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

Abstract

With the exception of germ-line mutations in ovarian cancer susceptibility genes, genetic predictors for women destined for ovarian serous cancer cannot be identified in advance of malignancy. We recently showed that benign secretory cell outgrowths (SCOUTs) in the oviduct are increased in frequency with concurrent serous cancer and typically lack PAX2 expression (PAX2-null). The present study examined the relationship of PAX2-null SCOUTs to high-grade serous cancers by comparing oviducts from women with benign gynecologic conditions and high-grade serous cancers. PAX2-null SCOUTs were identified by immunostaining and computed as a function of location, frequency (F) per number of cross-sections examined, and age. Six hundred thirty-nine cross-sections from 35 serous cancers (364) and 35 controls (275) were examined. PAX2-null SCOUTs consisted of discrete linear stretches of altered epithelium ranging from cuboidal/columnar, to pseudostratified, the latter including ciliated differentiation. They were evenly distributed among proximal and fimbrial tubal sections. One hundred fourteen (F ¼ 0.31) and 45 (F ¼ 0.16) PAX2-null SCOUTs were identified in cases and controls, respectively. Mean individual case-specific frequencies for cases and controls were 0.39 and 0.14, respectively. SCOUT frequency increased significantly with age in both groups (P ¼ 0.01). However, when adjusted for age and the number of sections examined, the differences in frequency between cases and controls remained significant at P ¼ 0.006. This study supports a relationship between discrete PAX2 gene dysregulation in the oviduct and both increasing age and, more significantly, the presence of co-existing serous cancer. We propose a unique co-variable in benign oviductal epithelium-the PAX2-null SCOUT-that reflects underlying dysregulation in genes linked to serous neoplasia.

Digital quantification of precursor frequency in the fallopian tube and its significance

“…With this approach, the proposed link between SCOUT frequency (per 10 5 microns or 10 centimeters) and neoplasia is validated. [11][12][13] We found in addition, as would be expected, that the mean amount of perimeter needed to identify the first SCOUT was less in cases of serous cancer. Moreover, the distribution of SCOUTs appeared to be random, without clustering in particular tissue sections of the fallopian tube ( Figure 5).…”

“…13 Follow-up studies recognized the need to account for both the age of the subjects and number of cross-sections examined. 12,13 When this was done, an additional link to age and a less pronounced (albeit still significant) relationship to malignancy was observed. This study was designed to more critically evaluate this relationship and create a method by which the surface area of the fallopian tube could be ascertained.…”

“…12 Each cross-section was immunostained with antibodies to PAX2p, as previously described and scored by two observers for linear segments of at least 30 consecutive non-ciliated cells exhibiting loss of PAX2p nuclear staining. [11][12][13] For each case, a tally of PAX2p-null SCOUT number following examination of a single section from each block was made. To provide a denominator for the scoring, the epithelium from each tubal section was digitized and an objective epithelial length obtained using a 10-step model (Table 1; Figure 1, center).…”

“…Although the p53 signature, by virtue of its location (fimbria), p53 staining, evidence of DNA damage and proximity to intraepithelial carcinomas, is a presumptive direct precursor to intraepithelial carcinoma, a range of other discrete epithelial cell expansions have been described, termed secretory cell outgrowths or SCOUTs. [11][12][13] SCOUTs share with p53 signatures a loss of PAX2 protein (PAX2p) expression but contain wild-type TP53 and are not restricted to the distal fallopian tube. In recent reports, SCOUTs, specifically those lacking expression of the paired box 2 protein (PAX2p) have been found in greater frequency-per histologic cross-section-in fallopian tubes of women with serous cancer vs controls.…”

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

“…However, other studies have suggested an association between STIC and endometrioid neoplasia [16,20]. Moreover, we have identified an association, albeit unclear, between benign proliferations with a "clonal" appearance (stem cell outgrowths (SCOUTs)) in the tube -some with endometrioid histology -and HGSC [21,22]. Thus it is conceivable that a small but unique subset of women have a vulnerability to both endometrioid and serous cancer precursor pathways or that both pathways share some yet to be clarified biologic underpinning.…”