INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

History of the Procedure

Over the greater part of the last century, all forms of breast cancer have been treated by aggressive surgical resection. In 1894, Halsted described the procedure of en bloc removal of all breast tissue, draining lymph nodes and pectoralis muscles for the treatment of breast cancer. This technique of radical mastectomy became the standard of care for decades based on an understanding that cancer growth proceeded in stepwise fashion via the lymphatics, thus could be controlled with surgical excision.

In 1971, Fisher et al challenged this standard and demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial that radical mastectomy had no survival benefit over mastectomy with radiation or mastectomy with delayed axillary dissection. In a subsequent study, NSABP B-06, patients were randomized to total mastectomy versus lumpectomy and radiation therapy (XRT), and no survival benefit of total mastectomy was found. However, benefit was observed in the decreased rate of local recurrence in women receiving XRT. Development of new chemotherapeutic and hormonal agents has further revolutionized the management of breast cancer.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center, Women's Health Center, and Imaging Center. Also, see eMedicine's patient education articles Breast Cancer, Mastectomy, Breast Lumps and Pain, Breast Self-Exam, and Mammogram.

Problem

Worldwide, the overall incidence of breast cancer varies markedly but appears to be rising. Far eastern countries such as Japan, which historically have enjoyed low rates in comparison to the United States, are seeing a rapid rise in incidence. Although the United States has the highest reported incidence of breast cancer in the world, several western European nations such as Iceland, Italy, France, Sweden, and the United Kingdom trail closely behind. Incidence has been historically lower in Eastern Europe, the Middle East, and the Far East, but countries such as Japan and Singapore have seen a 2-fold rise over the past few decades.

Frequency

Of American women, 13% will be diagnosed with breast cancer in their lifetimes, making it the most common nonskin cancer among women. In addition, more than 3% will die from the disease. Breast cancer has surpassed lung cancer as the leading cause of cancer death in women worldwide, accounting for more than 400,000 deaths per year. In the United States, breast cancer trails only lung cancer as the second most common cause of cancer death in women. In 2002, more than 1.15 million new cases were diagnosed worldwide. More than 200,000 of these were in the United States alone.

The 1980s saw the greatest rise in incidence, which may have been due to a combination of improvements in screening techniques, data collection, and treatment modalities. Despite this surge in newly-diagnosed cases, mortality rates have been declining over the last decade. The decline is widely attributed to earlier detection via screening mammography and improvements in hormonal therapy and chemotherapy.

Etiology

Risk factors for the development of invasive breast cancer include female gender, age, family history, age at the time of first parturition, personal history of previous breast cancer, hormone replacement therapy, history of atypical hyperplasia or noninvasive lesions, and genetics.

