Atypia predicts progression to endometrial cancer [Classics Series]

1. Among women with endometrial hyperplasia, cytologic atypia was the most important predictor of progression to carcinoma.

Original Date of Publication: July 1985

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials, 2e (The Classics Series).

Study Rundown: Endometrial cancer is the most common gynecologic malignancy and affects 3% of all American women in their lifetime. Further, the incidence of endometrial cancer is increasing in concert with the rising obesity epidemic in the United States. Risk factors for endometrial adenocarcinoma include obesity, anovulation and advanced age. Fortunately, the majority of these cancers are diagnosed early due to the common presenting symptom of post-menopausal bleeding. Evaluation of postmenopausal bleeding in women at increased risk for endometrial cancer typically includes endometrial sampling via endometrial biopsy or dilation and curettage. Pathology might reveal benign findings, malignancy, or a premalignant lesion: endometrial hyperplasia. Endometrial hyperplasia encompasses a group of heterogenous noninvasive endometrial proliferations that are histological precursors to cancer. Prior to the 1980s, physicians and scientists knew little about which histologic characteristics conveyed the highest risk for cancer progression. Previous investigations identified an increased risk of progression with complex atypical hyperplasia but did not parse out whether cytologic (typical or atypical) or architectural (simple or complex) characteristics were more predictive of progression to cancer. In the present work, researchers followed women with hyperplasia for an average of 13 years to determine the risk of progression by cytologic and architectural characteristics.

This landmark study demonstrated that cytologic atypia is the most important risk factor for progression of endometrial hyperplasia to cancer. Strengths included central pathology review and complete access to the clinical record. Limitations included observational design whereby women with the most strikingly abnormal histology and symptomatology might have undergone hysterectomy earlier and biased results toward the null. Findings of this investigation changed clinical practice such that women with hyperplasia with atypia who have completed childbearing are now recommended to undergo hysterectomy. Later studies would demonstrate that up to 43% of women with complex atypical hyperplasia on endometrial sampling are found to have endometrial cancer on hysterectomy.

Please click to read study in Cancer

In-Depth [retrospective cohort]: A total of 170 women underwent dilation and curettage that demonstrated some degree of hyperplasia from 1940-1970 and did not undergo hysterectomy for at least 1 year. The mean time between curettage and hysterectomy was 13.4 years. Simple hyperplasia was defined as an increased number of endometrial glands; complex hyperplasia was denoted by glands with irregular outlines with marked structural complexity and back-to-back crowding; atypical hyperplasia was defined as proliferation of cells demonstrating nuclear atypia and loss of polarity. The primary outcome assessed was progression of hyperplasia to carcinoma as evidenced on subsequent curettage or hysterectomy. The frequency of regression and persistence of hyperplasia were also assessed.

Among women with endometrial hyperplasia, progression to carcinoma occurred in 1% of patients with simple, typical hyperplasia, 3% of women with complex, typical hyperplasia, 8% of women with simple, atypical hyperplasia and 29% of women with complex, atypical hyperplasia. Only 1.6% of women with typical hyperplasia progressed to carcinoma compared with 23% of women with atypical hyperplasia (p = 0.001).

Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer. 1985;56(2):403-12.

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