Christopher W. Perrett

TP53 mutations in vulval lichen sclerosus adjacent to squamous cell carcinoma of the vulva

Non-neoplastic epithelial lesions of the vulva (NNEDV) lichen sclerosus (LS) and squamous hyperplasia (SH) have been implicated in the pathogenesis of squamous cell carcinoma of the vulva (SCC). To date, there have been no recognisable precursor lesions for SCC associated with NNEDV. TP53 is the most frequent genetic change in human cancers and can indicate both aetiology and molecular pathogenesis of tumours. A total of 27 SCC patients underwent immunohistochemistry (IHC) and TP53 mutational analysis using microdissection and direct sequencing. There were 19 patients with areas of adjacent epidermis: 17 had NNEDV (four SCCs had more than one adjacent lesion) and two had normal epidermis. In all, 70.4% of the SCCs, 40% LS and 22.2% SH demonstrated overexpression of p53. In total, 77.8% of SCCs, 46.7% of LS and 22.2% SH demonstrated mutations in TP53, with the majority of lesions having a mutation in codon 136. Eight cases were identified where the same mutation was identified in the SCC and in the adjacent area. These data suggest that TP53 mutations develop in NNEDV and are intrinsic to the clonal evolution that leads to SCC. The type of mutation detected is more likely to occur due to endogenous cellular changes rather than exogenous carcinogen exposure.

Estrogen receptor expression in vulvar vestibulitis syndrome

OBJECTIVE A pilot study was performed to investigate the relationship between vulvar vestibulitis syndrome and estrogen receptor expression. STUDY DESIGN Women with a diagnosis of vulvar vestibulitis syndrome had tissue samples taken for vulvar estrogen receptor-alpha expression and this was compared with a control group. RESULTS The study group showed a significant decrease in estrogen receptor expression, and 50% of the samples did not exhibit any receptor expression. CONCLUSION There appears to be a subgroup of women with vulvar vestibulitis syndrome who exhibit abnormal estrogen receptor-alpha expression. This may be helpful in explaining why some women are resistant to medical treatment and may allow treatment to be prescribed more effectively.

Reduced E-cadherin expression correlates with disease progression in Paget's disease of the vulva but not Paget's disease of the breast.

The growth and metastasis of many cancers is due in part to loss of cell–cell adhesion. E-cadherin, plakoglobin and β-catenin are important in cell adhesion. Our aim was to examine the presence of these molecules in Pagets disease of the vulva and Pagets disease of the breast, and to correlate any differences in their expression with the presence of invasive disease or an underlying carcinoma. Sixty-three archival cases of Pagets disease of the vulva, including eight associated with invasive disease, and 23 archival cases of Pagets disease of breast, which included 10 cases with ductal carcinoma in situ alone, four cases with both ductal carcinoma in situ and invasive carcinoma, and five cases with underlying invasive carcinoma alone, were analysed immunohistochemically for expression of E-cadherin, plakoglobin and β-catenin proteins. The respective mRNAs were also detected by in situ hybridisation using digoxigenin-labelled cRNA probes. Seventy-six percent (41/54) of Pagets disease of vulva cases had >50% of Paget cells expressing the E-cadherin protein, compared with 28 % (2/7) of Pagets disease vulva with invasive disease. This result was significant, with a P-value of 0.039. Twenty-five percent (14/55) of the intraepidermal Pagets disease of the vulva cases had >50% of Paget cells expressing the plakoglobin protein, compared with 12% (1/8) of cases of Pagets disease of vulva with invasive disease, and for β-catenin, 9% (5/55) of the non-invasive Pagets disease of the vulva had >50% of Paget cells expressing β-catenin, compared with 12% (1/8) of Pagets disease of the vulva cases with invasive disease. Sixty-five percent (15/23) of the Pagets disease of the breast had >50% of Paget cells expressing E-cadherin, and for plakoglobin and β-catenin it was 17% (4/23) and 28% (6/21), respectively. The results were not significant. The results suggest that reduced expression of E-cadherin may have a role to play in the pathogenesis of invasive Pagets disease of the vulva. Abnormal plakoglobin expression may be involved in the formation of some cases of Pagets of the vulva and the breast.

Expression of cyclin D1 and retinoblastoma protein in Paget's disease of the vulva and breast: an immunohistochemical study of 108 cases.

Aims:  Loss of retinoblastoma protein expression and overexpression of cyclin D1 have been implicated in the development and progression of some cancers. Paget’s disease of the vulva (PDV) and Paget’s disease of the breast (PDB) are uncommon conditions and the pathogenesis of these diseases is still unclear. The aim was to examine the expression of the retinoblastoma and cyclin D1 proteins in PDV and PDB and to correlate any differences between PDV and PDB, and in the presence or absence of an underlying carcinoma.

Angiogenesis in Paget's Disease of the Vulva and the Breast: Correlation with Microvessel Density

Our understanding of the pathogenesis of Pagets disease of the vulva and the breast remains limited. Current evidence supports the fact that angiogenesis plays an important role in the pathogenesis of several diseases. Therefore, we sought to define its role, as correlated with microvessel density, in Pagets disease of the vulva and the breast. Microvessels were analysed using anti-von Willebrand factor antibody in 105 cases of Pagets disease of the vulva and the breast comprising 71 cases of Pagets disease of the vulva, including 8 cases with invasive disease, and 34 cases of Pagets disease of the breast. The latter included 12 cases with DCIS, 5 cases with both DCIS and invasive carcinoma, and 6 with carcinoma alone. Eleven cases had no underlying tumour identified. Increased microvessel density was demonstrated in Pagets disease of the breast with DCIS and with carcinoma alone compared to Pagets disease of the breast alone, P < 0.08 and P < 0.013, respectively. There were no significant differences in microvessel density in the vulval cases. Neovascularisation is an important process in the development of Pagets disease of the breast. Other biological and molecular processes are more involved in the pathogenesis of Pagets disease of the vulva.