Identification of endometrial precancers by morphometric D-Score has proven to be both diagnostically reproducible and predictive of clinical outcome. We show that a subjective implementation of EIN diagnostic criteria is also highly reproducible, consistent with D-score predictions, and outperforms the WHO hyperplasia schema in predicting cancer risk.
The reviewed series contained 8 adenocarcinoma outcomes. A preceding diagnosis of EIN was 100% sensitive in predicting all 8 endometrial cancers, with 30% (8/27) of EIN diagnoses associated with concurrent or subsequent endometrial adenocarcinoma. This outcome predictive value of a consensus subjective diagnosis was similar to that seen previously for morphometrically diagnosed EIN using the D-Score as measured by image analysis(19
). In contrast a biopsy diagnosis of atypical hyperplasia was only 63% sensitive, predicting 5 out of 8 endometrial adenocarcinoma outcomes. The remaining 3 cases were initially diagnosed as simple non-atypical (1
) and complex non-atypical (2
) hyperplasias, resulting in all WHO hyperplasia categories being associated with some frequency of cancer, complex atypical (23%), complex non-atypical (10%) and simple non-atypical (2%) (). Therefore, it is impossible to exclude the possibility of future or concurrent cancer in most patients with a WHO hyperplasia diagnosis of any category.
This latter point highlights a useful aspect of EIN diagnostic scheme that is clinically important in patient management. The very robust negative predictive value of a non-EIN diagnosis (in this study 100%) essentially removes most patients from a high-risk category given none of the 59 patients in the non-EIN category were found to have cancer. In contrast many of these same patients would have been needlessly considered to be at increased cancer risk based on WHO classification, e.g. 29 of these 59 (16 complex atypical and 13 complex non-atypical hyperplasias) patients would be considered to have at least a 10% cancer risk. One of the arguments for implementation of the EIN system would be to decrease the frequency of false positive diagnoses, which have significant consequence for the patient.
Interobserver reproducibility of EIN was excellent, with all 3 pathologists agreeing in the first pass in 75% of cases. This compares to a recent Gynecologic Oncology group where a panel of 3 gynecologic pathologists agreed on WHO hyperplasia class assignment in only 39% of cases(20
). Improved reproducibility is an expected benefit of contraction of the number of classes to be distinguished. This has been cited by a European group as one justification to contract biopsy diagnosis of premalignant and well differentiated carcinoma into a single category (21
). The EIN schema continues to maintain adenocarcinoma as an entity separate from premalignant disease (EIN) because these may be treated differently in the United States, especially when EIN presents in women wishing to maintain fertility. Management of EIN is quite similar to that previously offered to women with an atypical hyperplasia diagnosis, and this may include an option in some cases for hormonal therapy with progestins and careful followup surveillance.
While morphometrically low risk (D-Score >1) endometria were consistently recognized as non-EIN in our series, morphometrically high risk endometria (D-Score≤1), comprised an admixture of subjectively benign and EIN endometria (). In this study, we performed morphometry on all intact tissues, irrespective of presence of endometrial polyps or secretory endometrium which are known benign processes that yield “high risk” D-Scores. All cases that went on to adenocarcinoma were high risk by both D-Score (≤1) and subjective (EIN) classification, emphasizing the need for the human element in diagnosis.
The most difficult part of EIN diagnosis is exclusion of the many benign mimics that overlap with EIN. Some can be instantly recognized as mimics using features that do not appear in the concise bullet lists of diagnostic criteria. For example, normal secretory endometrium is non-uniform throughout the endometrial thickness. Basal areas without significant stromal pre-decidual change have much more gland crowding than near the surface where expanding stromal cells push the glands apart. Combined with cytologic differences in secretory activity between the basal and superficial gland elements, it is very easy to misinterpret an isolated fragment of basal secretory endometrium as a localizing EIN lesion. Polyps present another problem, as about 15% of EIN lesions present within the context of the irregularly distributed glands of a polyp. EIN diagnostic criteria are maintained in a polyp, with the caveat that the polyp itself should be considered the background for comparison of cytology. The polyp context of EIN should always be mentioned in the report, as the entire lesion may be removed in some cases by simple polypectomy.
