Multiplicity of Benign Breast Cancer Lesions: Risk for Progression to Cancer

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: In an analysis of benign breast disease evaluated and treated within the Henry Ford Health system over a thirteen year period, the question of breast cancer risk was determined in the context of the number of benign breast lesions. Patient age and the histologic presence of "atypia" conferred increased risk of later breast cancer, as did the presence of multiple lesions, with or without histological "atypia" and when adjusted for age.

Source: Worsham MJ, et al. Multiplicity of benign breast lesions is a risk factor for progression to breast cancer. Clin Cancer Res. 2007;13:5474-5479.

Benign breast lesions are quite heterogeneous but of these, the best characterized premalignant lesions are atypical ductal hyperplasia, atypical lobular hyperplasia and lobular carcinoma in situ.1 Prior studies of benign breast disease have focused on the risks for subsequent breast cancer associated with benign lesions classified into one of three broad histopathologic categories: nonproliferative, proliferative, or proliferative with atypia.2-4 When concurrent lesions occur, the biopsy is usually classified in terms of the most serious of these three outcome categories. What remains uncertain, however, is whether the absolute number of benign lesions predicts a malignant outcome.

To address this, Worsham and colleagues examined data from a cohort of 4,544 patients evaluated within the Henry Ford Health system within the period from January 1981 through December 1994, with BBD lesions from which 4.5% (n=201) developed breast cancer during an average follow-up period of 10.3 years. From the univariate Poisson regression analysis of 19 variables, 11 individual risk factors were significant predictors

The survey demonstrated that the majority (70%) of BBD subjects had more than one breast lesion. Concurrent multiple nonproliferative or proliferative BBD lesions with or without atypia in a BBD biopsy and age turned out to be significant predictors of risk for progression of BBD to breast cancer. The presence of atypical hyperplasia in a BBD biopsy alone or in conjunction with other lesions without atypia conferred higher risks. Women with fibrosis had a reduced risk for progression to beast cancer. Race was not a significant predictor of progression to breast cancer. The effect of age, fibrosis and multiple lesions (whether nonproliferative, proliferative, or atypia) on breast cancer progression was not influenced by race.


The current report provides useful additional predictive information for women with benign breast lesions regarding the risk for breast cancer. As demonstrated in prior reports, 5,6 benign lesions in women over the age of 50 years or lesions with demonstrable atypia were once again shown to confer increased risk for the development of breast cancer. However, a new finding was an increased risk for those with multiple concurrent lesions, whether atypia was present or not. This increased risk with multiplicity was not statistically significant at 5 years after breast biopsy but was at 10 years. The presence of atypical hyperplasia in a breast biopsy solely or in conjunction with other nonatypical hyperplasia conferred higher risks, corroborating other studies which indicate the risk of developing breast cancer is directly related to the degree of epithelial atypia. With regard to number of breast lesions, the data is very thin. In one previously reported series, 38% of women with low-grade benign disease contained more than one lesion.7 In the current comprehensive review the percentage with multiple lesions was high (70%), and women with multiple nonproliferative or proliferative lesions with or without atypia were at an increased risk. Furthermore, these findings remained significant after adjusting for age. Thus, efforts to improve risk estimates for women with benign breast disease should include both qualitative and quantitative information. Hopefully, before long more precise indicators will become evident through advances in genomic and proteonomic technologies.


1. Arpino G, et al. Premalignant and in situ breast disease: biology and clinical implications. Ann Intern Med. 2005;143(6):446-457.

2. Hartmann LC, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353(3):229-237.

3. London SJ, et al. A prospective study of benign breast disease and the risk of breast cancer. JAMA. 1992;267(7):941-944.

4. Schnitt SJ. Benign breast disease and breast cancer risk: morphology and beyond. Am J Surg Pathol. 2003;27(6):836-841.

5. Tamimi RM, et al. Benign breast disease, recent alcohol consumption, and risk of breast cancer: a nested case-control study. Breast Cancer Res. 2005;7(4):R555-R562.

6. Worsham MJ, et al. Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population. Breast J. 2007;13(2):115-121.

7. Wang J, et al. Lower-category benign breast disease and the risk of invasive breast cancer. J Natl Cancer Inst. 2004;96(8):616-620.