Current issues of ACP Journal Club are published in Annals of Internal Medicine


Atypical hyperplastic benign breast disease increased the risk for breast cancer

ACP J Club. 1992 July-Aug;117:28. doi:10.7326/ACPJC-1992-117-1-028

Source Citation

London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. JAMA. 1992 Feb 19;267:941-4.



To investigate the association between proliferative breast disease with and without atypical hyperplasia and subsequent development of breast cancer.


Case-control study nested within a cohort.


Participants were followed within the Nurses Health Study from 1976 to 1986.


Every 2 years registered nurses completed questionnaires that included reporting ever having had benign breast disease, whether this entailed hospitalization, and whether it was diagnosed by biopsy. They were also asked to report a new diagnosis of breast cancer. Nurses reporting other diagnoses of cancer were excluded. Of 121 700 female nurses, satisfactory biopsy slides were obtained for 121 of 295 women reporting breast cancer, after self-reporting of a benign breast biopsy (cases), and for 488 of 1257 potential controls, individually matched to the cases by year of birth and year of diagnosis of benign breast disease.

Assessment of risk factors

Biopsy slides were reviewed by 2 pathologists blinded to the cancer-case status of the patients. Slides were classified as nonproliferative, proliferative without atypia, or with atypical hyperplasia. Age, menopausal status, and reproductive and family history were obtained from the questionnaires.

Main outcome measures

Association between categories of biopsy tissue histology and the subsequent development of breast cancer. All cancer cases were confirmed from hospital records or pathology reports.

Main results

Biopsy specimens from cases and controls showed nonproliferative disease in 38% and 53%, proliferative disease without atypia in 40% and 38%, and atypical hyperplasia in 22% and 10%, respectively. The median period between biopsy and the development of cancer was 9 years. The adjusted odds ratio (OR) for breast cancer was 1.6 (95% CI 1.0 to 2.5) for proliferative disease without atypia and 3.7 (CI 2.1 to 6.8) for proliferative disease with atypical hyperplasia, relative to women with nonproliferative disease. Risk for cancer appeared to be higher for atypical hyperplasia among premenopausal women (OR 5.9, CI 2.9 to 13.2) but not significantly different from risk among postmenopausal women (OR 2.3, CI 0.9 to 5.9).


Women who had benign proliferative breast disease with atypical hyperplasia were more likely to develop breast cancer than women with nonproliferative disease or no atypia.

Source of funding: National Institutes of Health.

Address for article reprint: Dr. S.J. London, University of Southern California School of Medicine, 1420 San Pablo Street, PMB B306, Los Angeles, CA 90033, USA.


The possible causes of breast cancer have received extensive attention, and some demographic, reproductive, and other risk factors for the disease have been identified. Most of these risk factors are associated with modest elevations in risk of the order of 2-fold or less. Histologic changes of atypical hyperplasia in the breast epithelium, however, appear to be associated with a greater risk for subsequent cancer than most other risk factors.

London and colleagues' study is a valuable addition to the existing literature on this topic, which comprises a total 18 articles, 11 of which are also cohort-based studies. Atypical hyperplasia is a relatively uncommon subcategory of the heterogeneous group of disorders known as benign breast disease. The usefulness of atypical hyperplasia as a risk factor for breast cancer is probably critically dependent on a stringent definition such as that described by Dupont and Page (1) and used by the present authors. Variations in the definition may be responsible for differences in the prevalence of atypical hyperplasia found in different studies and for variation in the associated risk for breast cancer. The recognition of types of lesions in the breast that may be precursors to cancer may offer the potential for prevention.

In clinical practice, women in whom atypical hyperplasia is found by means of breast biopsy are at increased risk for breast cancer, especially if they have first-degree relatives with the disease. They should be followed carefully. No data exist on how surveillance is best carried out, but a policy of annual physical examination and mammography seems reasonable.

N. F. Boyd, MD
Ontario Cancer InstituteToronto, Ontario, Canada


1. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146-51.