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.

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.

Reproductive factors, exogenous hormone use and risk of lymphoid neoplasms among women in the National Institutes of Health-AARP Diet and Health Study Cohort.

Reasons for higher incidence of lymphoid neoplasms among men than women are unknown. Because female sex hormones have immunomodulatory effects, reproductive factors and exogenous hormone use may affect risk for lymphoid malignancies. Previous epidemiologic studies on this topic have yielded conflicting results. Within the National Institutes of Health-AARP Diet and Health Study cohort, we prospectively analyzed detailed, questionnaire-derived information on menstrual and reproductive factors and use of oral contraceptives and menopausal hormone therapy among 134,074 US women. Using multivariable proportional hazards regression models, we estimated relative risks (RRs) for 85 plasma cell neoplasms and 417 non-Hodgkin lymphomas (NHLs) identified during follow-up from 1996 to 2002. We observed no statistically significant associations between plasma cell neoplasms, NHL, or the 3 most common NHL subtypes and age at menarche, parity, age at first birth, oral contraceptive use or menopausal status at baseline. For menopausal hormone therapy use, overall associations between NHL and unopposed estrogen and estrogen plus progestin were null, with the potential exception of an inverse association (RR = 0.49, 95% CI, 0.25-0.96) between use of unopposed estrogen and diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype, among women with a hysterectomy. These data do not support an important role for reproductive factors or exogenous hormones in modulating lymphomagenesis.

Prospective evaluation of risk factors for male breast cancer.

Most risk factors for male breast cancer have been derived from retrospective studies that may reflect selective recall. In the prospective National Institutes of Health-AARP Diet and Health Study, we studied 324 920 men, among whom 121 developed breast cancer. Men who reported a first-degree relative with breast cancer had an increased risk of breast cancer (relative risk [RR] = 1.92, 95% confidence interval [CI] = 1.19 to 3.09). Among the medical conditions examined, a new finding emerged regarding increased male breast cancer risk associated with a history of a bone fracture (RR = 2.20, 95% CI = 1.24 to 3.91). Obesity was positively related to risk (RR = 1.79, 95% CI = 1.10 to 2.91, for body mass indices of >or=30 vs <25 kg/m2) and physical activity inversely related, even after adjustment for body mass index. Smokers were at somewhat elevated risk, although trends with smoking characteristics were inconsistent. Alcohol consumption was not related to risk. The identified risk factors show some commonalities with female breast cancer and indicate the importance of hormonal mechanisms. Differences in risk factors may reflect unique mechanisms associated with androgens and their ratio to bioavailable estrogens.

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.

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.

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.

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.