Cyclooxygenase-2 in Vulvar Epithelial Neoplasia: Correlation with Invasion and Neutrophil Chemotaxis
AJ Finn, RA Ball. University of North Carolina Hospitals, Chapel Hill, NC; Greensboro Pathology Associates, Greensboro, NC
Background: Cyclooxygenase-2 (COX-2) is an inducible regulator of prostaglandin synthesis implicated in tumor proliferation, migration, and angiogenesis. Prior analyses of vulvar epithelial neoplasia have verified its intratumoral expression but provided conflicting data as to its utility in grading squamous dysplasia or distinguishing in situ from invasive carcinoma.
Design: We collected 147 vulvar epithelial lesions from a regional reference laboratory, nearly doubling the sample size of the largest prior study. We assessed the immunohistochemical staining pattern of COX-2 via the Chalkley point count method, which we deemed a superior means of quantification in light of typically discontinuous expression and the postulated role of the enzyme in potentiating focal microvascular proliferation. In addition, a subjective impression of increased tumor infiltration by neutrophils in cases with high levels of COX-2 prompted us to stain these specimens with anti-neutrophil elastase to assess for a correlation with COX-2 expression.
Results: Point count analysis revealed much higher levels of COX-2 expression in invasive squamous carcinoma versus all non-invasive lesions (mean counts of 9.9, S.D. 7.7, versus 0.6, S.D. 1.8, with p<0.0001 by the Welch's t-test). 26 of 31 invasive cases demonstrated significant foci of COX-2 staining versus only 12 of 116 non-invasive cases. Moreover, COX-2 expression in non-invasive lesions was uniformly restricted to basal epithelium overlying dermal papillae; this was distinct from the intraepithelial pattern observed in invasive carcinoma and not sufficiently robust to allow discriminaton between degrees of dysplasia. Staining with anti-neutrophil elastase also revealed a significant correlation between neutrophil aggregates and “hotspots” of intraepithelial COX-2 expression.
Conclusions: Intraepithelial COX-2 expression is a highly specific indicator of invasion in vulvar squamous neoplasia and could prove a useful diagnostic adjunct in superficial or tangential biopsies that complicate assessment of invasive potential. In addition, the correlation of intraepithelial COX-2 expression and intratumoral neutrophil chemotaxis supports a novel feed-forward mechanism for COX-2 upregulation in vulvar squamous carcinoma and suggests that neutrophilic microabscesses may be a histologic hallmark of susceptibility to topical or systemic COX-2 inhibition.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 63, Monday Morning