Polypoid or verrucous lesions in the genitofemoral area may be harmless seborrheic keratoses or contagious condyloma acuminata. A solitary lesion is particularly difficult to diagnose clinically, requiring pathological evaluation. A condyloma is an epithelial hyperplasia induced by infections with human papillomavirus (HPV). The histological gold standard for the diagnosis of condyloma is the presence of koilocytosis; however, it is not present in every lesion, and the histological diagnosis may be inaccurate. Therefore, the best way to diagnose a condyloma is to demonstrate the presence of γ-Secretase inhibitor IX in the lesion, especially the most common HPV types 6 and 11.
In the 1990s, several methods were developed for the detection of viral DNA. Articles were published describing genital seborrheic keratosis associated with HPV in up to 50% of cases. This raised the question of how many lesions diagnosed as genitofemoral seborrheic keratosis were in fact condyloma. These virologic tests, whether using in situ hybridization or the polymerase chain reaction (PCR), can accurately detect HPV DNA. However, test results must be correlated with clinical characteristics, pathologic characteristics, and HPV type to avoid false-positive diagnoses. Meanwhile, DNA extraction is not feasible in every case. We therefore decided to revisit the histological and immunohistochemical features that could reliably distinguish between condyloma and genitofemoral seborrheic keratosis.
Material and methods
A total of 64 patients with 67 lesions involving the genitalia, anal, or perianal area, pubic area, groin, inner thigh, lower abdomen near the pubis, or buttocks near the intergluteal cleft were retrieved (Table 2). The findings from the hematoxylin and eosin slides and immunohistochemical stains are summarized in Table 3.
For lesions that cannot easily be diagnosed using histopathological features, immunohistochemical stains for Ki-67 and p21 were helpful. The most frequently used immunohistochemical stains in the diagnosis of HPV-associated genital intraepithelial neoplasia are those for Ki-67 and p16. Condylomas have been demonstrated to be a proliferative keratinocytic lesion with Ki-67 expression; however, Ki-67 staining was normally present in the basal cell layer of all specimens, and interpretation required skill to distinguish normal from abnormal staining. p16 is a cell-cycle regulatory protein overexpressed in cell nuclei infected by high-risk HPV. It has been found that p16 expression is not helpful with vulvar lesions associated with low-risk HPV infection, including condylomas.
In recent research, another cell-cycle control protein, p21, was noted to be produced in cells infected with low-risk HPV types. Our study demonstrated a similar result. p21 is a cyclin-dependent kinase inhibitor that usually results in G1-phase cell-cycle arrest. One would expect p21 to be not expressed in the proliferation of HPV-infected keratinocytes. In contrast, increased p21 expression has been found in the suprabasal cells of condylomas, and this was confirmed in our study. HPV-infected keratinocytes expressing p21 can still proliferate, as shown by the co-expression of p21 and Ki-67 studies, might be attributed to host cell reaction. The findings are very useful in the diagnosis of condyloma because cells in normal epithelium do not show a concurrent expression of both positive and negative regulatory proteins. Moreover, p21 nuclear staining was present in the upper epidermis without basal cell positivity, which is easier to read compared to Ki-67 staining.
We thank Mr Po-Tsang Chen and Mr Schu-Rern Chern (Department of Medical Research, Mackay Memorial Hospital) and Dr Chih-Ping Chen (Department of Gynecology, Mackay Memorial Hospital) for their help with HPV DNA extraction and sequencing. This work was supported by grants from the Mackay Memorial Hospital MMH-E-9730.