• Female gender: The incidence of breast cancer in women exceeds that in men by 100:1. Overall, 1 of every 8 American women develops breast cancer in her lifetime.
• Age: In American women, risk increases from 1:5900 to 1:290 between the third and eighth decades. A woman aged 60-79 years has a 1:14 chance of developing invasive breast cancer, compared with a woman younger than 39 years, who has a 1:225 probability.
• Age at birth of first child: If aged 30 years or older, relative risk is 2 times that of patients who gave birth when younger than 20 years.
• Personal history of breast cancer: This also is a recognized risk factor. This factor depends on patient age at time of diagnosis. Risk is increased for younger women.
• Noninvasive carcinoma (ductal carcinoma in situ [DCIS]/lobular carcinoma in situ [LCIS]) on previous biopsy: This also is a marker for development of invasive lesions.
• Benign proliferative changes with atypical hyperplasia: These may increase relative risk by 4 times. Atypical hyperplasia may be observed in as many as 10% of specimens from biopsy.
• Early menarche and late menopause: These also are associated weakly with increased relative risk of breast cancer.
• Menopausal hormone replacement therapy: Multiple studies, including the Women's Health Initiative and the Million Women Study in the United Kingdom, have shown an increased risk of breast cancer in postmenopausal women who are either recent or current users of estrogen alone or in combination with progestin. In addition, the combination use of estrogen with progestin has been associated with an even greater risk of breast cancer, particularly of lobular carcinoma. Increased risk is also related to increased duration of use; this risk can be reduced over time, following the termination of hormone replacement therapy.
• Family history: Degree of relativity of the family member with breast cancer affects individual risk. For example, the relative risk of patients with an affected first-degree relative is 1.5-2 times higher when compared to controls without affected family members. Even more significantly, having two first-degree relatives affected (female or male) increases relative risk by more than 4-6 times when compared to patients without this risk factor. Third, age of the affected relative at time of diagnosis also influences risk. A patient with a mother diagnosed when younger than 60 years is at 2 times increased risk. Finally, bilateral cancer in a first-degree relative may increase risk by more than 6 times.
• Genetic predisposition: Approximately 5-10% of breast cancer cases are primarily attributable to inherited factors. Claus et al estimated that 36% of breast cancer cases in women aged 20-29 years can be attributed to a single dominant susceptibility gene, while only 1% of women diagnosed with breast cancer over the age of 80 have such a gene. The risk of breast cancer in carriers of BRCA1 mutation is estimated to be 36-87%. Male breast cancer is also seen with BRCA1 mutations with a lifetime risk of 5%. Lifetime breast cancer risk for carriers of BRCA2 is 45-84%. BRCA2 mutations are associated with a 6% lifetime risk of male breast cancer. Genetic breast cancer syndromes are outlined in Table 1.

  Table 1. Genetic Breast Cancer Syndromes.
  
  

  Syndrome	Gene	Inheritance	Cancers	Other Features
  Breast/ovarian	BRCA1	AD*	Breast, ovarian
  Cancer syndrome	BRCA2	AD	Breast, ovarian, prostate, pancreatic	Fanconi anemia in homozygotes
  Li-Fraumeni syndrome	TP53	AD	Breast, brain, soft tissue sarcomas, leukemia, adrenocortical, others
  Cowden disease	PTEN	AD	Breast, ovary, follicular thyroid, colon	Adenomas of thyroid, fibroids, GI polyps
  Peutz-Jegher syndrome	STKII/LKB1	AD	GI, breast	Hamartomas of bowel, pigmentation of buccal mucosa
  Ataxia-telangiectasia	ATM	AD	Breast	Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias
  Site-specific	CHEK2	AD	Breast	Low penetrance
  Muir-Torre syndrome	MSH2/MLH1	AD	Colorectal, breast

  *AD = autosomal dominant

More controversial risk factors include obesity, low-dose radiation, and oral contraceptive use. The Breast Cancer Detection Demonstration Project (BCDDP) defined several factors not associated with increased risk, including oral contraceptive use, long-term (>15 y) menopausal estrogen use, modest alcohol use, and cigarette smoking. Various analyses of data from the Nurses’ Health Study also have shown no association between oral contraceptive use and breast cancer. Conflicting data preclude the recommendation of guidelines for risk modification in these areas.

Pathophysiology

The World Health Organization classification of breast tumors organizes both benign and malignant lesions by histologic pattern. Epithelial tumors comprise the largest group, including intraductal papilloma, adenomas, intraductal and lobular carcinoma in situ, invasive (ductal and lobular) carcinoma, and Paget disease of the nipple. Invasive ductal carcinoma is by far the most common type.

Phyllodes tumor, benign and malignant, and carcinosarcoma are rare lesions grouped as mixed connective tissue and epithelial tumors. Other common nonadenocarcinoma lesions of the breast include angiosarcoma and primary lymphoma.

Invasiveness is a key determinant in the prognosis and treatment of breast malignancy. Noninvasive lesions are by definition limited by the basement membrane and may be classified as DCIS or LCIS.

