EIN A Comprehensive Model of a Precancerous Lesion

A broad foundation of molecular, histological, and clinical outcome data has established the entity of EIN as the biological precursor for endometrioid endometrial adenocarcinoma (29). EIN lesions are precancerous lesions with particular biological and histological features that confer a heightened risk for concurrent or future endometrioid endometrial cancer. EIN was defined through an open-ended discovery process, which correlated presence of those molecular features predicted in premalig-nant disease with histopathological presentation and clinical outcome (30). The result is a robust construct, which has practical application in clinical patient management, and provides a framework to explore those variables and factors that are relevant to the carcinogenesis process.

Because EIN diagnosis applies criteria, which have not been previously considered in the older WHO "hyperplasia" diagnostic schema, there is no direct or absolute concordance between EIN lesions and any specific subset of hyperplasias. For this reason, the EIN diagnostic schema replaces, rather than supplements, the old World Health Organization (WHO) hyperplasia classification. Although, approximately two-third of EIN lesions are culled from the pool of atypical hyperplasias, the balance come from a variety of heterogeneous entities, such as "metaplasias" and "nonatypical hyperplasias." Once EIN lesions are identified, the balance of "hyperplasias" falls into a variety of specific diagnostic categories corresponding to particular pathogenetic states, including anovulatory endometrium (unopposed estrogen effects), endometrial polyps, and a broad range of unusual presentations of reactive and normal processes.

5.4.1. Molecular Features of EIN

The latent or subclinical phase of endometrial carcinogenesis is followed by localized emergence of an aggregation of cytologically altered cells arrayed in an architecturally crowded focus known as EIN (Fig. 4) (31,32). Monoclonality of EIN lesions has been demonstrated by the presence of nonrandom X chromosome inactivation among the mutated lesion cells in contrast to the randomly inactivated polyclonal source field (33-35). Other genetic alterations that commonly characterize EIN lesions, such as MI (17,24), PTEN mutation (20), and KRAS (27) mutations are clonally present among the cells of affected EIN lesions. These genetic changes offset a discrete EIN lesion from its tissue background. This fact indicates that they are the product of somatically acquired mutation rather than inherited genetic changes that would otherwise affect the entire endometrial compartment. The clone, which consists an EIN lesion, may acquire additional mutations or genetic heterogeneity during subsequent clonal expansion, a key element of progression to carcinoma (17). However, not all EIN lesions progress. Some undergo complete involution, whereas others persist for long periods and expand to occupy the entire endometrial compartment as a premalignant lesion.

Adenocarcinoma tissues contain all of the PTEN, microsatellite, and X inactivation patterns seen in EIN lesions from the same patient, objective evidence of direct lineage continuity between premalignant and malignant phases of tumor evolution (18). Comparison of the extent and range of genomic damage between premalignant and malignant phases indicates a higher cumulative mutational load in cancers, a feature that must contribute to their differing morphology and behavior. For example, whereas 55% of EIN lesions have demonstrable PTEN inactivating events (mutation and/or deletion), the proportion rises to 83% in those cancers which follow an EIN lesion (20). Similarly, for those lesions with MI, the burden of altered microsatellite alleles increases between EIN and carcinoma (17,18). Although, it is convenient to label PTEN and microsatellite alterations as "early" events, inactivation of these genetic targets

Fig. 4. PTEN inactivation in an EIN lesion. PTEN mutant glands may progress to endometrial intraepithelial neoplasia (EIN), characterized by a focal point of origin and distinctive histological changes. Pale PTEN nonexpressing glands within this EIN lesion are larger in diameter and contain a taller epithelium than overrun PTEN expressing glands (arrowheads). This EIN lesion was photographed at its outer edge to emphasize its localized topography. Gland area within the lesion perimeter (left half of the image) exceeds that of stroma. PTEN immunohistochemistry with antibody 6h2.1.

Fig. 4. PTEN inactivation in an EIN lesion. PTEN mutant glands may progress to endometrial intraepithelial neoplasia (EIN), characterized by a focal point of origin and distinctive histological changes. Pale PTEN nonexpressing glands within this EIN lesion are larger in diameter and contain a taller epithelium than overrun PTEN expressing glands (arrowheads). This EIN lesion was photographed at its outer edge to emphasize its localized topography. Gland area within the lesion perimeter (left half of the image) exceeds that of stroma. PTEN immunohistochemistry with antibody 6h2.1.

occurs incrementally and can encompass both premalignant and malignant intervals. Clonal diversification and selection, which continue after malignant transformation, creates genetic heterogeneity within tumors, a feature that may polarize aggressiveness and therapeutic response among component cells of one tumor.

5.4.2. EIN Diagnostic Criteria

Criteria for diagnosis of EIN were developed by objective computerized histomor-phometric analysis of a series of individual lesions previously shown by genetic studies to be premalignant (18,30,31). Genetic evidence for premalignant behavior includes a monoclonal growth pattern and genetic alterations conserved in subsequent carcinomas. The histological pattern observed in genetically defined precancers was exactly similar to that documented by independent histomorphometry studies to confer an elevated risk for endometrial carcinoma during clinical follow-up (18). Molecular, diagnostic, and clinical outcome evidence has thus been tightly linked in the newly integrated EIN schema.

EIN can be diagnosed by formal computerized histomorphometric measurement of the D-Score, a quantitative threshold function incorporating architectural (volume percent

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