There was no evidence that cancer risk was associated with a longer time to surgery. Women who were found to have cancer had a shorter time to hysterectomy (mean 8.0 weeks, median 6.9 weeks) compared with women not found to have cancer (mean 8.9 weeks, median 7.9 weeks). Age was significantly related to the risk of having cancer at hysterectomy, with the mean age of women found to have cancer being 59 years, compared with 55 years for women not found to have cancer (P<.001), (Table 2).
The risk of cancer increased for each decade of life after age 50 years, with women aged younger than 50 years having a 40 % risk, compared with a 78% risk for women aged 80 years and older (P<.001). The severity of disease also correlated with age, with the risk of myometrial invasion increasing from 16% for women aged younger than 50 years to 72% for women aged older than 80 years (P<.001). The risk of deeply invasive disease, defined as invasion of more than 50% of the myometrium, or grade 3 disease, also increased with age up to age 80 years, with 5% of women aged younger than 50 years having such high-risk disease, compared with 17% of women aged 70–79 years (P<.002) (Table 3).
A multivariate logistic regression was performed. Controlling for evaluation strategy, advancing age by decade of life was again found to be associated with risk of unexpected cancer. Compared with women aged younger than 50 years, women aged 60–69 years were 1.9 times more likely to have unexpected cancer found at surgery (odds ratio 1.9, 95% confidence interval 1.2–2.9). The risk was 2.7 times higher for women aged 70–79 and 7.4 times higher for women aged 80 years or older. Controlling for age, the risk of unexpected cancer associated with a biopsy-based evaluation was double that found with a curettage-based evaluation (odds ratio 2.0, 95% confidence interval 1.4–2.9) (Table 4).
The high rate of unrecognized cancer among women diagnosed with complex atypical endometrial hyperplasia preoperatively is due in part to the fact that the histologic criteria for differentiating complex atypical endometrial hyperplasia from grade 1 adenocarcinoma on endometrial sampling are controversial and subject to different interpretation.7–9 In a recent Gynecologic Oncology Group study,10 a panel of three expert pathologists reviewed 306 biopsy or curettage specimens identified as atypical endometrial hyperplasia and agreed with the diagnosis in only 38% of cases, favoring in 29% of cases a more severe diagnosis and in 25%, a less severe diagnosis. Moreover, 19% of women diagnosed with normal or nonatypical hyperplasia by the expert panel still had cancer found at hysterectomy, whereas 36% of those diagnosed with cancer by the expert panel did not have cancer found. Numerous authors have suggested modifications of the standard World Health Organization classification system, and alternative terminology has been proposed that would establish a category called endometrial intraepithelial neoplasia.11–14 The criteria defining this category have been associated with cancer risk and seem to be more objective; however, it has not yet been widely adopted. One potential criticism of our study is that we did not include an expert pathology review. The purpose of such reviews is to confirm the diagnosis and therefore validate the inclusion of patients in a study. Given the findings of the Gynecologic Oncology Group study, expert pathology review for this diagnosis would not accomplish this goal, because, as demonstrated by their data, pathology expertise does not overcome the problems with the pathology criteria themselves. Furthermore, our study represents a “real world” cohort of women diagnosed with complex atypical endometrial hyperplasia by pathologists in a community setting.
We could find only one previously published study that specifically examined the question of whether D&C is more accurate than biopsy in detecting cancer among women with complex atypical endometrial hyperplasia. In this study of 70 patients, 45% were diagnosed with complex atypical endometrial hyperplasia by D&C and 55% by biopsy.15 No difference in the incidence of cancer at hysterectomy was observed between the two groups, but the conclusion is limited by sample size. Dijkhuizen et al16 published a literature review on the accuracy of endometrial sampling for detecting carcinoma and hyperplasia preoperatively and concluded that pipelle was the most accurate instrument, with 99.6% and 91% sensitivity for cancer and hyperplasia, respectively, and high specificity (more than 98%). However, of the 39 studies included in the review, only five that examined pipelle accuracy required hysterectomy final pathology for judgment of accuracy.17–22 Moreover, all five of these studies tested the pipelle in women with known endometrial cancer. There was only one study in the review that looked at the performance of pipelle in women not already known to have cancer and included hysterectomy data. In this study by Antoni et al23 365 women with perimenopausal or postmenopausal bleeding were evaluated by either cytospat or pipelle; 62 women subsequently had a hysterectomy. This study, in contrast to the studies on women known to have cancer, found only a 60% sensitivity of pipelle for cancer and 71% for hyperplasia of any degree. If hysterectomy had been required for all the women, these sensitivity rates would likely have been even lower. The poor performance of office biopsy for detecting cancer in women with complex atypical endometrial hyperplasia should not be seen as a contradiction of past data, but rather, underscores the fact that the accuracy of office biopsy for detecting cancer depends on the population in which it is studied. Here, office biopsy is less accurate because, with the current classification system, the subjectivity involved when interpreting a biopsy specimen becomes problematic when differentiating cancer from similar pathologic lesions.