• DCIS is by far more common than LCIS, and more importantly, it should be distinguished as a clearly malignant lesion. Ductal epithelial cells undergo malignant transformation and proliferate intraluminally. Eventually, the cells outstrip their blood supply and become necrotic centrally. This debris can calcify and be detected mammographically. Moreover, the lesions also may be palpable clinically. Five pathologic subtypes have been identified: comedo, papillary, micropapillary, solid, and cribriform. Most lesions represent a combination of at least two of these subtypes. The presence of comedo necrosis is an independent risk factor for subsequent ipsilateral breast cancer (NSABP-B17).
• LCIS also arises from epithelial cells; however, their growth continues in a lobular pattern. In contrast to DCIS, these lesions rarely develop central necrosis, calcify, or become palpable. For this reason, LCIS rarely is detected by examination or mammography preoperatively and usually presents as an incidental finding on histologic review. Clinically, LCIS is considered more of a marker for development of invasive cancer rather than a malignant lesion. The risk of subsequent breast cancer is equal for both breasts irrespective of the index site. Moreover, most invasive cancers that develop are infiltrating ductal, which supports the concept that LCIS is not a malignant lesion.
• Invasive breast cancers usually are epithelial tumors of ductal or lobular origin. Features such as size, status of surgical margin, estrogen receptors (ER) and progesterone receptors (PR), nuclear and histologic grade, DNA content, S-phase fraction, vascular invasion, tumor necrosis, and quantity of intraductal component are all important in deciding on a course of treatment for any breast tumor.
• Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor. This lesion, which accounts for 75% of breast cancers, has no specific histologic characteristics other than invasion through the basement membrane. DCIS may be a frequently associated finding on pathologic examination. It also has a tendency to metastasize via lymphatics.
• Infiltrating lobular carcinoma has a much lower incidence and comprises less than 15% of invasive breast cancer. It is characterized histologically by the Indian file arrangement of small tumor cells. Like ductal carcinoma, these typically metastasize to axillary lymph nodes first. However, it also has a tendency to be more multifocal. Despite this, the prognosis is comparable to that of ductal carcinoma.

Less common histologic subtypes of adenocarcinoma collectively comprise less than 25% of invasive breast cancers.

• The diagnosis of tubular carcinoma requires the presence of tubular formation in at least 75% of the specimen. This pathology is associated with improved prognosis.
• Mucinous (or colloid) carcinoma also has a favorable prognosis when compared with ductal carcinoma. These slow-growing lesions characteristically produce large amounts of mucin, thus are usually bulky. They, like tubular carcinoma, rarely metastasize.
• Medullary carcinoma, despite being a poorly differentiated tumor, also carries an improved prognosis.

ER and PR are valuable as predictors of disease-free survival and response to hormonal therapy. Studies in patients with ER(+) tumors who did not receive chemotherapy suggest they have a higher rate of disease-free survival than patients with ER(-) tumors. The presence of these nuclear steroid receptors on tumor staining should be considered, along with other histologic features, in determining the need for hormonal and adjuvant chemotherapy.

Human epidermal growth factor receptor (Her)-2/neu protein expression is associated with increased incidence of recurrence and shortened overall survival. Her-2/neu is overexpressed in 20-30% of breast cancers. Her-2/neu–positive lesions have also been associated with comedo-type DCIS, another poor prognostic indicator. Patients with Her-2/neu–positive breast cancer are candidates for treatment with combination chemotherapy and monoclonal antibody therapy.

S-phase (proliferative) fraction can be determined by flow cytometry. This fraction represents cells in the synthetic or replication phase of the cell cycle. High S-phase fraction is an indicator of more aggressive disease regardless of nodal status. It has not been shown to predict response to chemotherapy.

Other histologic factors, such as lymphatic invasion, an extensive DCIS component (>25% of the tumor), and Ki-67 staining, continue to be investigated as potential prognostic factors for breast cancer.

Clinical

When evaluating a patient with possible breast cancer, direct questions toward both assessment of risk and narrowing the differential diagnosis. Patient factors associated with increased risk of breast cancer are discussed in Etiology. In addition, inquiry regarding nipple discharge, fever, pain, rapid growth, duration of the mass, and changes with menses may be helpful in directing the workup for breast cancer.

Physical examination should include inspection of the patient in the upright as well as supine positions. With the patient upright, assessment for symmetry and changes in the nipple and skin may be performed. Obvious size discrepancy, nipple inversion, skin dimpling, scaling, and edema (peau d'orange) are suggestive findings. Supraclavicular, infraclavicular, and axillary lymphadenopathy also can be best detected in this position.

