Discovery and validation of methylation markers for endometrial cancer.

The prognosis of endometrial cancer is strongly associated with stage at diagnosis, suggesting that early detection may reduce mortality. Women who are diagnosed with endometrial carcinoma often have a lengthy history of vaginal bleeding, which offers an opportunity for early diagnosis and curative treatment. We performed DNA methylation profiling on population-based endometrial cancers to identify early detection biomarkers and replicated top candidates in two independent studies. We compared DNA methylation values of 1,500 probes representing 807 genes in 148 population-based endometrial carcinoma samples and 23 benign endometrial tissues. Markers were replicated in another set of 69 carcinomas and 40 benign tissues profiled on the same platform. Further replication was conducted in The Cancer Genome Atlas and in prospectively collected endometrial brushings from women with and without endometrial carcinomas. We identified 114 CpG sites showing methylation differences with p values of ≤ 10(-7) between endometrial carcinoma and normal endometrium. Eight genes (ADCYAP1, ASCL2, HS3ST2, HTR1B, MME, NPY and SOX1) were selected for further replication. Age-adjusted odds ratios for endometrial cancer ranged from 3.44 (95%-CI: 1.33-8.91) for ASCL2 to 18.61 (95%-CI: 5.50-62.97) for HTR1B. An area under the curve (AUC) of 0.93 was achieved for discriminating carcinoma from benign endometrium. Replication in The Cancer Genome Atlas and in endometrial brushings from an independent study confirmed the candidate markers. This study demonstrates that methylation markers may be used to evaluate women with abnormal vaginal bleeding to distinguish women with endometrial carcinoma from the majority of women without malignancy.

Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan.

Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.

Reproducibility of biopsy diagnoses of endometrial hyperplasia: evidence supporting a simplified classification.

BACKGROUND: Identifying which categories in the World Health Organization classification of endometrial hyperplasia contribute to suboptimal reproducibility is clinically important. METHODS: A 2-member panel reviewed 209 endometrial biopsy/curettage specimens originally diagnosed as incident endometrial hyperplasia as part of a progression study. Original diagnoses included the following: disordered proliferative endometrium, simple hyperplasia, complex hyperplasia, and atypical hyperplasia; panel diagnoses also included negative and carcinoma. We assessed percentage agreement and kappa statistics+/-standard errors (K+/-SE). RESULTS: Original and panel diagnoses (combining negative with disordered proliferative endometrium; atypical hyperplasia with carcinoma) agreed for 34.9% of biopsies (K-unweighted+/-SE=0.18+/-0.03; K-weighted+/-SE=0.27+/-0.04). Panelists' diagnoses agreed (using 6 categories) for 51.7% of biopsies, corresponding to K-unweighted+/-SE=0.37+/-0.03, improving with weighting to K-weighted+/-SE=0.63+/-0.05. Reproducibility based on a 2-tier classification ([negative, disordered proliferative endometrium, simple hyperplasia, or complex hyperplasia] versus [atypical hyperplasia or carcinoma]) increased agreement between original and panel diagnoses to 82.8%, K-unweighted+/-SE=0.37+/-0.06, and between panelists to 87.0%, K-unweighted+/-SE=0.63+/-0.07. Agreement between panelists at a cutpoint of complex hyperplasia and more severe versus simple hyperplasia or less severe was 88.0%, K-unweighted+/-SE=0.72+/-0.07. CONCLUSIONS: Developing and prospectively testing a binary system of classifying endometrial hyperplasia on endometrial biopsy may aid efforts to improve interobserver reproducibility.

Abnormal outcomes following cervical cancer screening: event duration and health utility loss.

