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

Abstract

A high frequency of precursor lesions is a risk factor for cancer in many organ systems but must be precisely quantified. Pelvic serous neoplasia is associated with an estimated increase in frequency of secretory cell outgrowths (SCOUTs) with loss of PAX2 protein (PAX2p) expression (PAX2p-null SCOUTs) in the fallopian tube. However, to confirm this, PAX2p-null SCOUTs must be precisely quantified relative to the epithelial surface. We developed a method by which fallopian tube sections were digitized using an iScan brightfield scanner (BioImagene) and uploaded in Adobe Photoshop CS3 Extended. Pixel length was translated into microns and epithelial length measured with the Magic Wand tool. SCOUTs were expressed as a function of total epithelial perimeter. Frequency, required perimeter length, topographic clustering tendency and effects of age were ascertained. SCOUT frequency per 10 cm was 0-4.60 for cases and 0-1.66 for controls, averaging 0.84 and 0.27, respectively, (P ¼ 0.007). Required perimeter length for SCOUT detection was less in serous cancer cases and topographic distribution followed a random pattern without aberrant clustering. Age was also associated with SCOUT frequency (P ¼ 0.025) and differences between cancers and controls were still significant after adjusting for age (P ¼ 0.001). We describe an efficient method for quantifying epithelial perimeter in the fallopian tube and verify its relevance to precursor frequency. This has important implications for assessing precursor frequency both in the fallopian tube and in other organs-such as prostate, pancreas and colon-where epithelial precursors are integral to carcinogenesis. Modern Pathology (2012) 25, 1654-1661; doi:10.1038/modpathol.2012.100; published online 6 July 2012 Keywords: fallopian tube; precancer; secretory cell; serous cancer Although traditionally presumed to originate primarily in the ovarian cortex, high-grade ovarian cancers, specifically serous cancers, have been reassessed based on recent observations in the fallopian tube. 1 These include the frequent discovery of early serous cancers-termed tubal intraepithelial carcinomas-in the tubal fimbriae of women undergoing risk reducing salpingo-oophorectomy for germ-line BRCA1 or BRCA2 mutations, the observation of similar early cancers in 35-60% of un-selected women with fully developed pelvic serous cancer, and the description of a precursor condition in benign tubal mucosa with altered TP53 expression, termed the 'p53 signature'. 2-10 The latter has focused attention on the early molecular changes that may occur before the onset of either tubal intraepithelial or invasive serous carcinoma in the fallopian tube. 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...

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

“…cell outgrowths or SCOUTs contain a number of perturbations similar to p53 signatures; they are typically PAX2-null with variable expression of ALDH1 and several other markers also dys-regulated in neoplasia (Figure 2D). Interestingly, they or similarly described variants appear to be more frequent in older women and in women with a HGSC [30;31] (Zheng W, personal communication). This paradox of association with HGSC despite the absence of p53 mutations suggests that SCOUTs are associated with some risk factors for HGSC but do not participate directly in the carcinogenic sequence.…”

“…Surrogate precursors (secretory/stem cell outgrowths or SCOUTs) more distantly related to HGSC also occur in the fallopian tube (29,30,31). …”

The PAX2‐null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium

“…Contiguous benign (p53 signatures) and malignant (STICs) epithelia have been documented with shared mutations in specific codons of TP53 . In addition, further studies have unearthed other benign epithelial alterations, termed secretory cell outgrowths (SCOUTs), that do not contain TP53 mutations or evidence of a DNA damage response, yet share with precursors and carcinomas loss of PAX2 expression . SCOUTs do not appear directly linked to HGSC, but have been documented at higher frequency in the normal tubes of postmenopausal women and those with HGSC .…”

Fallopian Tube Intraluminal Tumor Spread From Noninvasive Precursor Lesions

“…Like invasive carcinoma, they have a predominantly secretory phenotype and display frequent p53 expression and increased proliferation (Ki67) by immunohistochemistry. [17][18][19] STICs and p53 signatures are predominantly found in the infundibulum and fimbriae and thereby coincide with the region where early invasive carcinomas are often discovered. 14,16 Since then, other entities that may occur even earlier in tumor initiation and progression have been described.…”