Once the patient is in the supine position with the ipsilateral arm extended over the head, the breast parenchyma can be compressed against the chest wall, which allows for improved sensitivity for the examiner. The 2 most common techniques for supine examination are the clockwise radial pattern and the linear pattern. In the clockwise radial technique, examination begins at the 12-o'clock position near the clavicle and proceeds towards the nipple. This is repeated in a clockwise fashion around the entire breast.

The linear technique, when performed correctly, is arguably more sensitive, although time-consuming. Proponents of the linear technique recommend beginning in the axilla at the mid-axillary line, proceeding toward the inferior mammary fold, and then returning to the clavicle in a series of rows (12-15 rows, depending on the size of the breast). Using the pads of 3 fingertips, the examiner should palpate dime-sized circles in 3 different depths at each site before moving one finger width toward the inferior mammary fold and repeating the circular motion at the superficial, medium, and deep levels. Benign lesions are more frequently smaller, rubbery, well-circumscribed, and mobile. Characteristics suggestive of malignancy include skin involvement, fixation to the chest wall, irregular border, firmness, and enlargement.

Compression of the breast or nipple is no longer recommended to assess for discharge. However, visual inspection of the nipple/areola complex should be a routine part of the examination. Only spontaneous discharge should be considered clinically significant. Concerning characteristics include unilateral discharge, nonmilky fluid, and origin from a single duct. Intraductal papilloma, a benign finding, is the most common cause of unilateral bloody nipple discharge. Other benign pathology associated with nipple discharge includes subareolar duct ectasia and fibrocystic changes. Usually, malignant pathology presenting with nipple discharge is also associated with a palpable mass, suggestive mammographic findings, or both.

Breast self-examination, performed monthly, is still generally recommended for women beginning at age 18 years, although no strong statistical data exist to support its efficacy in the early detection of breast cancer. Physicians should examine patients aged 19-40 years approximately every 3 years. The American Cancer Society recommends annual evaluation by physician examination along with screening mammography for women aged 40 years and older, particularly if risk factors are present.

RELEVANT ANATOMY

Section 3 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

A thorough understanding of the relative anatomy of the breast and axilla is essential to successful and uncomplicated surgical treatment of breast cancer.

The breast is bounded by the clavicle superiorly, the sternum medially, the lateral border of the latissimus muscle laterally, and the inframammary fold inferiorly. The axillary tail of Spence extends into the deep fascia superior and lateral to the breast. The deep pectoral fascia defines the deep margin.

Fibrous bands, known as the suspensory ligaments of Cooper, divide the breast parenchyma into 12-20 separate lobules of glandular tissue. Separate branching lactiferous ducts drain each lobule. These ducts converge just beneath the nipple into sinuses that empty into a single terminal duct. Drainage from individual ducts can be localized for surgical excision.

The lateral pectoral nerve passes medially around the medial pectoralis minor, and the medial pectoral nerve passes laterally around the pectoralis minor. The names are based on the origin of the nerves from the lateral and medial cords of the brachial plexus rather than their orientation to the muscle. Injuries to these nerves are rare.

Injury to the brachial plexus can be avoided by keeping the superior extent of the axillary dissection inferior to the lower border of the axillary vein.

The thoracodorsal nerve is identifiable medial to the thoracodorsal vein running along to enter the latissimus dorsi. Injury may result in slight, if any, clinically evident weakening of the latissimus.

The long thoracic nerve is located more medially in the axilla. It runs just beneath the investing fascia of the serratus anterior, medial to the thoracodorsal complex. Injury to this nerve results in winging of the scapula on arm extension.

The skin of the axilla and upper arm is supplied by the intercostobrachial nerve, which often is sacrificed in the dissection of axillary nodes. Transection may result in numbness in these areas.

Axillary lymph nodes receive most mammary lymphatic drainage. The internal mammary nodes also receive some drainage medially. Axillary nodes are referred to by levels, which are defined by the pectoralis minor muscle. Level I nodes are lateral, II behind, and III medial to the muscle.

