The growth of cancerous cells usually, but not always, progresses from normal cellular tissue, to changes characterized by hyperplasia of normal cells and hyperplasia of atypical cells, to non-invasive lesions (carcinoma in situ), and finally to invasive carcinoma.

First, a brief review of breast anatomy

• The adult breast lies between the second and sixth ribs (A), between the sternal edge and the mid axillary line, and against the pectoralis muscle (B) on the chest wall. Breast tissue also projects into the axilla as the tail of Spence. The breast includes three major structures: skin, subcutaneous tissue, and breast tissue.
• The functional unit of breast tissue is called the "terminal duct-lobular unit." It is composed of milk glands (called "lobules," C) that empty into ducts (D), and is held in place by fat (E) and stroma (i.e., a connective tissue framework containing blood vessels, nerves, and lymphatics).
• The terminal duct-lobular unit drains into a series of branching ducts, which then empty into 12-15 major ducts converging behind the nipple (F) in a radial arrangement. The collecting ducts draining each segment empty into 5-10 subareolar lactiferous sinuses (G) that open at the nipple (Osborne, 2000).

Epithelial hyperplasia - ductal and lobular

• Also known as proliferative or benign breast disease.
• Characterized by excessive growth of non-malignant cells that line the ducts or lobules; these cells can vary in size, shape, and orientation (ACS, 2004a).

Clinical Pearl Women with biopsy results of proliferative changes without atypia, have double the normal risk of developing breast cancer than women without hyperplasia. They should get regular screening and follow-up (Hartmann, 2005).

Atypical hyperplasia - ductal and lobular

• Cells that are abnormal in size and shape and increased in number. Cells demonstrate some nuclear monomorphism; cells may have other architectural and cytologic features of in situ carcinoma, but they do not meet the complete diagnostic criteria for carcinoma in situ.
• Can be categorized as either ductal or lobular, based on biopsy results (Schnitt et al, 2000).

Clinical Pearl Women whose biopsies show atypical hyperplasia have four times the normal risk of later developing breast cancer and should be followed more closely (Hartmann, 2005).

Lobular carcinoma in situ (LCIS)

• Better described as lobular intraepithelial neoplasia (i.e., not a true cancer and not a pre-cancer).
• Usually includes multiple lesions and is bilateral.
• Incidental finding when breast biopsies are done for other reasons; usually no clinical or mammographic signs.
• Begins within but does not penetrate the walls of the milk-producing lobules.
• Is considered to be a "marker" that identifies women with a higher risk of subsequently developing invasive breast cancer that is usually ductal and can occur in either breast.

Clinical Pearl The increased risk can continue for 20+ years and women should be followed as higher risk for subsequent breast cancer (NCI, 2005c).

Ductal carcinoma in situ (DCIS)

• A non-invasive, proliferation of malignant epithelial cells within the duct system (some consider this to be pre-cancer) (NCI, 2005c).
• Accounts for about 18% of all breast cancers in the U.S. (invasive and non-invasive).
• Usually diagnosed by mammography, and can be seen with or without calcifications. Occasionally found by clinical breast exam, but usually nonpalpable.
• Frequency of diagnosis has increased with greater use of mammography.
• Frequently a single lesion.
• Classified into subtypes based on cell features and named for their histopathologic architectural growth patterns.
• The "comedo" pattern is the most aggressive subtype and is characterized by the presence of prominent necrosis within the duct. On macroscopic examination, this appears as pasty material exuding from divided ducts. This necrotic cellular debris within the centers of the ducts frequently becomes calcified, which then may be detected mammographically as linear, branching, or pleomorphic (i.e., varied shapes and sizes) microcalcifications (Fisher et al, 1999).
• DCIS begins within the duct system in either the terminal duct-lobular unit or larger ducts, but does not invade surrounding tissue.
• Can progress to become invasive cancer in the same breast, although the percentage that progress is not known. The natural progression of DCIS lesions is not known because most women receive at least surgical treatment.
• Subsequent risk of invasive cancer is slightly greater than with LCIS, the invasive cancer is in the same breast, and the risk can continue for decades. Women with DCIS are also at higher risk of developing cancer in the opposite breast.

