Breast cancer

Breast cancer is the most common cancer type and the leading cause of cancer-related death in women worldwide. It is exceedingly rare in males (around 1% of cases). The incidence is highest in high-income and high-middle income countries in Northern America, Australia, New Zealand, or Europe. Breast carcinoma is more common in women of Caucasian background opposite to Asian and Hispanic women. Even though the overall incidence of breast cancer started to decrease in the past two decades, it has increased in women younger than 50 years. Approximately half of the breast cancers develop in women with no identifiable breast cancer risk factors other than gender (female) and age (over 40 years). Well-known risk factors are obesity, history of radiation exposure, early onset of menarche, age at first pregnancy older than 30 years, tobacco use, and postmenopausal hormone therapy. Most breast cancers occur sporadically, but 5-10% of patients develop carcinoma in the context of inherited cancer syndromes. Mutations of BRCA1 and BRCA2 genes account for 20 - 60% of familial breast cancer and are associated with breast cancer at an early age. Women with ataxia telangiectasia and Li Fraumeni or Cowden’s syndrome have a higher risk for breast cancer as a consequence of mutations in ATM, PTEN, and TP53 genes.

Breast cancer can be detected by self-examination as a lump in the breast. Advanced tumors cause skin ulcerations, enlargement of lymph nodes, and so-called “orange skin” due to obstruction of lymphatic circulation in the breast and skin with tumor cells. Tumors are often detected by screening radiography (mammography).

The most common form of breast cancer is of breast carcinoma. It arises in the lining epithelium of the ducts (85%) or lobules (15%) in the glandular tissue of the breast. Initially, the cancerous growth is confined to the duct or lobule (“in situ”) and invasive carcinoma further develops from such precursor. Breast carcinoma is classified based on histological features and the two most common forms are ductal and lobular carcinoma.

Ductal carcinoma is the most common type of breast carcinoma (up to 80%). Tumor cells are pleomorphic and organized in tubules, sheets, nests, or cords or individual cells. Stroma is usually desmoplastic, and calcification is frequent, while necrosis is variable. A precursor lesion called ductal carcinoma in situ is often found adjacent to the invasive component of the tumor. It is recognized by increased layers of cells in ducts, which can give cribriform appearance or even fill the lumen of ducts. The myoepithelial cell layer surrounding ducts is intact.

Lobular carcinoma comprises about 10% of invasive breast carcinomas and frequently occurs in both breasts (bilateral tumor). The tumor is composed of small, discohesive, and monomorphic cells without marked atypia, and with round or notched ovoid nuclei and scant cytoplasm. Mitoses are infrequent. Tumor cells are arranged in single files, cords, and single cells, often concentrically around normal ducts, less frequently in solid nests. Stroma is not desmoplastic. A precursor is called lobular carcinoma in situ. It is recognized as lobulocentric proliferation of small uniform cells, which fill and distend most of the acini in the involved lobule.

A three-tiered grading system is used in breast carcinoma. It is utilizing the Nottingham Grading System, also termed the Elston-Ellis grading system, by evaluating three tumor parameters: extent of tubular differentiation, nuclear pleomorphism, and mitotic activity. Mitotic activity is assessed in ten high power fields and reported as the number of mitosis per square millimeter. Each parameter is given a score of 1 to 3 and the score of all three components are added together to a final score e.g. 1+1+1=3. The lowest final scores of 3, 4, and 5 represent well-differentiated tumors (Grade I) associated with better survival. The highest possible score is 9 (3+3+3=9) reflecting a poorly differentiated (Grade III) tumor associated with poor overall survival.

Immunohistochemistry is used routinely on all breast cancers to gain important information about the prognosis as well as for predicting response to specific anticancer therapies. The most commonly used antibodies include antibodies detecting the estrogen α receptor (ER, ESR1), progesterone receptor (PR, PGR), HER-2 (ERBB2), and the proliferation marker Ki-67 (MKI67). The tumor stage and grade, as well as results from immunohistochemistry, are used to personalize treatment options. The use of myoepithelial marker p63 is useful in the evaluation of invasion in ductal carcinoma in situ. Evaluation of amplification of HER2 gene by chromogenic or fluorescent in situ hybridization is performed in equivocal cases after immunohistochemical evaluation of HER2 expression. Detection of mutations in BRCA genes has a role in the diagnosis of familial cancer in an appropriate clinical context, but also for the selection of patients for treatment with PARP inhibitors.

Prognosis and treatment of breast cancer depend on the stage of the disease, and in part, on histological features of the tumor. Treatment of breast cancer generally consists of surgery and radiation therapy and systemic therapy including hormone therapy, chemotherapy, and in some cases targeted biologic therapy. The 5-year survival rate in women with localized diseases is 99%, while it is only 28% in distant disease. This reflects the importance of early cancer detection by screening methods.