Perineural invasion in cutaneous squamous cell carcinoma: role of immunohistochemistry, anatomical site, and the high-affinity nerve growth factor receptor TrkA

Perineural invasion (PNI) has been recently added to the American Joint Committee on Cancer cutaneous squamous cell carcinoma (cSCC) staging criteria as a high-risk tumor characteristic and is purportedly more common in cSCCs of the head and neck (H&N). Expression of the high-affinity nerve growth factor receptor TrkA has been shown to be associated with PNI in noncutaneous neoplasms. Given this, we sought to ascertain the incidence of PNI in cSCCs using double immunostaining (DIS) and to investigate PNI's relationship with TrkA and established histopathologic prognosticators. Fifty-seven cSCCs from the H&N and 53 from non-H&N areas were immunohistochemically analyzed for PNI (DIS with S-100 and p63) and TrkA expression. Comparing H&N versus non-H&N areas, using hematoxylin and eosin, PNI was detected in 11% versus 6% cases, respectively, and, using DIS, in 23% versus 15%, respectively, with significant disagreement between both methods (κ = 0.47; P = .002). There was a 2.33-fold increase in PNI detection with DIS compared to hematoxylin and eosin (95% confidence interval, 1.12-4.87; P = .02). TrkA expression was 1.96 times more frequently observed in cSCCs from the H&N compared to those from non-H&N areas (P = .01). Regardless of site, TrkA expression was associated with decreased degree of differentiation (odds ratio, 6.46; P = .0006) and high-risk morphologic variants (odds ratio, 6.53; P = .002) but not significantly associated with PNI (P = .33). Increased PNI detection with DIS underscores the adjunctive utility of immunohistochemistry in microstaging. Significantly more common TrkA expression in cSCCs of the H&N argues in favor of heterogeneity among SCCs from different anatomical sites.