p16(INK4a) is superior to high-risk human papillomavirus testing in cervical cytology for the prediction of underlying high-grade dysplasia.

BACKGROUND: The primary goal of this study was to compare the clinical performance of an optimized and rigorously controlled immunocytochemical (ICC) assay for p16(INK4a) to high-risk (HR) human papillomavirus (HPV) detection by polymerase chain reaction (PCR) as diagnostic adjuncts for cytology specimens from colposcopy patients. METHODS: : The study included 403 cervical cytology specimens collected within 3 months of colposcopy. The colposcopic impression and cervical biopsy diagnosis served as the standards for correlation with cytological, p16(INK4a), and HPV data. p16(INK4a) was evaluated using an immunoperoxidase-based assay that was linear over 4 logs for the detection of HeLa-spiked positive control cytology specimens, using a threshold for positive test results that was based on receiver operating characteristic curve analysis. HR-HPV was detected by multiplex PCR using genotype-specific primers. RESULTS: : In all combined diagnostic categories (negative for intraepithelial lesion and malignancy, atypical glandular cells, atypical squamous cells of undetermined significance, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion), the p16(INK4a) ICC and HR-HPV assays, respectively, had sensitivity of 81.7% and 83.3% (P = .81) and specificity of 78.1% and 50.9% (P < .001) for the detection of underlying > or =grade 2 cervical intraepithelial neoplasia (CIN) lesions on biopsy. Furthermore, the positive predictive value of p16(INK4a) ICC was greater than that of HR-HPV for patients with biopsies > or =CIN-2 (41.2% and 24.2%, respectively, P = .001). CONCLUSIONS: : This p16(INK4a) immunocytochemical assay has superior specificity but similar sensitivity to HR-HPV testing to predict underlying high-grade dysplastic lesions in patients who are referred for colposcopy. The determination of the overall performance characteristics of p16(INK4a) immunocytochemistry, as an independent test or in combination with HPV testing in low-risk screening populations, however, will require subsequent large-scale prospective clinical trials.

Effect of tamoxifen on endometrial histology, hormone receptors, and cervical cytology: a prospective study with follow-up.

OBJECTIVES: Our major hypothesis for these studies was that tamoxifen's varied effects on the endometrium might be due in part to differences in effect on estrogen and progesterone receptors [ER, progesterone receptor isoform A (PRA), and progesterone receptor isoform B (PRB)]. We aimed to evaluate the changes in histology in serial endometrial biopsies (Em bx), Papanicolaou smears (Pap smears), and endometrial ultrasounds as well as changes in the expression of ER, PRA, and PRB in response to tamoxifen. We propose that understanding and correlating the dynamics of receptor expression with histologic and cytologic changes will help us better understand the effect of tamoxifen on the endometrium and its role in the development of endometrial carcinoma in some patients. METHODS: Forty-two patients to be started on tamoxifen underwent a pretreatment Em bx and Pap smear. Follow-up serial Em bxs and Pap smears were obtained at sixth month and then at yearly intervals for up to 6 biopsies per case. Maturation indices (MIs) were determined on the Pap smears, and ER, PRA, and PRB immunostains were performed on the biopsies. Follow-up data is for a maximum of 10 years. Trends in changes in endometrial histology were analyzed and when atrophic or inactive endometrium changed to proliferative endometrium on treatment it was considered to be an increase in estrogen effect and the vice versa changes as a decrease in estrogen effect. RESULTS: None of the subjects developed hyperplasia or malignancy. Two patients' Em bx demonstrated atypical cells associated with eosinophilic metaplasia, but subsequent biopsies had no atypia. Of the 42 patients, 37 had serial Em bxs in which evaluation for trends could be performed. Twelve of 37 (32.4%) had an overall decrease in estrogen effect on endometrial histology with another 12/37 (32.4%) showing no estrogenic effect on endometrial histology. Six of 37 patients (16.2%) showed an increased estrogen effect on endometrial histology. Seven of 37 (18.9%) had variable endometrial histology with no definable pattern. There was a statistically significant increase in PRA expression compared with baseline as time progressed (P<0.05). The PRB showed a contrasting significant decrease in expression at 2.5 and 3.5 years (P<0.05). There was no significant change in ER expression over the course of the study (P>0.05). Seven of 12 (58.3%) with a decreased estrogenic effect on endometrial histology had a concordant decrease in PRB expression. Seven of 12 (58.3%) with no change in endometrial histology also had a concordant decrease in PRB expression. Comparing the MI of Pap smears with histologic activity of the endometrium revealed minimal correlation between the two. However, in the patients with an increased estrogen effect on endometrial histologic activity, there was no correlation with the MI. Additionally, 57% of patients showed no correlation between endometrial histologic activity and ultrasound findings. CONCLUSIONS: Tamoxifen had an antiestrogenic or neutral effect on endometrial histology and Pap smears of most subjects, but estrogenic, or variable effects were also observed in a minority of patients. Tamoxifen treatment was accompanied by an uncoupling of the regulation of PRA and PRB expression without effect on ER expression. Overall, expression of PRB decreased whereas that of PRA increased.