Through the glass darkly: intraepithelial neoplasia, top‐down differentiation, and the road to ovarian cancer

Abstract

The origins of pelvic high grade serous cancer (HGSC) have become a subject of intense scrutiny in view of proposals to reduce the incidence of the disease via opportunistic salpingectomy in healthy women. Accumulated data implicates the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are shared with malignancy. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Müllerian epithelium, essentially requiring mesothelial to Müllerian differentiation prior to or during malignant transformation to HGSC. However, there is emerging evidence that an embryonic or progenitor phenotype exists in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby embryonic progenitors give rise to immuno-phenotypically distinct neoplastic progeny under stromal influences via "top down" differentiation. A similar pattern of differentiation is implied in the endometrium and the juxtaposition of disparate epithelial immuno-phenotypes (POSE and underlying Müllerian inclusions) recapitulates this in the ovary. While a sudden mesothelial-Mullerian transition remains to be proven, it would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will be critical to both expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention.

Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations

“…This implies that many cancers are not initiated in recognizable HGTINs. 24 Interestingly, Powell et al noted that the mean age of their cases with invasion was significantly younger than those with intraepithelial neoplasia only (50 vs. 55, p= 0.04). 23 Whether these discrepancies are a function of demographics, tissue sampling, different transit times, or variable pathways and organs (peritoneum, ovary etc) involved in the pathogenesis of pelvic serous cancer remains to be determined.…”

“…Thus, more thorough analysis of high-grade serous cancers in symptomatic BRCA m+ women is needed to shed light on this question. 24 …”

Ovarian, fallopian tube and peritoneal cancer staging: Rationale and explanation of new FIGO staging 2013

“…Thus, embryonic progenitors would give rise to immunophenotypically distinct neoplastic progeny [10] which would support the old concept of "mullerian neometaplasia".…”

Preclinical Models of Ovarian Cancer: Pathogenesis, Problems, and Implications for Prevention

“…Two potential ovarian sources of HGSC have been proposed - the OSE and ovarian cortical epithelial inclusion cysts (CICs). 14, 33, 34 CICs are lined by OSE-type epithelium, tubal-type epithelium or a mixture of both. Since HGSC can arise from eutopic tubal epithelium in the fallopian tube fimbria, ectopic tubal epithelium in the ovary (in the form of tubal CICs, also called ovarian endosalpingiosis) is a plausible cell of origin for true intraovarian HGSC.…”