Histologic and Molecular Type Changes in Endometrial Cancer Recurrences in Comparison With Their Corresponding Primary Tumors

Abstract

In this study, molecular alterations in endometrial carcinoma (EC) recurrences were analyzed. We aimed to identify genes implicated in tumor progression and to evaluate whether histologic and molecular type shifting occurs in recurrences. Thus, we analyzed 50 samples corresponding to 24 primary ECs (15 low-grade endometrioid endometrial carcinomas [LG-EECs] and 9 high-grade endometrial carcinomas) and their corresponding 26 recurrences. These were studied by immunohistochemistry, next-generation sequencing, and MLH1 promoter methylation. We observed shared mutations in all primary tumors and their recurrences, indicating a clonal relationship between both lesions. Most morphologic and molecular changes associated with progression were found in LG-EEC. In this group, 6 patients (40%) presented additional mutations in the recurrence. These mutations more frequently affected genes of the PI3K/AKT/PTEN pathway, implicating this pathway not only in tumor initiation but also in progression. In addition, 2 patients (13%) in which the primary tumor belonged to the nonspecific molecular profile subtype, shifted to the mismatch repair deficient (MMRd) subtype after the acquisition of MLH1 promoter methylation in the recurrence lesions. In 3 patients (20%) with MMRd, there was a change from LG-EEC to G3-EEC. One TP53-mutated LG-EEC transformed into an undifferentiated carcinoma in a mediastinal lymph node metastasis after losing the expression of SMARCA2 while preserving SMARCA4 and SMARCB1. Morphologic and molecular changes in EC recurrences, especially dedifferentiation and the acquisition of MMRd, should be considered for a correct diagnosis and treatment. MMRd should be tested in metastatic lesions, if available, in patients with primary tumors reported to be of a molecular subtype different from MMRd.