Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study

Abstract

Atypical hyperplasia is a high-risk premalignant lesion of the breast, but its biology is poorly understood. Many believe that atypical ductal hyperplasia (ADH) is a direct precursor for low-grade ductal breast cancer, whereas atypical lobular hyperplasia (ALH) serves as a risk indicator. These assumptions underlie current clinical recommendations. We tested these assumptions by studying the characteristics of the breast cancers that develop in women with ADH or ALH. Using the Mayo Benign Breast Disease Cohort, we identified all women with ADH or ALH from 1967 to 2001 and followed them for later breast cancers, characterizing side of breast cancer versus side of atypia; time to breast cancer; type, histology, and grade of breast cancer, looking for patterns consistent with precursors versus risk indicators. A total of 698 women with atypical hyperplasia were followed a mean of 12.5 years; 143 developed breast cancer. For both ADH and ALH, there is a 2:1 ratio of ipsilateral to contralateral breast cancer. The ipsilateral predominance is marked in the first 5 years, consistent with a precursor phenotype for both ADH and ALH. For both, there is a predominance of invasive ductal cancers with 69% of moderate or high grade. Twenty-five percent are node positive. Both ADH and ALH portend risk for ductal carcinoma in situ and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. The ipsilateral breast is at especially high risk for breast cancer in the first 5 years after atypia, with risk remaining elevated in both breasts long term. ADH and ALH behave similarly in terms of later breast cancer endpoints.

Figure 1

Cumulative risk of breast cancer over time. Expected breast cancer events were calculated by applying age- and calendar period-stratified person-years of observation to Iowa SEER incidence rates. Observed and expected events cumulated after accounting for death as a competing risk.

Figure 2

A: Side of later breast cancer for women with ADH vs. ALH. Note that for two women with ADH, side of BC is missing; for four women with ALH, side is missing. B: Time to later BC, by side of BC, for women with ADH and ALH. C: Type of later breast cancer for women with ADH vs. ALH. Either side or type of BC is missing for two women with ADH and nine with ALH. D: Histology of later BCs in women with ADH vs. ALH. Note that seven mixed ductal lobular invasive cancers are included in the invasive ductal group in women with ADH, and nine in women with ALH. Either side or histology is missing for two women with ADH and nine women with ALH. E: Grade of later BCs in women with ADH vs. ALH. Both invasive BCs and DCIS displayed. Either side or grade is missing for 18 women with ADH and 26 women with ALH.