Ductal Carcinoma In Situ Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers. Published series suggest a detection frequency of 7% in all biopsy tissue specimens. The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for progression to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which leads to difficulty in distinguishing early DCIS from benign hyperplasia. The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show hyperchromasia and loss of polarity (cribriform growth pattern). Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend the ducts (solid growth pattern). With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 17-10). Based on multiple consensus meetings, grading of DCIS has been recommended. Although there is no universal agreement on classification, most systems endorse the use of cytologic grade and presence or absence of necrosis. 82 nvasive Breast Carcinoma Invasive breast cancers have been described as lobular or ductal in origin. 84–87 Early classifications used the term lobular to describe invasive cancers that were associated with LCIS, whereas all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by specific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. Eighty percent of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than
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Ductal Carcinoma In Situ
Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers. Published series suggest a detection frequency of 7% in all biopsy tissue specimens. The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for progression to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which leads to difficulty in distinguishing early DCIS from benign hyperplasia. The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show hyperchromasia and loss of polarity (cribriform growth pattern). Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend the ducts (solid growth pattern). With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 17-10). Based on multiple consensus meetings, grading of DCIS has been recommended. Although there is no universal agreement on classification, most systems endorse the use of cytologic grade and presence or absence of necrosis.82
nvasive Breast Carcinoma
Invasive breast cancers have been described as lobular or ductal in origin.84–87 Early classifications used the term lobular to describe invasive cancers that were associated with LCIS, whereas all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by specific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. Eighty percent of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classification for invasive breast cancer81:
1. Paget's disease of the nipple
2. Invasive ductal carcinoma
3. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST), 80%
4. Medullary carcinoma, 4%
5. Mucinous (colloid) carcinoma, 2%
6. Papillary carcinoma, 2%
7. Tubular carcinoma, 2%
8. Invasive lobular carcinoma, 10%
9. Rare cancers (adenoid cystic, squamous cell, apocrine)
Paget's disease of the nipple was described in 1874. It frequently presents as a chronic, eczematous eruption of the nipple, which may be subtle but may progress to an ulcerated, weeping lesion. Paget's disease usually is associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium. Paget's disease may be confused with superficial spreading melanoma. Differentiation from pagetoid intraepithelial melanoma is based on the presence of S-100 antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget's disease. Surgical therapy for Paget's disease may involve lumpectomy, mastectomy, or modified radical mastectomy, depending on the extent of involvement and the presence of invasive cancer.
Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 60% of cases. This cancer usually occurs in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologic types with variable cellular and nuclear grades (Fig. 17-20).
Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a frequent phenotype of BRCA1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physical examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by (a) a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (b) large pleomorphic nuclei that are poorly differentiated and show active mitosis; and (c) a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation (Fig. 17-21). Approximately 50% of these cancers are associated with DCIS, which characteristically is present at the periphery of the cancer, and <10% demonstrate hormone receptors. In rare circumstances, mesenchymal metaplasia or anaplasia is noted. Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma.
Mucinous carcinoma (colloid carcinoma), another special-type breast cancer, accounts for 2% of all invasive breast cancers and typically presents in the elderly population as a bulky tumor. This cancer is defined by extracellular pools of mucin, which surround aggregates of low-grade cancer cells. The cut surface of this cancer is glistening and gelatinous in quality. Fibrosis is variable, and when abundant it imparts a firm consistency to the cancer. Approximately 66% of mucinous carcinomas display hormone receptors. Lymph node metastases occur in 33% of cases, and 5- and 10-year survival rates are 73 and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopic sections, and analysis of multiple sections is essential to confirm the diagnosis of a mucinous carcinoma.
Papillary carcinoma is a special-type cancer of the breast that accounts for 2% of all invasive breast cancers. It generally presents in the seventh decade of life and occurs in a disproportionate number of nonwhite women. Typically, papillary carcinomas are small and rarely attain a size of 3 cm in diameter. These cancers are defined by papillae with fibrovascular stalks and multilayered epithelium. McDivitt and colleagues noted that these tumors showed a low frequency of axillary lymph node metastases and had 5- and 10-year survival rates similar to those for mucinous and tubular carcinoma.88
Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammographic screening and usually is diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will develop axillary lymph node metastases, which are usually confined to the lowest axillary lymph nodes (level I). However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%.
Invasive lobular carcinoma accounts for 10% of breast cancers. The histopathologic features of this cancer include small cells with rounded nuclei, inconspicuous nucleoli, and scant cytoplasm (Fig. 17-22). Special stains may confirm the presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). At presentation, invasive lobular carcinoma varies from clinically inapparent cancers to those that replace the entire breast with a poorly defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic features, invasive lobular carcinoma may be difficult to detect.
Diagnosis of Breast Cancer
In 33% of breast cancer cases, the woman discovers a lump in her breast. Other less frequent presenting signs and symptoms of breast cancer include (a) breast enlargement or asymmetry; (b) nipple changes, retraction, or discharge; (c) ulceration or erythema of the skin of the breast; (d) an axillary mass; and (e) musculoskeletal discomfort. However, up to 50% of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease.
Misdiagnosed breast cancer accounts for the greatest number of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and mammogram may be misleading. If a young
woman ( 45 years) presents with a palpable breast mass and equivocal mammographic findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis.
Examination
Inspection
The surgeon inspects the woman's breast with her arms by her side (Fig. 17-23A), with her arms straight up in the air (Fig. 17-23B), and with her hands on her hips (with and without
pectoral muscle contraction).89,90 Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d'orange), nipple or skin retraction, or erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.
Palpation
As part of the physical examination, the breast is carefully palpated. Examination of the patient in the supine position (see Fig. 17-23C) is best performed with a pillow supporting the ipsilateral hemithorax. The surgeon gently palpates the breast from the ipsilateral side, making certain to examine all quadrants of the breast from the sternum laterally to the latissimus dorsi muscle and from the clavicle inferiorly to the upper rectus sheath. The surgeon performs the examination with the palmar aspects of the fingers, avoiding a grasping or pinching motion. The breast may be cupped or molded in the surgeon's hands to check for retraction. A systematic search for lymphadenopathy then is performed. Figure 17-23D shows the position of the patient for examination of the axilla. By supporting the upper arm and elbow, the surgeon stabilizes the shoulder girdle. Using gentle palpation, the surgeon assesses all three levels of possible axillary lymphadenopathy. Careful palpation of supraclavicular and parasternal sites also is performed. A diagram of the chest and contiguous lymph node sites is useful for recording location, size, consistency, shape, mobility, fixation, and other characteristics of any palpable breast mass or lymphadenopathy (Fig. 17-24).
Imaging Techniques
Mammography
Mammography has been used in North America since the 1960s, and the techniques used continue to be modified and improved to enhance image quality (Fig. 17-25A and C).91–94 Conventional mammography delivers a radiation dose of 0.1 cGy per study. By comparison, chest radiography delivers 25% of this dose. However, there is no increased breast cancer risk associated with the radiation dose delivered with screening mammography. Screening mammography is used to detect unexpected breast cancer in asymptomatic women. In this regard, it supplements history taking and physical examination. With screening mammography, two views of the breast are obtained, the craniocaudal (CC) view (Fig. 17-25D) and the mediolateral oblique (MLO) view (Fig. 17-25E). The MLO view images the greatest volume of breast tissue, including the upper outer quadrant and the axillary tail of Spence. Compared with the MLO view, the CC view provides better visualization of the medial aspect of the breast and permits greater breast compression. Diagnostic mammography is used to evaluate women with abnormal findings such as a breast mass or nipple discharge. In addition to the MLO and CC views, a diagnostic examination may use views that better define the nature of any abnormalities, such as the 90-degree lateral and spot compression views. The 90-degree lateral view is used along with the CC view to triangulate the exact location of an abnormality. Spot compression may be done in any projection by using a small compression device, which is placed directly over a mammographic abnormality that is obscured by overlying tissues (Fig. 17-25F). The compression device minimizes motion artifact, improves definition, separates overlying tissues, and decreases the radiation dose needed to penetrate the breast. Magnification techniques (x1.5) often are combined with spot compression to better resolve calcifications and the margins of masses. Mammography also is used to guide interventional procedures, including needle localization and needle biopsy.
An experienced radiologist can detect breast cancer with a false-positive rate of 10% and a false-negative rate of 7%. Specific mammographic features that suggest a diagnosis of breast cancer include a solid mass with or without stellate features, asymmetric thickening of breast tissues, and clustered microcalcifications. The presence of fine, stippled calcium in and around a suspicious lesion is suggestive of breast cancer and occurs in as many as 50% of nonpalpable cancers. These microcalcifications are an especially important sign of cancer in younger women, in whom it may be the only mammographic abnormality. The clinical impetus for screening mammography came from the Health Insurance Plan study and the Breast Cancer Detection Demonstration Project, which demonstrated a 33% reduction in mortality for women after screening mammography. Mammography was more accurate than clinical examination for the detection of early breast cancers, providing a true-positive rate of 90%. Only 20% of women with nonpalpable cancers had axillary lymph node metastases, compared with 50% of women with palpable cancers.95 Current guidelines of the National
Comprehensive Cancer Network suggest that normal-risk women 20 years of age should have a breast examination at least every 3 years. Starting at age 40 years, breast examinations should be performed yearly and a yearly mammogram should be taken. Prospective randomized studies of mammography screening confirm a 40% reduction in stage II, III, and IV cancer in the screened population, with a 30% increase in overall survival.
Xeromammography techniques are identical to those of mammography with the exception that the image is recorded on a xerography plate, which provides a positive rather than a negative image (see Fig. 17-25B). Details of the entire breast and the soft tissues of the chest wall may be recorded with one exposure. Screen film mammography has replaced xeromammography because it requires a lower dose of radiation and provides similar image quality. Digital mammography was developed to allow the observer to manipulate the degree of contrast in the image. This is especially useful in women with dense breasts and women <50 years of age. Recently, investigators directly compared digital vs. screen film mammography in a prospective trial enrolling over 42,000 women.96 They found that digital and screen film mammography had similar accuracy; however, digital mammography was more accurate in women <50 years of age, women with mammographically dense breasts, and premenopausal or perimenopausal women.
Ductography
The primary indication for ductography is nipple discharge, particularly when the fluid contains blood. Radiopaque contrast media is injected into one or more of the major ducts and mammography is performed. A duct is gently enlarged with a dilator and then a small, blunt cannula is inserted under sterile conditions into the nipple ampulla. With the patient in a supine position, 0.1 to 0.2 mL of dilute contrast media is injected and CC and MLO mammographic views are obtained without compression. Intraductal papillomas are seen as small filling defects surrounded by contrast media (Fig. 17-26). Cancers may appear as irregular masses or as multiple intraluminal filling defects.
Ultrasonography
Second only to mammography in frequency of use for breast imaging, ultrasonography is an important method of resolving equivocal mammographic findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities. On ultrasound examination, breast cysts are well circumscribed, with smooth margins and an echo-free
center (Fig. 17-27). Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior margins. Breast cancer characteristically has irregular walls (Fig. 17-28) but may have smooth margins with acoustic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization of breast lesions. Its findings are highly reproducible and it
has a high patient acceptance rate, but it does not reliably detect lesions that are 1 cm in diameter.
Magnetic Resonance Imaging
In the process of evaluating MRI as a means of characterizing mammographic abnormalities, additional breast lesions have been detected. However, in the circumstance of negative findings on both mammography and physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in the use of MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women who have a strong family history of breast cancer or who carry known genetic mutations require screening at an early age, but mammographic evaluation is limited because of the increased breast density in younger women. In the second case, an MRI study of the contralateral breast in women with a known breast cancer has shown a contralateral breast cancer in 5.7% of these women.
Breast Biopsy
Nonpalpable Lesions
Image-guided breast biopsies are frequently required to diagnose nonpalpable lesions.97 Ultrasound localization techniques are used when a mass is present, whereas stereotactic techniques are used when no mass is present (microcalcifications only). The combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-needle aspiration (FNA) biopsy achieves almost 100% accuracy in the diagnosis of breast cancer. However, although FNA biopsy permits cytologic evaluation, core-needle or open biopsy also permits the analysis of breast tissue architecture and allows the pathologist to determine whether invasive cancer is present. This permits the surgeon and patient to discuss the specific management of a breast cancer before therapy begins. Core-needle biopsy is preferred over open biopsy for nonpalpable breast lesions because a single surgical procedure can be planned based on the results of the core biopsy. The advantages of core-needle biopsy include a low complication rate, avoidance of scarring, and a lower cost.
