Breast: Anatomy

The mammary gland lies over the pectoralis major muscle and extends from the second to the sixth rib in the vertical plane and from the sternum to the anterior or midaxillary line. The mamma consists of glandular tissue arranged in multiple lobes composed of lobules connected in ducts, areolar tissue, and blood vessels. A network of lymphatics is formed over the en tire surface of the chest, neck, and abdomen and becomes dense under the areola.

Natural History
As breast cancer grows, it travels along the ducts, eventually breaking through the basement membrane of the duct to invade adjacent lobules, ducts, fascial strands,mammary fat, and skin. It then spreads through the breast lymphatics and into the peripheral lymphatics; tumor can invade blood vessels. axillary nodal metastases; hematogenous metastases to the lungs, pleura, bone, brain, eyes, liver, ovaries, and adrenal and pituitary glands occurs, even with mall tumors.

Clinical Presentation
Most patients with carcinoma in situ, a painless or slightly tender breast mass or have an abnormal screening mammogram. mammography only

Pathologic Classification
The World Health Organization has classified proliferative conditions and tumors of the breast as benign mammary dysplasias, benign or apparently benign tumors,carcinoma, sarcoma, carcinosarcoma, and unclassified tumors . The American Joint Committee on Cancer has developed an alternate system. Intraductal carcinoma or ductal carcinoma in situ (DCIS) is a noninvasive lesion with five histologic subtypes: comedo, solid, cribriform, papillary, and micropapillary. Lobular carcinoma in situ (LCIS) is a noninvasive proliferation of abnormal epithelial cells in the lobules of the breast. Invasive (infiltrating) ductal carcinoma,

Prognostic Factors
Intrinsic Factors Tumor size and clinical stage are strong prognostic factors influencing local recurrence, nodal and distant metastases, and survival. Results of tumor excision and breast irradiation are equivalent in patients with infiltrating lobular or infiltrating ductal carcinoma. The incidence of local recurrence is greater and survival decreased with higher nuclear grade, vascular invasion, inflammatory infiltrate, and undifferentiation and necrosis of the tumor. Tumor location in the breast does not affect prognosis. Extrinsic (Host) Factors Young age may be a risk factor for breast recurrence in conservation surgery and irradiation; high tumor grade, and a major mononuclear cell reaction, Black women are commonly diagnosed with more advanced stages of breast cancer than white women. Although it was believed in the past that pregnancy after the diagnosis of breast cancer was associated with a worse prognosis, recent evidence suggests the opposite.

General Management
Ductal Carcinoma In Situ and Lobular Carcinoma In Situ Patients with LCIS also have a propensity to develop invasive lesions. DCIS that presents as a large mass (greater than 2.5 cm) has a significantly higher potential for occult invasion, multicentricity, axillary lymph node metastases, and local recurrence than nonpalpable lesions, as well as worse survival. Treatment of Ductal Carcinoma In Situ total mastectomy or breast-conserving surgery, with or (in selected patients) without irradiation. Treatment of Lobular Carcinoma In Situ Treatment options for LCIS include complete local excision of the lesion and close follow-up,

ipsilateral total mastectomy or, bilateral mastectomies, and hormonal manipulation in investigational protocols. The breast is treated with doses of 50 Gy and the axillary/supraclavicular lymph nodes with 50 Gy, with a boost of 10 to 15 Gy to the axillary fossa.

