Outcomes after an excisional procedure for cervical intraepithelial neoplasia in HIV-infected women.

OBJECTIVE: To determine predictors of treatment failure and recurrence after surgical excisional procedures for CIN in HIV-infected women. METHODS: A retrospective cohort study was conducted in which 136 eligible HIV-infected women treated for CIN between 1999 and 2005 were included. Data were abstracted from charts and computer databases. Treatment failures were defined as the presence of CIN 1+ at initial follow-up. Recurrences were defined as the presence of CIN 1+ subsequent to initial normal follow-up. RESULTS: Treatment failure at initial follow-up was common, occurring in 51% of CIN 1 and 55% of CIN 2+. Most lesions detected at treatment failure were high grade (>70%), regardless of the grade of initial lesion. Significant risk factors for treatment failure were loop electrosurgical excision procedure (LEEP) compared to cold knife conization (RR=1.76; 95% CI: 1.15-2.64), and low CD4+ count (p=0.04). Among those with an initial normal clinical evaluation, 55% eventually recurred. As with treatment failure, most lesions detected at recurrence were high grade. Risk factors for recurrence included use of LEEP (hazard ratio [HR]=3.38; 95% CI: 1.55-7.39), higher HIV RNA level, and the presence of positive margins at treatment (HR=6.12; 95% CI: 1.90-19.73). CONCLUSIONS: Most CIN treatment of HIV-infected women studied either failed or resulted in recurrence. Of particular concern, many of these subsequent lesions were high grade. Conization, however, was associated with significantly less failure/recurrence than LEEP. Clinicians treating CIN in HIV-infected women should avoid raising expectations of cure and instead focus on the achievable goal of cancer prevention until there are better therapies for this patient population.

Genetic variants in TAP are associated with high-grade cervical neoplasia.

PURPOSE: The transporter associated with antigen processing (TAP) is essential in assembling MHC-I proteins. Human papillomavirus (HPV) evades immune recognition by decreasing class I MHC cell surface expression through down-regulation of TAP1 levels. Consistent with heterogeneity in MHC expression is the individual variability in clearing detectable HPV infections. Genetic polymorphisms in TAP genes may affect protein structure, function, and the ability to clear HPV infection. EXPERIMENTAL DESIGN: Case-control study of women with cervical intraepithelial neoplasia (CIN) II or III (n = 114) and women without high-grade CIN (n = 366). Five nonsynonymous single nucleotide polymorphisms (SNP) in TAP1 and TAP2 were genotyped using DNA collected in cervicovaginal lavage samples using microsphere array technology (Luminex xMAP). HPV typing was done using a PCR-based system with MY09/MY11 primers. TAP1 and TAP2 SNPs were validated by direct sequencing. RESULTS: Differences in allele distribution between women with high-grade cervical neoplasia and women without was seen for TAP1 I333V (P = 0.02) and TAP1 D637G (P = 0.01). The odds ratios (OR) for CIN III were significantly lower among carriers of the TAP1 I333V polymorphism (OR, 0.28; 95% confidence interval, 0.1-0.8), and TAP1 D637G polymorphism (OR, 0.27; 95% confidence interval, 0.1-0.7). These associations remained significant even after restricting the evaluation to women who were positive for high-risk HPV types. CONCLUSIONS: In addition to the down-regulation of MHC-1 by oncogenic HPV, HPV pathogenesis might be facilitated by polymorphisms in the TAP proteins. Identifying TAP polymorphisms may potentially be used to identify women less susceptible to progression to high-grade CIN and cervical cancer.

Tissue microarray analysis of hormonal signaling pathways in uterine carcinosarcoma.

OBJECTIVES: To evaluate the relationship of hormone (estrogen receptor alpha, estrogen receptor beta, progesterone receptor) and growth factor receptor (insulin-like growth factor receptor, human epidermal growth factor receptor 2) expression with disease progression in uterine carcinosarcoma. STUDY DESIGN: Immunohistochemistry was performed on tissue arrays using standard methodology. Differences between groups were evaluated by the Wilcoxon rank-sum test. Interactions between tumor stage and receptor expression were determined by linear trend analysis. RESULTS: Compared with normal endometrium, carcinosarcomas exhibited low estrogen receptor alpha and progesterone receptor expression (all P < .01), but overexpressed estrogen receptor beta (P = .02). Estrogen receptor beta expression increased in advanced stage disease (P = .02). Insulin-like growth factor receptor expression was lower in carcinosarcoma compared with normal endometrium (P = .01). Human epidermal growth factor receptor 2 expression was elevated and increased with disease progression (P < .01). CONCLUSION: In uterine carcinosarcoma, estrogen receptor beta expression is elevated and increases with disease progression, whereas estrogen receptor alpha and progesterone receptor are suppressed. Human epidermal growth factor receptor 2 expression is increased, whereas insulin-like growth factor receptor is lower than in normal endometrium. These data support a potential role for estrogen receptor beta in disease progression via crosstalk with human epidermal growth factor receptor 2.

Serum CA125 predicts extrauterine disease and survival in uterine carcinosarcoma.

OBJECTIVE: The purpose of this study was to determine the clinical utility of CA125 measurement in patients with uterine carcinosarcoma (CS). METHODS: Ninety-five consecutive patients treated for CS at a single institution were identified. All 54 patients who underwent preoperative CA125 measurement were included in the study. Data were abstracted from the medical records. Tests of association between preoperative CA125 and previously identified clinicopathologic prognostic factors were performed using Fisher's exact test and Pearson chi-square test. To evaluate the relationship of CA125 elevation and survival, a Cox proportional hazard model was used for multivariate analysis, incorporating all of the prognostic factors identified by univariate analysis. RESULTS: Preoperative CA125 was significantly associated with the presence of extrauterine disease (P<0.001), deep myometrial invasion (P<0.001), and serous histology of the epithelial component (P=0.005). Using univariate survival analysis, stage (HR=1.808, P=0.004), postoperative CA125 level (HR=9.855, P<0.001), and estrogen receptor positivity (HR=0.314, P=0.029) were significantly associated with survival. In the multivariate model, only postoperative CA125 level remained significantly associated with poor survival (HR=5.725, P=0.009). CONCLUSION: Preoperative CA125 elevation is a marker of extrauterine disease and deep myometrial invasion in patients with uterine CS. Postoperative CA125 elevation is an independent prognostic factor for poor survival. These findings indicate that CA125 may be a clinically useful serum marker in the management of patients with CS.