Complex atypical endometrial hyperplasia is a histologic diagnosis that falls along a spectrum of endometrial pathology. Women with this diagnosis based on endometrial sampling are frequently found to have endometrial cancer at hysterectomy.1–5 In a recent study by the Gynecologic Oncology Group,6 42% of women diagnosed with complex atypical endometrial hyperplasia on office endometrial biopsy were found to have endometrial adenocarcinoma at surgery. The failure to accurately diagnose endometrial cancer preoperatively in these women can lead to inadequate staging and potentially suboptimal treatment for some women.
Given this high rate of concurrent adenocarcinoma, when a woman is found to have complex atypical endometrial hyperplasia on office endometrial biopsy, the clinical question of whether to do a dilation and curettage (D&C) before hysterectomy is frequently raised. There are no specific recommendations or guidelines for the preoperative evaluation of complex atypical endometrial hyperplasia, and there have been few published data on whether D&C actually excludes underlying cancer to a meaningful degree. We therefore sought to evaluate to what extent, if any, preoperative D&C lowers the risk of unexpected cancer at hysterectomy compared with biopsy alone.
MATERIALS AND METHODS
The study is a population-based retrospective cohort study within a large health maintenance organization setting. Kaiser Permanente Northern California is an integrated health plan with approximately 3.5 million members. The Kaiser Permanente Northern California system includes 17 separate medical centers, and its membership includes approximately 33% of the population in the geographic areas served by the health plan. This population is demographically similar to the general population in the area, with diverse racial and ethnic backgrounds: white/Caucasian (64%), Asian (16%), Hispanic (12%), African American (7%). It was estimated that the preoperative diagnosis of complex atypical endometrial hyperplasia would be based on office biopsy in 80% of patients and D&C in 20%. Using a 40% unexpected cancer rate from the literature, a power calculation was performed to determine the sample size necessary to detect a reduction in the rate of missed cancers to 20% for the D&C group. At an alpha level of 0.05, at least 59 women having D&C and 234 women having biopsy were required to provide 80% power.
After approval by the Kaiser Permanente Northern California Institutional Review Board, women with complex atypical endometrial hyperplasia on endometrial sampling (either D&C or office biopsy) were identified by searching a comprehensive pathology database, which stores data on all members of the health plan across all 17 medical centers. The database was searched from January 2000 to May 2008 because it was expected, based on pilot data, that this period would to provide the sample size needed, recognizing that the estimates used on the power calculation were inexact. Patients with definite coexisting carcinoma at the time of initial sampling were excluded. Patient age, date of sampling(s), date of hysterectomy, and all endometrial sampling procedures done preoperatively for each patient were identified. Patients were included only if all samples showing complex atypical hyperplasia occurred within 6 months of hysterectomy, without evidence of resolution to a lesser lesion before hysterectomy. An additional database that records outpatient visits and pathology reports as well as electronic medical records were reviewed to confirm accuracy of the data.
The preoperative evaluation for each woman was categorized as office biopsy-based or curettage-based. Cases were categorized as office biopsy-based if the only sampling done before hysterectomy was one or more office biopsies. Patients who had undergone a D&C procedure showing complex atypical endometrial hyperplasia were considered to have had a curettage-based evaluation, whether or not they had an office biopsy in addition to curettage. Instruments used for office biopsy in this setting are the pipelle, Novak biopsy curette (Gynamed Instruments, Sialkot, Pakistan), and Uterine Explora curette (Milex, Chicago, IL) devices, with the pipelle accounting for approximately 80% of procedures. The pathology findings from all endometrial samples as well as final hysterectomy were reviewed. For women found to have cancer, the grade and depth of invasion were recorded.
We compared the mean age between office biopsy and D&C groups using a t test and the median time to hysterectomy using Wilcoxon rank sum test. The association between rates of cancer and age by decade of life was evaluated using χ2 tests. A multivariate logistic regression was done to examine the association of evaluation strategy and unexpected cancer at hysterectomy when adjusting for age. Odds ratios and 95% confidence intervals were reported. The negative predictive value of a curettage-based evaluation and of a biopsy-based evaluation for the outcome of cancer and myometrial invasion was calculated as the number of patients without cancer who had a negative evaluation divided by the total number of patients with a negative evaluation. This represents the proportion of patients without disease that was correctly ruled out by the evaluation strategy. Analyses were performed using SAS 9.13 software (SAS Institute Inc, Cary NC), and a two-tailed P<.05 was considered significant.
We identified 824 women with complex atypical hyperplasia on endometrial sampling who underwent hysterectomy within 6 months and who did not have evidence of resolution before hysterectomy. The median age was 56 years (range 27–85 years). The initial sampling procedure was D&C for 91 (11%) women and office biopsy for 733 (89%) women. Of the 733 who had an initial office biopsy, 473 (65%) had no further sampling before hysterectomy, 89 (12%) had additional sampling that consisted of repeat office biopsy, and 171 (23%) underwent D&C. In 31 of 89 cases (35%), endometrial carcinoma was diagnosed by repeat biopsy, whereas 66 of 171 women (39%) having a subsequent D&C were diagnosed with cancer as a result. For two patients, initial office biopsy and D&C demonstrated complex atypical endometrial hyperplasia, but a subsequent repeat biopsy revealed cancer. One woman underwent two D&C procedures, with the second one showing cancer. Therefore, 100 of the 824 women (12%) had cancer diagnosed preoperatively due to additional sampling after initial office biopsy showing complex atypical endometrial hyperplasia.