Palpable Lesions
FNA biopsy of a palpable breast mass can easily proceed in an outpatient setting.98 A 1.5-in, 22-gauge needle attached to a 10-mL syringe is used. Use of a syringe holder enables the surgeon performing the FNA biopsy to control the syringe and needle with one hand while positioning the breast mass with the opposite hand. After the needle is placed in the mass, suction is applied while the needle is moved back and forth within the mass. Once cellular material is seen at the hub of the needle, the suction is released and the needle is withdrawn. The cellular material is then expressed onto microscope slides. Both air-dried and 95% ethanol–fixed microscopic sections are prepared for analysis. When a breast mass is clinically and mammographically suspicious, the sensitivity and specificity of FNA biopsy approaches
100%. Core-needle biopsy of palpable breast masses is performed using a 14-gauge needle, such as the Tru-Cut needle. Automated devices also are available. Tissue specimens are placed in formalin and then processed to paraffin blocks. Although the false-negative rate for core-needle biopsy specimens is very low, a tissue specimen that does not show breast cancer cannot conclusively rule out that diagnosis because a sampling error may have occurred. The clinical, radiographic, and pathologic findings should be in concordance. If the biopsy findings do not concur with the clinical and radiographic findings, the clinician should proceed with an image-guided or open biopsy to be certain that the target lesion has been adequately sampled for diagnosis.Breast Cancer Staging and Biomarkers
Breast Cancer Staging
The clinical stage of breast cancer is determined primarily through physical examination of the skin, breast tissue, and regional lymph nodes (axillary, supraclavicular, and cervical).99 However, clinical determination of axillary lymph node metastases has an accuracy of only 33%. Mammography, chest radiography, and intraoperative findings (primary tumor size, chest wall invasion) also provide necessary staging information. Pathologic stage combines the findings from pathologic examination of the resected primary breast cancer and axillary or other regional lymph nodes. Fisher and colleagues found that accurate predictions regarding the occurrence of distant metastases were possible after resection and pathologic analysis of 10 or more level I and II axillary lymph nodes.100 A frequently used staging system is the TNM (tumor, nodes, and metastasis) system. The American Joint Committee on Cancer (AJCC) has modified the TNM system for breast cancer (Tables 17-11 and 17-12). Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary lymph node metastases (see Fig. 17-18B). Others have shown an association between tumor size, axillary lymph node metastases, and disease-free survival. The single most important predictor of 10- and 20-year survival rates in breast cancer is the number of axillary lymph nodes involved with metastatic disease. Routine biopsy of internal mammary lymph nodes is not generally performed; however, with the advent of sentinel lymph node dissection and the use of preoperative lymphoscintigraphy for localization of the sentinel nodes, surgeons have begun to biopsy the internal mammary nodes in some cases. The sixth edition of the AJCC staging system does allow for staging based on findings from the internal mammary sentinel nodes.99 Drainage to the internal mammary nodes is more frequent with central and medial quadrant cancers. Clinical or pathologic evidence of metastatic spread to supraclavicular lymph nodes is no longer considered systemic or stage IV disease, but routine scalene or supraclavicular lymph node biopsy is not indicated.
Table 17-11 TNM Staging System for Breast Cancer
Primary tumor (T) Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3); if other measurements, such as mammographic or pathologic measurements, are used, the subsets of T1 can be used. Tumors should be measured to the nearest 0.1-cm increment.
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Tis (DCIS) Ductal carcinoma in situ
Tis (LCIS) Lobular carcinoma in situ
Tis (Paget's)
Paget's disease of the nipple with no tumor (NOTE: Paget's disease associated with a tumor is classified according to the size of the tumor)
T1Tumor 2 cm in greatest dimension
T1micMicroinvasion 0.1 cm or less in greatest dimension
T1a Tumor >0.1 cm but not >0.5 cm in greatest dimension
T1b Tumor >0.5 cm but not >1 cm in greatest dimension
T1c Tumor >1 cm but not >2 cm in greatest dimension
T2 Tumor >2 cm but not >5 cm in greatest dimension
T3 Tumor >5 cm in greatest dimension
T4 Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below
T4a Extension to chest wall, not including pectoralis muscle
T4b Edema (including peau d'orange), or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast
T4c Both T4a and T4b
T4d Inflammatory carcinoma
Regional lymph nodes—Clinical (N)
NX Regional lymph nodes cannot be assessed (e.g., previously removed)
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral axillary lymph node(s)
N2 Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparenta ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis
N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
N3 Metastasis only in clinically apparenta ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis; metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparenta ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
N3a Metastasis in ipsilateral infraclavicular lymph node(s)
N3b Metastasis in ipsilateral internal mammary lymph nodes(s) and axillary lymph node(s)
N3c Metastasis in ipsilateral supraclavicular lymph node(s)
Regional lymph nodes—Pathologic (pN)
pNX Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for pathologic study)
pN0b No regional lymph node metastasis histologically, no additional examination for isolated tumor cells [NOTE: Isolated tumor cells (ITC) are defined as single tumor cells or small cell clusters not >0.2 mm, which are usually detected only by immunohistochemical (IHC) or molecular methods but which may be verified on hematoxylin and eosin stains; ITCs do not usually show evidence of malignant activity (e.g., proliferation or stromal reaction)]
pN0(i–) No regional lymph node metastasis histologically, negative IHC results
pN0(i+) No regional lymph node metastasis histologically, positive IHC results, no IHC cluster >0.2 mm
pN0(mol–) No regional lymph node metastasis histologically, negative molecular findings [reverse-transcriptase polymerase chain reaction (RT-PCR)]
pN0(mol+) No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)
pN1 Metastasis in 1 to 3 axillary lymph nodes, and/or in internal mammary nodes with microscopic disease detected by sentinel lymph nodes dissection, not clinically apparentc
pN1mi Micrometastasis (>0.2 mm, none >2.0 mm)
pN1a Metastasis in 1 to 3 axillary lymph nodes
pN1b Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection, not clinically apparentc
pN1c Metastasis in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparentc (if associated with >3 positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden)
pN2 Metastasis in 4 to 9 axillary lymph nodes, or in clinically apparenta internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN2a Metastasis in 4 to 9 axillary lymph nodes (at least one tumor deposit >2.0 mm)
pN2b Metastasis in clinically apparenta internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN3Metastasis in 10 axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparenta ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in >3 axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes
pN3aMetastasis in 10 axillary lymph nodes (at lease one tumor deposit >2.0 mm), or metastasis to the infraclavicular lymph nodes
pN3b Metastasis in clinically apparenta ipsilateral internal mammary lymph nodes in
the presence of 1 positive axillary lymph nodes; or in >3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection, not clinically apparentc
pN3c Metastasis in ipsilateral supraclavicular lymph nodes
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
aClinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.
bClassification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without subsequent axillary lymph node dissection is designated (sn) for "sentinel node" e.g., pN–(l+) (sn).
cNot clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.
Source: Reprinted with permission from American Joint Committee on Cancer: AJCC Cancer Staging Manual, 6th ed. New York: Springer, 2002, p 227–228. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.
Biomarkers
Breast cancer biomarkers are of several types. Risk factor biomarkers are those associated with increased cancer risk.101–105 These include familial clustering and inherited germline abnormalities, proliferative breast disease with atypia, and mammographic densities. Exposure biomarkers are a subset of risk factors that include measures of carcinogen exposure such as DNA adducts. Surrogate endpoint biomarkers are biologic alterations in tissue that occur between cancer initiation and development. These biomarkers are used as endpoints in short-term chemoprevention trials and include histologic changes, indices of proliferation, and genetic alterations leading to cancer. Prognostic biomarkers provide information regarding cancer outcome irrespective of therapy, whereas predictive biomarkers provide information regarding response to therapy. Candidate prognostic and predictive biomarkers and biologic targets for breast cancer include (a) indices of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67; (b) indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio; (c) indices of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index; (d) growth factors and growth factor receptors such as human epidermal growth factor receptor 2 (HER-2)/neu, epidermal growth factor receptor (EGFr), transforming growth factor, platelet-derived growth factor, and the insulin-like growth factor family; (e) the steroid hormone receptor pathway; (f) the
cell cycle, cyclins, and cyclin-dependent kinases; (g) the proteasome; (h) the COX-2 enzyme; (i) the peroxisome proliferator-activated receptors (PPARs); (j) tumor-suppressor genes such as p53; and (k) the mammalian target of rapamycin (mTOR) signaling pathway.
Indices of Proliferation
PCNA is a nuclear protein associated with a DNA polymerase whose expression increases in phase G1 of the cell cycle, reaches its maximum at the G1/S interface, and then decreases through G2.106–109 Immunohistochemical staining for PCNA outlines the proliferating compartments in breast tissue. Good correlation is noted between PCNA expression and (a) cell-cycle distributions seen on flow cytometry based on DNA content, and (b) uptake of bromodeoxyuridine and the proliferation-associated Ki-67 antigen. Individual proliferation markers are associated with slightly different phases of the cell cycle and are not equivalent. PCNA and Ki-67 expression are positively correlated with p53 overexpression, high S-phase fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer specimens, and are negatively correlated with estrogen receptor content.
Indices of Apoptosis
Alterations in programmed cell death (apoptosis), which may be triggered by p53-dependent or p53-independent factors, may be important prognostic and predictive biomarkers in breast cancer.110–112 Bcl-2 family proteins appear to regulate a step in the evolutionarily conserved pathway for apoptosis, with some members functioning as inhibitors of apoptosis and others as promoters of apoptosis. BCL2 is the only oncogene that acts by inhibiting apoptosis rather than by directly increasing cellular proliferation. The death-signal protein bax is induced by genotoxic stress and growth factor deprivation in the presence of wild-type (normal) p53 and/or AP-1/fos. The bax:bcl-2 ratio and the resulting formation of either bax-bax homodimers, which stimulate apoptosis, or bax–bcl-2 heterodimers, which inhibit apoptosis, represent an intracellular regulatory mechanism with prognostic and predictive implications. In breast cancer, overexpression of bcl-2 and a decrease in the bax:bcl-2 ratio correlate with high histologic grade, the presence of axillary lymph node metastases, and reduced disease-free and overall survival rates. Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor response to chemotherapy, and decreased overall survival.
Indices of Angiogenesis
Angiogenesis is necessary for the growth and invasiveness of breast cancer and promotes cancer progression through several different mechanisms, including delivery of oxygen and nutrients and the secretion of growth-promoting cytokines by endothelial cells.113,114 VEGF induces its effect by binding to transmembrane tyrosine kinase receptors. Overexpression of VEGF in invasive breast cancer is correlated with increased microvessel density and recurrence in node-negative breast cancer. An angiogenesis index has been developed in which microvessel density (CD31 expression) is combined with expression of thrombospondin (a negative modulator of angiogenesis) and p53 expression. Both VEGF expression and the angiogenesis index may have prognostic and predictive significance in breast cancer. Antiangiogenesis breast cancer therapy is now being studied in human trials. The use of bevacizumab (a monoclonal antibody to VEGF) was recently approved by the U.S. Food and Drug Administration (FDA) for use in metastatic breast cancer in combination with paclitaxel chemotherapy. This approval was based on results from a phase III trial by the
Eastern Cooperative Oncology Group. The group's E2100 trial showed that when bevacizumab was added to paclitaxel chemotherapy, median progression-free survival increased to 11.3 months from the 5.8 months seen in patients who received paclitaxel alone.115
Growth Factor Receptors and Growth Factors
Overexpression of EGFr in breast cancer correlates with estrogen receptor–negative status and with p53 overexpression.116–118 Similarly, increased immunohistochemical membrane staining for the HER-2/neu growth factor receptor in breast cancer is associated with mutated p53 Ki-67 overexpression and estrogen receptor–negative status. HER-2/neu is a member of the EGFr family of growth factor receptors in which ligand binding results in receptor homodimerization and tyrosine phosphorylation by tyrosine kinase domains within the receptor. Tyrosine phosphorylation is followed by signal transduction, which results in changes in cell behavior. An important property of this family of receptors is that ligand binding to one receptor type also may result in heterodimerization between two different receptor types that are coexpressed; this leads to transphosphorylation and transactivation of both receptors in the complex (transmodulation). In this context, the lack of a specific ligand for the HER-2/neu receptor suggests that HER-2/neu may function solely as a coreceptor, modulating signaling by other EGFr family members. HER-2/neu is both an important prognostic factor and a predictive factor in breast cancer.119 When overexpressed in breast cancer, HER-2/neu promotes enhanced growth and proliferation, and increases invasive and metastatic capabilities. Clinical studies have shown that patients with HER-2/neu–overexpressing breast cancer have poorly differentiated tumors with high proliferation rates, positive lymph nodes, decreased hormone receptor expression, and an increased risk of recurrence and death due to breast cancer.119–123 Routine testing of the primary tumor specimen for HER-2/neu expression should be performed on all invasive breast cancers. This can be done with immunohistochemical analysis to evaluate for overexpression of the cell-surface receptor at the protein level or by using fluorescent in situ hybridization to evaluate for gene amplification. Patients whose tumors overexpress HER-2/neu are candidates for anti–HER-2/neu therapy. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against HER-2/neu. Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is an active and well-tolerated option for first-line treatment of women with HER-2/neu–overexpressing metastatic breast cancer. More recently, adjuvant trials demonstrated that trastuzumab also was highly effective in the treatment of women with early-stage breast cancer when used in combination with chemotherapy. Patients who received trastuzumab in combination with chemotherapy had a 52% reduction in the risk of breast cancer recurrence compared with those who received chemotherapy alone.124
Steroid Hormone Receptor Pathway
Hormones play an important role in the development and progression of breast cancer. Estrogens, estrogen metabolites, and other steroid hormones such as progesterone all have been shown to have an effect. Breast cancer risk is related to estrogen exposure over time. In postmenopausal women, hormone replacement therapy consisting of estrogen plus progesterone increases the risk of breast cancer by 26% compared to placebo.125 Patients with hormone receptor–positive tumors survive two to three times longer after a diagnosis of metastatic disease than do patients with hormone receptor–negative tumors. Patients with tumors negative for both estrogen receptors and progesterone receptors are not considered
candidates for hormonal therapy. Tumors positive for estrogen or progesterone receptors have a higher response rate to endocrine therapy than tumors that do not express estrogen or progesterone receptors. Tumors positive for both receptors have a response rate of >50%, tumors negative for both receptors have a response rate of <10%, and tumors positive for one receptor but not the other have an intermediate response rate of 33%. The determination of estrogen and progesterone receptor status used to require biochemical evaluation of fresh tumor tissue. Today, however, estrogen and progesterone receptor status can be measured in archived tissue using immunohistochemical techniques. Hormone receptor status also can be measured in specimens obtained with fine-needle aspiration biopsy or core-needle biopsy, and this can help guide treatment planning. Testing for estrogen and progesterone receptors should be performed on all primary invasive breast cancer specimens. The tumor hormone receptor status should be ascertained for both premenopausal and postmenopausal patients to identify patients who are most likely to benefit from endocrine therapy.
