ANATOMY AND PHYSIOLOGY
The breast extends from the clavicle (approximately the second rib) to the sixth rib and from the sternum to the mid axillary line. Approximately 10 to 100 alveoli (secretory units) form lobules that drain into ducts, which eventually lead to the nipple. The breast is surrounded by fascia connected by the suspensory ligaments of Cooper.
The blood supply to the breast is mostly from anterior perforating branches of the internal mammary artery, various branches of the axillary artery, and posterior intercostal arteries. The lymphatic drainage is primarily to axillary lymph nodes, internal mammary lymph nodes, and interpectoral nodes of Rotter. Axillary lymph nodes are stratified into three levels depending on their location relative to the pectoralis minor muscle. Level I lymph nodes are lateral to the muscle. Level II lymph nodes are deep to (behind) the muscle, and level III lymph nodes are medial to the muscle (Fig. 14-1).
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Figure 14-1 • Breast anatomy with blood supply and lymphatics. |
The nipple is innervated by T4, no matter how pendulous the breast. Although they do not innervate the breast, the long thoracic and thoracodorsal nerves are important because of their proximity to axillary lymph nodes. Injury to the long thoracic and thoracodorsal nerves during axillary nodal dissection may result in winged scapula or weakness in shoulder adduction, respectively. Additionally, the intercostal brachial cutaneous nerves pierce the tail of the breast parenchyma and, when divided, will cause paresthesias of the medial aspect of the upper arm.
Cyclic hormonal changes affect the breast. The breasts may feel lumpy and tender before menses. Pregnancy causes marked hypertrophy of the alveoli, lobules, and ducts in preparation for lactation. With menopause, the lobules become atrophic.
PATHOLOGY
Benign conditions of the breast include fibrocystic changes, fibroadenomas, simple cysts, intraductal papillomas, and gynecomastia. Phyllodes tumors can be benign, borderline, or malignant. High-risk and premalignant lesions include atypical ductal and lobular hyperplasia and lobular carcinoma in situ (LCIS). The most common malignancies are intraductal carcinoma (also known as ductal carcinoma in situ [DCIS], which is noninvasive because it does not penetrate the basement membrane), invasive ductal carcinoma, and invasive lobular carcinoma. Inflammatory breast cancer is characterized by skin involvement (invasion of the subdermal lymphatics). Paget disease of the nipple is an intraepithelial neoplasm that may be associated with an underlying breast cancer (invasive or in situ).
EPIDEMIOLOGY
Lifetime risk of American women for developing breast cancer is one in eight (12%). It is the most frequently diagnosed cancer in women and the second most frequent cause of cancer-related death among women. Incidence increases with age and varies among various ethnic groups: incidence of breast cancer in Hawaiians is greater than that in Whites, which is greater than that in Blacks, which is greater than that in Asians and Hispanics, which is greater than that in American Indians. Significant risk factors are female
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sex, age, BRCA gene mutations, hormone replacement therapy, personal history of breast cancer, radiation to the chest at age younger than 40 years, first-degree relative with breast cancer (higher if the relative was premenopausal), and prior biopsy-proven LCIS or atypical hyperplasia (ductal or lobular). The incidence of breast cancer in men is 1%. The most common tumor in young women is fibroadenoma.
HISTORY
Most women report finding a breast lump while showering or with breast self-examination. Breast pain is usually associated with benign lesions, but may occasionally be present with malignant lesions. Lumps that increase before menses and decrease after menses are usually benign simple cysts or fibrocystic changes. Spontaneous or bloody nipple discharge is associated with intraductal papillomas. Malignant lesions do not vary in size with the menstrual cycle. Patients with advanced stages may have weight loss, odor from ulcerating or fungating lesions, pain from bone metastasis (back, chest, or extremities), nausea or abdominal pain from liver metastasis, or headaches from brain metastasis.