Radiation Therapy Techniques for the Intact Breast

Treatment Volume The entire breast and chest wall should be included in the irradiated volume, along with a small portion of underlying lung. Radiopaque surgical clips placed at the margin of the tumor bed may assist in defining the target volume. When combined with a supraclavicular portal, the upper margin of the portal is placed at the second intercostal space (angle of Louie). If the regional lymph nodes are not to be irradiated, the upper margin of the portals should be placed at the head of the clavicle to include the entire breast (Fig. 2). If no internal mammary portal is used, the medial margin should be 1 cm over the midline. If an internal mammary field is used, the medial tangential portal is located at the lateral margin of the internal mammary field (Fig. 2). The lateral/posterior margin should be placed 2 cm beyond all palpable breast tissue. The inferior margin is drawn 2 to 3 cm below the inframammary fold. Irradiation in the prone position has been proposed for patients with large, pendulous breasts. Doses and Beams Minimal tumor doses of approximately 50 Gy are delivered to the entire breast in 5 to 6 weeks (1.8- to 2.0-Gy tumor dose daily, 5 weekly fractions). Minimum doses of 46.8 Gy (1.8-Gy daily fraction) are preferred for patients with large, pendulous breasts or when irradiation is combined with chemotherapy. X-ray energies of 4 to 6 MV are preferred to treat the breast. Photon energies greater than 6 MV may underdose superficial tissues beneath the skin surface, but higher-energy photons may be helpful in large breasts to decrease the integral breast doseBoost to Tumor Site The indications for boost irradiation are strongly supported by the pathologic findings Boost doses range from 10 to 20 Gy, depending on the size of the tumor and status of excision margins. Irradiation of Regional Lymphatics Supraclavicular Lymph Nodes If only the apex of the axilla is treated (after modified radical mastectomy or axillary dissection), the inferior border of the supraclavicular field is the first or second intercostal space. The medial border is 1 cm across the midline, extending upward, following the medial border of the sternocleidomastoid muscle to the thyrocricoid groove. The lateral border is a vertical line at the level of the anterior axillary fold. The humeral head is blocked as much as possible without compromising coverage of the high axillary lymph nodes (Fig. 33-2). This field is angled approximately 15 to 20 degrees laterally to spare the spinal cord. The low axilla is treated only when there is extracapsular tumor or if axillary dissection is not performed. The supraclavicular field is modified so that the inferior border comes down to split the second rib (angle of Louie), and the lateral border is drawn to just block falloff across the skin of the anterior axillary fold. Total dose to the supraclavicular field is 46 Gy at 2 Gy per day (calculated at 3-cm depth) in 5 fractions per week; an alternative schedule is 50.4 Gy in 1.8-Gy fractions. Axillary Lymph Nodes The medial border of this field is drawn to allow 1.5 to 2 cm of lung to show on the portal film. The inferior border is at the same level as the inferior border of the supraclavicular field; the lateral border just blocks falloff across the posterior axillary fold. The superior border splits the clavicle, and the superior-lateral border shields or splits the humeral head. The dose to the midplane of the axilla from the supraclavicular field is calculated at a point approximately 2 cm inferior to the midportion of the clavicle. The dose to the midplane of the axilla is supplemented by a posterior axillary field. Additional dose to the axilla midplane is administered to complete 46 to 50 Gy (2 Gy daily). When indicated, a boost of 10 to 15 Gy is delivered with reduced portals. Internal Mammary Lymph Nodes The benefit of treating internal mammary lymph nodes is unresolved, since clinical failures at this

site are very rare. The medial border of the internal mammary field is the midline. The lateral border is usually 5 cm lateral to the midline; the superior border abuts the inferior border of the supraclavicular field; and the inferior border is at the xiphoid. If only the internal mammary nodes are treated, the superior border of the field is at the superior surface of the head of the clavicle. The field is set with an oblique incidence to match the medial tangential portal. The dose to the internal mammary field (45 to 50 Gy at 1.8 to 2.0 Gy per day) is calculated at a point 4 to 5 cm beneath the skin surface. CT scans of the chest are very helpful in determining dose-prescription depth. To spare underlying lung, mediastinum, and spinal cord, 12- to 16-MeV electrons are preferred for a portion of the treatment. The usual proportion is 14.4 Gy delivered with 4- to 6-MV photons and 30.6 to 35.6 Gy with electrons (1.8 Gy daily). Timing of Irradiation after Conservation Surgery The optimal sequence for combining breast-conserving surgery, irradiation, and chemotherapy for patients with T1, T2, and selected T3 breast cancer is unknown. At present, it is generally agreed that irradiation optimally should be started within 6 weeks from breast surgery for patients not receiving chemotherapy and within 16 weeks for those treated with adjuvant chemotherapy.