Clinical Pearl Women should be referred for appropriate treatment and followed as high risk for subsequent breast cancer (Bleiweiss, 12/03; NCI, 2005c; NCI, 2005d; Sanders et al, 2005).

Invasive ductal or lobular carcinoma

• Malignant cells have invaded (i.e., infiltrated) the basement membrane of the duct or lobule, and have invaded the breast stroma (ACS, 2004e).
• Infiltrating ductal carcinoma accounts for about 80% of invasive breast cancers.
• Invasive lobular carcinoma accounts for about 5% of invasive breast cancers.
• Spread: Has the potential to grow progressively in all directions, including deep to the fascia of the chest wall and becoming fixed in position or extending to the skin causing fixation, retraction, and skin dimpling. Retraction of the nipple may develop when invasion involves the main excretory ducts.
• Lymph invasion: Growth can also progress into the lymphatics, blocking skin drainage and causing lymphedema with thickening of the skin (i.e., peau d'orange).
• Pattern of lymph spread: Is influenced by the location of the malignancy within the breast. Lymph flow in the normal breast is from superficial to deep, and the major lymphatic drainage is then to the axillary and internal mammary chains. The usual directions of drainage are the axillary nodes and nodes along the internal mammary artery.
• Determination of axillary lymph node involvement is accomplished by either axillary lymph node dissection or, more recently, sentinel lymph node biopsy (i.e., identifies the first lymph node(s) that drains the breast of lymphatic fluid and potentially malignant cells).
• Metastasis: Invasion can metastasize to other parts of the body; favored sites include the bones, lungs, liver, and adrenal glands. Macroscopic systemic metastases may be discovered by radiological tests such as chest x-ray, whole body bone scan, CT scans of the chest, abdomen, and pelvis, or positron emission tomography (PET) scan (Schnitt SJ and Guidi AJ, 2000).
• Staging of cancers integrates the primary tumor size, spread to lymph nodes, and metastasis to help determine treatment and follow-up (Bleiweiss, 2005).

Inflammatory breast cancer

• Uncommon type of carcinoma, about 2% of all breast cancers.
• May be the primary tumor or be associated with a recurrence.
• Malignant cells block the lymph vessels in the skin of the breast and cause the associated signs and symptoms.
• Signs and symptoms usually develop quickly, within weeks.
• Skin on the breast is red/bruised, swollen, warm, and may be pitted (i.e., peau d'orange). Axillary or clavicular lymph nodes may also be swollen.
• Diagnosis is based on clinical judgment and biopsy; may not be visible on a mammogram (ACS, 2004e; NCI, 2003).
• Average age of diagnosis is 58.8 years compared to 62-69 years for other types of breast cancer, and African American women have a higher incidence.

Clinical Pearl May not be visible on a mammogram. Prognosis is poorer than with other breast cancers, with a survival time of 2.9 years after diagnosis compared to 6.4 to 10 years for other breast cancers (Hance, 2005).

Paget's disease of the nipple

• Uncommon type of carcinoma, about 1-4% of all breast cancers.
• Usually characterized by itching, burning, redness, and scaling of the skin on the nipple, only later involving the areola. This progression differs from that of benign eczema, which primarily involves the areola and spreads to the nipple only secondarily.
• Sometimes includes a discharge
• 30% of cases have no visible skin changes, 50% of cases have an underlying breast lump.
• Almost always associated with an underlying breast cancer (e.g., DCIS or invasive).
• Two current theories for causation: (a) cancer cells from an underlying breast cancer move through ducts to the nipple, or (b) a spontaneous mutation of nipple cells.

Clinical Pearl The progression of skin changes with Paget's Disease (nipple to areola) differs from that of benign eczema (primarily involves areola and spreads to nipple only secondarily). Assessment for underlying breast cancer is needed (ACS, 2004e; NCI, 2002).

Other uncommon types of breast cancer are beyond the scope of this module to address (e.g., medullary, mucinous, and tubular carcinoma).