Endometrial hyperplasia, a noninvasive proliferation of the endometrial epithelium, is generally classified as simple (nonneoplastic) or complex (sometimes neoplastic), with or without atypia (neoplastic), based on architectural complexity and nuclear cytology and is a precursor to endometrial carcinoma.1 Endometrial hyperplasia with atypia is the least common type of hyperplasia but is the type most likely to progress to type 1 endometrial carcinoma,1–3 which accounts for 97% of uterine cancers, whereas simple hyperplasia rarely progresses to carcinoma.1,4 Known risk factors for endometrial hyperplasia are related to an excess of estrogen relative to progesterone5,6; therefore, progestin is used to treat endometrial hyperplasia.
There are no large population-based studies describing the incidence of progression of endometrial hyperplasia among women treated and not treated with progestin. In 1985, Kurman et al1 described an increased risk of progression to carcinoma among lesions classified as complex hyperplasia with atypia (23%) in contrast to lesions classified as hyperplasia without atypia (2%) within a mean follow-up of 13.4 years. A recent large study has confirmed the higher risk of progression associated with atypical endometrial hyperplasia.3 However, these studies combined women treated and not treated with progestin. Data from women who developed endometrial hyperplasia while using postmenopausal hormone therapy have confirmed that progestins uniformly result in regression of endometrial hyperplasia without atypia.7,8 Others have described regression of atypical endometrial hyperplasia, well-differentiated carcinoma, or both with various forms of progestin, although these reports lacked control groups.9–12 Despite this, there are limited data regarding long-term outcomes for women with endometrial hyperplasia treated with progestin therapy. Consequently, endometrial hyperplasia, especially hyperplasia with atypia, is commonly treated with hysterectomy because of fear of progression to endometrial carcinoma, concern that unsampled carcinoma may already be present, or both.13–15
The objective of this study was to estimate the incidence of endometrial carcinoma, hysterectomy, or both associated with complex or atypical endometrial hyperplasia, comparing progestin users with nonusers, among women who did not have a hysterectomy, a diagnosis of endometrial carcinoma, or both within 8 weeks of endometrial hyperplasia diagnosis.
MATERIALS AND METHODS
After Institutional Review Board approval from the Group Health Research Institute, this retrospective cohort study was conducted among female enrollees at Group Health, a mixed-model integrated health plan with more than 500,000 enrollees in Washington State. Automated pathology, enrollment, pharmacy, inpatient, and outpatient databases were linked for data on all women older than 18 years diagnosed with complex, atypical endometrial hyperplasia, or both between January 1, 1985, and April 1, 2005. Women were followed from the time of hyperplasia diagnosis until an outcome occurred (endometrial carcinoma, hysterectomy, or both), disenrollment, death, or until September 30, 2005. Eligibility criteria included no prior diagnosis of endometrial carcinoma and an intact uterus. Because the most commonly recommended progestin treatment duration for endometrial hyperplasia is at least 8 weeks,16–18 women who had outcomes before 8 weeks were excluded. In addition, women who took primarily unopposed estrogen for greater than 6 months at any time during the study period or who left Group Health for more than 2 months during the study period were excluded.
Automated databases were linked through a unique identifier assigned to each woman when she first joined Group Health and reassigned on each subsequent enrollment. Disenrollment was ascertained by computerized membership files.
The pathology database includes unique pathology accession numbers, specimen collection dates, and test results entered as text fields. Text searches indicating possible diagnoses of complex or atypical hyperplasia were conducted to identify women with the conditions of interest. Details of this methodology have been previously described.19 The primary goal of this study was to answer the question, “in a given population of women with a clinical diagnosis of either complex or atypical endometrial hyperplasia, what is the risk of endometrial carcinoma or hysterectomy occurring at least 8 weeks after the endometrial hyperplasia diagnosis, with and without progestin exposure?”
A diagnosis of endometrial carcinoma was ascertained from linkage with records of the Cancer Surveillance System of Western Washington, a population-based cancer registry that participates in the Surveillance Epidemiology and End Results cancer registry. Hysterectomy, including date, was determined during review of the medical record (yes or no) and was confirmed by the presence of a uterine specimen in the pathology record.