The remaining biomarkers and biologic targets listed earlier are still in preclinical and clinical trials evaluating their importance in breast cancer for both prognostic and predictive purposes.
Coexpression of Biomarkers
Selection of optimal therapy for breast cancer requires both an accurate assessment of prognosis and an accurate prediction of response to therapy. The breast cancer markers that are most important in determining therapy are estrogen receptor, progesterone receptor, and HER-2/neu. Clinicians evaluate clinical and pathologic staging and the expression of estrogen receptor, progesterone receptor, and HER-2/neu in the primary tumor to assess prognosis and assign therapy. Adjuvant! Online (http://www.adjuvantonline.com) is a program available to clinicians that incorporates clinical and pathologic factors for an individual patient and calculates risk of recurrence and death due to breast cancer and then provides an assessment of the reduction in risk of recurrence that would be expected with the use of combination chemotherapy, endocrine therapy, or both of these. Adjuvant! Online was developed using information from the SEER database, the Early Breast Cancer Trialists' Collaborative Group overview analyses, and results from other individual published trials.126 The website is updated and modified as new information becomes available. Clinicopathologic factors are used to separate breast cancer patients into broad prognostic groups, and treatment decisions are made on this basis (Table 17-13). When this approach is used, up to 70% of early breast cancer patients receive adjuvant chemotherapy that is either unnecessary or ineffective. As described earlier, a wide variety of biomarkers have been shown to individually predict prognosis and response to therapy, but they do not improve the accuracy of either the assessment of prognosis or the prediction of response to therapy.
Table 17-13 Traditional Prognostic and Predictive Factors for Invasive Breast Cancer
Tumor Factors Host Factors
Nodal status Age
Tumor size Menopausal status
Histologic/nuclear grade Family history
Lymphatic/vascular invasion Previous breast cancer
Pathologic stage Immunosuppression
Hormone receptor status Nutrition
DNA content (ploidy, S-phase fraction) Prior chemotherapy
Extent of intraductal component Prior radiation therapy
HER-2/neu expression
Source: Modified with permission from Beenken SW, et al: Breast cancer genetics, in Ellis N (ed): Inherited Cancer Syndromes. New York: Springer-Verlag, 2003, p 112. With kind permission of Springer Science + Business Media.As knowledge regarding cellular, biochemical, and molecular biomarkers for breast cancer increases, prognostic indices are being developed that combine the predictive power of several individual biomarkers with the relevant clinicopathologic factors.
Most recently, technologic advances have led to the ability to measure the expression of multiple genes in a tumor sample simultaneously. This gene expression profiling can provide information about tumor behavior that can be used in determining prognosis and therapy.127 These high-throughput analyses require bioinformatics support that can categorize and analyze the immense amount of data that are generated. This allows for a detailed stratification of breast cancer patients for assessment of prognosis and for prediction of response to therapy. The Oncotype DX is a 21-gene assay that has been validated in newly diagnosed patients with node-negative, estrogen receptor–positive breast cancer.128 A recurrence score is generated, and those patients with high recurrence scores are found to benefit the most from chemotherapy, whereas those with low recurrence scores benefit most from tamoxifen and may not require chemotherapy. There is currently an ongoing clinical trial, the Trial Assessing Individualized Options for Treatment for breast cancer (TAILORx), that randomly assigns patients with an intermediate recurrence score to hormonal therapy alone or to chemotherapy followed by hormonal therapy. The MammaPrint test was recently approved by the FDA for use in patients with newly diagnosed, node-negative breast cancer. The MammaPrint test is based on a 70-gene profile, and fresh tissue is required to perform the assay. The Oncotype DX assay is performed using paraffin-embedded tumor tissue and therefore can be carried out on archived samples.Overview of Breast Cancer Therapy
Before diagnostic biopsy, the surgeon must discuss with the patient the possibility that a suspicious mass or mammographic finding may be a breast cancer. Once a diagnosis of breast cancer is made, the type of therapy offered to a breast cancer patient is determined by the stage of the disease. Laboratory tests and imaging studies are performed based on the initial stage as presented in Table 17-14. Before therapy is initiated, the patient and the surgeon must share a clear perspective on the planned course of treatment.
Table 17-14 Diagnostic Studies for Breast Cancer Patients
Cancer Stage
0 I II III IV
History & physical X X X X X
Complete blood count, platelet count X X X X
Liver function tests and alkaline phosphatase level X X X X
Chest radiograph X X X X
Bilateral diagnostic mammograms, ultrasound as indicated X X X X X
Hormone receptor status X X X X
HER-2/neu expression X X X X
Bone scana X X X
Abdominal (without or without pelvis) computed tomographic scan or ultrasound or magnetic resonance imaging
X X X
a Bone scan performed for stage II only if localized symptoms are present or serum alkaline phosphatase level is elevated.
Abdominal imaging and bone scanning are indicated for evaluation of symptoms or abnormal laboratory test results at any presenting stage.
Source: Adapted with permission from Carlson RW, et al: Breast cancer, in NCCN Practice Guidelines in Oncology. Fort Washington, Penn: National Comprehensive Cancer Network, 2006.In Situ Breast Cancer (Stage 0)
Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from cancers with early invasion.50,129–134 Expert pathologic review is required in all cases. Bilateral mammography is performed to determine the extent of the in situ cancer and to exclude a second cancer. Because LCIS is considered a marker for increased risk rather than an inevitable precursor of invasive disease, the current treatment options for LCIS include observation, chemoprevention with tamoxifen, and bilateral total mastectomy. The goal of treatment is to prevent or detect at an early stage the invasive cancer that subsequently develops in 25 to 35% of these women. There is no benefit to excising LCIS, because the disease diffusely involves both breasts in many cases and the risk of invasive cancer is equal for both breasts. The use of tamoxifen as a risk reduction strategy should be considered in women with a diagnosis of LCIS.
Women with DCIS and evidence of extensive disease (>4 cm of disease or disease in more than one quadrant) usually require mastectomy. For women with limited disease, lumpectomy and radiation therapy are recommended. Low-grade DCIS of the solid, cribriform, or papillary subtype that is <0.5 cm in diameter may be managed by lumpectomy alone without radiation if the margins of resection are widely free of disease. For nonpalpable DCIS, needle localization techniques are used to guide the surgical resection. Specimen mammography is performed to ensure that all visible evidence of cancer is excised. Adjuvant tamoxifen therapy is considered for DCIS patients. The gold standard against which breast conservation therapy for DCIS is evaluated is mastectomy. Women treated with mastectomy
have local recurrence and mortality rates of <2%. Women treated with lumpectomy and adjuvant radiation therapy have a similar mortality rate, but the local recurrence rate increases to 9%. Forty-five percent of these recurrences will be invasive cancer when radiation therapy is not used. The use of radiation therapy markedly decreases the risk of in-breast recurrence and significantly reduces the risk that any recurrence will be invasive disease. Both Lagios and Gump noted that recurrence of DCIS was greatest when the cancers were >2.5 cm in size, the criteria for histologic confirmation of clear margins were not rigorously applied, and the DCIS was of the comedo type. They noted that recurrences frequently occurred within the original surgery site, which indicates that inadequate clearance of DCIS, rather than the biology of the cancer, was responsible.135
Early Invasive Breast Cancer (Stage I, IIA, or IIB)
NSABP B-06 compared total mastectomy to lumpectomy with or without radiation therapy in the treatment of women with stage I and II breast cancer.136–143 After 5- and 8-year follow-up periods, the disease-free, distant disease-free, and overall survival rates for lumpectomy with or without radiation therapy were similar to those observed after total mastectomy. However, the incidence of ipsilateral breast cancer recurrence (in-breast recurrence) was higher in the lumpectomy group not receiving radiation therapy. These findings supported the use of lumpectomy and radiation therapy in the treatment of stage I and II breast cancer. Reanalysis of the study results was undertaken after 20 years of follow-up. The reanalysis confirmed that there was no difference in disease-free survival rates after total mastectomy or after lumpectomy with or without adjuvant radiation therapy. The in-breast recurrence rate was higher in the lumpectomy alone group (39.2%) than in the lumpectomy plus adjuvant radiation therapy group (14.3%). These findings are detailed in Fig. 17-29.
Currently, mastectomy with assessment of axillary lymph node status and breast conserving surgery with assessment of axillary lymph node status and radiation therapy are considered equivalent treatments for patients with stage I and II breast cancer. Axillary lymphadenopathy confirmed to be metastatic disease or metastatic disease in a sentinel lymph node (see later) necessitates an axillary lymph node dissection. Breast conservation is considered for all patients because of the important cosmetic advantages. Relative contraindications to breast conservation therapy include (a) prior radiation therapy to the breast or chest wall, (b) involved surgical margins or unknown margin status after re-excision, (c) multicentric disease, and (d) scleroderma or lupus erythematosus.
Traditionally, dissection of the level I and II axillary lymph nodes has been performed in early invasive breast cancer. Sentinel lymph node dissection is now considered the standard for evaluation of the axillary lymph node status in women who have clinically negative lymph nodes. Candidates for this procedure have clinically uninvolved axillary lymph nodes with a T1 or T2 primary breast cancer. Controversy remains about the suitability of sentinel node dissection in women with larger primary tumors (T3) and those treated with neoadjuvant chemotherapy.144 If the sentinel lymph node cannot be identified or is found to harbor metastatic disease, then an axillary lymph node dissection should be performed.
Adjuvant chemotherapy for patients with early invasive breast cancer is considered for all patients with node-positive cancers, all patients with cancers that are >1 cm, and patients with node-negative cancers of >0.5 cm when adverse prognostic features are present. Adverse
prognostic factors include blood vessel or lymph vessel invasion, high nuclear grade, high histologic grade, HER-2/neu overexpression, and negative hormone receptor status. Tamoxifen therapy is considered for women with hormone receptor–positive cancers that are >1 cm. HER-2/neu expression is determined for all patients with newly diagnosed breast cancer and may be used to provide prognostic information in patients with node-negative breast cancer and predict the relative efficacy of various chemotherapy regimens. Trastuzumab is the only HER-2/neu–targeted agent that is currently approved for use in the metastatic and the adjuvant setting. The FDA approved trastuzumab in November 2006 for use as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for treatment of HER-2/neu–positive, node-positive breast cancer.
Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB)
Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but have no clinically detected distant metastases.145 In an effort to provide optimal local-regional disease-free survival as well as distant disease-free survival for these women, surgery is integrated with radiation therapy and chemotherapy (Fig. 17-30). Neoadjuvant chemotherapy should be considered in the initial management of all patients with locally advanced stage III breast cancer. Surgical therapy for women with stage III disease is usually a modified radical mastectomy, followed by adjuvant radiation therapy. Chemotherapy is used to maximize distant disease-free survival, whereas radiation therapy is used to maximize local-regional disease-free survival. In selected patients with stage IIIA cancer, neoadjuvant (preoperative) chemotherapy can reduce the size of the primary cancer and permit breast-conserving surgery. Investigators from the M. D. Anderson Cancer Center reported that low local-regional failure rates could be achieved in selected patients with stage III disease treated with neoadjuvant chemotherapy followed by breast-conserving surgery and radiation.146 The 5-year actuarial ipsilateral breast tumor recurrence–free survival rates in this study were 95%. They noted that the ipsilateral breast tumor recurrence rates increased when patients had clinical N2 or N3 disease, >2 cm of residual disease in the breast at surgery, a pattern of multifocal residual disease in the breast at surgery, and lymphovascular space invasion in the primary tumor. This study and others demonstrate that breast-conserving surgery can be used for appropriately selected patients with locally advanced breast cancer who achieve a good response with neoadjuvant chemotherapy. For patients with stage IIIA disease who experience minimal response to chemotherapy and for patients with stage IIIB breast cancer, neoadjuvant chemotherapy can decrease the local-regional cancer burden enough to permit subsequent modified radical mastectomy to establish local-regional control. In both stage IIIA and IIIB disease, surgery is followed by adjuvant radiation therapy.
