67 POLE-wild-type endometrioid and 15 POLE-wild-type serous ECs were included (total N=133). An expert gynaecopathologist, blinded for molecular features, evaluated each case (≥2 slides) for 16 morphological characteristics. Immunohistochemistry was performed for p53, p16, MLH1, MSH2, MSH6, PMS2. POLE-mutant ECs were characterised by a prominent immune infiltrate: 80% showed peritumoural lymphocytes and 59% tumour-infiltrating lymphocytes, compared to 43% and 28% of POLE-wild-type endometrioid and 27% and 13% of serous counterparts (P<0.01, all comparisons). Of POLE-mutants, 33% contained tumour giant cells, which was significantly higher than in POLE-wild-type endometrioid (10%; P=0.003), but not significantly different from serous cancers (53%). Serous-like features were as often (focally) present in POLE-mutant as in POLE-wild-type endometrioid cases (6-24% depending on the feature). The majority of POLE-mutant ECs showed wild-type p53 (86%), negative/focal p16 (82%) and normal mismatch repair protein expression (90%).

Conclusions

A simple combination of morphological and immunohistochemical characteristics (tumour type, grade, peritumoural lymphocytes, MLH1, p53 expression) can assist in pre-screening for POLE exonuclease domain mutations in EC, increasing the probability of a mutation being present from 7% to 33%. This facilitates the implementation of this important prognostic biomarker in routine pathology.

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