The exposure of interest, progestin prescriptions, was ascertained from the Group Health pharmacy database. Group Health pharmacy databases capture all medications dispensed to enrollees through Group Health pharmacies, including the specific drug, drug class, date and amount dispensed, and dosing instructions. Surveys among female Group Health members aged 50–80 years have shown that 97% of hormone therapy prescriptions are filled at Group Health pharmacies.20
All progestin dispensings from 1 week before the index biopsy up until the outcome or censoring date were identified. Women were classified as progestin “ever users” if they were dispensed at least 15 days of progestin and as “never users” if they had 14 days or less of progestin dispensed. Duration of exposure (less than 56 days and 56 days or more of progestin dispensed) was evaluated in subanalyses.
For time-dependent analyses, days of use was calculated from the time of the index biopsy to the outcome or censoring within 6-month blocks. Women were classified as progestin “ever users” or as “never users” as described within each 6-month block. We created progestin and estrogen exposure variables for each time period that reflected exposure in the previous 6-month period.
Progestins were categorized by type: megestrol acetate, medroxyprogesterone acetate, and norethindrone acetate. Women who were given oral contraceptives were included in the progestin user group because all of these formulations are progestin-dominant. We classified women as unopposed progestin users if they were dispensed progestin without an estrogen or if the number of estrogen pills dispensed was less than one-third the number of progestin pills dispensed. Women were classified as estrogen plus progestin users if the number of estrogen pills dispensed was at least one-third of the number of progestin pills dispensed. We classified women as unopposed estrogen users if they were dispensed estrogen alone or if the number of progestin pills dispensed was less than one-third of the estrogen pills dispensed.
Three trained abstractors reviewed archived paper charts and the electronic medical records. Variables ascertained included medical and family history; demographic, reproductive, and physical characteristics, including height and weight at the time of the index biopsy; bleeding patterns preceding the biopsy; ultrasonography findings; age at menopause; race; parity; history of breast, colon, or ovarian cancer; diabetes; hypertension; and smoking status. Indications for hysterectomy and endometrial biopsies were recorded. Last clinical contact date (including date of death) and, if dead, whether death was related to endometrial carcinoma, were assessed.
Analyses were performed separately for complex and atypical hyperplasia. We computed the proportion of women with each type of hyperplasia (complex, atypical) who subsequently had a diagnosis of endometrial carcinoma, a hysterectomy, or both. We calculated the adjusted rates of endometrial carcinoma and hysterectomy by computing the number of events by person-years at risk for “ever users” compared with “never users” and by duration of progestin use (less than 56 days, 56 days or more). Absolute risk differences were calculated. Time to event was estimated using Kaplan-Meier survival functions. We computed adjusted Cox proportional hazard ratios with progestin exposure as a time-dependent variable. The time between index and censoring was divided into 6-month periods. Only cohort members who had been followed for 1 year or more were included in the analyses using time-dependent variables.
We considered and evaluated confounding factors and adjusted for variables that influenced the risk estimates associated with progestin dispensing by more than 10%, specifically, age (younger than 50, 50 years or older) and body mass index (less than 30, 30 kg/m2 or more). Analyses were performed using STATA 9.2 (STATA Corporation, College Station, TX). All reported P values are two-sided.
A total of 2,030 potentially eligible women, aged 18–88 years (1,544 complex, 486 atypia), were identified from the automated pathology database (Fig. 1). Of these, 315 were ineligible (204 complex, 111 atypia) and an additional 272 women (139 complex, 133 atypia) were excluded; 74 had a diagnosis of endometrial carcinoma within 8 weeks of index diagnosis (six complex, 68 atypia) and 67 took unopposed estrogen during the study period (59 complex, 8 atypia). The remaining 1,443 women (1,201 complex, 242 atypia) were followed for a median of 5.3 years (range 8 weeks to 20.8 years).
Cohort characteristics (Table 1) did not differ by progestin exposure (ever compared with never) with the exception that those women dispensed progestin were more likely to have been dispensed estrogen or estrogen plus progestin in the 6 months before the index diagnosis. During follow-up, 42% (45% complex, 25% atypia) were dispensed estrogen plus progestin for at least one 6-month period and 24% (25% complex, 15% atypia) were dispensed estrogen plus progestin during at least 50% of their follow-up period. Among women dispensed estrogen plus progestin or progestin, 80% used medroxyprogesterone acetate (more than 80% of the time), 11.5% used megestrol acetate (more than 80% of the time), and 8.5% used other progestins or combinations of progestins such that there was no predominant type used.
