GATA3 Is Underexpressed in Penile Neoplasia: Potential Implications in Diagnosis and Pathogenesis

Penile squamous cell carcinoma (PSCC) and its established precursor, penile intraepithelial neoplasia (PeIN), are classified as HPV-associated and HPV-independent. However, there is a spectrum of precursor lesions, which presents diagnostic challenges due to morphologic overlap. Immunohistochemical loss of GATA3, a tumor suppressor gene, has recently been reported in vulvar neoplasia. In this study, we evaluate the expression and diagnostic utility of GATA3 immunohistochemistry (IHC) in penile neoplasia. GATA3, p53, and p16 IHC was performed on 97 penile lesions, including lichen sclerosus (LS, N=14), condyloma acuminatum (N=11), squamous hyperplasia (SH, N=9), verrucous lesions (N=3), HPV-independent (N=12) and HPV-associated (N=18) PeIN, invasive HPV-independent, (N=19) and HPV-associated (N=11) PSCC, and normal skin (NL, N=41). GATA3 expression was scored as >75% basal/parabasal staining (pattern 0), 25% to 75% (pattern 1), 5% to 25% (pattern 2), and <5% (pattern 3). GATA3 was retained in NL (90%) and condyloma (73%) ( P =0.15). LS and SH combined had significant GATA3 loss (44% pattern 0, 17% pattern 1, and 39% patterns 2 to 3) ( P <0.001 vs. NL). HPV-independent PeIN had decreased GATA3 expression compared to NL (100% patterns 1 to 3, 87% patterns 2 to 3) ( P <0.001), and LS-SH ( P =0.003), but had similar expression to HPV-independent PSCC ( P =1.00). HPV-associated PeIN and invasive PSCC had similar GATA3 loss (patterns 1 to 3, P =0.096). HPV-associated PSCC had a more severe loss (91%) than HPV-associated PeIN (39%) ( P =0.008). These findings suggest that GATA3 alterations may be an early event during tumorigenesis, and that this marker may represent a useful complement to p16 and p53 in the differential diagnosis of HPV-independent PeIN from benign mimickers.