Fig. 17-30.
Treatment pathways for stage IIIA and stage IIIB breast cancer.Internal Mammary Lymph Nodes
Metastatic disease to internal mammary lymph nodes may be occult, may be evident on chest
radiograph or CT scan, or may present as a painless parasternal mass with or without skin involvement. There is no consensus regarding the need for internal mammary lymph node radiation therapy in women who are at increased risk for occult involvement (cancers involving the medial aspect of the breast, axillary lymph node involvement) but who show no signs of internal mammary lymph node involvement. Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly involved internal mammary lymph nodes.
Distant Metastases (Stage IV)
Treatment for stage IV breast cancer is not curative but may prolong survival and enhance a woman's quality of life.147 Hormonal therapies that are associated with minimal toxicity are preferred to cytotoxic chemotherapy. Appropriate candidates for initial hormonal therapy include women with hormone receptor–positive cancers; women with bone or soft tissue metastases only; and women with limited and asymptomatic visceral metastases. Systemic chemotherapy is indicated for women with hormone receptor–negative cancers, symptomatic visceral metastases, and hormone-refractory metastases. Women with stage IV breast cancer may develop anatomically localized problems that will benefit from individualized surgical treatment, such as brain metastases, pleural effusion, pericardial effusion, biliary obstruction, ureteral obstruction, impending or existing pathologic fracture of a long bone, spinal cord compression, and painful bone or soft tissue metastases. Bisphosphonates, which may be given in addition to chemotherapy or hormone therapy, should be considered in women with bone metastases. Whether to perform surgical resection of the local-regional disease in women with stage IV breast cancer has recently been debated after several reports have suggested that women who undergo resection of the primary disease have improved survival over those who do not. Khan and associates used the National Cancer Data Base to identify patterns of treatment in women with metastatic breast cancer and found that those who had surgical resection with negative margins had a better prognosis than those women who did not have surgical therapy.148 Gnerlich and colleagues reported similar findings using the SEER database, and there have been several reports subsequent to this study from single institutions that have confirmed these findings.149 Some have suggested that the findings of improved survival are due to selection bias and that local therapy should be reserved for palliation of symptoms. A proposal has recently gone forward to study this question in a randomized fashion through the Breast Cancer Intergroup of North America. In the meantime, surgical management of patients with stage IV disease should be addressed by obtaining multidisciplinary input and by considering the treatment goals of each individual patient and the patient's treating physicians.
Local-Regional Recurrence
Women with local-regional recurrence of breast cancer may be separated into two groups: those who have had mastectomy and those who have had lumpectomy. Women treated previously with mastectomy undergo surgical resection of the local-regional recurrence and appropriate reconstruction. Chemotherapy and antiestrogen therapy are considered, and adjuvant radiation therapy is given if the chest wall has not previously received radiation therapy. Women treated previously with a breast conservation procedure undergo a mastectomy and appropriate reconstruction. Chemotherapy and antiestrogen therapy are considered.
Breast Cancer Prognosis
Survival rates for women diagnosed with breast cancer between 1983 and 1987 have been calculated based on SEER program data. The 5-year survival rate for patients with stage I disease is 94%; for patients with stage IIA disease, 85%; and for patients with stage IIB tumors, 70%. For patients with stage IIIA disease the 5-year survival rate is 52%; for patients with stage IIIB cancers, 48%; and for patients with stage IV tumors, 18%. Breast cancer survival has significantly increased over the past 2 decades due to improvements in screening and local and systemic therapies. Data from the American College of Surgeons National Cancer Data Base indicate the 5-year survival for patients with stage I cancer to be 100%; for those with stage IIA tumors, 92%; for those with stage IIB disease, 81%; for patients with stage IIIA cancers, 67%; and for those with stage IIIB disease, 54%.150
Surgical Techniques in Breast Cancer Therapy
Excisional Biopsy with Needle Localization
Excisional biopsy implies complete removal of a breast lesion with a margin of normal-appearing breast tissue. In the past, surgeons would obtain prior consent from the patient allowing mastectomy if the initial biopsy results confirmed cancer. Today it is important to consider the options for local therapy (lumpectomy vs. mastectomy with or without reconstruction) and the need for nodal assessment with sentinel node dissection. Figure 17-31 illustrates methods of obtaining a cosmetically acceptable breast scar. Excellent scars generally result from circumareolar incisions through which subareolar and centrally located breast lesions may be approached. Elsewhere, incisions that parallel Langer's lines, which are lines of tension in the skin that are generally concentric with the nipple-areola complex, result in acceptable scars except in the lower half of the breast, where the use of radial incisions typically provides the best outcome. Whenever possible, the surgeon should consider keeping the biopsy incision within the boundaries of the skin excision that may be required as part of a subsequent mastectomy (Fig. 17-32). When the tumor is quite distant from the central breast, the biopsy incision can be excised separately from the primary mastectomy incision, should a mastectomy be required. Radial incisions in the upper half of the breast are not recommended because of possible scar contracture resulting in displacement of the ipsilateral nipple-areola complex. Similarly, curvilinear incisions in the lower half of the breast may displace the nipple-areolar complex downward.
Fig. 17-31.
Breast biopsy incisions. Circumareolar incisions or incisions that parallel Langer's lines are recommended. Thin skin flaps are avoided to ensure viable periareolar tissues and good cosmesis. Radial incisions are preferred in the inferior breast.
(Reproduced with permission from Souba et al,157 p 802. Copyright Elsevier.)
Fig. 17-32.
Placement of breast biopsy incisions. Breast biopsy incisions are positioned within the boundaries of subsequent mastectomy skin incisions, and their placement allows for 1-cm or larger margins around the biopsy scar.
(Reproduced with permission from Souba et al,157 p 802. Copyright Elsevier.)
After excision of a suspicious breast lesion, the biopsy tissue specimen is orientated for the pathologist using sutures, clips, or dyes. Additional margins (superior, inferior, medial, lateral, superficial, and deep) may be taken from the surgical bed to confirm complete excision of the suspicious lesion. Electrocautery or absorbable ligatures are used to achieve wound hemostasis. Although approximation of the breast tissues in the excision bed is usually not necessary, cosmesis may occasionally be facilitated by approximation of the surgical defect using 3-0 absorbable sutures. A running subcuticular closure of the skin using 4-0 or 5-0 absorbable monofilament sutures is performed, followed by approximation of the skin edges with adhesive skin closure strips (Steri-Strips). Wound drainage is avoided.
Excisional biopsy with needle localization requires a preoperative visit to the mammography suite for placement of a localization wire. The lesion can also be targeted by sonography in the imaging suite or in the operating room. The lesion to be excised is accurately localized by mammography, and the tip of a thin wire hook is positioned close to the lesion (Fig. 17-33). Using the wire hook as a guide, the surgeon subsequently excises the suspicious breast lesion while removing a margin of normal-appearing breast tissue. Before the patient leaves the operating room, specimen radiography is performed to confirm complete excision of the suspicious lesion (Fig. 17-34).
Fig. 17-33.
Nonpalpable breast cancer. A and B. Craniocaudal (A) and mediolateral oblique (B) mammography views of the breast demonstrate an 8-mm spiculated mass (arrows) subsequently shown to be a cancer. C and D. Method of needle localization. The numbers
and letters of the localization plate allow biplanar positioning of the guidewire (arrows).
(Courtesy of Dr. B. Steinbach.)
Fig. 17-34.
Specimen mammography. The specimen mammogram contains the suspicious mass (arrow) seen on preoperative imaging.
(Courtesy of Dr. B. Steinbach.)Sentinel Lymph Node Dissection
Sentinel lymph node dissection is primarily used to assess the regional lymph nodes in women with early breast cancers who are clinically node negative by physical examination and imaging studies.151–159 This method also is accurate in women with larger tumors (T3 N0), but nearly 75% of these women will prove to have axillary lymph node metastases on histologic examination. A recent publication of the American Society of Clinical Oncology made recommendations for the use of sentinel lymph node dissection in patients with early-stage breast cancer.144 To develop practice guidelines analysts used data from one prospective randomized trial comparing sentinel node dissection with axillary node dissection, four meta-analyses, and published results from 69 single-institution and multicenter trials in which sentinel node dissection test performance was evaluated along with axillary node dissection. The American Society of Clinical Oncology guidelines did not recommend using sentinel node dissection in patients with T3, T4, or inflammatory breast cancers because the current level of evidence was felt to be insufficient. Other clinical situations in which the guidelines recommended against the use of sentinel node dissection included cases involving palpable axillary lymphadenopathy, pregnancy, DCIS without mastectomy, prior axillary surgery, or prior nononcologic breast surgery, and after preoperative chemotherapy. Although limited data are available, it was felt that sentinel node dissection was acceptable under the circumstances of multicentric tumors, DCIS with mastectomy, older age, obesity, male breast cancer, need for evaluation of internal mammary lymph nodes, and prior diagnostic or excisional biopsy, and before the use of preoperative systemic chemotherapy.
Evidence from large prospective studies suggests that the combination of intraoperative gamma probe detection of radioactive colloid and intraoperative visualization of isosulfan blue dye (Lymphazurin) is more accurate for identification of sentinel nodes than the use of either agent alone. Some surgeons use preoperative lymphoscintigraphy, although it is not required for identification of the sentinel nodes. On the day before surgery, or the day of surgery, the radioactive colloid is injected either in the breast parenchyma around the primary tumor or prior biopsy site or into the subareolar region or subdermally in proximity to the
primary tumor site. With a 25-gauge needle, 0.5 mCi of 0.2- m technetium 99m–labeled sulfur colloid is injected for same-day surgery or a higher dose of 2.5 mCi of technetium-labeled sulfur colloid is administered when the isotope is to be injected on the day before surgery. Subdermal injections are given in proximity to the cancer site or in the subareolar
location. Later, in the operating room, 3 to 5 mL of isosulfan blue dye is injected either in the breast parenchyma or in the subareolar location. It is not recommended that the blue dye be used in a subdermal injection because this can result in tattooing of the skin. For nonpalpable cancers, the injection of the technetium-labeled sulfur colloid solution can be guided by either intraoperative ultrasound or by a localization wire that is placed preoperatively under ultrasound or stereotactic guidance. It is helpful for the radiologist to mark the skin overlying the breast cancer at the time of needle localization using an indelible marker. In women who have undergone previous excisional biopsy, the injections are made in the breast parenchyma around the biopsy cavity but not into the cavity itself. Women are told preoperatively that the isosulfan blue dye injection will cause a change in the color of their urine and that there is a very small risk of allergic reaction to the dye (1 in 10,000). Anaphylactic reactions have been documented. The use of radioactive colloid is safe, and radiation exposure is very low.
A hand-held gamma counter is used to transcutaneously identify the location of the sentinel lymph node. This can help to guide placement of the incision. A 3- to 4-cm incision is made in line with that used for an axillary dissection, which is a curved transverse incision in the lower axilla just below the hairline. After dissecting through the subcutaneous tissue, the surgeon dissects through the axillary fascia, being mindful to identify blue lymphatic channels. Following these channels can lead directly to the sentinel node and limit the amount of dissection through the axillary tissues. The gamma counter is used to facilitate the dissection and to pinpoint the location of the sentinel lymph node. As the dissection continues, the signal from the probe increases in intensity as the sentinel lymph node is approached. The sentinel lymph node also is identified by visualization of isosulfan blue dye in the afferent lymph vessel and in the lymph node itself. Before the sentinel lymph node is removed, a 10-second in vivo radioactivity count is obtained. After removal of the sentinel lymph node, a 10-second ex vivo radioactive count is obtained, and the lymph node is then sent to the pathology laboratory for either permanent- or frozen-section analysis. The lowest false-negative rates for sentinel lymph node dissection have been obtained when all blue lymph nodes and all lymph nodes with radiation counts >10% of the 10-second ex vivo count of the sentinel lymph node are harvested (10% rule). Based on this, the gamma counter is used before closing the axillary wound to measure residual radioactivity in the surgical bed. A search is made for additional sentinel lymph nodes. This procedure is repeated until residual radioactivity in the surgical bed is less than 10% of the 10-second ex vivo count of the most radioactive sentinel lymph node and all blue nodes have been removed.