Among women with complex and atypical hyperplasia, the rates of endometrial carcinoma among progestin users were 3.6 and 20.5 per 1,000 women years, respectively, (as compared with 10.8 and 101.4 among nonusers) (Table 2). Absolute rate differences between progestin users and nonusers were 7.2 and 80.9 per 1,000 women years for women with complex and atypical hyperplasia, respectively. Adjusted incidence rate ratios associated with the use of a progestin were 0.35 (95% CI 0.16–0.78) for complex hyperplasia and 0.23 (95% CI 0.12–0.44) for atypical hyperplasia.
Among women with complex and atypical hyperplasia, the rate of hysterectomy in progestin users was less than that in nonusers: adjusted incidence rate ratio 0.47 (95% CI 0.33–0.67) and adjusted incidence rate ratio 0.23 (95% CI 0.16–0.34), respectively.
There were 1,159 women remaining in the cohort after 1 year (Fig. 2). There were too few women with atypical hyperplasia (n=150) to assess the impact of duration or recency of progestin use on risk for endometrial carcinoma or hysterectomy among women who remained in the cohort at 1 year. However, among the 1,009 women with complex hyperplasia who remained in the cohort at 1 year, the risk of endometrial carcinoma was decreased among women who used progestin 56 days or more: relative risk 0.29 (95% CI 0.12–0.68) (data not shown), and among recent users, hazard ratio 0.42 (95% CI 0.18–1.01) (data not shown). The incidence of hysterectomy was not decreased among women with complex hyperplasia who used progestin who remained in the cohort at 1 year, either for 56 days or more (relative risk 0.66, 95% CI 0.37–1.14) or among recent users (hazard ratio 1.08, 95% CI 0.74–1.58) (data not shown).
A total of 71 women were diagnosed with endometrial carcinoma (35 complex, 36 atypia) during follow-up (Fig. 2; Table 3), and 30 of these were diagnosed in the first year (8 complex, 22 atypia). Median interval between index biopsy and carcinoma diagnosis was 1.3 years (range 8 weeks to 11.6 years). Of the women who developed carcinoma, 49 (67.1%) had at least 14 days of progestin treatment. Median time to diagnosis of endometrial carcinoma among women diagnosed 1 year after index diagnosis of endometrial hyperplasia was longer for women with complex (5.1, range 1.1–11.6 years) than for women with atypical hyperplasia (2.5, range 1.01–7.9 years).
There were 131 deaths during follow-up, including 11 in women with endometrial carcinoma. Of these 11 women, four died with documented complications related to endometrial carcinoma; two had stage 1 grade 2 endometrial carcinoma, one of whom was considered too high risk for surgery as a result of multiple comorbidities; and two had either a type 2 endometrial carcinoma (serous carcinoma) or a poorly differentiated adenocarcinoma (both with normal body mass index). Of the four women who died from their disease, two had a family history of breast or endometrial carcinoma.
In this cohort study, among women who did not have a diagnosis of carcinoma, hysterectomy, or both within 8 weeks of hyperplasia diagnosis, 2.9% of women with complex hyperplasia and 14.9% of women with atypical hyperplasia were subsequently diagnosed with endometrial carcinoma during a median follow-up of 5.5 years. Of the 71 women who developed endometrial carcinoma, 30 were diagnosed between 8 weeks and 1 year after the endometrial hyperplasia diagnosis, suggesting they may have had concomitant carcinoma at the time of index biopsy; the majority of these cases (73.3%) had atypical endometrial hyperplasia at index. Whereas among the remaining endometrial carcinomas diagnosed at least 1 year after index, the majority (65.9%) had complex hyperplasia at index. Any use of progestin decreased the risk of endometrial carcinoma by approximately 65% and 77% in women with complex or atypical hyperplasia, respectively. Four women (0.3%) died from endometrial carcinoma.
Although endometrial carcinoma is undoubtedly the most important outcome, the rates of hysterectomy in our study were considerable and thus have a significant societal and economic effect. Others estimate that hysterectomy is performed in 75–80% of women with atypical hyperplasia.21 Progestin therapy decreased the risk of hysterectomy in our study by 53% and 77% in women with complex and atypical hyperplasia, respectively. It should be noted that among those women excluded from this study, a larger proportion of women with atypia had hysterectomy within 8 weeks of index hyperplasia diagnosis (119 of 376 [31.7%]) than women with complex hyperplasia (56 of 1,340 [4.2%]).
