Original contributionLack of PTEN expression in endometrial intraepithelial neoplasia is correlated with cancer progression
Introduction
Endometrioid endometrial adenocarcinoma may be preceded by premalignant lesions, ablation of which can be cancer preventive. Accurate identification of these premalignant lesions in routine endometrial biopsy samples is thus of great clinical value in patient management. Approximately 5% to 8% of endometrial hyperplasias progress to carcinoma, many but not all of these falling into the subgroup of atypical endometrial hyperplasias according to the World Health Organization histological classification schema of hyperplasias (WHO94) [1]. Poor reproducibility and limited clinical predictive value of these hyperplasia diagnoses as formulated in 1994 [2], [3], [4], [5] have propelled a search for improved diagnostic strategies. The past few years have seen progress in this area, with discovery of precise histological correlates of genetically and clinically defined premalignant endometrial diseases. This group of high cancer risk endometrial lesions, termed endometrial intraepithelial neoplasia (EIN), can be recognized in routinely stained tissue sections by either objective morphometry or subjective pathologist interpretation of EIN criteria designed to mimic morphometric classification [6], [7].
Morphometric studies of endometrial hyperplasias have identified a unique multivariate prognostic combination of quantitative architectural and nuclear features, called the D score (DS), that corresponds well with both cancer risk [8] and biologic lesion properties [9]. The DS, as calculated from 3 morphometric variables objectively measured in routine hematoxylin-eosin (H&E)–stained endometrial biopsy slides, is the most sensitive and specific method of endometrial cancer risk prediction currently available. Accuracy of prediction of endometrial cancer outcome by the DS [8] has now been confirmed in several large (prospective or multicenter) studies, with a sensitivity higher than 98% and specificity of 80% [10], [11], [12], [13]. Unpublished meta-analysis data from our groups have shown that high-risk lesions identified by DS (<1) are approximately 90 times more likely to progress to endometrial carcinoma than lesions with low-risk (DS >1). Moreover, molecular genetic studies have found that endometrial lesions with a DS lower than 1 are often monoclonal physical progenitors of subsequent endometrial adenocarcinoma whereas cases with a DS higher than 1 are virtually all polyclonal [9]. Genetic, morphometric, and outcome data together constitute the foundation of the EIN classification [9]. Endometrial intraepithelial neoplasia is thus defined as a neoplastic, initially focal lesion with cytological demarcation, crowded gland architecture, and a volume percentage stroma less than 55%, with a minimum size of 1 mm and careful exclusion of mimics [6]. Endometrial intraepithelial neoplasia can be identified by subjective evaluation of standard H&E–stained standard histological sections [7]. Such subjective assessments are reasonably well reproducible [14]; however, DS assessment has much better reproducibility. Therefore, we have recently also morphometrically defined EIN as any hyperplasia with a DS lower than 1 [7].
Daily morphometric DS application gives superior prognostic results, is easy, inexpensive, time effective, has therapeutic significance [11], and is implemented in routine surgical pathology laboratories where it is feasible and well accepted [15]; nonetheless, it is currently not widely used except in The Netherlands and Norway. Central reference laboratories could provide access to the benefits of DS evaluation but it is preferable to involve local pathologists in these determinations.
Although prediction of cancer outcome is greatly improved by use of the EIN schema, only a fraction of DS-defined high-risk EIN lesions will progress to carcinoma. This could be caused either by an inefficient progression rate among a biologically homogenous group of EIN lesions or by heterogeneity of malignant potential among EIN lesions. If the latter is correct, further subdivision of the EIN group along biologic lines may improve clinical predictive value. There are, however, currently no biomarkers with known additional prognostic value to the DS.
In this study, we test the hypothesis that EIN lesions that have lost PTEN tumor suppressor function confer a greater cancer risk compared with EIN lesions with an intact PTEN gene. The PTEN tumor suppressor gene is the most frequently inactivated gene in the premalignant and malignant phases of endometrioid endometrial cancer [16], [17]. Functional inactivation of PTEN results in upregulation of proliferation and association with endometrial hyperplasia and cancer has been confirmed in knockout mice [18]. Recently, the monoclonal antibody 6h2.1 has been used for routine immunohistochemical evaluation of PTEN activity, confirming that up to 83% of the endometrioid type endometrial cancers and 63% of EIN lesions are aberrantly PTEN null [16]. Loss of PTEN function precedes any histological change evident by light microscopy [16].
Section snippets
Case selection
One hundred thirty-five cases were collected from the archives of the Department of Pathology of the Stavanger University Hospital. Apart from an original diagnosis of hyperplasia, a second inclusion criterion was adequate follow-up of at least 1 year, unless cancer was detected earlier. Twenty-one patients were excluded because of hysterectomy for non–cancer-related reasons such as intractable bleeding shortly (1-8 weeks) after the index curettage. Two patients who developed cervical
Results
Of the 103 patients, 7 (7%) developed cancer in the follow-up. The previously established prognostic threshold for the morphometric DS (<1 versus >1) also held in the present material because none of the 82 cases with a DS higher than 1 progressed, contrasting 7 of 21 (33%) biopsy specimens with a DS lower than 1 (Table 1). Other thresholds (DS <0 versus >0) gave worse results. None of the 60 biopsy specimens without PTEN-null glands progressed, but 7 of 43 (16%) biopsy specimens with PTEN-null
Discussion
Several studies have found that PTEN inactivation is correlated with clonal growth patterns seen in EIN and carcinoma. However, the present study is the first one in endometrial hyperplasias in which PTEN expression is correlated with clinical outcome (progression to cancer during follow-up). The morphometric DS is the strongest single prognostic factor, thus confirming earlier study results [8], [10], [11], [12], [13]. PTEN expression had additional prognostic value to the DS but only in the
Acknowledgments
We thank Mrs Silje Lyse for her skilled technical assistance.
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