Alcoholism and risk for cancer of the cervix uteri, vagina, and vulva. (33/364)

We conducted a population-based cohort study to analyze the risk of developing cancers of the female genitals among 36,856 patients with a hospital discharge diagnosis of alcoholism (ICD-7: 307, 322; ICD-8: 291, 303; ICD-9: 291, 303, 305A) in Sweden between 1965 and 1995. The follow-up was done by linkages of national registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed based on nationwide specific cancer rates. The first year of follow-up was excluded from all analyses to minimize the impact of selection bias. We found that alcoholic women had excess risks for in situ cervical cancer (SIR, 1.7; 95% CI, 1.6-1.9), for invasive cervical cancer (SIR, 2.9; 95% CI, 2.4-3.5), and for cancer of the vagina (SIR, 4.6; 95% CI, 2.2-8.5) but not for cancer of the vulva (SIR, 1.0; 95% CI, 0.4-2.0). The fact that alcoholics had an excess risk also for the in situ cancer suggests that the observed excess in invasive cervical cancer may not only be attributable to less use of Pap smear screening among them. The alcoholic women may be at higher risk for the progression from human papillomavirus infection to a malignant lesion for lifestyle-related reasons (promiscuity, smoking, use of contraceptive hormones, and dietary deficiencies). We conclude that alcoholic women are at high risk for in situ and invasive cervical cancer and for cancer of the vagina.  (+info)

A clinico-pathological study of vulval dermatoses. (34/364)

A long-term review of 108 women suffering from various forms of vulval dermatosis is described and a detailed analysis of those with chronic hypertrophic vulvitis, lichen sclerosus et atrophicus, and neurodermatitis is made. One case of neurodermatitis and two cases of lichen sclerosus progressed to carcinoma but no case of chronic hypertrophic vulvitis became malignant. It is possible that vulval dermatoses occur more commonly in the nulliparous than in the parous women and there is a slight preponderance of women who are blood group A. It is suggested that the term "leukoplakia" should be abandoned and that vulval lesions should be described in precise and meaningful histological terms.  (+info)

Clinical and molecular responses in high-grade intraepithelial neoplasia treated with topical imiquimod 5%. (35/364)

OBJECTIVE: To assess the clinical and molecular response of patients with recurrent high-grade vulvar, vaginal, or cervical intraepithelial neoplasia treated with topical 1-2(2-methylpropyl)-1H-imidazo [4,5-c] quinolin-4-amine (imiquimod) cream 5%, an immune response modifier with known efficacy in the treatment of external genital warts. METHODS: This is the first case series in the peer-reviewed literature reporting the use of imiquimod in high-grade intraepithelial neoplasia of the lower genital tract. Eight patients with high-grade intraepithelial neoplasia were treated with imiquimod in the gynecological oncology clinic and the HIV gynecology clinic at The University of Texas Medical Branch at Galveston. Frozen biopsies were available for RNA extraction on four patients before and after therapy. Using semiquantitative reverse transcription-PCR, we measured RNA levels of IFNs alpha and gamma, 2',5'-oligoadenylate synthetase, as well as CD4 and CD8 lymphocyte markers. RESULTS: Of the patients treated, four had complete responses, two had partial responses, one progressed, and one did not tolerate the therapy. Of the four complete responders, two remained disease-free (mean follow-up, 33 months). 2',5'-Oligoadenylate synthetase RNA expression showed an increased trend after therapy. CONCLUSIONS: These results obtained in this small and heterogeneous group merit further study in the use of topical 5% imiquimod use in the treatment of intraepithelial neoplasia. An important mechanism of action of imiquimod may involve 2',5'-oligoadenylate synthetase antiviral activity.  (+info)

p73 is over-expressed in vulval cancer principally as the Delta 2 isoform. (36/364)

p73 was studied in squamous cancers and precursor lesions of the vulva. Over-expression of p73 occurred commonly in both human papillomavirus (HPV)-positive and -negative squamous cell cancers (SCC) and high-grade premalignant lesions. Whereas expression in normal vulval epithelium was detected only in the basal and supra-basal layers, expression in neoplastic epithelium increased with grade of neoplasia, being maximal at both protein and RNA levels in SCC. p73 Delta 2 was the principal over-expressed isoform in the majority of cases of vulval SCC and often the sole form expressed in SCC. Over-expression of p73 was associated with expression of HPV-encoded E7 or with hypermethylation or mutation of p16(INK4a) in HPV-negative cases. There was a close correlation between expression of p73 and p14(ARF) in cancers with loss of p53 function. The frequent over-expression of p73 Delta 2 in neoplastic but not normal vulval epithelium, and its co-ordinate deregulation with other E2F-1 responsive genes suggests a role in the oncogenic process.  (+info)

The prognostic value of immunohistochemically detected CD44v3 and CD44v6 expression in patients with surgically staged vulvar carcinoma: a multicenter study. (37/364)