BACKGROUND: For decision analytic models, little empirical data are available from which to model the amount of time women spend with various cervical cytologic and histologic diagnoses following an abnormal Pap smear or the associated loss in quality-adjusted life-years (QALYs). METHODS: The authors retrospectively examined administrative and cytopathology data for women with abnormal routine cervical smears within the Kaiser Permanente Northwest (Portland, OR) health plan during 1998. Data were examined through the conclusion of follow-up, with final outcomes categorized as cervical intraepithelial neoplasia (CIN) grades 1 to 3 (n = 201) or a false-positive result (n = 722) if no CIN or cancer was detected on follow-up. CIN outcomes were assigned according to the initial grade of dysplasia observed during the care episode in the primary analysis. The number of months spent with various cytologic and histologic diagnoses during the course of follow-up was tabulated, and utility weights were assigned using data from a prior study reporting time tradeoff scores for cervical health states. RESULTS: The average total duration of follow-up was between 18 and 22 months for women with CIN, compared with 10 months for a false-positive Pap smear. The number of months spent with either an abnormal cytologic or histologic diagnosis was greater (P = 0.01) for women with CIN 1 (12.6 months) than CIN 3 (9.2 months), although this relationship was reversed for time spent receiving negative follow-up Pap smears and biopsies to rule out the presence of CIN and cancer. Total QALY losses per episode of care were estimated to be 0.11 for all 3 grades of CIN and 0.04 for a false-positive Pap smear. CONCLUSIONS: The health and psychosocial burdens associated with follow-up for abnormal Pap smears translate into tangible QALY losses in a decision analytic context, with women receiving many months of follow-up and a variety of cytologic and histologic diagnoses over the course of a care episode.

Polycyclic aromatic hydrocarbon-DNA adducts in cervix of women infected with carcinogenic human papillomavirus types: an immunohistochemistry study.

Among women infected with carcinogenic human papillomavirus (HPV), there is a two- to five-fold increased risk of cervical precancer and cancer in women who smoke compared to those who do not smoke. Because tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons (PAHs), it was of interest to examine human cervical tissue for PAH-DNA adduct formation. Here, we measured PAH-DNA adduct formation in cervical biopsies collected in follow-up among women who tested positive for carcinogenic HPV at baseline. A semi-quantitative immunohistochemistry (IHC) method using antiserum elicited against DNA modified with r7,t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) was used to measure nuclear PAH-DNA adduct formation. Cultured human cervical keratinocytes exposed to 0, 0.153, or 0.331microM BPDE showed dose-dependent increases in r7,t8,t9-trihydroxy-c-10-(N(2)deoxyguanosyl)-7,8,9,10-tetrahydro-benzo[a]pyrene (BPdG) adducts. For BPdG adduct analysis, paraffin-embedded keratinocytes were stained by IHC with analysis of nuclear color intensity by Automated Cellular Imaging System (ACIS) and, in parallel cultures, extracted DNA was assayed by quantitative BPDE-DNA chemiluminescence immunoassay (CIA). For paraffin-embedded samples from carcinogenic HPV-infected women, normal-appearing cervical squamous epithelium suitable for scoring was found in samples from 75 of the 114 individuals, including 29 cases of cervical precancer or cancer and 46 controls. With a lower limit of detection of 20 adducts/10(8) nucleotides, detectable PAH-DNA adduct values ranged from 25 to 191/10(8) nucleotides, with a median of 75/10(8) nucleotides. PAH-DNA adduct values above 150/10(8) nucleotides were found in eight samples, and in three samples adducts were non-detectable. There was no correlation between PAH-DNA adduct formation and either smoking or case status. Therefore, PAH-DNA adduct formation as measured by this methodology did not appear related to the increased risk of cervical precancer and cancer among carcinogenic HPV-infected smokers.

A prospective study of high-grade cervical neoplasia risk among human papillomavirus-infected women.

