Table 1 Evidence supporting a tubal origin for extra-uterine high-grade serous carcinoma, with caveats

Supporting a tubal origin

 Serous tubal intraepithelial carcinoma is the most common early malignancy in asymptomatic BRCA+ women.

 Low-volume HGSCs found in women with or without germline BRCA mutations through increased surveillance are usually tubal in origin.

 Intraepithelial carcinoma is associated with from 19–60% of advanced high-grade serous carcinomas.

 Latent precursors with p53 mutations (p53 signatures) have been isolated in the fallopian tube, localize to the same (fimbria) region as intraepithelial carcinoma, are seen in continuity with intraepithelial carcinoma and share identical p53 mutations or other genomic changes with cancer.

 Lesions intermediate between p53 signatures and intraepithelial carcinoma (tubal intraepithelial lesions) have been identified in the fallopian tube.

 A spectrum of accumulated genomic disturbances link p53 signatures, intraepithelial carcinomas, and invasive/metastatic carcinomas.

 Animal models of fallopian tube carcinoma have been constructed.

 Fallopian tube secretory cells can be transformed, producing serous carcinomas.

 ‘Precursor escape’ could occur, whereby populations of non-malignant p53 mutated epithelial cells spread beyond the tube and eventually evolve into a pelvic carcinoma.

Caveats

 In a significant number of high-grade serous carcinomas in which the fallopian tubes can be evaluated a tubal precursor or obvious tubal mucosal origin cannot be identified (see text for caveats).

 Some subsets of carcinoma (pseudoendometrioid) are less likely to be associated with STIC.

 In a percentage of carcinomas the intraepithelial carcinoma is particularly high-grade without an adjacent lower grade precursor, leaving open the possibility some of these lesions are mucosal metastases.

 Some bilateral intraepithelial carcinomas share the same p53 mutation, suggesting one or both may not be a primary lesion (EK Meserve, K Strickland, B Howitt, C Crum, unpublished data).

 Tubal intraepithelial carcinomas and tumors of the uterus share the same p53 mutations, leaving open the possibility that some intraepithelial carcinomas are metastatic deposits.