Karyometry in atypical endometrial hyperplasia: a Gynecologic Oncology Group study

Abstract

Objectives: Treatment for atypical endometrial hyperplasia (AEH) is based on pathologic diagnosis. About 40% of AEH is found to be carcinoma at surgery. This study's objective is to derive an objective characterization of nuclei from cases diagnosed as AEH or superficially invasive endometrial cancer (SIEC).

Methods: Cases from GOG study 167A were classified by a central pathology committee as AEH (n=39) or SIEC (n=39). High resolution digitized images of cell nuclei were recorded. Features of the nuclear chromatin pattern were computed. Classification rules were derived by discriminant analysis.

Results: Nuclei from cases of AEH and SIEC occupy the same range on a progression curve for endometrial lesions. Cases of AEH and SIEC both comprise nuclei of two phenotypes: hyperplastic characteristics and premalignant/neoplastic characteristics. The principal difference between AEH and SIEC is the percentage of premalignant/neoplastic nuclei. When this percentage approaches 50-60% superficial invasion is likely. SIEC may develop already from lesions at the low end of the progression curve.

Conclusions: AEH comprises cases which may constitute a low risk group involving <40% of AEH cases. These cases hold a percentage of <20% of nuclei of a preneoplastic phenotype. AEH cases from the central and high end of progression have >40% of nuclei of preneoplastic phenotype. Nuclei of the preneoplastic phenotype in AEH lesions are almost indistinguishable from nuclei in SIEC, where this percentage exceeds 60%. The percentage of nuclei of the preneoplastic phenotype in AEH esions might serve as criterion for assessment of risk for the development of invasive disease.

Fig. 1

Progression curve of endometrial lesions. The distributions of case mean values for AEH and for SIEC, with their 95% confidence ellipses, fall between normal proliferative endometrial epithelium, and deeply invasive endometrial carcinoma.

Fig. 2

Case mean values for AEH and SIEC. The “+” mark indicates the subgroup centroids.

Fig. 3

Distribution of discriminant function scores for nuclei from AEH and SIEC cases. Shift to higher score values indicates higher deviation from normal tissue. The dark bars indicate the relative frequency of occurrence of nuclei of the phenotype II with a discriminant score in each interval of the discriminant function score axis, the grey bars indicate those for the nuclei of phenotype I.

Fig. 4

Discrimination of phenotype I from phenotype II.

Fig. 5

5a, Plot of the percentage of AEH cases having a certain percentage of nuclei classified as SIEC for the low end of progression and 5b, for the central and high end of progression, in comparison to 5c, cases of SIEC.