Education and training are a critical element in achieving diagnostic reproducibility for community deployment of any new diagnostic procedure. To this end, we have developed an online interactive tutorial and deposited online a training series of 50 outcome-annotated endometrial biopsies (the “EIN Diagnosis Library”) at www.endometrium.org
. It was this material, coming from patients independent of those studied in the current report, which was used to prepare the least experienced pathologist (JH) to participate in this study. Once learned, EIN diagnoses are robustly applied by pathologists, as indicated by our excellent intra-observer reproducibility (kappa 0.73-0.90). Online teaching resources are increasingly popular in many disciplines, but limitations in image resolution and field selection are significant barriers in mimicking the real-time experience of viewing glass slides under the microscope. An example of hardware induced diagnostic compromise emerged during training for this project. One pathologist had a steady habit of under-diagnosing EIN lesions. Further inquiry revealed that the microscope he was using did not have a 2x objective, necessary for low magnification intercomparison of architectural patterns amongst the many tissue fragments scattered throughout the slide. Without this low power perspective, subtle localizing architectural clues were lost, and the relevant fragments overlooked. When supplied with a 2x objective, that individual suddenly could quickly recognize the fragment of interest and became concordant with the rest of the group.
The EIN versus benign distinction has been better characterized than that between EIN and cancer. Resolution of EIN from well differentiated carcinoma relies on histopathologic criteria of solid epithelium, cribriform architecture, mazelike lumens, or myoinvasion. Previous morphometric analysis of endometrial biopsy material from patients with and without myoinvasive cancer on hysterectomy have identified variables such as volume percentage lumen, volume percentage epithelium, and epithelial thickness as features of carcinoma that may predict myoinvasion(22
). These have not yet been extensively tested on new patient series, nor have they been extrapolated to readily applicable subjective criteria. This is a subject which requires more attention, both in terms of developing new molecular markers or criteria for improved diagnostic segregation, and in defining relevant therapeutic thresholds. In particular, there is renewed clinical interest in managing subsets of well differentiated adenocarcinoma with locally (24
) or systemically delivered hormonal agents. It may become necessary in the near future to critically evaluate new strategies for stratification suited to triage into therapies that are not currently part of our clinical repertoire.
The relationship between EIN and that group of lesions previously diagnosed as endometrial hyperplasia is relevant to practicing pathologists contemplating transition to the EIN diagnosis schema. The canon of “endometrial hyperplasia,” as defined by the WHO encompasses a biologically diverse assemblage of lesions inconsistently assigned to one of four groups based upon presence or absence of cytologic atypia and simple or complex architecture. This approach largely derived from a 1985 clinical outcome study of 170 patients in which lesions with cytologic atypia conferred an approximately 14-fold elevated risk for endometrial carcinoma(25
). Although the WHO 4-class endometrial hyperplasia schema is currently the most widely used classification system for premalignant endometrial lesions, reproducibility of the key assessment of presence or absence of cytologic atypia is poor, with inter-observer kappa values of 0.3 to 0.47 (20
). Fixed translation of a specific hyperplasia subtype to EIN category is not possible, because of the poorly defined nature of hyperplasia subgroups, and absence of key EIN criteria such as lesion size and relative standard for cytologic change in the hyperplasia system. Rather than seeking a translation between the systems, EIN criteria must be applied to each case individually in order to achieve the reproducibility and outcome predictive benefits seen in this study.
The EIN diagnostic schema was introduced at Brigham and Women’s Hospital in 2002, to replace a local version of the older hyperplasia-based nomenclature. EIN implementation has been very well received by our clinical colleagues, who were primed by a series of explanatory conferences and memos in advance of a go-live date. The ease of pairing each diagnostic entity with clinical management facilitates clear communication. It has, however, raised new questions. Now that we are increasingly conscious of lesion size and extent while making the diagnosis, there is interest in exploration of whether further subdivision by any of these variables (other than the simple 1mm size threshold) has any clinical meaning. Further studies are needed to resolve these issues.