By enlisting two panels of gynecologic pathologists to independently review the same original diagnostic slides from women with who clinically progressed to carcinoma and matched controls who did not progress, our analysis provides useful evidence on the association between diagnosis of EIN at endometrial biopsy and subsequent cancer risk. The EIN and WHO systems use different criteria and numbers of categories to classify endometrial lesions, but the progression risk for dichotomous EIN (RR=7.76 for EIN vs. benign) was quantitatively similar to the progression risk for a dichotomous WHO scheme (RR=9.19 for AH vs. DPEM, SH, or CH). Thus, both systems identified women whose endometrial biopsies reflect an almost ten-fold higher risk of progressing to carcinoma. Both review panels generally agreed on what constituted a low-risk lesion; index biopsies called DPEM or SH by our WHO panel were almost always called benign by our EIN panel. This suggests that both systems identify key features (i.e., normal-appearing architecture and nuclei) that characterize low-risk lesions.
AH was more strongly associated with carcinoma when compared with DPEM only (RR=14.21) than with DPEM, SH, and CH together (RR=9.19) because the latter used a broader reference (i.e., comparison) group that included everything from the equivocal DPEM to CH lesions with severe architectural complexity. We previously concluded (7
) that the strong association between progression and AH (but not SH or CH) could justify treatment decisions based on a non-atypical EH vs. AH dichotomy. The similar association between EIN and carcinoma (RR=7.76 for EIN vs. benign) could provide support for a similar approach to clinical management for EIN (12
). Although the relative risks were nearly identical, the two systems had different strengths when predicting subsequent progression to carcinoma. EIN had a higher sensitivity than AH (37% vs. 31%, respectively) but a lower specificity (71% vs. 86%, respectively). As applied by our pathology panels in this dataset, both systems better predicted which lesions did not progress (i.e., high specificity) than which lesions did progress (i.e., low sensitivity). However, given the sampling errors inherent in endometrial biopsy specimens and the unpredictable natural history of endometrial precursors, it might be unrealistic to expect any classification system to possess both high sensitivity and specificity.
Secretory endometrium, basalis, polyps, or other benign lesions that mimic glandular proliferative lesions can be misclassified under both WHO (i.e., as EH) and EIN (i.e., as EIN) classification systems (12
). Because all EIN lesions are also considered EH (12
), we excluded patients who had an index biopsy that our WHO panel classified as being less severe than DPEM. This removed many of the benign lesions from the EIN diagnostic review. The overall severity of our benign group is therefore higher than the severity of benign groups in other EIN studies that include patients whose endometrial biopsies would have been classified as less-than-EH. Our results on progression risk associated with EIN should therefore be generalized only to women whose community WHO diagnoses are likely to be considered DPEM or EH and who remain at-risk for at least one year after their index biopsy. Our results are not necessarily generalizable to all women who undergo endometrial biopsy, particularly women whose community WHO diagnoses overestimate their true lesion severity (5
) or who have occult carcinoma at the time of their EH is diagnosed (22
At the other end of the spectrum, EIN is a premalignant lesion distinct from carcinoma. Distinguishing a severe premalignant lesion from carcinoma is especially difficult with biopsy specimens (13
), but the EIN panel felt that 13 cases and 10 controls had cancer at their index biopsies. Nine of these 13 cases (69%) had a panel WHO diagnosis of AH; on average, they were diagnosed with carcinoma 4.2 years (range, 1.2–11.1 years) after their index biopsy. For 7 of these 13 cases, at least one of the WHO panelists interpreted the biopsy as mucinous carcinoma, which can be difficult to recognize (23
). Two of these 10 controls had a panel WHO diagnosis of AH and 7 had CH. The average disease-free interval after EH for these 10 controls was 10.6 years (range, 2.4–17.1 years). Thresholds for distinguishing precursors (e.g., AH or EIN) from carcinoma in biopsies vary among pathologists and by classification system, but all of these lesions warrant close follow-up. A bigger challenge may be how to evaluate and manage the larger group of women with less severe abnormalities. Variable thresholds across schema will affect how patients are clinically managed, precursors are studied, and performance of classification systems is evaluated.
In our analysis, EIN diagnoses were more common (29% of all index biopsies) than AH diagnoses (20% of all index biopsies), especially among controls (i.e., N=65 EIN vs. N=34 AH). These factors tended to reduce the progression risk and specificity associated with EIN relative to those for AH. The RR of 7.76 for EIN in our study was much lower than the relative risk of 45 for EIN in a study of 477 women who originally received a community diagnosis of EH and were followed for at least one year by Baak et al (16
). In contrast to previous studies, our report included a matched control group with equivalent progression risk who received similar treatment and had complete clinical follow-up data available. Our two pathology panels included experienced gynecologic pathologists who independently reviewed the original slides and were masked to case-control status and clinical outcomes. The higher prevalence of EIN than AH among our study’s controls indicates that the true progression risk for EIN relative to benign lesions is much closer to the RR of 10 that we observed, because EIN would need to have nearly perfect predictive power among women who progressed in order to generate the 45-fold increased RR of 45 that has been previously reported (16
). Other strengths of our study, such as the ability to control for treatment, repeat biopsies, and other confounders, lend further validity to our findings.
Our study possesses some limitations. Few women with severe EH were followed for long intervals, so statistical power for some regression models was low. The wide confidence intervals for the risk estimates are a result of the conditional logistic regression and careful individual matching on age, length of follow-up, and calendar period. Some of the older slides were in suboptimal condition, and all endometrial biopsies suffer from tissue sampling variability. All of these issues would equally affect both the WHO and EIN classifications. We did not incorporate an intra-observer reproducibility analysis for the EIN classifications. Reported reproducibility is high, however (16
). Although we had both community and panel WHO classifications, our study did not include EIN classifications that were assigned by community pathologists.
We designed this analysis to test the association between EIN classification at index biopsy and subsequent risk of carcinoma. For practical reasons, we selected patients using a modified WHO classification system; we combined SAH and CAH because too few women at KPNW had index biopsies that were classified as SAH by the community pathologists or our pathology review panel to consider SAH and CAH as separate entities for analysis or when selecting counter-matched controls. Such modifications commonly occur in clinical practice and are not surprising because assigning a WHO classification requires pathologists to subjectively weight the relative importance of multiple histologic criteria (8
). Those challenges might contribute to better correlation between our WHO and EIN panel diagnoses than between either panel and the community WHO diagnoses, although the changing WHO nomenclature used over the 34-year period of our data collection also contributed to those differences (Sherman ME, et al., In press). Our results show that, despite different formal classification criteria and application of those criteria, high-risk lesions within dichotomous WHO (AH vs. non-atypical EH or DPEM) and EIN (EIN vs. benign) classification systems had similar associations with subsequent carcinoma. Dichotomous systems would simplify classification of endometrial biopsies and subsequent clinical management, but simply giving pathologists fewer choices would not eliminate the difficult task of assigning a single classification to lesions that are neither entirely benign nor obviously severe.
Problems with the WHO classification system persist, in part, because of the low reproducibility of EH in both community and research settings (8
). Comparable evaluations of EIN reproducibility among community pathologists, plus additional population-based studies of EIN in diverse clinical settings, are needed in order to continue to evaluate the performance of EIN compared with existing application of WHO-based critera. We observed that the progression risk associated with EIN is lower than what has previously been reported and quantitatively similar to the progression risk associated with AH when both systems are applied by experienced pathologists as we have done here. Continued efforts to improve histopathologic diagnosis of endometrial biopsies could potentially lead to improved clinical management.