Histological and molecular determinants in fertility-sparing treatment of endometrial cancer

Purpose: The aim of this study was to evaluate the clinical outcomes, molecular signatures, and prognostic implications of histological features, including squamous metaplasia (SM), in endometrial cancer (EC)/ atypical hyperplasia (AH) patients under the age of 40 years with early-stage EC or AH and who received fertility-sparing treatment. Materials and Methods: This retrospective study included 16 patients who met the following criteria: EC or AH, aged ≤40 years, with no myometrial invasion or ≤50% depth of invasion, and a strong desire for fertility. The treatment consisted of oral progestins (megestrol acetate [MA]) combined with LNG-IUS for 3–12 months. Investigations included immunohistochemical analyses to assess the expression levels of p53 and mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2). The cases were divided into three molecular groups (MMR-deficient [MMRd], p53 mutant [p53abn], and p53 wild-type [p53wt]). Results: All tumors were p53 wild-type (p53wt). Complete remission (CR) occurred in 38% (6/16) of cases, and stable disease was observed in 62% (10/16). SM was observed in 37.5% (6/16) of patients, and only one SM-positive patient achieved CR (p=0,182). Four patients (3 spontaneous, 1 assisted reproductive technologies) conceived 3 full-term pregnancies. CR was not associated with age, BMI, comorbidities, or the type of treatment. Conclusion: By highlighting the potential association between SM and lower CR rates, we provide a basis for future investigations into the clinical significance of this histological feature. SM may indicate resistance to hormonal therapy.