PHYSICAL EXAMINATION
When examining the breasts, one looks for skin changes, asymmetry (visible bulge or dimpling of skin), nipple retraction, palpable masses, and lymphadenopathy in the axilla and supraclavicular fossa. Well-circumscribed, mobile, nontender lumps in young women are usually fibroadenomas or phyllodes tumors. Breast tenderness is associated with fibrocystic changes or simple cysts. Vague masses or firm lumps with indistinct borders are suggestive of malignancy. With advanced stages, there may be skin changes such as dimpling, peau d'orange (edema of the skin, making it look like an orange peel), ulceration, erythema, or fixation to the skin or chest
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wall. Enlarged or matted lymph nodes may indicate metastasis. Paget disease usually presents with nipple or areolar rash or excoriation. Inflammatory breast cancer may have erythema, peau d'orange, or skin thickening.
DIAGNOSTIC EVALUATION
With the increase in breast cancer awareness, screening mammograms initially led to an increase in breast cancer diagnoses. This increased incidence has subsequently reached a plateau. Screening mammograms have resulted in diagnosing breast cancer at an earlier stage, with improved survival and decreased mortality.
Mammograms miss 15% of palpable breast cancers and should be done in conjunction with clinical breast examination. Mammographic signs that suggest malignancy include a density with indistinct margins, spiculated mass (Fig 14-2), and clusters of or linear/branching microcalcifications. Lesions not seen on prior mammograms need further work up. Also, if the patient reports a palpable lump, then a diagnostic mammogram (additional views to magnify and/or compress the breast are obtained to identify or characterize the lesion) and breast ultrasound are performed.
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Figure 14-2 • Craniocaudal (CC) (A) and oblique (MLO) (B) views of mammogram showing a breast cancer (circle). Image courtesy of Rhona Chen, MD. |
Ultrasound can differentiate between solid and cystic masses (Fig. 14-3). It is not optimal for screening because it rarely detects microcalcifications and is extremely dependent on the experience of the person performing the examination.
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Figure 14-3 • Solid (fibroadenoma) and cystic (simple cyst) lesions on ultrasound. Image courtesy of Rhona Chen, MD. |
Breast magnetic resonance imaging (MRI) is rapidly increasing in popularity. Current indications include identifying occult primary cancer with axillary metastasis in women with no clinical breast mass and normal mammogram, screening women at very high risk (>25%) for developing breast cancer, determining
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extent of breast cancer to help with surgical planning, and measuring response to neoadjuvant therapy. Advantages of breast MRI include creation of three-dimensional images, minimal or no breast compression, effectiveness in women with dense breasts, and high sensitivity for detecting breast cancer. Disadvantages are moderate to low specificity (false-positive results lead to unnecessary biopsies and patient anxiety), expensive cost, long time to perform examination (30 to 40 minutes, as compared with 5 to 10 minutes for mammogram), requirement of contrast, and inability to demonstrate microcalcifications.
Table 14-1 includes the American Cancer Society recommendations for breast cancer screening.
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TABLE 14-1 American Cancer Society Guidelines for Breast Cancer Screening |
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Lesions suggestive of malignancy on diagnostic examination are biopsied with image guidance: mammographic, ultrasonographic, or MRI guided core needle biopsy. Palpable masses not seen with imaging can be biopsied with fine-needle aspiration (FNA), core needle biopsy, excisional open biopsy, or incisional biopsy. A benign lesion can be observed radiographically and clinically. Malignant lesions require surgical consultation. If the pathology report shows atypia or LCIS or is discordant with radiologic or clinical findings, then an open biopsy should be performed. This may require wire localization by the radiologist. If the patient presents with skin changes over the breast mass, an incisional biopsy should be considered, taking an ellipse of skin with the mass to check for cancer involvement of dermal lymphatics.
