Estrogen Receptor, GATA-3, TTF-1 and KRAS in Endometrial Carcinoma of No Specific Molecular Profile: Prognostic or Diagnostic Markers?

Endometrial carcinoma with no specific molecular profile (NSMP) is a clinicopathologically heterogeneous group of diseases with overall intermediate prognosis. Prognostic refinement is needed for better personalized treatment. The updated European ESGO-ESTRO-ESP guidelines for endometrial carcinoma stratify NSMP according to histotype and estrogen receptor (ER) status. ER (with other ancillary markers) also helps differentiate histotypes of endometrial carcinoma. This study describes clinicopathological characteristics of ER-positive and negative NSMP endometrial carcinoma. Further, we investigate the prognostic and diagnostic significance of ER, GATA3, TTF1 and KRAS in a large relatively unselected NSMP carcinoma cohort. POLE sequencing results and immunohistochemistry for p53, mismatch repair proteins and ER were available for 930 samples of endometrial carcinoma. Within NSMP cases (n=377), 22 samples presented ER staining in <1% of the carcinoma cells, 5 cases in 1-9% and 350 cases in ≥10%. ER expression ≥10% predicted excellent outcome (comparable to POLE-mutated cases) in univariable analysis, where ER-negativity (<10%) was associated with poor outcome (comparable with p53 abnormal cases). Most ER-positive NSMP cases were low-grade endometrioid carcinomas, whereas most ER-negative NSMP cases were non-endometrioid or high-grade endometrioid carcinomas. In addition to high-risk histotype, ER-negativity was associated with various other clinicopathological risk factors. In multivariable analysis adjusting for histotype and other risk factors, ER did not independently predict disease progression (p=0.814). No disease-related deaths were observed in the rare (n=3) patients with ER-negative low-grade endometrioid carcinoma. GATA3/TTF1 positivity and KRAS mutation were discovered in mesonephric-like carcinoma but also in endometrioid carcinoma. No prognostic relevance was found for these markers. In conclusion, the different prognosis of ER-positive vs ER-negative NSMP endometrial carcinoma is not attributable to ER status itself, but rather to its strong correlation with histotype and other clinicopathological risk factors. Limited specificity of GATA3, TTF1 and KRAS warrant caution in their use as diagnostic markers of mesonephric-like carcinoma.