For women with complex hyperplasia, a low risk of progression to endometrial carcinoma supports current clinical standards for nonsurgical treatment.17 Findings from earlier studies using the current World Health Organization classification scheme for endometrial hyperplasia4 also support this management strategy for complex hyperplasia.1,7,22–25 However, only one of these studies compared women with complex hyperplasia treated with progestin with those untreated, and women were followed for only a median of 4.8 months.22 Among 208 women with complex hyperplasia treated with progestin for 3–5 months, two (1%) were diagnosed with endometrial carcinoma, whereas six (3.3%) of 182 not treated with progestin developed endometrial carcinoma.
More controversial is whether clinicians should use nonsurgical approaches to treat women with atypical endometrial hyperplasia. Currently, in the United States, hysterectomy is commonly recommended for atypical hyperplasia rather than a trial of hormonal therapy as a result of concern for development of carcinoma or concurrent carcinoma,13,16 although many clinicians do treat and follow women who desire fertility conservation. There are no other studies with substantial numbers of women with atypical hyperplasia treated with progestin compared with those untreated to comment on endometrial cancer risk. Our data suggest that among women who did not have a hysterectomy, a diagnosis of endometrial carcinoma, or both within 8 weeks of their atypical hyperplasia diagnosis, the risk of endometrial carcinoma in women treated with progestin was fourfold to fivefold lower than in women not treated with progestin. The majority of these women were diagnosed with carcinoma in the year after their atypical hyperplasia diagnosis and none of those women died from complications related to their disease. Therefore, our data suggest that with close follow-up progestin therapy may be safely used to treat atypical endometrial hyperplasia in select patients.
Of concern to patients and clinicians is a concomitant endometrial carcinoma at the time of diagnosis of atypical endometrial hyperplasia. Of women who had a hysterectomy performed within 12 weeks of an atypical endometrial hyperplasia diagnosis with no intervening therapy, up to 46% had concomitant endometrial carcinoma.14,21,26–32 A second related concern is the reliability of the pathologist's diagnosis of atypical hyperplasia compared with well-differentiated carcinoma.3,14,15,33–36 In studies by Kurman1 and others,3 the presence of cytologic atypia has been associated with the highest risk of developing carcinoma; hence, the current World Health Organization terminology divides endometrial hyperplasia into typical (simple and complex hyperplasia) and atypical hyperplasia.4 Regrettably, others have shown that the diagnosis of atypical hyperplasia is one of the least reproducible in the current World Health Organization scheme.14,15,33–36
More important than diagnostic accuracy may be the ability to predict therapeutic response to progestin therapy. Multiple studies have assessed progestin treatment of atypical hyperplasia and well-differentiated endometrial carcinoma.9–12 A literature review of women diagnosed with endometrial carcinoma showed an overall histologic response of 76% in 81 patients at a median time of 12 weeks; 15 of the women who had an initial response (24%) recurred at a median of 19 months. No patients died of their disease.10
There are limitations to our study. We were unable to control for unmeasured factors related to whether a patient and her physician opted for progestin therapy and those related to the incidence of carcinoma or hysterectomy. In addition, the study was designed to only include those women who did not undergo hysterectomy or have a diagnosis of endometrial carcinoma within 8 weeks of their endometrial hyperplasia diagnosis. The challenges with standardization of diagnostics in endometrial tissues are well established.33 We could not control for the method of endometrial sampling. The number of women included in our study limited our ability to fully assess the possible impact of progestin duration, dose, and type on the likelihood of progression to endometrial carcinoma, particularly for women with atypical hyperplasia. Finally, we were unable to assess compliance and a central pathology review was not used for these analyses.
Several study strengths bear mentioning. Few studies have compared risks of endometrial carcinoma among women treated and untreated with progestin and the number of women in our cohort is much greater than has been previously studied. The pharmacy data has been shown to be reliable at our institution20 and the methods used for case and outcome identification were rigorous.19 We had extensive data on multiple potential covariates and controlled for age, body mass index, estrogen use during the study, and prior hormone therapy exposure.
In summary, the decision whether to attempt hormonal therapy with progestins or to proceed immediately to hysterectomy is influenced by the perceived risk of progression to invasive carcinoma that each histology-based diagnosis carries. Our work would suggest that among women with a diagnosis of complex or atypical hyperplasia who do not choose immediate hysterectomy, a 3-month trial of progestin with strict surveillance for recurrence is relatively safe with regard to risk of endometrial carcinoma. This strategy does not completely negate endometrial carcinoma risk. Whether women with endometrial hyperplasia need continued ongoing progestin therapy for a number of years remains unanswered.
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