A candidate precursor to serous carcinoma that originates in the distal fallopian tube

Abstract

The tubal fimbria is a common site of origin for early (tubal intraepithelial carcinoma or TIC) serous carcinomas in women with familial BRCA1 or 2 mutations (BRCA+). Somatic p53 tumour suppressor gene mutations in these tumours suggest a pathogenesis involving DNA damage, p53 mutation, and progressive loss of cell cycle control. We recently identified foci of strong p53 immunostaining-termed 'p53 signatures'-in benign tubal mucosa from BRCA+ women. To examine the relationship between p53 signatures and TIC, we compared location (fimbria vs ampulla), cell type (ciliated vs secretory), evidence of DNA damage, and p53 mutation status between the two entities. p53 signatures were equally common in non-neoplastic tubes from BRCA+ women and controls, but more frequently present (53%) and multifocal (67%) in fallopian tubes also containing TIC. Like prior studies of TIC, p53 signatures predominated in the fimbriae (80-100%) and targeted secretory cells (HMFG2 + /p73-), with evidence of DNA damage by co-localization of gamma-H2AX. Laser-capture microdissected and polymerase chain reaction-amplified DNA revealed reproducible p53 mutations in eight of 14 fully-analysed p53 signatures and all of the 12 TICs; TICs and their associated ovarian carcinomas shared identical mutations. In one case, a contiguous p53 signature and TIC shared the same mutation. Morphological intermediates between the two, with p53 mutations and moderate proliferative activity, were also seen. This is the first report of an early and distinct alteration in non-neoplastic upper genital tract mucosa that fulfils many requirements for a precursor to pelvic serous cancer. The p53 signature and its malignant counterpart (TIC) underline the significance of the fimbria, both as a candidate site for serous carcinogenesis and as a target for future research on the early detection and prevention of this disease.

Frequency of “incidental” serous tubal intraepithelial carcinoma (STIC) in women without a history of or genetic risk factor for high-grade serous carcinoma: A six-year study

“…Beginning in 2000, a progressive accumulation of data has implicated the distal fallopian tube as a site of origin of HGSC by identification of precursors in tubal epithelium [2][3][4][5]. As a consequence, in addition to clinical management guidelines recommending salpingo-oophorectomy for women with germ-line mutations in BRCA1 or BRCA2, recommendations have been published for opportunistic salpingectomy as a cancer preventive in women who are not at increased risk for ovarian cancer [9][10][11].…”

“…As a consequence, attention is now heavily focused on therapies and interventions aimed at prevention. Due to research on early serous carcinogenesis in the last 10-15 years, many cases of HGSC are now believed to arise from the distal fallopian tube in the form of serous tubal intraepithelial carcinoma (STIC) [2][3][4][5]. Thus, in addition to prophylactic salpingo-oophorectomy, which is a powerful risk-reducing intervention for women with germ line BRCA1 or BRCA2 mutations, [6,7] [8,9] the Society of Gynecologic Oncology (2013) and American College of Obstetricians and Gynecologists (2015) have suggested that opportunistic salpingectomy be considered at the time of hysterectomy for "averagerisk" (alternatively "low-risk") women after the completion of child bearing to reduce the risk of a later HGSC [10,11].…”

PAX2-null secretory cell outgrowths in the oviduct and their relationship to pelvic serous cancer

“…8 These expansions, termed 'p53 signatures' are currently the most plausible precursor candidates to high-grade serous cancers developing in the oviduct. 8,10,16 However, it is known that in addition to loss of TP53 function, numerous other disturbances in gene expression characterize high-grade serous cancers, and it is logical to presume that precursors contain some of these functional alterations. 17,18 One of these genes, PAX2, has been shown to be down-regulated in both high-grade mü llerian (endometrioid or serous) pelvic carcinomas and in benign and neoplastic endometrium.…”

“…Nevertheless, loss of PAX2 staining was also highly prevalent in p53 signatures, secretory cell expansions with p53 mutations that are candidate precursors. 8 The presence of two forms of secretory cell expansion showing PAX2 dysregulation in the oviduct underscored the need to understand the distribution of this phenomenon and its relationship to age and neoplasia.…”

“…This precursor, termed the 'p53 signature,' shares several attributes with serous cancer and has been demonstrated to exist in anatomic continuity with serous intraepithelial carcinoma, the earliest form of serous cancer. [8][9][10] Serous intraepithelial carcinoma is the most common (B80-85%) gynecologic malignancy detected in risk reducing salpingo-oophorectomies of women at genetic risk (BRCA1 or BRCA2 mutations) and has been detected in approximately one-half of randomly selected women with advanced serous cancer. 3,7,11 For this reason, the distal tube is now considered an important site of origin for serous cancer.…”