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cribriforming

All must be met.

All must be met.

stroma, gland outer surface density) and cytological (standard deviation of the shortest nuclear axis) variables (36,37). Histomorphometry has the advantage of an extraordinarily high level of reproducibility and standardization in a commercially available platform (QProdit system manufactured by Leica Microsystems, Cambridge, UK). This provides a durable standard for diagnosis, which has value as a reference and training tool. Morphometric EIN diagnosis for clinical application is in use in some European centers, but practical considerations discourage implementation in the United States. Fortunately, it has been possible to individually extrapolate criteria from the histomor-phometric experience into a set of diagnostic rules applicable by pathologists at a standard microscope (Table 3) (38).

Routine EIN diagnosis requires presence of specific topographic, architectural, and cytological features, and exclusion of carcinoma, and benign mimics (Table 3) (29). The clonal origin of EIN lesions begins with localized topography with increasing size over time. Some lesions will be diagnostic only within a single fragment of an endometrial sample, whereas approx 15-20% of lesions will occupy the entire endometrial compartment at time of diagnosis. Lesions smaller than 1mm in maximum dimension do not have a dramatically elevated cancer risk, so this lower size cut off defines the smallest EIN lesion. This measurement is made within a single fragment, by referencing the perimeter as defined by an epicenter of crowded and cytologically altered glands.

The cardinal structural changes of EIN are concurrent changes in both cytology and architecture that offset the lesion from the background endometrial pattern. Crowded glands with a regional surface area more than that of intervening stroma are made up of cells with a different cytology than the background. Significant cytological change must be interpreted relative to the background, as there is no consensus or stereotypical cytological appearance shared by all EIN lesions. Many, but not all, have the nuclear rounding and prominent nucleoli, historically associated with "atypia." Rather, some EIN lesions have an elongated nuclear cytology, and in other examples the most prominent cytological alteration is cytoplasmic rather than nuclear.

EIN mimics are numerous and must be recognized at a glance. Normal secretory endometrium may have crowded glands, especially in the low functionalis where stro-mal expansion is minimal. Anovulatory endometria is present as a diffused, nonlocal-ized, disordered mixture of cysts and proliferative glands. Approximately 15% of EIN lesions occur within endometrial polyps, in which case the polyp must serve as the counterpoise for diagnosis, not the native functionalis. EIN lesions grow as aggregates of individual glands lined by a single layer epithelium, usually, tubular or with simple branching. Neoplastic epithelium that grows in solid masses, complex folded sheets (with a mazelike interconnected luminal profile), or significantly cribriform lumens should be diagnosed as adenocarcinoma. Interested readers are referred to the educational website www.endometrium.org for more extensive discussion and illustrations on how to diagnose EIN.

5.4.3. EIN Clinical Outcome Prediction

Patients with EIN lesions have a very high risk for progression to adenocarcinoma, approx 89 times that of women without an EIN lesion. Several clinical outcome studies of women with morphometrically diagnosed EIN (36,39-41) have recently been assembled as a large meta-analysis encompassing 674 endometrial "hyperplasia" patients with clinical follow-up (42). Stratification of the endometrial hyperplasias as EIN vs non-EIN showed an 89-fold increased frequency of endometrial cancer in the EIN group. Depending on the interval between EIN and cancer diagnosis, these cancers might be construed either as concurrent or progression events. Thirty nine percent of patients with an EIN diagnosis were diagnosed with endometrial adenocarcinoma within 1 year, compared with no patients in the non-EIN group. More than 1 year after EIN diagnosis, progression to endometrial adenocarcinoma is 45-fold higher for patients with EIN compared with those without. This is compared with a sevenfold cancer risks for atypical hyperplasia vs nonatypical hyperplasia in the same patient population.

Subjective EIN diagnosis also provides excellent cancer risk prediction (38). A group of 84 women with various endometrial hyperplasias and known clinical outcome included eight cancer occurrences, of which five were in the atypical and three nonatyp-ical hyperplasia groups. When rediagnosed using the EIN schema, all eight cancer occurrences were in women with previous EIN lesions. The number of patients in the high-risk groups was approximately equal for WHO and EIN classifications, including 21 atypical hyperplasias and 25 EINs.

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