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.

Keywords: NGS; endometrial cancer; molecular subtypes; recurrence.

FIGURE 1

Oncoplot showing the mutations present in paired samples of each case (2 cases with 2 recurrences).

FIGURE 2

Histologic images showing hematoxylin-eosin and MLH1 immunohistochemistry. The length of the branches in the evolutionary trees is proportional to the number of mutated genes in each sample. A, Case 13. The evolutionary tree shows that the recurrence acquires MLH1 methylation. B, Case 17. The primary tumor evolves to different recurrences acquiring different mutations, also including MLH1 methylation. Note that R2 in case 17 has progressed to HG-EC. Scale bar: 50 μm. FOne indicates FoundationOne; N, normal tissue; P, primary tumor; R, recurrence; R1, recurrence 1; R2 recurrence 2; R3, recurrence 3.

FIGURE 3

Case 20, which changed from LG-EEC in the primary tumor to G3-EEC in the recurrence. Evolutionary trees show different mutations in the primary tumor and in the recurrence. The length of the branches in the evolutionary tree is proportional to the number of mutated genes in each sample. Histologic images show hematoxylin-eosin and MLH1 immunohistochemistry. Molecular studies performed with NGS custom panel. Scale bar: 50 μm. N indicates normal tissue; P, primary tumor; R, recurrence.

FIGURE 4

Timeline of case 24. LG-EEC in primary tumor and liver metastasis, changing to UEC/DEC in mediastinal lymph node metastasis. IHC images include p53, SMARCA4 and SMARCA2. Scale bar: 50 μm. LVI indicates lymphatic and/or vascular invasion.