BACKGROUND: In case-control studies, smoking, parity, and oral contraceptive use have been associated with an increased risk of cervical intraepithelial neoplasia grade 3 (CIN3) and cervical cancer among women who are infected with oncogenic human papillomavirus (HPV). However, these potential risk factors have not been adequately studied in prospective studies. METHODS: We studied 1812 women who were enrolled in a 10-year prospective study of cervical neoplasia at Kaiser Permanente in Portland, Oregon, and who at enrollment had tested positive for oncogenic HPV DNA and had responded to a questionnaire that included questions on smoking, oral contraceptive use, and parity. Absolute risks and crude relative risks (RRs) with 95% confidence intervals (CIs) for CIN3 or cervical cancer were computed for three time intervals (0-8, 9-68, and 69-122 months after enrollment) using the Kaplan-Meier method. Conditional logistic regression models were used to control for factors that may have influenced our risk estimates, specifically the cytologic interpretation of baseline Pap smear, number of Pap smears during follow-up, age at enrollment, age at prediagnosis visit, and age at diagnosis. All statistical tests were two-sided. RESULTS: Oral contraceptive use and parity were not associated with risk of CIN3 or cervical cancer. Former smokers, women who smoked less than one pack of cigarettes per day, and women who smoked one or more packs per day had crude RRs for CIN3 or cervical cancer for the entire follow-up period of 2.1 (95% CI = 1.1 to 3.9), 2.2 (95% CI = 1.2 to 4.2), and 2.9 (95% CI = 1.5 to 5.6), respectively, compared with never smokers. In the multivariable model, former smokers, women who smoked less than one pack/day, and women who smoked one or more packs/day had RRs of 3.3 (95% CI = 1.6 to 6.7), 2.9 (95% CI = 1.4 to 6.1), and 4.3 (95% CI = 2.0 to 9.3), respectively, for CIN3 or cervical cancer compared with never smokers. CONCLUSIONS: Smoking is associated with an increased risk of invasive cervical cancer in women who are infected with oncogenic HPV. Subsequent studies should examine the role of smoking in the multistage pathogenesis of cervical cancer.

Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis.

BACKGROUND: Annual Pap smear screening has been favored over less frequent screening in the United States to minimize the risk of cervical cancer. We evaluated whether simultaneous screening with a Pap test and human papillomavirus (HPV) testing is useful for assessing the risk for cervical intraepithelial neoplasia (CIN) 3 or cervical cancer. METHODS: We enrolled 23 702 subjects in a study of HPV infection at Kaiser Permanente, Northwest Division, Portland, OR. Data were analyzed for 20 810 volunteers who were at least 16 years old (mean = 35.9 years) with satisfactory baseline Pap tests and suitable samples for HPV testing. Women were followed for up to 122 months (from April 1, 1989, to June 30, 1999) to determine the risk for histopathologically confirmed CIN3 or cancer. RESULTS: Among 171 women with CIN3 or cancer diagnosed over 122 months, 123 (71.9%, 95% confidence interval [CI] = 65.2% to 78.7%) had baseline Pap results of atypical squamous cells or worse and/or a positive HPV test, including 102 (86.4%, 95% CI = 80.3% to 92.6%) of the 118 cases diagnosed within the first 45 months of follow-up. During this 45-month period, the cumulative incidence of CIN3 or cancer was 4.54% (95% CI = 3.61% to 5.46%) among women with a Pap test result of atypical squamous cells or worse, positive HPV tests, or both compared with 0.16% (95% CI = 0.08% to 0.24%) among women with negative Pap and HPV tests. Age, screening behavior, a history of cervical cancer precursors, and a history of treatment for CIN minimally affected results. CONCLUSIONS: Negative baseline Pap and HPV tests were associated with a low risk for CIN3 or cancer in the subsequent 45 months, largely because a negative HPV test was associated with a decreased risk of cervical neoplasia. Negative combined test results should provide added reassurance for lengthening the screening interval among low-risk women, whereas positive results identify a relatively small subgroup that requires more frequent surveillance.

What makes a good nurse? Views of patients and carers.

Ninety-six patients, service users and carers were consulted about what makes a good nurse in an exercise designed to inform a Diploma in Nursing curriculum at the University of Nottingham, but the results are relevant across the nursing profession. Good communication, respect, appropriate appearance, attention to hygiene and detailed knowledge of patients' conditions and treatments were the areas that generated the most frequent comments. Participants give an insight into the experiences of care they had received and by implication provide a worrying indictment of current nursing practice. The authors recommend that the findings be used to inform nursing curricula and to highlight patient and carer needs for a quality nursing service.

Semiquantitative human papillomavirus type 16 viral load and the prospective risk of cervical precancer and cancer.

