Benign And Malignant Diseases Of The Breast
Breast complaints are common in women and most diseases of the breast (96%) are nonmalignant. Histologic subcategorization of breast masses, based upon cellular proliferation and the presence or absence of hyperplasia, divides these lesions into three subgroups. Nonproliferative lesions include simple and complex cysts. While most cystic lesions do not increase breast cancer risk, complex cysts containing solid and cystic components on ultrasound have increased malignant potential. Proliferative lesions without atypia include fibroadenomas, simple ductal and intraductal hyperplasia, sclerosing adenosis and papillomas. The latter are often associated with unilateral nipple discharge. All of these solid lesions increase breast cancer risk with a relative risk (RR) of 1.6–1.9. Proliferative lesions with atypia (atypical hyperplasia) can be of ductal or lobular origin. They increase the risk of breast cancer 3.7–5.3-fold.
Other common breast disorders include mastitis, cyclical breast pain and nipple discharge. Mastitis affects 3–10% of lactating women and typically presents as unilateral breast pain and high fever. Cyclical breast pain is often related to the hormonal changes of the menstrual cycle. Risk of malignancy after normal exam and imaging of the painful breast is very low. Most women of reproductive age can express discharge from their nipples. However, unilateral discharge, the presence of blood, age greater than 40 and association with a breast mass are concerning and require additional testing.
Breast cancer is the most common malignancy in women. In addition to occuring almost exclusively in women, it is also a disease of aging. The lifetime risk of developing breast cancer (1 in 8) is largely concentrated in the perimenopausal and postmenopausal years. Risk in the 30-year-old is 1 in 2525, that in a 45-year-old 1 in 93 and that in a 65-year-old 1 in 17. Older women tend to underestimate their risk and many women under 50 years of age grossly overestimate their risk. Consequently, these two groups of women misjudge the benefits of breast cancer screening programs.
Breast cancer can arise anywhere in the mammary gland. Tumors are typically classified by their cells of origin: lobular or ductal. Ductal carcinomas account for 85% of breast cancers and can be either non-invasive (intraductal) or infiltrating. Those ductal carcinomas that are histologically confined by the basement membrane of the duct are called intraductal carcinomas or ductal carcinoma in situ (DCIS). DCIS is considered a precursor lesion to invasive carcinoma. At least 33% of these lesions will progress to invasive cancer within 5 years. Once the basement membrane of the duct is breached, an infiltrating carcinoma has developed. The most common type of invasive carcinoma is ductal carcinoma, which accounts for 79% of invasive carcinomas. The next most common type is lobular carcinoma. These lesions arise from the terminal ductules of the alveoli and comprise approximately 10% of invasive breast cancers. Less common types of infiltrating carcinomas include medullary carcinomas, mucinous (colloid) carcinomas and Paget disease. Paget disease is a special subtype of infiltrating ductal carcinoma localized to a main lactiferous duct. In Paget disease, eczematous changes develop in the nipple and areola overlying the affected duct. These skin changes are often the first sign of disease although the cancer may have been present for some time.
Breast cancer metastasizes first to the regional axillary lymph nodes. The most frequent distant metastatic sites are bone, liver, lung, pleura and brain. Patients with histologically negative axillary nodes have a much higher likelihood of survival than do patients with positive nodes. The ultimate prognosis for the disease depends on the size of the tumor, the number of involved lymph nodes and whether or not lymphovascular invasion (LVI) is present.
Treatment of invasive breast cancer is typically multimodal, but ultimately depends on the stage of the disease at the time of diagnosis. Surgical options include a modified radical mastectomy or lumpectomy with local irradiation. Ipsilateral axillary lymph node dissection is also typically performed. Women with positive lymph nodes will usually receive additional antineoplastic chemotherapy. Those with negative nodes will receive adjuvant chemotherapy if they have large primary tumors or LVI, because both confer a high risk of tumor recurrence. Tamoxifen is a medication with estrogenic and antiestrogenic properties; it is the most widely used endocrine therapy for breast cancer. Before employing endocrine therapy, it is important to know the estrogen and progesterone receptor status of the tumor because only receptor-positive tumors predictably respond to medications like tamoxifen.
Treatment of DCIS is controversial and includes mastectomy or wide local excision plus irradiation. Recurrence rates following excision plus radiation are approximately 10%; half of these are invasive.
Epidemiology of breast cancer
The epidemiology of breast cancer in women suggests that it is an endocrine disorder related to prolonged exposure to ovarian hormones (Fig. 39.1). Ovarian hormones have been shown to increase the mitotic activity of mammary cells in culture. In addition to the factors listed in Table 39.1, hormonal treatment in the form of postmenopausal hormone replacement therapy may contribute to a higher lifetime risk of breast cancer.
There are also large ethnic and geographic differences in the prevalence of breast cancer. Asian women born and raised in Asia have one-fifth the risk of developing breast cancer that American women have. The risk rises toward the American level if Asians live in the USA for two or more generations, suggesting an environmental or lifestyle influence on the disease. Even within a single large country, breast cancer incidence and mortality rates can vary by location. In more affluent areas, breast cancer rates are elevated. This may be related to delayed child-bearing among more affluent and better educated women. The association of alcohol intake with increased breast cancer risk suggests there is an environmental influence on its development.
Familial breast cancer
About 10% of breast cancer is familial. The clustering of breast cancers with ovarian cancers in many familial cases led to the discovery of two genes, BRCA1 and BRCA2. Individuals with germline mutations in these genes are at high risk for the development of specific cancers. Current evidence indicates that 25% of inherited cases of breast cancer result from mutations involving BRCA1 and BRCA2. Both BRCA1 and BRCA2 are tumor suppressor genes and mutation in a single allele of either gene confers an increased cancer risk. The ethnic and geographic distributions of BRCA1 and BRCA2 are discussed in more detail in Chapter 42.
Molecular biology of sporadic (nonfamilial) breast cancer
Molecular studies have identified several genetic loci that are frequently abnormal in breast cancer specimens but not in normal breast tissues. The most commonly encountered abnormalities involve the oncogenes, ERBB2 and c-myc, the tumor suppressor gene TP53, and telomerase. Both oncogenes are amplified or overexpressed in about 30% of breast cancers; telomerase activity is elevated in 80–90%. Breast tissue with ERBB2 abnormalities appears to be resistant to the effects of the antiestrogen tamoxifen but more sensitive to standard chemotherapeutic agents. TP53 abnormalities interfere with normal apoptosis, thereby making affected tumors more resistant to chemotherapy and radiation therapy. Like most malignancies, breast cancer probably results from the effects of environmental triggers on genetically susceptible tissues.