Results from the NSABP B-32 randomized trial on the technical aspects of sentinel node surgery were recently published.160 This trial compared sentinel node dissection alone with sentinel node dissection plus immediate axillary dissection in women with early-stage breast cancer. The overall success rate for identification of a sentinel node was 97.2%. The false-negative rate was reported to be 9.8% and was influenced by tumor location, type of diagnostic biopsy, and number of sentinel nodes removed at surgery. The authors reported that tumors located in the lateral breast were more likely to have a false-negative sentinel node. This may be explained by difficulty in discriminating the hot spot in the axilla when the radioisotope has been injected at the primary tumor site in the lateral breast. Those patients who had undergone an excisional biopsy before the sentinel node procedure were significantly more likely to have a false-negative sentinel node. This report further confirms that surgeons should use needle biopsy for diagnosis whenever possible and reserve excisional biopsy for the rare situations in which needle biopsy findings are nondiagnostic. Finally, removal of a larger number of sentinel nodes at surgery appears to reduce the false-negative rate. In the NSABP B-32 trial, the false-negative rate was reduced from 17.7 to 10%
when two sentinel nodes were recovered and to 6.9% when three sentinel nodes were removed. Yi and associates recently reported that the number of sentinel nodes that need to be removed for accurate staging is influenced by individual patient and primary tumor factors.161
Investigators in the NSABP B-32 trial reported finding sentinel nodes outside of the level I and II axillary nodes in 1.4% of cases. This finding was significantly influenced by the site of radioisotope injection. When a subareolar or periareolar injection site was used, there were no instances of sentinel nodes identified outside of the level I or II axilla, compared with a rate of 20% when a peritumoral injection was used. This supports the overall concept that the sentinel node is the first site of drainage from the lymphatic vessels of the primary tumor. Although many patients will have similar drainage patterns from injections given at the primary tumor site and at the subareolar plexus, some patients will have extra-axillary drainage, either alone or in combination with axillary node drainage, and this is best assessed with a peritumoral injection of the radioisotope.
The morbidity of sentinel node dissection alone vs. sentinel node dissection with a completion axillary node dissection has been reported by investigators from the American College of Surgeons Oncology Group Z0010 and Z0011 trials.162,163 Immediate effects of sentinel node dissection alone in the Z0010 trial included wound infection in 1%, axillary seroma in 7.1%, and axillary hematoma in 1.4%.162 At 6 months after surgery, axillary paresthesias were reported in 8.6% of patients, decreased range of motion in the upper extremity was present in 3.8%, and 6.9% had a change in arm circumference of >2 cm on the affected side, which was reported as lymphedema. Younger patients were more likely to experience paresthesias, whereas increasing age and body mass index were more predictive of lymphedema. When adverse surgical effects were examined in the Z0011 trial, patients who underwent sentinel node dissection with axillary dissection had more wound infections, seromas, and paresthesias than those patients who underwent sentinel node dissection alone. Lymphedema at 1 year after surgery was reported by 13% of patients in the sentinel node plus axillary dissection group but by only 2% in the sentinel node alone group. Arm circumference measurements were greater at 1 year in the group undergoing sentinel node plus axillary dissection, but the difference between the two groups was not statistically significant.163
The initial publications from the NSABP and American College of Surgeons Oncology Group multicenter trials provide important information to clinicians regarding the use of sentinel node dissection in early-stage breast cancer patients. Information on recurrence patterns, survival differences, and the impact of micrometastases in the sentinel nodes on outcomes requires further maturation of the data. These trials do not address the use of sentinel node dissection in other patient populations, such as patients with DCIS, patients receiving preoperative chemotherapy, and patients with prior breast or axillary surgery.
Another area of sentinel node technology that requires standardization is the pathologic processing of the sentinel nodes. Most pathology laboratories perform a more detailed analysis of the sentinel nodes than is routinely done for axillary nodes recovered from a level I and II axillary node dissection. This can include examining thin sections of the node with step sectioning at multiple levels through the paraffin blocks or performing immunohistochemical staining of the sentinel node for cytokeratin or a combination of these techniques. Intraoperative assessment of sentinel nodes also varies for different clinicians and
pathology laboratories. Some centers prefer to use touch preparation cytologic analysis of the sentinel nodes, whereas others use frozen-section analysis, and the sensitivity and specificity of these assays vary considerably. The GeneSearch Breast Lymph Node Assay is a real-time reverse-transcriptase polymerase chain reaction assay that detects breast tumor cell metastasis in lymph nodes through the identification of the gene expression markers mammaglobin and cytokeratin 19. These markers are present in higher levels in breast tissue and not in nodal tissue (cell type–specific messenger RNA). The GeneSearch assay generates expression data for genes of interest, which are then evaluated against predetermined criteria to provide a qualitative (positive/negative) result. The assay is designed to detect foci that correspond to metastases which are seen with examination by standard hematoxylin and eosin staining and measure >0.2 mm. The GeneSearch assay results have been compared with permanent-section histologic analysis and frozen-section analysis of sentinel nodes in a prospective trial, and the assay was recently approved by the FDA for the intraoperative assessment of sentinel nodes.164 When a positive node is identified intraoperatively by touch preparation, frozen-section analysis, or GeneSearch assay, the surgeon can proceed with immediate completion of axillary node dissection. Although there are a number of nomograms and predictive models designed to determine which patients with a positive sentinel node are at risk for harboring additional positive nonsentinel nodes in the axilla, completion axillary dissection remains the standard practice.165
Breast Conservation
Breast conservation involves resection of the primary breast cancer with a margin of normal-appearing breast tissue, adjuvant radiation therapy, and assessment of regional lymph node status.166,167 Resection of the primary breast cancer is alternatively called segmental mastectomy, lumpectomy, partial mastectomy, wide local excision, and tylectomy. For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is preferable to total mastectomy because BCT produces survival rates equivalent to those after total mastectomy while preserving the breast.168 Six prospective randomized trials have shown that overall and disease-free survival rates are similar with BCT and mastectomy. Three of the studies showed higher local-regional failure rates in patients undergoing BCT; however, in two of these studies, there were no clear criteria for histologically negative margins.166–169 Recent data from the Early Breast Cancer Trialists' Collaborative Group revealed that avoiding local recurrence translates into a survival advantage.169 When all of this information is taken together, BCT is considered to be oncologically equivalent to mastectomy.
In addition to being equivalent to mastectomy in terms of oncologic safety, BCT appears to offer advantages over mastectomy with regard to quality of life and aesthetic outcomes. BCT allows for preservation of breast shape and skin as well as preservation of sensation, and provides an overall psychologic advantage associated with breast preservation.
Breast conservation surgery is currently the standard treatment for women with stage 0, I, or II invasive breast cancer. Women with DCIS require only resection of the primary cancer and adjuvant radiation therapy without assessment of regional lymph nodes. When a lumpectomy is performed, a curvilinear incision lying concentric to the nipple-areola complex is made in the skin overlying the breast cancer when the tumor is in the upper aspect of the breast. Radial incisions are preferred when the tumor is in the lower aspect of the breast. Skin encompassing any prior biopsy site generally is excised, but skin excision is not otherwise necessary unless there is direct involvement of the overlying skin by the primary tumor. The
breast cancer is removed with an envelope of normal-appearing breast tissue that is adequate to achieve at least a 2-mm cancer-free margin. Specimen orientation is performed by the surgeon. Additional margins from the surgical bed are taken as needed to provide a histologically negative margin. Requests for determination of hormone receptor status and HER-2/neu expression are conveyed to the pathologist.
Sentinel lymph node dissection is now the preferred staging procedure with a clinically node-negative axilla. When the procedures are sequenced in the operating room, the sentinel node procedure usually is performed before removal of the primary breast tumor. When indicated, intraoperative assessment of the sentinel node can proceed while the segmental mastectomy is being performed. When the sentinel lymph node does not contain metastatic disease, axillary lymph node dissection is avoided. It is the surgeon's responsibility to ensure complete removal of cancer in the breast. Ensuring surgical margins that are free of breast cancer will minimize the chances of local recurrence and will enhance cure rates. Local recurrence of breast cancer after conservation surgery is determined primarily by the adequacy of surgical margins. Cancer size and the extent of skin excision are not significant factors in this regard. It is the practice of many North American and European surgeons to undertake re-excision when residual cancer within 2 mm of a surgical margin is determined by histopathologic examination. If clear margins are not obtainable with re-excision, mastectomy is required.
The use of oncoplastic surgery can be entertained at the time of segmental mastectomy or at a later time to improve the overall aesthetic outcome. Oncoplastic techniques range from a simple reshaping of breast tissue to local tissue rearrangement to the use of pedicled flaps or breast reduction techniques. The overall goal is to achieve the best possible aesthetic result. In determining which patients are candidates for oncoplastic breast surgery, several factors should be considered, including the extent of the resection of breast tissue necessary to achieve negative margins, the location of the primary tumor within the breast, and the size of the patient's breast and body habitus. Oncoplastic techniques are of prime consideration when (a) a significant area of breast skin will need to be resected with the specimen to achieve negative margins; (b) a large volume of breast parenchyma will be resected resulting in a significant defect; (c) the tumor is located between the nipple and the inframammary fold, an area often associated with unfavorable cosmetic outcomes; or (d) excision of the tumor and closure of the breast may result in malpositioning of the nipple.
Mastectomy and Axillary Dissection
A skin-sparing mastectomy removes all breast tissue, the nipple-areola complex, and scars from any prior biopsy procedures.170,171 There is a recurrence rate of less than 6 to 8%, comparable to the long-term recurrence rates reported with standard mastectomy, when skin-sparing mastectomy is used for patients with T1 to T3 cancers. A total (simple) mastectomy without skin sparing removes all breast tissue, the nipple-areola complex, and skin. An extended simple mastectomy removes all breast tissue, the nipple-areola complex, skin, and the level I axillary lymph nodes. A modified radical mastectomy removes all breast tissue, the nipple-areola complex, skin, and the level I and level II axillary lymph nodes. The Halsted radical mastectomy removes all breast tissue and skin, the nipple-areola complex, the pectoralis major and pectoralis minor muscles, and the level I, II, and III axillary lymph nodes. The use of systemic chemotherapy and hormonal therapy as well as adjuvant radiation therapy for breast cancer have nearly eliminated the need for the radical mastectomy.
For a variety of biologic, economic, and psychosocial reasons, some women desire mastectomy rather than breast conservation. Women who are less concerned about cosmesis may view mastectomy as the most expeditious and desirable therapeutic option because it avoids the cost and inconvenience of radiation therapy. Women whose primary breast cancers cannot be excised with a reasonable cosmetic result or those who have extensive microcalcifications are best treated with mastectomy. Women with large cancers that occupy the subareolar and central portions of the breast and women with multicentric primary cancers also undergo mastectomy.
Modified Radical Mastectomy
A modified radical mastectomy preserves both the pectoralis major and pectoralis minor muscles, allowing removal of level I and level II axillary lymph nodes but not the level III (apical) axillary lymph nodes (Figs. 17-35 and 17-36).170 The Patey modification removes the pectoralis minor muscle and allows complete dissection of the level III axillary lymph nodes (Figs. 17-37 and 17-38). A modified radical mastectomy permits preservation of the medial (anterior thoracic) pectoral nerve, which courses in the lateral neurovascular bundle of the axilla and usually penetrates the pectoralis minor to supply the lateral border of the pectoralis major. Anatomic boundaries of the modified radical mastectomy are the anterior margin of the latissimus dorsi muscle laterally, the midline of the sternum medially, the subclavius muscle superiorly, and the caudal extension of the breast 2 to 3 cm inferior to the inframammary fold inferiorly (see Fig. 17-35 inset). Skin-flap thickness varies with body habitus but ideally is 7 to 8 mm inclusive of skin and tela subcutanea. Once the skin flaps are fully developed, the fascia of the pectoralis major muscle and the overlying breast tissue are elevated off the underlying musculature, which allows for the complete removal of the breast.
Fig. 17-35.
Modified radical mastectomy: elevation of skin flaps. Skin flaps are 7 to 8 mm in thickness, inclusive of the skin and tela subcutanea. Inset depicts the limits of the modified radical mastectomy.
(Reproduced with permission from Bland et al,170 p 905. Copyright Elsevier.)
Fig. 17-36.
Modified radical mastectomy: resection of breast tissue. The pectoralis major muscle is cleared of its fascia as the overlying breast is elevated. The latissimus dorsi muscle is the lateral boundary of the dissection.
(Reproduced with permission from Bland et al,170 p 906. Copyright Elsevier.)
Fig. 17-37.
Modified radical mastectomy (Patey): axillary lymph node dissection. The dissection proceeds from lateral to medial, with complete visualization of the anterior and inferior aspects of the axillary vein. Loose areolar tissue at the junction of the axillary vein and the anterior margin of the latissimus dorsi muscle is swept inferomedially inclusive of the lateral (axillary) lymph node group (level I). Care is taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space. The lateral lymph node group is resected in continuity with the subscapular lymph node group (level I) and the external mammary lymph node group (level I). Dissection anterior to the axillary vein allows removal of the central lymph node group (level II) and the apical (subclavicular) lymph node group (level III). The superomedial limit of this dissection is the clavipectoral fascia (Halsted's ligament). Inset depicts division of the insertion of the pectoralis minor muscle at the coracoid process. The surgeon's finger shields the underlying brachial plexus.
