We examined patient characteristics and rates of ADH with and without cancer in a population of women screened with mammography. As the diagnosis of ADH is associated with the use of mammography, we chose to examine a screened population in order to minimize the trends that are due to changes in use of screening mammography over time. We found that the rates of both ADH and cancer associated with ADH were significantly increased among women with a positive family history of breast cancer and current postmenopausal HT users.
When examining risk factors for ADH, several reports found a positive association between increasing age and rates of ADH, (1
) whereas others did not (2
). None of these studies adjusted rates for other possible risk factors associated with ADH and age. In our population, the highest rates of ADH were in the 50–59 year age group; however, after adjusting these rates for risk factors, ADH was not significantly associated with age.
Similar to our finding of a significant association between use of postmenopausal HT and ADH, women in the Nurses’ Health Study with ADH were more likely to have used postmenopausal HT for more than 5 years than were women with proliferative biopsies without atypia or non-proliferative breast biopsies (6
). The Women’s Health Initiative found a higher rate of benign proliferative breast disease in women using estrogen plus progestin (16
). A higher rate of atypical hyperplasia was not found in these women, but the authors noted the small numbers of biopsies with atypical hyperplasia in their study. Earlier studies found no association between use of postmenopausal HT and ADH (17
). It is difficult to compare the different study results, because postmenopausal HT composition has changed over time (i.e. combined estrogen and progesterone vs. estrogen alone) and the exact treatment is not available in most studies, including ours.
As for family history, Webb (14
) reported an association between atypical hyperplasia and a positive family history (when comparing to women with benign breast biopsy with no atypia) in the Nurses’ Health Study II participants; and Hartmann found a similar association using the Mayo Clinic dataset (15
), consistent with our results. Others have not found such an association (2
In our study, we found ADH in 3.4% of biopsies done within one year of screening mammography in women with a screening examination within the previous 5 years. Reported rates of ADH vary widely from 2% to 12% of biopsies across studies (1
). Page (1
) reported a rate of 2% in all surgical biopsies done between 1950 and 1968, whereas de Mascarel(18
)included all surgical biopsies for microcalcifications between 1975 and 2002 and found a rate of 8%. Eby et al (19
) reported even higher rates in percutaneous biopsies in Seattle, WA (12% after excluding cases upgraded to cancer); which they hypothesized was due to geographical variance. Other explanations of the variability in rates include the specimen analysis protocol; de Mascarel (18
) reports the most exhaustive analysis (median of 26 slides per specimen, compared to 1–5 slides in most of the cases Page reported), hence the higher rate of abnormal findings in this study. Page previously noted this finding (1
): as the number of slides per specimen examined increases, a higher rate of atypical lesions is identified. Another reason for variation may be different definitions of ADH, some including other lesions such as flat epithelial atypia and atypical columnar hyperplasia.
Reported rates of ADH associated with cancer also vary considerably. In this study, 7% of invasive cancers were associated with ADH in the same breast, as were 19% of DCIS cases. Fowble (20
) found ADH in 22% of patients undergoing breast-conserving surgery for invasive carcinoma. This rate, however, was significantly increased from a previous report from the same center, which emphasizes the fact that rates of ADH are associated not only with the study population and criteria for diagnosis, but with the effort made to identify it.
The recent decrease in incidence of breast cancer in the United States has been ascribed to the decreased use of postmenopausal HT (10
), suggesting a role for postmenopausal HT as a promoter of breast cancer. Use of postmenopausal HT in our population decreased since 2000 in the 40–49 age group and since 2001 in the 50–69 and 70+ age groups. The rates of pure ADH in the same population decreased in 1999–2000 and again starting in 2002. Changes in use of postmenopausal HT may explain the second decline that occurred in the rates of ADH. The rates of cancer associated with ADH decreased after peaking in 2002–2003, depending on the age group. Use of postmenopausal HT has been associated with higher rates of both advanced and early-stage breast cancer (25
), as well as higher rates of breast biopsies in general (25
) and benign proliferative breast disease (16
). Postmenopausal HT may promote breast epithelium proliferation differently depending on genetic mutations and patient risk factors, resulting in increased rates of ADH, early cancer, and advanced cancer.
The trend in rates of cancer associated with ADH (peaking in 2002–2003, then decreasing) maybe explained by differences in pathologic reporting of the benign tissue surrounding cancer and the increased use of core biopsies. It is possible that when excisional biopsies were used as the first biopsy, the entire lesion was excised and the pathologist limited the report to the most severe diagnosis in the specimen, reducing the reporting of ADH associated with cancer. Although we found an association between cancer with ADH and use of core biopsy as first biopsy, controlling for type of first biopsy did not change the trends in rates of cancer associated with ADH over time (data not shown). Changes in the definition of ADH may have contributed to these changes as well, as the diagnosis of ADH and low-grade DCIS can overlap; however, overall rates of DCIS with ADH were stable since 1998 (data not shown). The decrease in cancer with ADH since 2002–2003 may be due to other variables that this study did not examine, such as increased use of tamoxifen. However, the decrease cannot be explained by decreases in screening utilization, because we examined women undergoing screening mammography and controlled for the time since last screening mammography.
In our patient population, cancer associated with ADH was more likely to be of low stage and grade and estrogen and progesterone receptor positive when compared to cancer with no associated ADH. An association with low stage (18
) and low grade (18
) was previously reported. These findings support the theory of separate pathways for low grade and high grade breast cancers, with ADH possibly being a precursor of some low grade cancers. We found a non-significant increase with mixed ductal and lobular cancers; others reported an association with invasive lobular and tubular carcinoma (18
This is the largest study reviewing patients with ADH. However, our study has several limitations. First, no central pathologic review of the slides was performed, and the diagnosis of ADH is complicated and may differ by mammography registry and over time. Therefore, all three groups of outcomes may include patients with incorrect diagnoses either because of under- or over-diagnosis. This misclassification can cause under- or overestimation of the associations we found. The diagnosis of ADH with cancer was based on the finding of both diagnoses in the same patient in the same breast within 3 months from the first biopsy. Therefore patients diagnosed with cancer and ADH in the same breast may actually have these two diagnoses in two separate foci. The cohort of patients is not constant over time, as can be seen from the fairly constant age of the cohort over the 10 years; therefore, a certain percentage of women are lost every year, and new women are continually added. In an attempt to examine the trend in diagnosis of ADH in a screened population, we included only women with a prior screening mammogram within 5 years. This selection criterion on the one hand may limit the generalizability of our results as women undergoing regular mammography screening have been shown to be a selected group of women. On the other hand, over 70% of women undergo screening mammography so that our results apply to a large proportion of women. Finally, association between use of postmenopausal HT and different outcomes is limited to current use of any postmenopausal HT at the time of the mammogram. Our findings relate only to current users of postmenopausal HT. As the dataset does not include the type of hormone treatment, the associations found are probably due to use of combined estrogen and progesterone treatment as only combined therapy has been shown to increase the risk breast cancer.
In conclusion, ADH with and without cancer is associated with use of postmenopausal HT. Rates of ADH and cancer associated with ADH in this screened population have decreased over time. This finding may be partially explained by the decrease in rates of use of postmenopausal HT.