Immunohistochemical analysis of p53 in vulval intraepithelial neoplasia and vulval squamous cell carcinoma

Abstract

Human papillomavirus (HPV) is thought to cause some vulval squamous cell carcinomas (VSCC) by degrading p53 product. Evidence on whether HPV-negative VSCC results from p53 mutation is conflicting. We performed immunohistochemistry for p53 product on 52 cases of lone vulval intraepithelial neoplasia (VIN), 21 cases of VIN with concurrent VSCC and 67 cases of VSCC. We had previously performed HPV detection and loss of heterozygosity (LOH) analyses on these samples. Abnormal p53 immunoreactivity (p53-positive) rates in HPV-positive VSCC and HPV-negative VSCC were 22% (12/54) and 31% (4/13), respectively (Po0.74). p53 immunoreactivity was associated with LOH at the p53 locus (Po0.004), but neither technique differentiated between HPV-positive and HPV-negative VSCC. p53 immunoreactivity was associated with overall LOH rates (p53-positive VSCC vs p53-negative VSCC mean fractional regional allelic loss 0.41 vs 0.24, respectively, Po0.027). LOH at 3p25 was more frequent in p53-positive VSCC cf p53-negative VSCC (70 vs 21%, respectively, Po0.007). There was a trend in p53 disruption associated with invasive disease; HPVpositive VSCC demonstrated more disruption than VIN associated with VSCC, which had more disruption than lone VIN III (22 vs 10 vs 0%, respectively, Po0.005). In all, three out of 73 cases of VIN were p53-positive. All three were associated with concurrent or previous VSCC. Meta-analysis of previous studies revealed significantly more p53 disruption in HPV-negative VSCC cf HPV-positive VSCC (58 vs 33%, respectively; Po0.0001). p53 immunoreactivity/mutation in VIN only appeared in association with VSCC. These data suggest that HPV-independent vulval carcinogenesis does not exclusively require disruption of p53, p53 disruption may work synergistically with LOH at specific loci and p53-positive VIN should be checked carefully for the presence of occult invasion.

MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva

“…31 The role of the regulator of apoptosis, p53, and its mutations, in differentiated VIN and HPV-negative vulvar carcinoma remains to be elucidated. 8,[32][33][34] In conclusion, the use of MIB1 in the diagnosis of premalignant vulvar lesions might prove helpful, especially to discern differentiated VIN from normal vulvar epithelium. In all vulvar premalignancies, the relationship between basal and parabasal cell layers seems to be disturbed.…”

Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

“…21 In contrast, p53 immunohistochemistry signals in differentiated vulvar intraepithelial neoplasia have been described as strong and constant, and often involving more than a single layer of basal-type cells, as observed in the majority (4/5) of our cases (Figures 1b, 2a-c). 12,22,23 The immunohistochemistry signal observed in this context has been presumed to derive from an abnormal (mutated) p53 protein. This argument is supported by: (1) a significant association of p53 immunoreactivity with loss of heterozygosity (LOH) at different chromosomal loci, including the Tp53 locus, 17p13; and (2) the detection of Tp53 mutations in p53 immunohistochemistry-positive atypical lichen sclerosus (or differentiated vulvar intraepithelial neoplasia).…”

Squamous Vulvar Intraepithelial Neoplasia

“…50,54-57 A significant correlation between p53 immunoreactivity and LOH at p53 in VSCC and VIN was found. 57 In an earlier study, it was established that there is a lower frequency of arginine homozygotes in HPV-associated vulvar cancer and patients with VIN than in healthy control subjects, suggesting that arginine polymorphism may confer protection against the development of HPV-associated vulvar neoplasia. 58 p16 protein is a cyclin-dependent kinase (cdk) inhibitor, decelerating the cell cycle by inactivating the cdks that phosphorylate the retinoblastoma suppressor gene protein (pRb).…”