The external mammary artery and perforators of the internal mammary artery supply blood to the breast. Venous drainage follows arterial anatomy.

CONTRAINDICATIONS

Section 4 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Contraindications to surgical resection depend on the procedure in question. Breast conservation therapy is applicable in most patients with early stage invasive carcinoma. Relative contraindications include small breast size, large tumor size (>5 cm), and collagen vascular disease. Absolute contraindications include multi-focal disease, history of prior radiation to the area of treatment, first or second trimester of pregnancy, and persistent positive margins following attempts at conservation.

Factors that often are considered but should not be absolute deterrents include axillary node involvement and tumor location. Consideration of cosmesis, while important, should never outweigh the clinical priority of obtaining negative surgical margins. For example, lesions involving Paget's disease of the nipple may be treated with excision of the nipple-areolar complex and reconstruction. Larger lesions in patients with concerns regarding cosmesis may be better served by standard modified radical mastectomy and immediate reconstruction.

A relative contraindication to modified radical mastectomy is locally advanced cancer requiring neo-adjuvant therapy prior to surgical intervention.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Lab Studies

• For patients undergoing breast biopsy, few, if any, lab tests are necessary. These procedures usually are performed routinely in an outpatient setting under local anesthesia. Order a complete blood count and basic chemistries for more extensive procedures such as modified radical mastectomy requiring general endotracheal anesthesia. Additional testing depends on the individual patient history, age, and comorbid conditions.
• Genetic testing for BRCA1 and BRCA2 can be performed in selected patients with a strong family history of breast or ovarian carcinoma. However, genetic counseling and discussion of subsequent management and treatment options should be performed prior to testing. The criteria for referral for genetic counseling and testing of high-risk individuals include the following:
• • Any patient diagnosed with breast cancer who is aged less than 40 years
  • Males with breast cancer, especially if they are of Jewish ancestry
  • Any patient with 2 or more first-degree relatives, or 2 or more second-degree relatives (on the same side of the family) who meet any of the following conditions:
  • • Breast cancer diagnosed at in patient aged less than 50 years
    • Breast and ovarian cancer in the same bloodline or in the same individual
    • Male relative diagnosed with breast cancer when aged less than 50 years
    • Family members with bilateral breast cancer
• According to the American Society of Clinical Oncology, serum markers that may be used in the workup for breast cancer include carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, and CA 27.29. These are not recommended routinely, and indications for their use have not been standardized.
• However, once a diagnosis of breast cancer has been made, additional testing may be performed to determine a patient's likelihood of response to chemotherapy. Specifically, the Oncotype DX assay is a 21-gene assay first announced in 2003 by NSABP researchers. The Oncotype DX provides a score that predicts the likelihood of distant recurrence in a select group of patients who have node-negative and estrogen-receptor–positive breast cancer. Resulting scores may assist in determining the potential benefit or necessity of chemotherapy in these patients.

Imaging Studies

• Mammography has become the standard tool for screening and initial evaluation of breast cancer. Multiple prospective randomized controlled trials have demonstrated that mammography can reduce the mortality from breast cancer in women aged 50-74 years. A great deal of controversy surrounds the use of mammography in younger women, particularly those aged 40-49 years. Currently, the American Cancer Society recommends annual mammography and examination by a physician beginning at age 40 years with no maximum upper age limit. Obviously, this should be taken with the caveat that patients who fall outside these guidelines need to be assessed individually.

  For instance, women younger than 40 years who have extensive family histories for breast cancer may benefit from beginning screening earlier. Conversely, older women with significant comorbidities, which may be prohibitive in the treatment of breast cancer, may not derive any benefit from mammography. In addition, the sensitivity of mammography is decreased significantly in young patients with dense breast tissue and possibly with augmentation prosthesis. Mammography seldom is recommended in patients younger than 30 years.