In our study, we had 91 women who were initially evaluated by D&C and 171 others who underwent D&C after an initial office biopsy. The decision to evaluate some patients initially by D&C rather than biopsy is often driven by patient factors, such as poor tolerance of office biopsy, body habitus, or cervical stenosis. However, for women with complex atypical endometrial hyperplasia on initial office biopsy, performing a subsequent D&C before hysterectomy often reflects an increased level of clinical suspicion and a desire for a more “thorough” evaluation. The decision to perform curettage in women for whom the clinical suspicion is greater could therefore be expected to cause patients with cancer to be over-represented in the curettage-evaluation group compared with the biopsy-evaluation group. This could potentially bias the results toward increased detection of cancer by curettage. However, we did not find cancer to be more prevalent among women who underwent D&C, with 123 of 262 (47%) having cancer, compared with 269 of 562 (48%) of women who underwent biopsy alone (P=.81).
One potential limitation of our study is that we were not able to elicit accurate data on hormone use during the period between initial endometrial sampling and hysterectomy. The use of progestins in women with complex atypical endometrial hyperplasia is usually given either as a temporizing measure before surgery to control bleeding, or caused by a patient’s desire to preserve fertility and avoid surgery. The study required hysterectomy to be done within 6 months of the initial sample; the median time to surgery was 7.3 weeks for the 724 women with a prehysterectomy diagnosis of complex atypical endometrial hyperplasia. Most patients who undergo progestin therapy to avoid surgery will delay hysterectomy for longer than 6 months to allow response and therefore would have been excluded. Although it is possible that brief hormone use could have affected the results at hysterectomy for some patients, we feel the effect of this is likely to be minimal. If brief hormone therapy were significantly affecting pathology during the time between sampling and hysterectomy, one would expect this to bias the results toward a lower, not higher, incidence of cancer. Other limitations are that we did not compare the different biopsy instruments available, because the pipelle accounts for the vast majority of office biopsies performed in the system. It is possible that differences exist in the accuracy of various biopsy instruments in this setting. We also did not evaluate whether there was any effect of hysteroscopy. Because the determination of complex atypical endometrial hyperplasia compared with cancer rests entirely with the pathology diagnosis, regardless of hysteroscopic findings, our study focused on the question of whether the greater amount of tissue provided by D&C improves preoperative detection of cancer.
We found that preoperative D&C was associated with a statistically significant decrease in the risk of having both cancer and invasive cancer found at surgery when compared with biopsy alone. However, the rate of unrecognized cancer remained of concern, with 30% of women still having cancer and 18% having myometrial invasion at hysterectomy despite D&C. The current American College of Obstetricians and Gynecologists Practice Bulletin on the Management of Endometrial Cancer recommends that “most women” with endometrial cancer be offered staging, with “exceptions to this includ(ing) young or perimenopausal women with grade 1 endometrioid adenocarcinoma associated with atypical endometrial hyperplasia.”24 In our study, the rates of invasive and deeply invasive/grade 3 disease correlated strongly with age. However, 201 of the 824 women with complex atypical endometrial hyperplasia on initial sampling were aged younger than 50 years, and of these, 40% had cancer, 16% had invasive cancer, and 5% had deeply invasive or grade 3 disease at hysterectomy. Therefore, the notion of age being an important determinant of disease, as reflected in the American College of Obstetricians and Gynecologists recommendation, is generally supported by our data, although it could be argued that the risk for women aged younger than 50 years is still significant.
Recognizing that there continues to be debate over the optimal management strategy for women with endometrial cancer, the implications of these data will depend on the management strategy followed. If one accepts a potential benefit of making staging available for women with apparent early stage disease, based on these findings, it is logical for the same benefit to be extended to women with complex atypical endometrial hyperplasia on sampling given the large degree of overlap between the two groups. For providers who would manage women with a preoperative diagnosis of complex atypical endometrial hyperplasia differently from women with a preoperative diagnosis of low-grade endometrial cancer, it is important to recognize the limitations of D&C in reliably distinguishing between these two groups and to be cognizant of the strong correlation between the risk of invasive disease and age.
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© 2009 The American College of Obstetricians and Gynecologists
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