Mod Pathol. 2025 Sep 12. pii: S0893-3952(25)00188-7. [Epub ahead of print] 100890
In patients with high-grade endometrial carcinoma (HG-EC), concurrent isolated serous tubal intraepithelial carcinoma (STIC) or STIC-like lesions (STIC-LLs) in the fallopian tube(s) may be found. We sought to determine whether concurrently diagnosed HG-ECs and STIC-LLs are genetically related. Six HG-ECs, including serous carcinomas (n=4) and carcinosarcomas with serous epithelial component (n=2), with co-occurring STIC-LLs were identified, and subjected to microdissection, DNA extraction and panel sequencing targeting 468 cancer-related genes, or, if DNA quantities were limited, to Sanger sequencing. WT1 and p53 protein expression was assessed by immunohistochemistry (IHC). We found that three HG-ECs and concurrent STIC-LLs shared pathogenic mutations, such as TP53 hotspot, NF2, FBXW7 and PIK3CA mutations. IHC analysis revealed that the HG-EC of case 5 lacked WT1 expression and had p53 aberrant expression, while the matched STIC-LL displayed diffuse WT1 expression. Of the remaining three cases that did not show evidence of genetic relatedness based on the targeted sequencing panel, one STIC-LL harbored a clonal TP53 missense mutation, whereas the matched HG-EC had a distinct clonal TP53 hotspot mutation, a clonal FBXW7 hotspot mutation, and ERBB2 amplification. At the protein level, the p53 expression patterns of the HG-ECs and STIC-LLs were concordant in these three cases. Here we demonstrate that co-occurring HG-ECs and STIC-LLs are genetically related in a subset of cases.
Keywords: carcinosarcomas; genetic relatedness; sequencing; serous endometrial carcinoma; serous tubal intraepithelial carcinoma