We examined whether higher human papillomavirus type 16 (HPV16) viral load predicted risk of cervical intraepithelial neoplasia 3 (CIN3) or cancer (together termed > or =CIN3) within a cohort of 20,810 women followed for 10 years with cytologic screening. Semiquantitative viral load for HPV16 was measured on baseline cervicovaginal specimens using a type-specific hybridization probe test with signal amplification. An increased risk of > or =CIN3 associated with higher HPV16 viral load was found only among cytologically negative women in early follow-up, suggesting that these cases were related to the detection of prevalent lesions missed at baseline. Women with higher HPV16 viral load were more likely to undergo ablative treatment during follow-up than those with lower viral load (P(trend) = 0.008), possibly diminishing any additional risk for > or =CIN3 attributable to higher HPV16 viral loads.

Pap screening in a U.S. health plan.

The U.S. Preventive Services Task Force recommends cervical cancer screening begin with the onset of sexual activity and be repeated at least every 3 years until age 65. Previous studies examining the annual utilization and frequency of Pap screening have relied on patient self-report, found to be less reliable than medical records and administrative data. We estimate the age-specific rate and frequency of Pap screening in a U.S. health plan using 1998-2002 administrative data on 150,052 female enrollees within the Kaiser Permanente Northwest health plan, Portland, OR. We analyze the age-specific rate of cervical and vaginal Pap screening and age-specific proportion of routinely screened women receiving cervical screening at various yearly intervals. Of the enrolled women, 31.2% received a Pap smear in 1998, with utilization highest for ages 25-29 (62.4%). Among routinely screened women, 36% were estimated to receive annual cervical smears, versus 22% biennial, 13% triennial, and 29% less frequent screening. Less frequent screening was observed with increasing age. These are the first age-specific estimates of Pap screening frequency and annual utilization in a general healthcare setting, derived from administrative data, rather than self-report. Overall Pap utilization was lower than found in national surveys based on self-report. Despite limited evidence of benefit from more frequent screening, a substantially higher proportion of women was found to receive annual rather than either biennial or triennial screening. Sporadic screening was also more prevalent than expected based on prior self-reported data. Further opportunities exist for improving screening adherence, even within traditionally less vulnerable populations.

Participation in clinical supervision (PACS): an evaluation of student nurse clinical supervision facilitated by mental health service users.

This paper discusses an innovative learning approach in which people having experience of mental health services facilitated humanistic clinical supervision with groups of student nurses in the classroom. A four-day course of preparation for the role of supervisor is described and the results of subsequent clinical supervision sessions are analysed. Seven service users who had previous experience of teaching students in the classroom and fifty students on a Diploma/BSc in mental health nursing course participated in the project, which was evaluated through focus groups. The results indicated that the service user supervisors appreciated the skills they had gained on the course and felt that they were more appropriate than lecturers to facilitate clinical supervision sessions. Some students expressed initial uncertainty about the appropriateness of service users as supervisors but as changes to the pedagogical process of supervision were made and the supervisors gained more experience and confidence, students expressed greater satisfaction. The authors conclude that clinical supervision facilitated by service users who have preparation and continual support can add considerable value to the learning experience of student nurses.

Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up.

PURPOSE: To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction. METHODS: Cervicovaginal lavages collected from 19,512 women attending a health maintenance program were retrospectively tested for HPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a research test. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance (ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively with routine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervical intraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated. RESULTS: A baseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up than a normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who would develop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+ 10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevated risk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk of CIN3+ compared with women with a low-grade squamous intraepithelial Pap. CONCLUSION: HPV testing to rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16 and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficient algorithm for cervical cancer screening, especially in women age 30 years or older.

A clinical practice teaching and learning observatory: The use of videoconferencing to link theory to practice in nurse education.

This paper discusses the implementation and evaluation of an innovative approach using videoconferencing to help student nurses to link theory to practice. A Clinical Practice Teaching and Learning Observatory (CP-TLO) was established to provide a synchronous learning opportunity for students in a university classroom observing and interacting with a specialist nurse, patients and carers in a diabetes clinic. Thirty eight students on a BSc/Diploma in Nursing course in the United Kingdom participated in the project which involved partnership working between lecturers, clinical and management staff, IT personnel and patients and their relatives. Student evaluations described the CP-TLO as an enjoyable and valuable learning experience. It is concluded that whilst the project focussed on nurse education and a diabetes clinic, videoconferencing between clinical placements and a classroom has the potential to strengthen links between theory and practice in other areas of nursing and health and social care professions.