(Reproduced with permission from Bland et al,170 p 908.)
Fig. 17-38.
Modified radical mastectomy (Patey): completed dissection. The completed dissection includes the pectoralis minor muscle from its insertion to its origin from the second to fifth ribs. Rotter's lymph nodes (level I) are left attached to the pectoralis minor muscle as it is removed. Both medial and lateral pectoral nerves are preserved to ensure innervation of the lateral and medial heads (respectively) of the pectoralis major muscle. Inset depicts the positioning of closed-suction catheters, which are brought out through the inferior flap. The lateral catheter is placed 2 cm inferior to the axillary vein. The medial catheter is positioned anterior to the pectoralis major muscle.
(Reproduced with permission from Bland et al,170 p 909. Copyright Elsevier.)Subsequently, an axillary lymph node dissection is performed. The most lateral extent of the axillary vein is identified and the areolar tissue of the lateral axillary space is elevated as the vein is cleared on its anterior and inferior surfaces. The areolar tissues at the junction of the axillary vein and the anterior edge of the latissimus dorsi muscle, which include the lateral and subscapular lymph node groups (level I), are cleared in an inferomedial direction. Care is taken to preserve the thoracodorsal neurovascular bundle. The dissection then continues medially with clearance of the central axillary lymph node group (level II). The long thoracic nerve of Bell is identified and preserved as it travels in the investing fascia of the serratus
anterior muscle. Every effort is made to preserve this nerve, because permanent disability with a winged scapula and shoulder weakness will follow denervation of the serratus anterior muscle. If there is palpable lymphadenopathy at the apex of the axilla, the tendinous portion of the pectoralis minor muscle is divided near its insertion onto the coracoid process (see Fig. 17-37 inset), which allows dissection of the axillary vein medially to the costoclavicular (Halsted's) ligament. Finally, the breast and axillary contents are removed from the surgical bed and are sent for pathologic assessment. The Patey modification originally involved removal of the pectoralis muscle (see Fig. 17-38). However, some surgeons now divide only the tendon of the pectoralis minor muscle at its insertion onto the coracoid process while leaving the rest of the muscle intact.
Seromas beneath the skin flaps or in the axilla represent the most frequent complication of mastectomy and axillary lymph node dissection, reportedly occurring in as many as 30% of cases. The use of closed-system suction drainage reduces the incidence of this complication. Catheters are retained in the wound until drainage diminishes to <30 mL per day. Wound infections occur infrequently after a mastectomy and the majority are a result of skin-flap necrosis. Cultures of specimens taken from the infected wound for aerobic and anaerobic organisms, débridement, and antibiotic therapy are effective management. Moderate or severe hemorrhage in the postoperative period is rare and is best managed with early wound exploration for control of hemorrhage and re-establishment of closed-system suction drainage. The incidence of functionally significant lymphedema after a modified radical mastectomy is 10 to 20%. Extensive axillary lymph node dissection, the delivery of radiation therapy, the presence of pathologic lymph nodes, and obesity are predisposing factors. The use of individually fitted compressive sleeves and intermittent compression devices may be necessary.
Reconstruction of the Breast and Chest Wall
The goals of reconstructive surgery after a mastectomy for breast cancer are wound closure and breast reconstruction, which is either immediate or delayed.172 For most women, wound closure after mastectomy is accomplished with simple approximation of the wound edges. However, if a more radical removal of skin and subcutaneous tissue is necessary, a pedicled myocutaneous flap from the latissimus dorsi muscle is generally the best approach for wound coverage. A skin graft provides functional coverage that will tolerate adjuvant radiation therapy; however, this is not preferred, because poor graft adherence may delay delivery of radiation therapy. Breast reconstruction after prophylactic mastectomy or after mastectomy for early invasive breast cancer is performed at the same time as the mastectomy. This allows for a skin-sparing mastectomy to be performed, which offers the best overall cosmetic outcomes. Reconstruction can proceed with an expander/implant reconstruction or with autologous tissue such as a pedicled myocutaneous flap or a free flap using microvascular techniques. In patients with advanced breast cancer reconstruction is delayed until after completion of adjuvant radiation therapy to ensure that local-regional control of disease is obtained. If chest wall coverage is needed to replace a large skin or soft tissue defect, many different types of myocutaneous flaps are employed, but the latissimus dorsi and the rectus abdominus myocutaneous flaps are most frequently used. The latissimus dorsi myocutaneous flap consists of a skin paddle based on the underlying latissimus dorsi muscle, which is supplied by the thoracodorsal artery with contributions from the posterior intercostal arteries. A transverse rectus abdominis myocutaneous (TRAM) flap consists of a skin paddle based on the underlying rectus abdominis muscle, which is supplied by vessels from the deep inferior epigastric artery. The free TRAM flap uses microvascular anastomoses to establish blood
supply to the flap. When the bony chest wall is involved with cancer, resection of a portion of the bony chest wall is indicated. If only one or two ribs are resected and soft tissue coverage is provided, reconstruction of the bony defect is usually not necessary, because scar tissue will stabilize the chest wall. If more than two ribs are sacrificed, it is advisable to stabilize the chest wall with prosthetic material, which is then covered with soft tissue by using a latissimus dorsi or TRAM flap.Nonsurgical Breast Cancer Therapies
Radiation Therapy
Radiation therapy is used for all stages of breast cancer depending on whether the patient is undergoing BCT or mastectomy.173–179 For women with limited DCIS (stage 0) in whom negative margins are achieved by segmental mastectomy, adjuvant radiation therapy is given to reduce the risk of local recurrence. Low-grade DCIS of the solid, cribriform, or papillary subtypes that is <0.5 cm in diameter and is excised with widely negative margins may be managed by excision alone. For women with stage I, IIA, or IIB breast cancer in which negative margins are achieved by segmental mastectomy, adjuvant radiation therapy is given to reduce the risk of local recurrence. Those women treated with mastectomy who have cancer at the surgical margins are at sufficiently high risk for local recurrence to warrant the use of adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes. Women with metastatic disease involving four or more axillary lymph nodes and premenopausal women with metastatic disease involving one to three lymph nodes also are at increased risk for recurrence and are candidates for the use of chest wall and supraclavicular lymph node radiation therapy. In advanced local-regional breast cancer (stage IIIA or IIIB), women are at high risk for recurrent disease after surgical therapy, and adjuvant radiation therapy is used to reduce the recurrence rates (Fig. 17-39). Current recommendations for stages IIIA and IIIB breast cancer are (a) adjuvant radiation therapy to the breast and supraclavicular lymph nodes after neoadjuvant chemotherapy and segmental mastectomy with or without axillary lymph node dissection, (b) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after neoadjuvant chemotherapy and mastectomy with or without axillary lymph node dissection, and (c) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after segmental mastectomy or mastectomy with axillary lymph node dissection and adjuvant chemotherapy.
Fig. 17-39.
Radiation therapy for stage IIIA and stage IIIB breast cancer. A. Comprehensive chest wall and regional lymph node radiation therapy. B. Cross-sectional view showing the tangential field.
[Reproduced with permission from Beenken SW, et al: Radiation therapy for stage IIIA and stage IIIB breast cancer, in Bland KI (ed): The Practice of General Surgery. Philadelphia: WB Saunders, 2002, p 983. Copyright © Elsevier.]The use of partial breast irradiation (PBI) for patients treated with breast-conserving surgery
is currently being compared with whole-breast irradiation in a phase III randomized trial. PBI can be delivered via brachytherapy, external beam radiation therapy using three-dimensional conformal radiation, or intensity-modulated radiation therapy. Although initial results are promising in highly selected low-risk populations, PBI should be used in the clinical setting only as part of a prospective trial.
Chemotherapy
Adjuvant Chemotherapy
The Early Breast Cancer Trialists' Collaborative Group overview analysis of adjuvant
chemotherapy demonstrated reductions in the odds of recurrence and of death in women
70 years of age with stage I, IIA, or IIB breast cancer.180–185 For those 70 years of age, the lack of definitive clinical trial data regarding adjuvant chemotherapy prevented definitive recommendations. Adjuvant chemotherapy is of minimal benefit to women with negative
nodes and cancers 0.5 cm in size and is not recommended. Women with negative nodes and cancers 0.6 to 1.0 cm are divided into those with a low risk of recurrence and those with unfavorable prognostic features that portend a higher risk of recurrence and a need for adjuvant chemotherapy. Adverse prognostic factors include blood vessel or lymph vessel invasion, high nuclear grade, high histologic grade, HER-2/neu overexpression, and negative hormone receptor status. Adjuvant chemotherapy is recommended for women with these unfavorable prognostic features. Table 17-15 lists the frequently used chemotherapy regimens for breast cancer.
Table 17-15 Adjuvant Chemotherapy Regimens for Breast Cancer
HER-2/neu Negative (Non–Trastuzumab-Containing Regimens)
HER-2/neu Positive (Trastuzumab-Containing Regimens)
FAC/CAFAC T + concurrent trastuzumab (T = paclitaxel)
FEC/CEF
AC or ECDocetaxel + trastuzumab FEC
TAC (T = docetaxel) TCH (docetaxel, carboplatin, trastuzumab)
A CMFChemotherapy followed by trastuzumab sequentially
E CMF
CMFAC docetaxel + trastuzumab
AC x 4
A T C (T = paclitaxel)
FEC T (T = docetaxel)
TC (T = docetaxel)
A = Adriamycin (doxorubicin); C = cyclophosphamide; E = epirubicin; F = 5-fluorouracil; M
= methotrexate; T = Taxane (docetaxel or paclitaxel); = followed by.
Source: Adapted with permission from Carlson RW, et al: Breast cancer, in NCCN Practice Guidelines in Oncology. Fort Washington, Penn: National Comprehensive Cancer Network, 2006.For women with hormone receptor–negative cancers that are >1 cm in size, adjuvant chemotherapy is appropriate. However, women with node-negative hormone receptor–positive cancers and T1 tumors are candidates for antiestrogen therapy with or without chemotherapy. For special-type cancers (tubular, mucinous, medullary, etc), adjuvant chemotherapy or antiestrogen therapy for cancers <3 cm in size is controversial. For women with node-positive tumors or with a special-type cancer that is >3 cm, the use of chemotherapy is appropriate. Those with hormone receptor–positive tumors should receive antiestrogen therapy as well. Current treatment recommendations for stage IIIA breast cancer include preoperative chemotherapy with a doxorubicin (Adriamycin)-containing regimen followed by either a modified radical mastectomy or segmental mastectomy with axillary dissection followed by adjuvant radiation therapy. These recommendations are based in part on the results of the NSABP B-15 trial. In this study, women with node-positive, tamoxifen-
nonresponsive cancers who were 59 years of age were randomly assigned to receive either 2 months of therapy with doxorubicin and cyclophosphamide or 6 months of cyclophosphamide, methotrexate, and cyclophosphamide, methotrexate, 5-fluorouracil. There was no difference in relapse-free survival or overall survival rates, and women preferred the shorter regimen.186
Neoadjuvant (Preoperative) Chemotherapy
In the early 1970s, the National Cancer Institute in Milan, Italy, initiated two prospective randomized multimodality clinical trials for women with T3 or T4 breast cancer.187 The best results were achieved when surgery was interposed between chemotherapy courses, with 82% local-regional control and 25% 5-year disease-free survival. The NSABP B-18 trial evaluated the role of neoadjuvant chemotherapy in women with operable stage II and III breast cancer.188 Women entered into this study were randomly assigned to receive either surgery followed by chemotherapy or neoadjuvant chemotherapy followed by surgery. There was no difference in the 5-year disease-free survival rates for the two groups, but after neoadjuvant chemotherapy there was an increase in the number of lumpectomies performed and a decreased incidence of node positivity. It was suggested that neoadjuvant chemotherapy be considered for the initial management of breast cancers judged too large for initial lumpectomy.
The use of neoadjuvant chemotherapy has expanded from its initial use in the setting of large and locally advanced breast cancers to use in any patient who is deemed to be a candidate for
systemic chemotherapy based on primary tumor factors or nodal staging. The use of neoadjuvant chemotherapy offers the opportunity to observe the response of the intact primary tumor and any regional nodal metastases to a specific chemotherapy regimen.189 For patients whose tumors remain stable in size or even progress with the initial neoadjuvant chemotherapy regimen, a new regimen can be instituted that uses another class of agents.
After treatment with neoadjuvant chemotherapy, patients are assessed for clinical and pathologic response to the regimen. Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy have been shown to have survival outcomes far superior to those of patients whose tumors demonstrate only a partial response or remain stable. Patients who experience progression of disease during neoadjuvant chemotherapy have the poorest survival.190
Current recommendations for treatment of operable advanced local-regional breast cancer are neoadjuvant chemotherapy with a doxorubicin-containing or taxane-containing regimen, followed by mastectomy or lumpectomy with axillary lymph node dissection if necessary, followed by adjuvant radiation therapy. For inoperable stage IIIA and for stage IIIB breast cancer, neoadjuvant chemotherapy is used to decrease the local-regional cancer burden. This may then permit subsequent modified radical or radical mastectomy, which is followed by adjuvant radiation therapy.