• • The American College of Radiology established the standard for classification of radiographic abnormalities, known as the Breast Imaging Reporting and Data System (BI-RADS), as follows:

    0. Incomplete examination - Usually requiring further imaging or evaluation

    I. Normal - With follow-up study recommended in 1 year

    II. Benign - Follow-up study in 1 year

    III. Likely to be benign - Follow-up mammogram in 6 months

    IV. Suspicious - Consider biopsy

    V. Highly suspicious for malignancy - Biopsy recommended

  • In addition to evaluating parenchymal masses, mammography can be useful in evaluating the breast for calcifications, architectural distortion, skin thickening, nipple changes, and axillary adenopathy. Enlargement, stellate shape, irregular or spiculated margins, and the presence of pleomorphic calcifications less than 0.5 mm in a given lesion all are suggestive of malignancy.
• As an adjunct to mammography, ultrasonography (US) can be particularly useful in younger patients or women with fibrocystic change. Its main use remains in distinguishing solid from cystic lesions. In the workup of nonpalpable lesions, US can be used to guide a needle biopsy or to place a localizing wire to direct an excisional biopsy. Ultrasonography may also be useful in the workup of palpable masses not visualized by mammography.
• Magnetic resonance imaging (MRI) of the breast is a relatively new modality that is being widely utilized for multiple applications in the screening, diagnosis, and treatment of breast cancer.

  Although little argument exists regarding the utility of MRI in screening patients at high risk, the appropriate interval remains a gray area that is currently under study. Patients at high risk who would be excellent candidates for MRI screening include women with a personal history of breast cancer not visualized by mammography and women with a strong familial or genetic predisposition (carriers of BRCA1 or BRCA2) for breast cancer. In 2004, Kriege et al studied screening modalities in nearly 1,900 women at high risk. MRI was shown to have a significantly increased sensitivity over mammography in the early detection of invasive breast cancer. However, the specificity of MRI was significantly lower than mammography, leading to more than twice as many unnecessary biopsies.

  MRI can also be useful in the evaluation of patients with suspected or known breast cancer. For example, it can be applied to patients with axillary lymphadenopathy and an otherwise undetectable primary tumor. Also, patients with palpable lesions not visualized by diagnostic mammography or ultrasonography should be strongly considered for MRI. In these patients, the advantage of MRI as an adjunct to core biopsy lies in its ability to accurately assess for size, multi-focal disease, and synchronous lesions. As a result, patients would potentially be spared additional surgical procedures for positive margins or multi-focal findings. Finally, MRI may have use in the follow-up with patients who have advanced breast cancer and are undergoing chemotherapy.

  The use of screening and diagnostic MRI in all patients (including those with lesions clearly visualized by standard diagnostic mammography and ultrasonography) remains much more controversial.

• Other imaging modalities include CT and positron emission tomography (PET). CT is primarily used to evaluate for extramammary involvement of the tumor. PET scanning is another tool being increasingly used in the workup for metastatic lesions.

Diagnostic Procedures

• Fine needle aspiration

  Fine needle aspiration (FNA) is no longer the criterion standard for initial evaluation of all palpable breast masses. However, it is particularly useful in the evaluation of cystic lesions detected by ultrasonography. FNA results are reported as benign, suggestive of malignancy, or nondiagnostic. Aspiration of a benign cystic lesion should result in collapse of the cavity. Documentation of complete collapse by follow-up ultrasonography may be helpful in decreasing the incidence of recurrence. Persistence of a palpable mass and recurrence following aspiration are general indications for further workup. Importantly, note that the cytopathologist cannot distinguish invasive carcinoma from DCIS. To rule out DCIS, histologic confirmation of invasion with core needle biopsy or excisional biopsy is obtained prior to axillary staging.

• Core needle biopsy

  Core needle biopsy (CNB) is a more useful alternative than FNA for initial diagnosis of breast cancer. One advantage is that a surgical pathologist can distinguish between invasive cancer and DCIS based on architectural information provided by the larger tissue sample in CNB. Another advantage to CNB is that a well-trained surgical pathologist can examine the specimen; with FNA, a highly-skilled cytopathologist is required for accurate results. The adoption of image-guided needle biopsy of nonpalpable lesions has defrayed cost and improved patient care by eliminating cosmetic deformity associated with excisional biopsy. Since CNB removes only part of the lesion, one must ensure that the results are concordant with radiographic findings and that proper follow-up is initiated with the patient. With the use of large bore needles and vacuum-assisted devices, adequate sampling of the lesion is much more likely.

