Should lymph node staging be tailored according to molecular profile in endometrial cancer?

This study investigates whether the specific molecular profile of endometrial cancer is associated with propensity for lymph node metastasis.

Patients undergoing primary surgery between 2015 and 2023 were reviewed. Clinicopathological, lymph node metastasis, recurrence, and survival patterns were compared between molecular sub-groups: no specific molecular profile, p53-abnormal, POLE-mutated, and mismatch repair-deficient, with a sub-group analysis of MLH1 promoter methylated and non-MLH1 promoter methylated mismatch repair-deficient cases.

Of 537 patients, 239 (45%) were no specific molecular profile, 145 (27%) were p53-abnormal, 109 (20%) were MLH1 promoter methylated, 40 (7%) were non-MLH1 promoter methylated mismatch repair-deficient, and 4 (1%) were POLE-mutated. Lymph node assessment was done in 420 patients (78%), with lymph node metastases present in 92 (22%). There was no significant difference in lymph node metastasis between molecular groups (p =.080). However, MLH1 promoter methylated tumors had the highest incidence of lymphovascular space invasion (48%, p <.001) and microcystic, elongated, and fragmented pattern of invasion (17%, p <.001). The p53-abnormal sub-group had the highest median tumor volume (12.7 cm³, 0.0-781.5, p =.013), followed by MLH1 promoter methylated (12.2 cm³, 0.0-375.8). The median follow-up was 2.4 years (0.05-7.67). Two-year estimated progression-free survival was as follows: non-MLH1 promoter methylated mismatch repair-deficient (92.1%, 95% confidence interval 83.9% to 100%), no specific molecular profile (92.3%, 95% confidence interval 88.7% to 96.0%), MLH1 promoter methylated (83.1%, 95% confidence interval 76.0% to 90.8%), and p53-abnormal (75.0%, 95% confidence interval 67.9% to 82.9%) (p <.001). Two-year estimated overall survival was as follows: non-MLH1 promoter methylated mismatch repair-deficient (100%), no specific molecular profile (98.2%, 95% confidence interval 96.5 to 100.0), MLH1 promoter methylated (92.6%, 95% confidence interval 87.4% to 98.1%), and p53-abnormal (92.0%, 95% confidence interval 87.3% to 96.9%) (p <.001).

Currently, there is not enough evidence to tailor lymph node staging according to molecular profile. Special attention should be paid to MLH1 promoter methylated tumors due to high-risk features and poor outcomes.