Nodal Evaluation in Patients Receiving Neoadjuvant Chemotherapy
The management of the axilla after neoadjuvant chemotherapy has not been specifically addressed in randomized trials. Standard practice has been to perform an axillary lymph node dissection after chemotherapy or to perform a sentinel lymph node dissection before chemotherapy for nodal staging before chemotherapy is initiated. A number of small single-institution studies, one multicenter study, and a recent meta-analysis have explored the use of sentinel lymph node dissection at the completion of chemotherapy. The published results from these studies have demonstrated the feasibility of sentinel lymph node dissection in breast cancer patients after neoadjuvant chemotherapy and have suggested that the procedure is accurate for nodal staging in this patient population.191,192 Although the issue has not been specifically addressed in the published trials, the presence of suspected or documented axillary metastases at initial presentation generally is considered a relative contraindication to sentinel lymph node dissection after neoadjuvant chemotherapy, and these patients usually undergo axillary lymph node dissection after completion of chemotherapy.
Neoadjuvant Endocrine Therapy
Neoadjuvant endocrine therapy has most commonly been used in elderly women who were deemed poor candidates for surgery or cytotoxic chemotherapy. However, as clinicians have gained experience with neoadjuvant treatment strategies, it is now clear from examination of predictors of complete pathologic response that estrogen receptor–positive tumors do not shrink in response to chemotherapy as readily as estrogen receptor–negative tumors.193 Fisher and colleagues examined the results of the NSABP B-14 and B-20 trials and found that, as age increased, women obtained less benefit from chemotherapy. They recommended that factors194 including tumor estrogen receptor concentration, nuclear grade, histologic grade, tumor type, and markers of proliferation should be considered in these patients before choosing between the use of chemotherapy and hormonal therapy. If in fact the tumor is
estrogen receptor rich, these patients may benefit more from endocrine therapy in the neoadjuvant setting than they might if they received standard chemotherapy. Neoadjuvant endocrine therapy has been shown to shrink tumors, enabling breast-conserving surgery in women with hormone receptor–positive disease who otherwise would have to be treated with mastectomy.
With the use of neoadjuvant chemotherapy or endocrine therapy, observation of the response of the intact tumor and/or nodal metastases to a specific regimen could ultimately help to define which patients will benefit from specific therapies in the adjuvant setting. In adjuvant trials the primary endpoint is typically survival, whereas in neoadjuvant trials the endpoints are more often clinical or pathologic response rates. There are a number of clinical trials underway comparing neoadjuvant chemotherapy and endocrine therapy regimens with pretreatment and posttreatment biopsy samples obtained from the primary tumors in all of the participants. These samples are being subjected to intensive genomic and proteomic analyses that may help to define a more personalized or individualized approach to breast cancer treatment in the future.
For women with stage IV breast cancer, an antiestrogen (tamoxifen for premenopausal women or an aromatase inhibitor for postmenopausal women) is the preferred therapy. However, women with hormone receptor–negative cancers with symptomatic visceral metastasis or with hormone-refractory cancer may receive systemic chemotherapy. Pamidronate may be given to women with osteolytic bone metastases in addition to hormonal therapy or standard chemotherapy.195 Women with metastatic breast cancer also may be enrolled into clinical trials exploring novel biologic therapies alone or in combination with chemotherapeutics.
Antiestrogen Therapy
Within the cytosol of breast cancer cells are specific proteins (receptors) that bind and transfer steroid moieties into the cell nucleus to exert specific hormonal effects.184,196–200 The most widely studied hormone receptors are the estrogen receptor and progesterone receptor. Hormone receptors are detectable in >90% of well-differentiated ductal and lobular invasive cancers. Sequential studies of hormone receptor status reveal no differences between the primary cancer and metastatic disease in the same patient.
After binding to estrogen receptors in the cytosol, tamoxifen blocks the uptake of estrogen by breast tissue. Clinical responses to antiestrogen are evident in >60% of women with hormone receptor–positive breast cancers but in <10% of women with hormone receptor–negative breast cancers. An overview analysis by the Early Breast Cancer Trialists' Collaborative Group showed that adjuvant therapy with tamoxifen produced a 25% reduction in the annual risk of breast cancer recurrence and a 7% reduction in annual breast cancer mortality.201 The analysis also showed a 39% reduction in the risk of cancer in the contralateral breast. The antiestrogens do have defined toxicity, including bone pain, hot flashes, nausea, vomiting, and fluid retention. Thrombotic events occur in <3% of treated women. Cataract surgery is more frequently performed in patients receiving tamoxifen. A long-term risk of tamoxifen use is endometrial cancer, although it occurs rarely. Tamoxifen therapy usually is discontinued after 5 years. In postmenopausal women, aromatase inhibitors are now considered as first-line therapy in the adjuvant setting or as a secondary agent after 1 to 2 years of adjuvant tamoxifen therapy. The aromatase inhibitors are less likely to cause
endometrial cancer but do lead to changes in bone mineral density that may result in osteoporosis and an increased rate of fractures in postmenopausal women.
The NSABP P-1 trial was the first large-scale U.S. breast cancer prevention trial, and it demonstrated a 49% reduction in the incidence of invasive breast cancer in high-risk women who were treated with tamoxifen.50 This reduction was demonstrated for all age groups treated, for all projected levels of risk, and for women with a prior history of either LCIS or atypical ductal hyperplasia. The reduction was demonstrable within the first year of follow-up and continued through a 6-year follow-up period. This led to approval of tamoxifen as a chemopreventive agent for women with a Gail relative risk of 1.70 or greater. Treatment consists of tamoxifen (20 mg/d) for up to 5 years to reduce the risk of breast cancer. The NSABP P-2 prevention trial compared the use of raloxifene, a selective estrogen receptor modulator used to prevent osteoporosis in postmenopausal women, with the use of tamoxifen in postmenopausal women at increased risk for breast cancer (Study of Tamoxifen and Raloxifene, or STAR trial). In the STAR trial, 19,747 postmenopausal women were randomly assigned to receive tamoxifen (20 mg daily) or raloxifene (60 mg daily) for 5 years. The initial results revealed 163 invasive breast cancers in the tamoxifen group and 168 invasive breast cancers in the raloxifene group.60 Fewer noninvasive cancers were diagnosed in the tamoxifen group. An important outcome was the finding of 36% fewer cases of uterine cancer in the raloxifene group. Overall there were no differences between tamoxifen and raloxifene with respect to the risks of other invasive cancers, ischemic heart disease events, numbers of stroke, or osteoporotic fractures reported. The number of thromboembolic events and incidence of cataracts were lower in the raloxifene group. Overall, the STAR trial revealed that raloxifene is as effective as tamoxifen for reducing the risk of invasive breast cancer in high-risk women. There was a difference in favor of tamoxifen with respect to number of noninvasive breast cancers, but this was not statistically significant. Perhaps most importantly when a chemoprevention regimen is considered, raloxifene appears to have a better toxicity profile than tamoxifen, including both a lower risk of thromboembolic events and a lower risk of cataracts.
Tamoxifen therapy is also considered for women with DCIS that is found to be estrogen receptor positive on immunohistochemical studies. The goals of such therapy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event.
Node-negative women with hormone receptor–positive breast cancers that are 1 to 3 cm in size are candidates for adjuvant endocrine therapy with or without chemotherapy. For node-positive women and for all women with a cancer that is >3 cm in size, the use of endocrine therapy in addition to adjuvant chemotherapy is appropriate. Women with hormone receptor–positive cancers achieve significant reduction in risk of recurrence and mortality due to breast cancer through the use of endocrine therapies. For women with stage IV breast cancer, an antiestrogen is the preferred initial therapy. For women with prior antiestrogen exposure, recommended second-line hormonal therapies include aromatase inhibitors in postmenopausal women and progestins, androgens, high-dose estrogen, or oophorectomy (medical, surgical, or radioablative) in premenopausal women. Women who respond to hormonal therapy with either shrinkage of their breast cancer or long-term stabilization of disease receive additional hormonal therapy at the time of progression. Women with hormone receptor–negative cancers, with symptomatic visceral metastasis, or with hormone-refractory
disease receive systemic chemotherapy rather than hormone therapy.
Ablative Endocrine Therapy
In the past, oophorectomy, adrenalectomy, and/or hypophysectomy were the primary endocrine modalities used to treat metastatic breast cancer, but today they are rarely used. Oophorectomy was used in premenopausal breast cancer patients who presented with skin or bony metastases after a disease-free interval that exceeded 18 months. In contrast, pharmacologic doses of exogenous estrogens were given to postmenopausal women with similar recurrences. For both groups, the response rates were nearly 30%. Adrenalectomy and hypophysectomy were effective in individuals who had previously responded to either oophorectomy or exogenous estrogen therapy, and the response to these additional procedures was nearly 30%. Visceral metastases (lung, liver) responded infrequently to any form of hormonal manipulation. Aminoglutethimide blocks enzymatic conversion of
cholesterol to -5-pregnenolone and inhibits the conversion of androstenedione to estrogen in peripheral tissues. Dose-dependent and transient side effects include ataxia, dizziness, and lethargy. After treatment with this agent (medical adrenalectomy), adrenal suppression necessitates glucocorticoid therapy. Neither permanent adrenal insufficiency nor acute crises have been observed. Because the adrenal glands are the major site for production of endogenous estrogens after menopause, treatment with aminoglutethimide has been compared prospectively with surgical adrenalectomy and hypophysectomy in postmenopausal women and is equally efficacious.
Anti–Her-2/Neu Antibody Therapy
The determination of tumor HER-2/neu expression for all newly diagnosed patients with breast cancer is now recommended.201–204 It is used for prognostic purposes in node-negative patients to assist in the selection of adjuvant chemotherapy because response rates appear to be better with doxorubicin-based adjuvant chemotherapy in patients with tumors that overexpress HER-2/neu, and as baseline information in case the patient develops recurrent disease that may benefit from anti–HER-2/neu therapy (trastuzumab). Patients with tumors that overexpress HER-2/neu may benefit if trastuzumab is added to paclitaxel chemotherapy. Cardiotoxicity may develop if trastuzumab is delivered concurrently with doxorubicin-based chemotherapy.
Trastuzumab was initially approved for the treatment of HER-2/neu–positive breast cancer in patients with metastatic disease. Once efficacy was demonstrated for patients with metastatic disease, the NSABP and the North Central Cancer Treatment Group conducted phase III trials evaluating the impact of adjuvant trastuzumab therapy in patients with early-stage breast cancer. After approval from the FDA, these groups amended their adjuvant trastuzumab trials (B-31 and N9831, respectively), to provide for a joint efficacy analysis. The first joint interim efficacy analysis demonstrated an improvement in 3-year disease-free survival from 75% in the control arm to 87% in the trastuzumab arm (hazard ratio = 0.48, P <.0001). There was an accompanying 33% reduction in mortality in the patients who received trastuzumab (hazard ratio = 0.67, P = .015). The magnitude of reduction in hazard for disease-free survival events crossed prespecified early reporting boundaries, so the data-monitoring committees for both groups recommended that randomized accrual to the trials be
ended, and the results were subsequently published.124
Buzdar and colleagues at the M. D. Anderson Cancer Center reported the results of a randomized phase II neoadjuvant trial of trastuzumab in combination with sequential paclitaxel followed by FEC-75 (5-fluorouracil, epirubicin, cyclophosphamide) vs. the same chemotherapy regimen without trastuzumab in 42 women with early-stage operable breast cancer. The pathologic complete response rates in this trial increased from 25 to 66.7% when chemotherapy was given concurrently with trastuzumab. None of the patients receiving the concurrent trastuzumab and FEC regimen developed symptoms of congestive heart failure. However, given the small sample size in this report, the 95% confidence interval for developing heart failure was 0 to 14.8%.205 A subsequent report which included additional patients treated with concurrent chemotherapy and trastuzumab further confirmed the high pathologic complete response rates and continued to show that cardiac function was preserved.206 This regimen is currently being tested in a phase III multicenter trial sponsored by the American College of Surgeons Oncology Group.Special Clinical Situations
Nipple Discharge
Unilateral Nipple Discharge
Nipple discharge is a finding that can be seen in a number of clinical situations. It may be suggestive of cancer if it is spontaneous, unilateral, localized to a single duct, present in
women 40 years of age, bloody, or associated with a mass. A trigger point on the breast may be present so that pressure around the nipple-areolar complex induces discharge from a single duct. In this circumstance, mammography and ultrasound are indicated for further evaluation. A ductogram also can be useful and is performed by cannulating a single discharging duct with a small nylon catheter or needle and injecting 1.0 mL of water-soluble contrast solution. Nipple discharge associated with a cancer may be clear, bloody, or serous. Testing for the presence of hemoglobin is helpful, but hemoglobin may also be detected when nipple discharge is secondary to an intraductal papilloma or duct ectasia. Definitive diagnosis depends on excisional biopsy of the offending duct and any associated mass lesion. A 3.0 lacrimal duct probe can be used to identify the duct that requires excision. Another approach is to inject methylene blue dye within the duct after ductography. The nipple must be sealed with collodion or a similar material so that the blue dye does not discharge through the nipple but remains within the distended duct facilitating its localization. Needle localization biopsy is performed when there is an associated mass that lies >2.0 to 3.0 cm from the nipple.