BACKGROUND: Isoforms of the adhesion molecule CD44 are involved in carcinogenesis and the metastatic cascade of tumor cells by increasing the affinity of malignant cells to their extracellular matrix. Preliminary data with respect to the prognostic value of the CD44 isoforms CD44v3 and CD44v6 in patients with vulvar carcinoma showed promising results. The current multicenter study aimed to determine the prognostic value of CD44v3 and CD44v6 in patients with surgically staged vulvar carcinoma. METHODS: Expression of CD44v3 and CD44v6 in vulvar carcinoma tissue was assessed by immunohistochemistry. Immunohistochemical staining was performed according to established protocols. Results were correlated to clinical data. RESULTS: A positive CD44v3 and CD44v6 staining was detected in 33.3% (33 out of 99) and 39.4% (39 out of 99) of the tumor samples, respectively. Overexpression of CD44v6 was associated with an impaired prognosis with respect to disease-free survival (P = 0.01) and overall survival (P = 0.04). Multivariate analysis showed that CD44v6 provided prognostic information with respect to disease-free survival (P = 0.001) and overall survival (P = 0.005) independently of the two established prognosticators, tumor stage and groin lymph node involvement. Overexpression of CD44v3 had no impact on patient survival. CONCLUSIONS: The current multicenter study, involving a large series of patients with surgically staged vulvar carcinoma, allowed for multivariate survival analysis and showed that CD44v6 confers prognostic information in addition to that provided by the established clinicopathologic parameters of tumor stage and lymph node status.  (+info)

Analysis of CHK2 in vulval neoplasia. (38/364)

Structure and expression of the Rad53 homologue CHK2 were studied in vulval neoplasia. We identified the previously described silent polymorphism at codon 84 (A>G at nucleotide 252) in the germ-line of six out of 72, and somatic mutations in two out of 40 cases of vulval squamous cell carcinomas and none of 32 cases of vulval intraepithelial neoplasia. One mutation introduced a premature stop codon in the kinase domain of CHK2, whereas the second resulted in an amino acid substitution in the kinase domain. The two squamous cell carcinomas with mutations in CHK2 also expressed mutant p53. A CpG island was identified close to the putative CHK2 transcriptional start site, but methylation-specific PCR did not detect methylation in any of 40 vulval squamous cell carcinomas, irrespective of human papillomavirus or p53 status. Consistent with this observation, no cancer exhibited loss of CHK2 expression at mRNA or protein level. Taken together, these observations reveal that genetic but not epigenetic changes in CHK2 occur in a small proportion of vulval squamous cell carcinomas.  (+info)

Monoclonal gamma-T-cell receptor rearrangement in vulvar lichen sclerosus and squamous cell carcinomas. (39/364)

Risk factors for vulvar squamous cell carcinoma (SCC) are human papilloma virus (HPV) infections and lichen sclerosus (LS). The significance of monoclonal gamma-T-cell receptor (gamma-TCR) rearrangement in the lymphoid infiltrate of LS and the consequence for vulvar carcinogenesis is unknown. One hundred sixty-one biopsies of vulvar LS and SCC, with and without LS, were examined for monoclonal gamma-TCR rearrangement and HPV16 expression, and for the expression of B- and T-cell markers and fascin. Monoclonal gamma-TCR rearrangement was identified in 8 of 17 patients with LS and 11 of 21 patients with SCC arising in LS with only occasional HPV16 DNA detection. None of the 19 SCC without LS showed monoclonal gamma-TCR rearrangement, but 14 of 19 patients had strong HPV16 detection. The lichenoid infiltrate of LS with germline configuration consisted predominantly of T cells (CD8 > CD4), along with numerous B cells. However, in biopsies with monoclonally rearranged gamma-TCR, CD4-positive T cells dominated along with B cells and fascin-positive cells in the lichenoid infiltrate and in deeply located lymphocyte aggregates (LAs). These LAs additionally contained fascin-positive dendritic cells with only individual CD8, CD57, and granzyme-positive cells. LAs in biopsies with germline configuration demonstrated numerous T cells (CD8 >CD4), but only single peripheral B cells, CD57, and fascin-positive lymphocytes. Our data suggest that monoclonal gamma-TCR rearrangement is characteristic for and limited to LS and SCC arising in LS, raising the question for a LS-associated antigen. We interpret B cells, CD4-positive T cells, and fascin-expressing dendritic cells within LS as a cellular immune response to antigen or proliferating T-cell clones. The resulting local immune dysregulation in LS may provide a permissive environment for the development of a SCC.  (+info)

Coincident inactivation of 14-3-3sigma and p16INK4a is an early event in vulval squamous neoplasia. (40/364)

The structure and expression of 14-3-3 sigma(sigma) was analysed in squamous carcinomas (SCC) of the vulva and in the vulval pre-malignant lesion vulval intraepithelial neoplasia (VIN). Sequence analysis of the sigma coding region did not detect mutations in any case of SCC or VIN III and loss of heterozygosity (LOH) occurred in only 2 out of 27 informative cases. In contrast to the absence of genetic change, methylation-specific PCR (MSP) analysis revealed dense CpG methylation within the sigma gene in approximately 60% of cases of vulval SCC, but methylation was not detected in matched, normal epithelial tissue. Methylation was associated in all cases with reduced or absent expression of sigma mRNA. There was no correlation between sigma methylation and HPV or p53 status. Analysis of pre-malignant vulval intraepithelial neoplasia (VIN) revealed that sigma methylation was detectable early in neoplastic development. Co-incident methylation, accompanied by loss of expression, of sigma and p16INK4a was commonly detected in both SCC and VIN III, suggesting that epigenetic silencing of these two genes is an early and important event in vulval neoplasia.  (+info)