Sequelae of Therapy
Radical Mastectomy A comprehensive article detailed the following complications in 1,198 patients after radical mastectomy: death (1.2%), skin flap necrosis (36%), hematoma under the flap (4%), serum collection under the flap (40%), wound dehiscence (3%), chest wound infection (14%), loss of skin graft (32%), arm edema (31%), pneumothorax (6%), and infection of the donor site (8%) Conservation Surgery and Irradiation The most frequent complications associated with conservation surgery and irradiation are arm or breast edema, breast fibrosis, painful mastitis or myositis, pneumonitis, and rib fracture (seen in approximately 10% of patients). Apical pulmonary fibrosis occasionally is noted when the regional lymph nodes are irradiated. Symptomatic pneumonitis is infrequent and may be related to the volume of lung irradiated.

Breast: Locally Advanced (T3 and T4), Inflammatory, and Recurrent Tumors
Clinical or pathologic findings of locally advanced carcinoma at presentation include the following: tumor size greater than 5 cm; clinically or pathologically positive axillary lymph nodes; tumor of any size with direct extension to ribs, intercostal muscles, or skin; edema (including peau d'orange), ulceration of skin of breast, or satellite skin nodules confined to the same breast; inflammatory carcinoma (T4d); and metastases to ipsilateral internal mammary lymph nodes or ipsilateral axillary lymph nodes fixed to one another or other structures.

Locally Advanced (T3 and T4) Tumors Locally advanced breast cancer may evolve from a mass to infiltration of the deep lymphatics of dermis, causing edema of the skin. More pronounced edema (peau d'orange) usually indicates superficial and deep lymphatic involvement. Fixation of the skin over the tumor and localized redness occur, followed by ulceration and infiltration of overlying skin. Skin retraction may be caused by tumor invasion of Cooper's ligament. Further extensive involvement includes satellite nodules and carcinoma en cuirasse, in which the skin becomes plaque-like and yellowish, red, or gray. Lymphatic spread to axillary, internal mammary, or supraclavicular lymph nodes frequently occurs. Common initial sites of hematogenous spread are, in order, bone, lung, and pleura. Inflammatory Carcinoma Clinical definition of inflammatory carcinoma is the presence of warmth, erythema, and peau d'orange in the involved breast. The pathologic criterion is the presence of tumor emboli in the dermal lymphatics.

Diagnostic Workup
Physical examination must give special attention to documenting locoregional extent of tumor and checking potential sites of spread. Laboratory studies include a complete blood cell count, serum chemistry profile, and full liver function tests. If liver function values are abnormal, a computed tomography (CT) scan of the abdomen should be obtained.

If anemia, leukopenia, or thrombocytopenia is present, bone marrow biopsy is necessary. Radiographic studies include chest x-ray, bone scans, and plain radiographs of symptomatic regions or suspicious areas of increased uptake on bone scans. If neurologic symptoms suggest cerebral metastases, a contrast-enhanced CT scan or gadolinium-enhanced magnetic resonance imaging scan of the brain should be obtained. Factors associated with increased local recurrence include larger, more diffuse tumors, presence of edema, and number of involved axillary nodes. Patients without estrogen/progesterone receptors have a significantly lower survival rate, and are not likely to respond to hormonal therapy. Her-2-neu overexpression is associated with poor prognosis. Tumor and axillary nodal response to neoadjuvant chemotherapy is an indicator for disease-free survival. multiagent chemotherapy plays a primary role in the treatment of these patients. Radiation therapy and surgery each have important roles in optimizing locoregional tumor control. Surgery should be performed on all patients with technically resectable disease. Borderline resectable and unresectable locally advanced breast cancers have been treated with irradiation alone. Neoadjuvant chemotherapy (with or without hormone therapy) before surgical resection and irradiation plays a prominent role.