If DCIS or invasive breast cancer is diagnosed pathologically, additional pathologic tests are performed. The tumor is checked for hormone receptors, HER-2/neu receptor, and, occasionally, various other biologic markers. Tumors with better prognostic indicators are well differentiated (low-grade cancer), have overexpression of estrogen receptors or progesterone receptors, and do not overexpress HER-2/neu receptor. The Oncogene DX test helps determine whether a woman will benefit from chemotherapy in borderline situations.
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TREATMENT
Simple cysts may be aspirated if large or symptomatic. If the fluid is bloody, it should be sent for cytology to check for malignancy. If the cyst does not resolve completely after aspiration or recurs after three aspirations, it should be excised to rule out malignancy.
Solid lumps should be excised if enlarging or symptomatic or if other diagnostic studies have been inconclusive (pathology from image-guided biopsy is discordant with radiographic or clinical findings).
Treatment recommendations for LCIS have evolved from bilateral mastectomies to the current recommendation of close observation with annual mammogram and frequent clinical breast examination. LCIS is usually an incidental finding on a biopsy performed for other reasons. Although it does increase the risk for developing subsequent cancer in either breast, it is no longer thought to be a precursor of breast cancer.
For intraductal (noninvasive, in situ) or invasive breast cancers, surgical treatment options are breast-conserving therapy (lumpectomy with or without radiation therapy) or mastectomy. Lumpectomy is the removal of the cancer with a rim of normal breast tissue to obtain clear or negative margins to ensure the cancer has been completely removed. If there is cancer at the surgical margin, the patient should undergo re-excision to obtain clear margins or consider mastectomy. Mastectomy is the removal of the breast and nipple/areolar complex (from clavicle to rectus muscle and sternum to latissimus dorsi, taking pectoralis fascia with the breast tissue). Statistically, long-term survival is approximately the same, but local recurrence is slightly higher with breast-conserving therapy (BCT): 7% to 10% with radiation and up to 25% without radiation, as compared with mastectomy (3%). If the patient elects BCT and develops a recurrent cancer in the same breast, then mastectomy is usually recommended, especially if the breast has been previously irradiated.
Although BCT is being performed more often as a result of earlier stage at diagnosis, there are still some circumstances when mastectomy should be recommended: multicentric cancers (cancer in more than one quadrant of the breast), extensive high-grade DCIS, large tumor relative to size of breast where lumpectomy would result in poor cosmetic outcome, and when clear margins have not been obtained after re-excision.
In addition, lymph nodes should be checked for metastasis for staging purposes. Sentinel lymph node (SLN) biopsy is rapidly replacing the complete axillary lymph node dissection (CALND) for stage I and II breast cancer as the standard of care. SLN biopsy involves injection of a radioactive isotope and/or a vital blue dye (isosulfan blue or methylene blue) into the breast (subareolar, intradermal or intraparenchymal) to locate the first few draining lymph nodes the cancer is most likely to involve. The "hot" (radioactive) and/or blue lymph nodes are removed. The axilla is also palpated and any enlarged lymph nodes are also removed. The average number of sentinel lymph nodes removed is 2.8. The procedure is 97% accurate. If no SLN is found or if the SLN has metastasis, then CALND is performed, removing level I and II axillary lymph nodes. When CALND is performed with mastectomy, the procedure is called a modified radical mastectomy. The advantage of SLN biopsy is more intensive pathologic evaluation of fewer lymph nodes for more accurate staging and avoidance of lymphedema, which occurs in approximately 15% of patients who undergo CALND.
Radiation therapy is most commonly performed with external-beam irradiation to the breast and may include the axillary and supraclavicular nodal regions. Whole-breast radiation usually involves daily treatments over 4 to 6 weeks. Sometimes a boost dose is given to the lumpectomy site. Interest in partial breast irradiation has re-emerged with the advent of the Mammosite balloon. The balloon is inserted into the lumpectomy cavity and radioactive beads are implanted into the balloon (similar to brachytherapy). This permits high doses of radiation to be administered to the adjacent breast tissue in a shorter period of time (usually 4 to 5 days). The balloon is subsequently removed as a minor procedure.