Bilateral Nipple Discharge
Nipple discharge is suggestive of a benign condition if it is bilateral and multiductal in origin,
occurs in women 39 years of age, or is milky or blue-green. Prolactin-secreting pituitary adenomas are responsible for bilateral nipple discharge in <2% of cases. If serum prolactin levels are repeatedly elevated, plain radiographs of the sella turcica are indicated and thin section CT scan is required. Optical nerve compression, visual field loss, and infertility are associated with large pituitary adenomas.
Axillary Lymph Node Metastases in the Setting of an Unknown Primary Cancer
A woman who presents with an axillary lymph node metastasis that is consistent with a breast cancer metastasis has a 90% probability of harboring an occult breast cancer.207 However, axillary lymphadenopathy is the initial presenting sign in only 1% of breast cancer patients. Fine-needle aspiration biopsy, core-needle biopsy, or open biopsy of an enlarged axillary lymph node is performed to confirm metastatic disease. When metastatic cancer is found, immunohistochemical analysis may classify the cancer as epithelial, melanocytic, or lymphoid in origin. The presence of hormone receptors (estrogen or progesterone receptors) suggests metastasis from a breast cancer but is not diagnostic. The search for a primary cancer includes careful examination of the thyroid, breast, and pelvis, including the rectum. The breast should be examined with diagnostic mammography, ultrasonography, and MRI to evaluate for an occult primary lesion. Further radiologic and laboratory studies should include chest radiography and liver function studies. Chest, abdominal, and pelvic CT scans also are indicated, as is a bone scan to rule out distant metastasis. Suspicious findings on mammography, ultrasonography, or MRI necessitate breast biopsy. When a breast cancer is found, treatment consists of an axillary lymph node dissection with a mastectomy or preservation of the breast followed by whole-breast radiation therapy. Chemotherapy and endocrine therapy should be considered.
Breast Cancer during Pregnancy
Breast cancer occurs in 1 of every 3000 pregnant women, and axillary lymph node metastases are present in up to 75% of these women.208 The average age of the pregnant woman with breast cancer is 34 years. Fewer than 25% of the breast nodules developing during pregnancy and lactation will be cancerous. Ultrasonography and needle biopsy are used in the diagnosis of these nodules. Open biopsy may be required. Mammography is rarely indicated because of its decreased sensitivity during pregnancy and lactation; however, the fetus can be shielded if mammography is needed. Approximately 30% of the benign conditions encountered will be unique to pregnancy and lactation (galactoceles, lobular hyperplasia, lactating adenoma, and mastitis or abscess). Once a breast cancer is diagnosed, complete blood count, chest radiography (with shielding of the abdomen), and liver function studies are performed.
Because of the potential deleterious effects of radiation therapy on the fetus, radiation cannot be considered until the fetus is delivered. A modified radical mastectomy can be performed during the first and second trimesters of pregnancy, even though there is an increased risk of spontaneous abortion after first-trimester anesthesia. During the third trimester, lumpectomy with axillary node dissection can be considered if adjuvant radiation therapy is deferred until after delivery. Lactation is suppressed. Chemotherapy administered during the first trimester carries a risk of spontaneous abortion and a 12% risk of birth defects. There is no evidence of teratogenicity resulting from administration of chemotherapeutic agents in the second and third trimesters. For this reason, many clinicians now consider the optimal strategy to be delivery of chemotherapy in the second and third trimesters as a neoadjuvant approach, which allows local therapy decisions to be made after the delivery of the baby. Pregnant women with breast cancer often present at a later stage of disease because breast tissue changes that occur in the hormone-rich environment of pregnancy obscure early cancers. However, pregnant women with breast cancer have a prognosis, stage by stage, that is similar to that of nonpregnant women with breast cancer.
Male Breast Cancer
Fewer than 1% of all breast cancers occur in men.209,210 The incidence appears to be highest among North Americans and the British, in whom breast cancer constitutes as much as 1.5% of all male cancers. Jewish and African American males have the highest incidence. Male breast cancer is preceded by gynecomastia in 20% of men. It is associated with radiation exposure, estrogen therapy, testicular feminizing syndromes, and Klinefelter's syndrome (XXY). Breast cancer is rarely seen in young males and has a peak incidence in the sixth decade of life. A firm, nontender mass in the male breast requires investigation. Skin or chest wall fixation is particularly worrisome.
DCIS makes up <15% of male breast cancer, whereas infiltrating ductal carcinoma makes up >85%. Special-type cancers, including infiltrating lobular carcinoma, have occasionally been reported. Male breast cancer is staged in the same way as female breast cancer, and stage by stage, men with breast cancer have the same survival rate as women. Overall, men do worse because of the advanced stage of their cancer (stage III or IV) at the time of diagnosis. The treatment of male breast cancer is surgical, with the most common procedure being a modified radical mastectomy. Sentinel node dissection has been shown to be feasible and accurate for nodal assessment in men presenting with a clinically node-negative axillary nodal basin. Adjuvant radiation therapy is appropriate in cases in which there is a high risk for local-regional recurrence. Eighty percent of male breast cancers are hormone receptor positive, and adjuvant tamoxifen is considered. Systemic chemotherapy is considered for men with hormone receptor–negative cancers and for men with large primary tumors, multiple positive nodes, and locally advanced disease.
Phyllodes Tumors
The nomenclature, presentation, and diagnosis of phyllodes tumors (including cystosarcoma phyllodes) have posed many problems for surgeons.211 These tumors are classified as benign, borderline, or malignant. Borderline tumors have a greater potential for local recurrence. Mammographic evidence of calcifications and morphologic evidence of necrosis do not distinguish between benign, borderline, and malignant phyllodes tumors. Consequently, it is difficult to differentiate benign phyllodes tumors from the malignant variant and from fibroadenomas. Phyllodes tumors are usually sharply demarcated from the surrounding breast tissue, which is compressed and distorted. Connective tissue composes the bulk of these tumors, which have mixed gelatinous, solid, and cystic areas. Cystic areas represent sites of infarction and necrosis. These gross alterations give the gross cut tumor surface its classical leaf-like (phyllodes) appearance. The stroma of a phyllodes tumor generally has greater cellular activity than that of a fibroadenoma. After microdissection to harvest clusters of stromal cells from fibroadenomas and from phyllodes tumors, molecular biology techniques have shown the stromal cells of fibroadenomas to be either polyclonal or monoclonal (derived from a single progenitor cell), whereas those of phyllodes tumors are always monoclonal.
Most malignant phyllodes tumors (Fig. 17-40) contain liposarcomatous or rhabdomyosarcomatous elements rather than fibrosarcomatous elements. Evaluation of the number of mitoses and the presence or absence of invasive foci at the tumor margins may help to identify a malignant tumor. Small phyllodes tumors are excised with a margin of normal-appearing breast tissue. When the diagnosis of a phyllodes tumor with suspicious
malignant elements is made, re-excision of the biopsy site to ensure complete excision of the tumor with a 1-cm margin of normal-appearing breast tissue is indicated. Large phyllodes tumors may require mastectomy. Axillary dissection is not recommended because axillary lymph node metastases rarely occur.
Fig. 17-40.
A. Malignant phyllodes tumor (cystosarcoma phyllodes). B. Histologic features of a malignant phyllodes tumor (hematoxylin and eosin stain, x100).Inflammatory Breast Carcinoma
Inflammatory breast carcinoma (stage IIIB) accounts for <3% of breast cancers. This cancer is characterized by the skin changes of brawny induration, erythema with a raised edge, and edema (peau d'orange).212 Permeation of the dermal lymph vessels by cancer cells is seen in skin biopsy specimens. There may be an associated breast mass (Fig. 17-41). The clinical differentiation of inflammatory breast cancer may be extremely difficult, especially when a locally advanced scirrhous carcinoma invades dermal lymph vessels in the skin to produce peau d'orange and lymphangitis (Table 17-16). Inflammatory breast cancer also may be mistaken for a bacterial infection of the breast. More than 75% of women who have inflammatory breast cancer present with palpable axillary lymphadenopathy, and distant metastases also are frequently present. A report of the SEER program described distant metastases at diagnosis in 25% of white women with inflammatory breast carcinoma.
Fig. 17-41.
Inflammatory breast carcinoma. Stage IIIB cancer of the breast with erythema, skin edema (peau d'orange), nipple retraction, and satellite skin nodules.
Table 17-16 Inflammatory vs. Noninflammatory Breast Cancer
Inflammatory Noninflammatory
Dermal lymph vessel invasion is present with or without inflammatory changes.
Inflammatory changes are present without dermal lymph vessel invasion.
Cancer is not sharply delineated. Cancer is better delineated.
Erythema and edema frequently involve Erythema is usually confined to the lesion,
>33% of the skin over the breast. and edema is less extensive.
Lymph node involvement is present in >75% of cases.
Lymph nodes are involved in approximately 50% of the cases.
Distant metastases are present in 25% of cases.
Distant metastases are less common at presentation.
Distant metastases are more common at initial presentation.
Source: Modified with permission from Chittoor SR, et al: Locally advanced breast cancer: Role of medical oncology, in Bland KI, et al (eds): The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders, 1998, p 1281. Copyright Elsevier.Surgery alone and surgery with adjuvant radiation therapy have produced disappointing results in women with inflammatory breast cancer. However, neoadjuvant chemotherapy with a doxorubicin-containing regimen may effect dramatic regressions in up to 75% of cases. In this setting, modified radical mastectomy is performed to remove residual cancer from the chest wall and axilla. Adjuvant chemotherapy may be indicated depending on final pathologic assessment of the breast and regional nodes. Finally, the chest wall and the supraclavicular, internal mammary, and axillary lymph node basins receive adjuvant radiation therapy. This multimodal approach results in 5-year survival rates that approach 30%.
Rare Breast Cancers
Squamous Cell (Epidermoid) Carcinoma
Squamous cell (epidermoid) carcinoma is a rare cancer that arises from metaplasia within the duct system and generally is devoid of distinctive clinical or radiographic characteristics.213 Regional metastases occur in 25% of patients, whereas distant metastases are rare.
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma is very rare, accounting for <0.1% of all breast cancers. It is typically indistinguishable from adenoid cystic carcinoma arising in salivary tissues. These cancers are generally 1 to 3 cm in diameter at presentation and are well circumscribed. Axillary lymph node metastases are rare, but deaths from pulmonary metastases have been reported.
Apocrine Carcinoma
Apocrine carcinomas are well-differentiated cancers that have rounded vesicular nuclei and prominent nucleoli. There is a very low mitotic rate and little variation in cellular features. However, apocrine carcinomas may display an aggressive growth pattern.
Sarcomas
Sarcomas of the breast are histologically similar to soft tissue sarcomas at other anatomic sites. This diverse group includes fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, malignant schwannoma, rhabdomyosarcoma, osteogenic sarcoma, and
chondrosarcoma. The clinical presentation is typically that of a large, painless breast mass with rapid growth. Diagnosis is by core-needle biopsy or by open incisional biopsy. Sarcomas are graded based on cellularity, degree of differentiation, nuclear atypia, and mitotic activity. Primary treatment is wide local excision, which may necessitate mastectomy. Axillary dissection is not indicated unless there is palpable lymphadenopathy. Angiosarcomas are classified as de novo, as postradiation, or as arising in association with postmastectomy lymphedema. In 1948, Stewart and Treves described lymphangiosarcoma of the upper extremity in women with ipsilateral lymphedema after radical mastectomy.214Angiosarcoma is now the preferred name. The average interval between modified radical or radical mastectomy and the development of an angiosarcoma is 10.5 years. Sixty percent of women developing this cancer have a history of adjuvant radiation therapy. Forequarter amputation may be necessary to palliate the ulcerative complications and advanced lymphedema.
Lymphomas
Primary lymphomas of the breast are rare, and there are two distinct clinicopathologic
variants. One type occurs in women 39 years of age, is frequently bilateral, and has the
histologic features of Burkitt's lymphoma. The second type is seen in women 40 years of age and is usually of the B-cell type. Breast involvement by Hodgkin's lymphoma has been reported. An occult breast lymphoma may be diagnosed after detection of palpable axillary lymphadenopathy. Treatment depends on the stage of disease. Lumpectomy or mastectomy may be required. Axillary dissection for staging and for clearance of palpable disease is appropriate. Recurrent or progressive local-regional disease is best managed by chemotherapy and radiation therapy. The prognosis is favorable, with 5- and 10-year survival rates of 74 and 51%, respectively.
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