Prognostic Factors

General Management

Radiation Therapy Techniques

Irradiation of the Inoperable Breast Patients with technically inoperable tumors should be irradiated to the breast, supraclavicular nodes, and axillary nodes. Treatment of the ipsilateral internal mammary lymph nodes may be indicated if medial chest wall/ breast disease is present or if there is clinical or radiographic involvement of the internal mammary node chain. The breast is treated with photons through tangential fields with borders similar to those used in early breast cancer, ensuring that all potential tumor-bearing tissues are adequately covered. Irradiation of the Chest Wall Irradiation of the chest wall after mastectomy can be accomplished with tangential photon fields (as in the intact breast) or with appositional electron beams. Bolus is necessary over the entire field for part of the treatment, and should be added to the scar alone for an additional part of the treatment. Several electron-beam techniques can be used as an alternative to tangential photon treatment; the simplest is a single appositional field using 6- to 12-MeV electrons. CT scans assist in determining the thickness of the chest wall to select the optimal electron-beam energy. Field Borders Anatomic landmarks defining the field borders for treatment of breast/chest wall tangentials, supraclavicular nodes, internal mammary nodes, and axilla are similar to those used to treat early breast ancer. Matchline Technique Many methods have been used to achieve an ideal match of the anterior-oblique supraclavicularfield caudal edge and the cephalad edge of the tangential field. A nondivergent supraclavicular-field edge is achieved by blocking the inferior half of the field. Various methods achieve a nondivergent edge from the tangential beams, including blocking and table angulation with collimator angulation combined. Doses Total dose to the entire breast or chest wall is 50 Gy in 1.8- to 2.0-Gy daily fractions. If surgery is not feasible, the breast should be given an additional 10 to 25 Gy with external irradiation (electrons or photons). This should be performed with shrinking fields or with an iridium-192 implant to a total dose of 75 to 80 Gy. The boost dose is determined by the volume of residual disease. In patients with close or positive margins, a boost of 10 to 15 Gy is given to a reduced volume with "minitangential" photon or appositional electron beam portals. Internal mammary nodes, supraclavicular fossa nodes, and axillary nodal areas should receive 45 to 50 Gy over 5 to 6 weeks if no macroscopic tumor is present. Any gross nodal disease should be boosted with an additional 10 to 15 Gy using a reduced appositional electron beam field.

Postmastectomy Radiation Therapy

In general, postmastectomy irradiation is recommended for lesions larger than 5 cm in diameter; any skin, fascial, or skeletal muscle involvement; poorly differentiated tumors; positive or close

surgical margins (less than 3 mm); lymphatic permeation; matted lymph nodes; two or more positive axillary lymph nodes; or gross extracapsular tumor extension. Adjuvant irradiation can be effectively given before, concurrent with, or after chemotherapy. Doses for subclinical disease in electively treated areas is 50 Gy in 1.8- to 2.0-Gy fractions. Bolus frequently is used in the mastectomy scar and for 50% of treatments to the chest wall. For close or positive margins, an additional 10 to 15 Gy is administered with reduced fields. Locoregional recurrence after mastectomy is recurrent cancer in the bone, muscle, skin, or subcutaneous tissue of the chest wall. Regional involvement may include lymph nodes in the axilla, supraclavicular, or infraclavicular region; ipsilateral internal mammary lymph nodes; or retropectoral lymph nodes. Locoregional recurrences may be isolated or concomitant with distant metastases; complete restaging workup is mandatory. Patients developing locoregional recurrence may be treated with a combination of irradiation, surgery, systemic therapy, or hyperthermia. Surgical management may consist of local excision for purposes of debulking or may be extensive, as in chest wall resection. A second issue in the treatment of isolated locoregional recurrences is elective irradiation of the chest wall and regional lymphatics to prevent second recurrences in these sites. Irradiation doses of 50 Gy are given to electively treated areas and to areas where recurrent tumors have been completely excised. For unresected lesions smaller than 3 cm, 60 to 65 Gy should be given; larger masses require 65 to 75 Gv .

Locoregional Recurrence After Mastectomy