A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study.

BACKGROUND: Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 3 and cancer (≥CIN3). Adding HPV testing to cytology is recommended for women ≥30 but long-term prospective studies of HPV testing are rare. METHODS: Beginning in 1989-1990, ~20,000 women in a prepaid health maintenance organization (median age = 34) were followed passively by recommended annual cytology. We tested archived cervicovaginal lavage specimens collected at enrollment, primarily by MY09-MY11 PCR-based methods, for carcinogenic HPV types. We calculated positive and negative predictive values for the entire study period, and Kaplan-Meier estimates of cumulative probability for ≥CIN3, up to 18 years of follow-up. RESULTS: We observed 47 cases of invasive cervical cancer during the study period, and 156 cases of CIN3. Predictive values and Kaplan-Meier analyses yielded the same conclusions. In women 30 and older, the reassurance against ≥CIN3 following a single negative HPV test was long-lasting (cumulative probability = 0.7% during follow-up). In this age group, a single HPV test (positive vs. negative, hazard ratio of 8.5, 95% CI = 4.8-15.1) provided greater long-term risk stratification than a single cytologic result (abnormal vs. normal, HR = 2.9, 95% CI = 1.2-6.6). The risk for ≥CIN3 was higher for HPV16 than for the average of the other carcinogenic types (hazard ratio = 2.7). CONCLUSION AND IMPACT: The data from this cohort study show the long-term predictive value of HPV testing, particularly in women ≥30, and a possible role for distinguishing particularly carcinogenic types like HPV16.

Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia.

PURPOSE The severity of endometrial hyperplasia (EH)-simple (SH), complex (CH), or atypical (AH)-influences clinical management, but valid estimates of absolute risk of clinical progression to carcinoma are lacking. Materials and METHODS We conducted a case-control study nested in a cohort of 7,947 women diagnosed with EH (1970-2002) at one prepaid health plan who remained at risk for at least 1 year. Patient cases (N = 138) were diagnosed with carcinoma, on average, 6 years later (range, 1 to 24 years). Patient controls (N = 241) were matched to patient cases on age at EH, date of EH, and duration of follow-up, and they were counter-matched to patient cases on EH severity. After we independently reviewed original slides and medical records of patient controls and patient cases, we combined progression relative risks (AH v SH, CH, or disordered proliferative endometrium [ie, equivocal EH]) from the case-control analysis with clinical censoring information (ie, hysterectomy, death, or left the health plan) on all cohort members to estimate interval-specific (ie, 1 to 4, 5 to 9, and 10 to 19 years) and cumulative (ie, through 4, 9, and 19 years) progression risks. Results For nonatypical EH, cumulative progression risk increased from 1.2% (95% CI, 0.6% to 1.9%) through 4 years to 1.9% (95% CI, 1.2% to 2.6%) through 9 years to 4.6% (95% CI, 3.3% to 5.8%) through 19 years after EH diagnosis. For AH, cumulative risk increased from 8.2% (95% CI, 1.3% to 14.6%) through 4 years to 12.4% (95% CI, 3.0% to 20.8%) through 9 years to 27.5% (95% CI, 8.6% to 42.5%) through 19 years after AH. CONCLUSION Cumulative 20-year progression risk among women who remain at risk for at least 1 year is less than 5% for nonatypical EH but is 28% for AH.

PTEN expression in endometrial biopsies as a marker of progression to endometrial carcinoma.

