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PERSPECTIVE NEJM
There is great variation among women in the density of breast parenchyma as seen on mammograms. Mammographic density also varies inversely with age. Thus, younger women tend to have denser breasts than older women, but many older women also have dense breasts. The mammographic density of breast parenchyma depends on the amount of connective tissue and glandular tissue in the breast. Breasts dominated by adipose tissue, which appear less dense, are easy to assess with mammography. Thus, the most important clinical implication of denser breasts is that they are more difficult to evaluate with mammography. Small breast cancers presenting as masses without spiculations or calcifications can be missed in dense breasts. A poorly differentiated breast cancer that is 1 cm in diameter is easily diagnosed in a breast containing substantial fat tissue but would be difficult to detect in a dense breast if it were superimposed on the dense tissue (see Figure). Ultrasonography should therefore be used along with mammography as an adjunctive diagnostic method in women with dense breasts.
The matter is complicated by the fact that women with dense breasts are also at increased risk for breast cancer. Four different mammographic patterns have been identified by John Wolfe: two are dominated by adipose tissue and two by dense tissue. These patterns or the percentage of dense tissue in the breast have been used to show that increased breast density is a risk factor for breast cancer. It is important to note that in population-based screening, most breast cancers were found by Laszlo Tabar in breasts dominated by adipose tissue. Why are dense breasts a risk factor for breast cancer? The simple explanation might be that there is more glandular tissue in a dense breast and therefore more cells with the potential to transform into cancer cells. But it is not clear exactly which mechanisms or genes lead to dense breasts. Risk factors for breast cancer such as early menarche, low parity, and late menopause are clearly related to hormones. Hormone-replacement therapy places a woman in double jeopardy in terms of breast cancer. First, such therapy increases breast density in many women and can lead to impaired sensitivity of mammographic screening. Second, long-term hormone-replacement therapy increases the risk of breast cancer. Heredity is also a risk factor, but known mutations (BRCA1 and BRCA2) cannot explain all familial aggregation of breast cancer. In a report on a large study involving 571 pairs of monozygotic twins and 380 pairs of dizygotic twins in this issue of the Journal, Boyd et al. (see pages 886�894) show that mammographic density has a strong heritable component. Since dense breasts are common, heritability of this risk factor might contribute to the familial aggregation of breast cancer. What are the clinical implications for a woman with dense breasts? She should undergo regular mammographic screening examinations following the same recommendations that apply to all women in her age group. When there is a palpable lump in a dense breast and the mammographic examination is inconclusive, ultrasonography should be used (although this is the responsibility of the radiologist). I would not inform a woman that the mammographic density of her breast increases her risk of breast cancer, since the absolute increase in risk is small. The provision of such information might lead only to unnecessary anxiety.
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