Among 7,947 women with incident EH who remained at risk for at least 1 year and who were treated and observed according to community standards, fewer than one in 20 women with DPEM, SH, or CH developed carcinoma during 20 years. In contrast, one in eight women with AH developed carcinoma within 10 years, and one in three developed carcinoma within 20 years.
Fifty-year old women in the United States have a 1.3% probability of being diagnosed with endometrial cancer before age 70 years.22
In this study, the average age at EH was 52 years, and the 20-year cumulative risk among women with nonatypical EH was 4.6%. Therefore, endometrial carcinoma risk among women with nonatypical EH, who represent the majority of all EH diagnoses, is three times higher than the average population risk. Risk among women with AH (27.5%) is 21 times higher than the average population risk.
that nonatypical EH among older, postmenopausal women has substantial progression risk, and therefore warrants hysterectomy, has not been rigorously tested. In one report, 30% of women with nonatypical EH underwent hysterectomy; fear of progression motivated half of those surgeries.3
On the basis of the 5% cumulative progression risk in our data, hysterectomy as primary treatment for 30% of women with nonatypical EH might represent overly aggressive management,3
but numerous factors could influence individual risk thresholds for patients and their gynecologic health care providers.
Previous estimates of EH progression risk come from limited case series with no controls and few clinical end points.11–14,23
The reported percentages of women who developed carcinoma (eg, 0% to 27% of women with nonatypical EH, and 20% to 100% of women with AH) are imprecise, assumed to be constant with time, and suffer from biased losses-to-follow-up and end point ascertainment. In one of the larger studies, the 52% progression risk for AH after 22 months was likely biased by occult carcinoma among women diagnosed with carcinoma in the first few months after their AH diagnosis.15
In a widely cited 1985 case series of 13 cancers among 170 patients with EH, diagnosed between 1940 and 1970 and observed for at least 1 year and for an average of 13 years, two (2%) of 122 women with nonatypical EH and 11 (23%) of 48 women with AH developed carcinoma.23
Kurman et al23
advocated conservative treatment for nonatypical EH and hysterectomy for AH, especially among perimenopausal or postmenopausal women. This analysis showed that cumulative risks are slightly higher and increase three-fold in the 20 years after index biopsy.
In this study, almost one third of women with AH who did not undergo hysterectomy were diagnosed with carcinoma within 20 years. The approximate doubling of cumulative risk after 10 years—from 12% to 28%—may help inform decision making regarding how long patients might wish to rely on hormonal treatment and repeat assessment if hysterectomy is not performed within the first year after a diagnosis of AH.
For patients who undergo hysterectomy within the first 3 months after a diagnosis of AH, the recent data from Trimble et al7
provide the best estimate of prevalence of occult carcinoma (43%) at the time of AH diagnosis. Patients at KPNW who had similar experiences as those in that Gynecologic Oncology Group (GOG) study were not eligible for this analysis, because we required all of our case patients and control patients to remain at risk for at least 1 year after index biopsy. These two studies together describe both a high short-term risk of having an occult carcinoma when AH is diagnosed and a high long-term risk of being diagnosed with carcinoma years after the initial AH diagnosis.
This large, population-based study included a full range of EH, complete follow-up, independent pathology panel review, and absolute risks and RRs unbiased by age, calendar period, or follow-up time.16
Some risk estimates were based on small numbers, but our sample size exceeds what previous studies reported. Our risks are based on our pathology panel's interpretation and application of the current WHO classification criteria,4
which have inherent limitations10
but which remain widely used. Our panel downgraded many of the case patient and control patient index biopsies that were initially classified as EH by the pathologists at KPNW.24
This probably reflects overdiagnosis of EH severity among community pathologists.5
That overdiagnosis of less-than-EH lesions implies that the progression risks for groups of women with community-based EH diagnoses would be lower than what we observed. Regardless of how EH diagnoses are assigned, better tools to identify characteristics of high-risk EH in endometrial biopsy specimens are needed.
Limitations of this analysis warrant discussion. Our AH risk estimates had wide CIs, because patients with AH who remain at risk (ie, did not undergo hysterectomy) for long intervals are rare. We employed counter matching to maximize the number of patients with AH, but those stratified sampling methods reduce overall analytic precision. Nonetheless, the CIs for nonatypical EH versus for AH only overlapped in the first 1 to 4 years after index biopsy. For both nonatypical EH and AH, the discrete risks were higher 1 to 4 years after index biopsy than 5 to 9 years after index biopsy. This may reflect occult carcinomas that went undetected in the first year after index biopsy but were diagnosed in years 2 to 4, especially among women with AH.5
Although missed occult carcinoma at index biopsy doesn't alone explain the high progression risk with AH,16
it could artificially inflate short-term risks. Even with this potential misclassification, cumulative risks for both nonatypical EH and AH more than doubled after 10 years. Our results are not generalizable to women whose endometrial biopsies show or are strongly suspicious for carcinoma, because our analysis excluded carcinomas diagnosed within 1 year of an index biopsy. Our study in the KPNW health plan included primarily white women, so our results might be less generalizable to other ethnic groups.
In conclusion, our rigorous, population-based study of women with EH who remained at risk for at least 1 year indicates that the overall progression risk for EH is three times higher than the average population risk of endometrial carcinoma. Fewer than 5% of women with nonatypical EH will experience progression to carcinoma, but 28% of women with AH progress to carcinoma during 20 years. The lower risks for women with nonatypical EH than AH can assist decision making for nonsurgical clinical management of EH, whereas the higher risks of AH progressing to carcinoma warrant consideration of appropriately aggressive approaches.