Inactivation of PTEN tumor suppressor gene is common in endometrial carcinoma and its precursor, atypical endometrial hyperplasia (EH). We compared PTEN expression via immunohistochemistry in endometrial biopsies diagnosed as EH in 138 cases, who were diagnosed with EH and then endometrial carcinoma at least 1 year later (median, 6 years), and 241 individually matched controls, who were diagnosed with EH but did not progress to carcinoma during equivalent follow-up. We assessed PTEN status (normal versus null) in index biopsies containing EH to estimate the relative risk (RR) of developing endometrial carcinoma up to 25 years later. Analysis of 115 cases and 193 controls with satisfactory assays revealed PTEN-null glands in index biopsies of 44% of cases and 49% of controls [P = 0.85; RR, 1.51; 95% confidence interval (CI), 0.73-3.13]. For predicting progression to carcinoma, PTEN-null status had low sensitivity (44%; 95% CI, 45-54%) and specificity (51%; 95% CI, 44-58%). Among 105 cases with PTEN results for both index biopsy and carcinoma, 16% had a PTEN-null index biopsy, 23% had PTEN-null carcinoma, and 26% had both a PTEN-null index biopsy and carcinoma. Loss of PTEN expression in endometrial biopsies was neither associated with nor a sensitive and specific marker of subsequent progression to endometrial carcinoma.

Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies.

BACKGROUND: Histopathologic diagnosis of endometrial biopsies is used to estimate the risk of progression to carcinoma and guide clinical management. Problems with the widely used World Health Organization (WHO) system for classifying endometrial hyperplasia (EH) have prompted the development of an alternative system based on endometrial intraepithelial neoplasia (EIN). The authors estimated progression risk associated with EIN among endometrial biopsies in a nested case-control study of EH progression. METHODS: Index biopsies with original community pathology diagnoses of disordered proliferative endometrium (DPEM) or EH that were independently confirmed by a panel of pathologists were independently reviewed and assigned EIN classifications (inadequate, benign, EIN, or cancer) by a second panel of pathologists. Cases (N = 138) progressed to carcinoma at least 1 year (median, 6 years) after their index biopsy. Controls (N = 241) also had EH, did not progress to carcinoma, and were individually matched to cases based on age at EH, date of EH, and length of follow-up. By using conditional logistic regression, the authors estimated relative risks (RRs) with 95% confidence intervals (95% CIs) for progression to carcinoma for EIN versus benign. RESULTS: In the EIN system, 71 (52.6%) cases and 159 (66.8%) controls were classified as benign and 42 (31.1%) cases and 65 (27.3%) controls were classified as EIN. The RR for EIN versus benign was 7.76 (95% CI, 3.36-17.91). In the WHO system, the RR for atypical hyperplasia (AH) versus DPEM, simple hyperplasia, or complex hyperplasia was 9.19 (95% CI, 3.87-21.83). CONCLUSIONS: Among women observed for at least 1 year after receiving a biopsy-based EH diagnosis, EIN and AH were both found to have similarly increased risks of progression to carcinoma.

Human papillomavirus (HPV) genotyping using paired exfoliated cervicovaginal cells and paraffin-embedded tissues to highlight difficulties in attributing HPV types to specific lesions.

Defining type-specific human papillomavirus (HPV) infections within cervical tissues is important for understanding the pathogenesis of cervical neoplasia and assessing the effectiveness of prophylactic vaccines with limited type-specific spectra. We compared HPV DNA-testing results from 146 matched exfoliated-cell and formalin-fixed-tissue specimens collected by cervicovaginal lavage (CVL) within 90 days of each other from women with histologically confirmed cervical intraepithelial lesions (CIN). The CVL specimens were HPV typed using a MY09/11 L1 consensus primer PCR method followed by dot blot hybridization. The tissue specimens were HPV typed using an SPF(10) line probe assay HPV detection system. Of the 146 specimen pairs with evidence of CIN in the tissue, 91.8% were positive for one or more HPV types in both the tissue and cellular specimens. Tissue sections were more likely to be HPV negative (P < 0.01). Typing directly from tissue sections resolved multiple infections detected in exfoliated cells to a single HPV type in only 46.9% of cases. Combined use of both specimen types to attribute lesions to HPV type 16 (HPV-16) and/or -18 led to 43.1% attributed to HPV-16 and/or -18 by both specimen types and 19.9% attributed to HPV-16 and/or -18 by one, but not both, specimen types. Unambiguous attribution of cervical lesions to a single, specific HPV type remains a difficult proposition. Use of multiple specimen types or the development of highly sensitive and robust in situ hybridization HPV-testing methods to evaluate the certainty of attribution of lesions to HPV types might provide insights in future efforts, including HPV vaccine trials.