A major problem in the diagnosis of verrucous
squamous cell carcinoma is the lack of readily reproducible objective criteria for distinguishing this malignant lesion from reactive epithelial
hyperplasia. Both lesions are characterized by thickened (well-differentiated) squamous epithelium without cellular atypia and subjacent stroma densely infiltrated by lymphocytes and plasma cells. This study was carried out to evaluate the use of cell cycle and apoptosis-related regulatory
proteins in the diagnosis of
verrucous carcinoma. The study materials consisted of representative
formalin-fixed and
paraffin-embedded tissue blocks from 19 cases of
verrucous carcinoma, 18 classic
squamous cell carcinoma, and 14 squamous epithelial
hyperplasia (acanthosis). The immunohistochemical expression of the following of cell cycle and apoptosis-related regulatory
proteins was evaluated using
avidin-
biotin complex detection technique: p16, p21, p53, Ki67, and retinoblastoma gene product (RBGP) (also known as
retinoblastoma protein [pRb]). Expression of Ki67 was detected only in the single basal layer of the epithelium in all 14 cases of acanthosis. In
verrucous carcinoma, Ki67 was detected in basal and suprabasal cells in the lower third of the neoplastic epithelium in 19 of 19 cases (100%). In neoplastic squamous epithelium with frankly invasive
squamous cell carcinoma, Ki67 was diffusely expressed throughout the entire thickness of the epithelium as well as in the underlying invasive
tumor nests. The pattern of p53 expression was similar to that of Ki67 in all the experimental groups, with a Pearson correlation coefficient of 0.98. In addition, immunohistochemical expression of p53 in the hyperplastic squamous epithelium was very weak, in contrast to the more intense immunoreactivity observed in
verrucous carcinoma and classic
squamous cell carcinoma. There was an overlapping in the expression of p16, p21, and RGBP in all the experimental groups, being present in more than half the thickness of the epithelium in 50% to 100% cases in each study group. We therefore conclude that the pattern of Ki67 and p53 expression in
verrucous carcinoma is readily reproducible and distinctly different from that observed in epithelial
hyperplasia and that seen in invasive
squamous cell carcinoma. Thus Ki67, and p53 immunostains are reliable adjuncts that may be helpful in resolving diagnostic problems associated with
verrucous carcinoma.