EH which is the precursor lesion of most endometrial cancers of endometrioid type is usually diagnosed through evaluation of women with abnormal uterine bleeding by endometrial biopsy.3,14
Despite several advances in non-invasive techniques to detect coexistent EC or risk of progression to EC during the initial diagnosis of EH, currently available studies failed to reveal conclusive results.15
According to the widely used WHO classification, patients with atypical EH are at risk of developing EC when left untreated. Although some of these lesions may coexist with EC at the time of EH diagnosis, others may progress to EC in course of time. Also, among patients with atypical EH, the risk of coexisting EC or to progress to EC is greater when the architecture is complex.6
Therefore, the majority of women with complex atypical EH who do not have desire for further fertility are treated by hysterectomy. On the other hand, patients with non-atypical EH undergo treatment including surgical and non-surgical management strategies that indicates the lack of consensus for the management of such patients.8
Also, there may be some difficulties of differential diagnosis between atypical EH and well-differentiated EC.16
Thus, it appears that some problems arise during diagnostic processes, which consequently influence clinical management significantly. The evaluation of endometrial biopsy specimens and the classification of results are extremely important due to these problems.
An ideal classification system for diagnostic biopsies including endometrial biopsy should be biologically meaningful, predictive of the lesion, and highly reproducible among pathologists. However, the widely used WHO 1994 classification system does not fulfill all these criteria adequately.17
Therefore, more reproducible alternative classification systems have been searched in an attempt to prevent diagnostic failures and to guide clinical management. Among these, EIN system uses objective criteria which distinguish neoplastic from non-neoplastic changes.12,18-21
However, these complex and impractical criteria were successfully adopted to routine practice and Hecht et al.,13
and Mutter et al.22
showed that subjective EIN criteria reproduces and more precisely identifies endometrial precancers on hematoxylen-eosin stained sections.
In the current series, all women with EC had complex atypical EH on biopsy according to the WHO classification. Complex non-atypical or simple atypical EH was not found to be associated with EC. Therefore, neither complex architecture, nor atypical cytology alone was sufficient to consider a co-existent EC in this group of patients, but this may definitely be a result of the limited number of patients in different EH categories of the WHO classification system. On the other hand, when the EIN system was used in the same cohort, no EC was detected in women without EIN. As a result, the sensitivity and negative predictive value of complex atypical EH and EIN were 100% in predicting coexistent EC. Therefore, either of these two classification systems was highly successful for guiding the management of cases. In this context, the clinician may safely decide to manage patients conservatively without hysterectomy if the biopsy does not yield complex atypical EH or EIN. From this point of view, both classification systems appeared to be useful in terms of decreasing the rates of unnecessary surgical interventions. Nevertheless, EIN was diagnosed in more than 40% of patients with complex non-atypical EH in this study. This was associated with a lower specificity of the EIN system. Actually, similar results were obtained in another study in which 44% of patients with complex non-atypical EH and even 4% of women with simple non-atypical EH had EIN.12
Hysterectomy may be considered to be an over-treatment for these women when the operation is decided based only on presence of EIN, since no EC was detected among them. The reason for such an over-treatment may be related to term "neoplasia," which may result in more anxiety among both patients and the clinicians.
Another risk for women with EH or EIN is the possibility of progression to cancer. Women diagnosed with atypical EH are greater than 10 times more likely to develop EC compared with women diagnosed with nonatypical EH.23
On the other hand, women with EIN were reported to be 45 times more likely than patients diagnosed with a benign endometrium to progress to EC.24
A recent study by Lacey et al.25
revealed that women who were observed at least 1 year after diagnoses of EIN and atypical EH had similarly increased risk of progression to EC. However, the risk of progression to cancer could not be evaluated in this study due to the fact that all patients were treated with surgery within 2 weeks following a diagnosis of EH.
According to the results of the current study, none of the patients without EIN or complex atypical EH had co-existent cancer. Therefore, we suggest that women without EIN or complex atypical EH may be observed conservatively without hysterectomy. Again, according to our results, the risk of a co-existent EC is 26.4% in a patient with complex atypical EH and 24.3% in EIN. Therefore, if patients with complex atypical EH or EIN are subjected to hysterectomy after biopsy, nearly one fourth will be diagnosed to have a co-existent EC. This means that most of them (almost 75%) will receive surgery because of a non-malignant condition. On the other hand, having atypical EH or EIN necessitates at least hormonal treatment and close follow-up, since these lesions precede cancer by several years.13,23,24
Hence the options of surgery vs. conservative treatment may be decided after discussing these carefully with the patient and her family.
There are definitely some limitations of the current study. First of all, it was designed retrospectively. Also, the number of patients is limited. The limited number of the patients in the study did not allow the authors to compare the results according to age, preoperative risk factors, symptoms, concomitant pathologies, biopsy methods, and menopausal status. Accordingly, multivariate analysis was not possible. However, the re-evaluation of the specimens was performed by a pathologist who specializes in gynecologic pathology and was blinded to the initial pathologic results. Therefore, the diagnostic errors and recall biases were kept as minimal as possible.
In conclusion; the diagnoses of complex atypical EH and EIN had similar sensitivities with 100% negative predictive values for the prediction of coexistent EC in patients with abnormal uterine bleeding. Therefore, when a pathologist who is frequently exposed to such available specimens, either of these two classification systems may be used, and patients without EIN or complex atypical EH may safely be managed conservatively without hysterectomy. However, given the objective diagnostic criteria compared to the traditional WHO classification, the use of the objective EIN system, rather than the subjective EIN system should be preferred whenever possible to prevent diagnostic errors, and to avoid unnecessary surgical interventions in centers where an experienced pathologist is not available.