Highlighting the molecular refinement of NSMP endometrial cancer in a case of mesonephric-like adenocarcinoma

• ER-negative NSMP tumors may harbor aggressive molecular features. • Mesonephric-like adenocarcinoma is a frequent diagnostic pitfall in low-grade EC. • L1CAM positivity and KRAS mutation indicate high-risk NSMP disease. • Chromosome 1q gain refines risk stratification in NSMP tumors. • Extended molecular profiling can alter adjuvant treatment decisions. The 2025 ESGO/ESTRO/ESP guideline for endometrial carcinoma (EC) integrates molecular classification into clinical decision-making and, for the first time, recommends the subdivision of carcinomas with no specific molecular profile (NSMP) according to estrogen receptor (ER) status and histological grading. However, NSMP carcinomas remain a highly heterogeneous subgroup, posing challenges in terms of diagnosis and therapy. We report the case of a 71-year-old female patient with low-grade NSMP EC. Due to ER-negativity and strong L1 cell adhesion molecule (L1CAM) expression, the German/Austrian/Swiss S3 guideline at that time required comprehensive histopathological reassessment, which reclassified the tumor as mesonephric-like adenocarcinoma. Extended molecular profiling further identified a KRAS mutation and the absence of common alterations in PTEN , PIK3CA , and PIK3R1 . These features correspond to the aggressive “Cluster 3” subgroup of NSMP tumors, characterized by ER-negativity, L1CAM positivity, KRAS mutations, and frequent chromosome 1q gain. The patient therefore underwent adjuvant carboplatin/paclitaxel chemotherapy followed by vaginal brachytherapy and has remained recurrence-free for five years. This case demonstrates molecular classification of an unusual histological type of EC exhibiting an extremely short-term risk of early distant metastasis and its implication on aggressive adjuvant therapeutical approach. It, furthermore, exemplifies the pronounced heterogeneity of the NSMP subgroup.