Antiestrogen hormonal therapy is given to patients if breast cancer is estrogen or progesterone receptor positive. It can reduce the risk of recurrence by approximately 50%. Tamoxifen is given to premenopausal women. Aromatase inhibitors (e.g., anastrozole, letrozole, and exemestane) are now the recommended hormonal therapy for postmenopausal women because of the lower incidence of endometrial cancer and thromboembolic events. However, there is a higher incidence of osteoporosis and fractures. Ongoing clinical trials will determine whether premenopausal women will benefit from aromatase inhibitors. Sometimes premenopausal women are treated with chemical or surgical oophorectomy.
Chemotherapeutic options have also evolved. Doxorubicin (Adriamycin) and cyclophosphamide is used predominantly over the combination of cyclophosphamide, methotrexate, and fluorouracil. In addition, taxanes (taxoids) or anthracyclines may be added to the regimen. Trastuzumab (Herceptin), a monoclonal antibody, has been shown to improve survival in patients
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whose tumors test positive for the HER-2/neu receptor. Other monoclonal antibody drugs are currently being evaluated in clinical trials.
For patients who have mastectomy, reconstruction can be done immediately (at the same operation as the mastectomy) or delayed (requiring a second or third anesthetic). Reconstructive options include saline or silicone implants and a wide assortment of flaps. Flaps composed of muscle, subcutaneous fat, and skin can be transferred to the chest to recreate the breast mound. These can be pedicle flaps or free flaps. Latissimus dorsi muscle or rectus muscle flaps are the most common. The nipple/areolar complex can also be recreated and tattooed, resulting in excellent cosmesis. If the patient is not interested in reconstruction, then an external prosthesis should be prescribed. This prevents neck, shoulder, and upper back pain from the body compensating for the uneven weight on the chest from the remaining breast.
Surgery and radiation therapy are performed for local control of breast cancer, whereas chemotherapy and hormonal therapy are initiated for systemic control. A select group of patients with small, low-grade DCIS may be treated by lumpectomy without radiation. Stage 0, I, and II breast cancers are usually treated with surgery first. The resulting pathology then guides subsequent adjuvant therapy (chemotherapy, hormonal therapy, radiation therapy, or a combination). Stage III and IV breast cancers are usually treated with neoadjuvant chemotherapy (and sometimes hormonal and/or radiation therapy) followed by surgery and radiation. Sometimes an advanced-stage breast cancer can be reduced in size to permit breast-conserving surgery. If the patient is a candidate, hormonal therapy may also be given preoperatively (neoadjuvant) or postoperatively once the chemotherapy and/or radiation therapy has finished.
Tables 14-2 and 14-3 show TNM Staging and American Joint Committee on Cancer Classification for Breast Cancer, respectively.
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TABLE 14-2 TMN Staging for Breast Cancer |
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TABLE 14-3 AJCC Classification for Breast Cancer Based on TNM Criteria |
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As mentioned earlier, screening mammography has resulted in the diagnosis and treatment of earlier-staged breast cancers. In addition, improved understanding of molecular biology of breast cancer has resulted in the development and use of new hormonal and chemotherapeutic agents. All of this has resulted in longer survival rates and lower mortality (Table 14-4).
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TABLE 14-4 2004 Breast Cancer Prognosis Based on Stage |
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PROPHYLAXIS
In women with breast atypia and LCIS, clinical trials have shown that tamoxifen decreases the risk of developing breast cancer. Tamoxifen is usually administered for 5 years. Some experts postulate that it should be given longer. The Study of Tamoxifen and Raloxifene (STAR) trial showed that raloxifene is as effective as tamoxifen and is associated with 30% fewer thromboembolic events and 36% fewer uterine cancers.
For high-risk women who do not want to take drugs to reduce the risk of breast cancer, an alternative is prophylactic mastectomy. This reduces the risk of breast cancer by 97%.
KEY POINTS