Excluding these 100 cases of cancer diagnosed preoperatively, there were 724 women who went to hysterectomy with a preoperative diagnosis of complex atypical endometrial hyperplasia. A diagram showing the numbers of patients in each sampling group and subsequent cancer outcome is shown in Figure 1. The median time from initial sample to surgery for this group was 7.3 weeks (mean 8.5 weeks). Two hundred and ninety-eight women (41%) were found to have unexpected cancer at hysterectomy. There were no significant differences in age or race between women evaluated by biopsy and those evaluated by curettage (Table 1). For 531 women (73%) the preoperative diagnosis of complex atypical endometrial hyperplasia was based solely on office biopsy, whereas for 193 women (27%), the diagnosis was based on sampling that included a D&C. Women who had a curettage-based evaluation had a longer time to hysterectomy compared with those who had a biopsy-based evaluation (median 8.9 compared with 7.0 weeks, P<.001) (Table 1). Of the 531 women who had a biopsy-based evaluation, cancer was found in 240 (45%) and myometrial invasion in 133 (25%). Of the 193 women undergoing curettage-based evaluation, cancer was found in 58 (30%) and myometrial invasion in 35 (18%). The differences in the unexpected cancer and myometrial invasion rates were statistically significant between the two evaluation strategies (45% compared with 30%, P<.001 and 25% compared with 18%, P=.05, respectively). The negative predictive of a curettage-based evaluation for excluding cancer was 69%, compared with 55% for biopsy-based evaluation (P<.001). The negative predictive value of a curettage-based evaluation for excluding myometrial invasion was 82%, compared with 75% for biopsy-based evaluation (P=.05) (Table 1).
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.
1. Widra EA, Dunton CJ, McHugh M, Palazzo JP. Endometrial hyperplasia and the risk of carcinoma. Int J Gynecol Cancer 1995;5:233–5.
2. Xie X, Lu WG, Ye DF, Chen HZ, Fu YF. The value of curettage in diagnosis of endometrial hyperplasia. Gynecol Oncol 2002;84:135–9.
3. Lambert B, Muteganya D, Lepage Y, Boivin Y. Complex hyperplasia of the endometrium. Predictive value of curettage vs. hysterectomy specimens. J Reprod Med 1994;39:639–42.
4. Janicek MF, Rosenshein NB. Invasive endometrial cancer in uteri resected for atypical endometrial hyperplasia. Gynecol Oncol 1994;52:373–8.
5. Hunter JE, Tritz DE, Howell MG, DePriest PD, Gallion HH, Andrews SJ, et al. The prognostic and therapeutic implications of cytologic atypia in patients with endometrial hyperplasia. Gynecol Oncol 1994;55:66–71.
6. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ 2nd, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:812–9.
7. Allison KH, Reed SD, Voigt LF, Jordan CD, Newton KM, Garcia RL. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol 2008;32:691–8.
8. Kendall BS, Ronnett BM, Isacson C, Cho KR, Hedrick L, Diener-West M, et al. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am J Surg Pathol 1998;22:1012–9.
9. Silverberg SG. Problems in the differential diagnosis of endometrial hyperplasia and carcinoma. Mod Pathol 2000;13:309–27.
10. Zaino RJ, Kauderer J, Trimble CL, Silverberg SG, Curtin JP, Lim PC, et al. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:804–11.
11. Mutter GL. Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The Endometrial Collaborative Group. Gynecol Oncol 2000;76:287–90.
12. Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL. Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol 2005;18:324–30.
13. Mutter G, Baak J, Crum C, Richart R, Ferenczy A, Faquin W. Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry. J Pathol 2000;190:462–9.
14. Mutter G, Ince T, Baak J, Kust G, Zhou X, Eng C. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res 2001;61:4311–4.
15. Merisio C, Berretta R, De Ioris A, Pultrone DC, Rolla M, Giordano G, et al. Endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia. Eur J Obstet Gynecol Reprod Biol 2005;122:107–11.
16. Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000;89:1765–72.
17. Machado F, Moreno J, Carazo M, León J, Fiol G, Serna R. Accuracy of endometrial biopsy with the Cornier pipelle for diagnosis of endometrial cancer and atypical hyperplasia. Eur J Gynaecol Oncol 2003;24:279–81.
18. Stovall TG, Photopulos GJ, Poston WM, Ling FW, Sandles LG. Pipelle endometrial sampling in patients with known endometrial carcinoma. Obstet Gynecol 1991;77:954–6.
19. Zorlu CG, Cobanoglu O, Işik AZ, Kutluay L, Kuşçu E. Accuracy of pipelle endometrial sampling in endometrial carcinoma. Gynecol Obstet Invest 1994;38:272–5.
20. Guido RS, Kanbour-Shakir A, Rulin MC, Christopherson WA. Pipelle endometrial sampling. Sensitivity in the detection of endometrial cancer. J Reprod Med 1995;40:553–5.
21. Larson DM, Krawisz BR, Johnson KK, Broste SK. Comparison of the Z-sampler and Novak endometrial biopsy instruments for in-office diagnosis of endometrial cancer. Gynecol Oncol 1994;54:64–7.
22. Ferry J, Farnsworth A, Webster M, Wren B. The efficacy of the pipelle endometrial biopsy in detecting endometrial carcinoma. Aust N Z J Obstet Gynaecol 1993;33:76–8.
23. Antoni J, Folch E, Costa J, Foradada CM, Cayuela E, Combalia N, et al. Comparison of cytospat and pipelle endometrial biopsy instruments. Eur J Obstet Gynecol Reprod Biol 1997;72:57–61.
24. American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413–25.