Intraepithelial Carcinoma of the Fimbria and Pelvic Serous Carcinoma: Evidence for a Causal Relationship

Abstract

Proposed origins of pelvic serous carcinoma include the ovary, fallopian tube, and peritoneum. Prophylactic salpingo-oophorectomies in BRCA+ women have recently identified the fimbria as a site of origin for early serous carcinoma (tubal intraepithelial carcinoma or TIC). We explored the relationship of TIC to pelvic serous carcinomas in consecutive cases with complete adnexal exam (SEE-FIM protocol). Cases positive (group A) or negative (group B) for endosalpinx (including fimbria) involvement, were subclassified as tubal, ovarian, or primary peritoneal in origin. Coexisting TIC was recorded in group A when present and p53 mutation status was determined in 5 cases. Of 55 evaluable cases, 41 (75%) were in group A; including tubal (n = 5), peritoneal (n = 6), and ovarian (n = 30) carcinomas. Foci of TIC were identified in 5 of 5, 4 of 6, and 20 of 30, respectively. Ninety-three percent of TICs involved the fimbriae. Five of 5 TICs and concurrent ovarian carcinomas contained identical p53 mutations. Thirteen of 14 cases in group B were classified as primary ovarian carcinomas, 10 with features supporting an origin in the ovary. Overall, 71% and 48% of "ovarian" serous carcinomas had endosalpinx involvement or TIC. TIC coexists with all forms of pelvic serous carcinoma and is a plausible origin for many of these tumors. Further studies are needed to elucidate the etiologic significance of TIC in pelvic serous carcinoma, reevaluate the criteria for tubal, peritoneal, and ovarian serous carcinoma, and define the role of the distal tube in pelvic serous carcinogenesis.

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].…”

“…Later that year, Cass and colleagues reported that most fallopian tube carcinomas arose in or near the fimbria [17]. Subsequently, Medeiros et al and Callahan et al reported that virtually all incidentally discovered HGSCs in RRSOs from women at genetic risk were found in the distal fallopian tube, and Kindelberger et al showed that over 40% of women with HGSC had evidence of STIC in their distal fallopian tube [3,12,18]. Thus, in our practice, the SEE-FIM protocol or a protocol in which the entire distal fallopian tube was submitted is followed in all salpingectomy specimens.…”

“…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].…”

Potentially important microRNA cluster on chromosome 17p13.1 in primary peritoneal carcinoma

“…4,40,41,47 Recent work proposes that epithelial ovarian cancer arises from three proposed origins, including the ovarian surface epithelium or mullerian inclusions, fallopian tube mucosa and mullerian epithelium elsewhere in the peritoneal cavity. 2,[48][49][50][51] Specifically, there is a growing body of evidence to suggest that both ovarian serous carcinoma and primary peritoneal carcinoma may arise from a precursor lesion in the distal tubal fimbria, [49][50][51] and thus both tumour types may be genetically related. Importantly, our results do not preclude a common site of origin; they probably reflect temporal 19 described DNA copy number alterations at all genomic loci for our selected microRNAs in ovarian serous carcinoma.…”

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

“…2 Efforts to identify the source of serous cancers have revealed that the oviduct, particularly the fimbriated end, is responsible for a larger proportion of serous cancers than previously thought, both in women with BRCA1 or BRCA2 mutations and the general population. [3][4][5][6][7] A serous cancer precursor has been proposed to arise in the distal oviduct. It may begin with TP53 mutations in secretory cells, leading to a clonally derived population with altered expression of p53 in the setting of DNA damage (H2AX).…”