• Image-guided breast biopsy

  This is an alternative useful for workup of nonpalpable lesions. Ultrasonography, mammography, and MRI may all be used to perform image-guided core needle biopsies. Advantages of this modality include the ability to perform localization and excision in a single procedure. Limitations include cost, availability, and inability to perform biopsy on lesions located close to the chest wall or in patients with small breast volume.

• Excisional biopsy

  Complete surgical removal of a palpable breast lesion is referred to as an excisional biopsy. This technique is indicated if (1) neither FNA nor CNB is technically feasible, (2) attempts have produced nondiagnostic results, or (3) pathology is discordant with radiographic imaging. The specimen should always be carefully oriented by the surgeon to aid the pathologist in assessing margins.

Histologic Findings

See Images 6-15.

Staging

The standard staging system is that of the American Joint Committee on Cancer (AJCC). The system is based on primary tumor size (T), lymph node involvement (N), and metastatic disease (M).

• Primary tumor = T
• • Tx - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • Tis - Carcinoma in situ
  • • Tis (DCIS) - Only ductal carcinoma in situ
    • Tis (LCIS) - Only lobular carcinoma in situ
    • Tis (Paget) - Paget disease of the nipple with no tumor (Note: Paget disease associated with a tumor is classified according to the size of the tumor)
  • T1 - Tumor £2 cm in greatest dimension
  • • T1mic - £0.1 cm
    • T1a - >0.1cm but <0.5 cm
    • T1b - >0.5 cm but <1 cm
    • T1c - > 1 cm but <2 cm
  • T2 - Tumor > 2 cm but £ 5 cm
  • T3 - Tumor > 5 cm
• T4 - Tumor of any size with direct extension to chest wall or skin (including inflammatory carcinoma)
• • T4a - Extension to the chest wall, not including the pectoralis muscle
  • T4b - Extension to the skin with edema (peau d'orange) or ulceration of the skin or satellite nodules confined to the same breast
  • T4c - Both T4a and T4b
  • T4d - Presence of inflammatory carcinoma
• Regional lymph nodes (clinical lymph node status) = N
• Nx - Regional lymph nodes cannot be assessed (eg, they were previously removed)
• N0 - No regional lymph node metastases
• N1 - Metastases to ipsilateral axillary lymph nodes without fixation
• N2 - Metastases to ipsilateral axillary lymph nodes with fixation to each other (matted), with fixation to other structures such as the chest wall, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases
• • N2a - Metastases in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
  • N2b - Metastases only in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases
• N3 - Infraclavicular nodes have metastases with or without axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph nodes in the presence of clinically evident axillary lymph node metastases, or metastases in the supraclavicular lymph nodes with or without axillary or internal mammary lymph node involvement
• • N3a - Metastases in ipsilateral infraclavicular lymph nodes
  • N3b - Metastases in ipsilateral internal mammary lymph nodes and axillary lymph nodes
  • N3c - Metastases in ipsilateral supraclavicular lymph nodes
• Regional lymph nodes (pathologic lymph node status)
• pNx - Axillary nodes cannot be assessed (eg, they were not removed during surgery and cannot be viewed)
• pN0 - Lymph nodes do not have metastases
• • pN0 (i-) - No regional lymph node metastases histologically, negative immunohistochemistry (IHC)
  • pN0 (i+) - No regional lymph node metastases histologically, positive IHC, no IHC cluster >0.2 mm
• pN1 - One to three axillary lymph nodes have metastases or internal mammary lymph nodes with microscopic disease detected by sentinel node but not clinically apparent
• • pN1mi - Micrometastasis >0.2 mm but <2.0 mm
  • pN1a - Metastases in 1-3 axillary lymph nodes
  • pN1b - Metastases in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node (SLN) dissection but not clinically apparent
  • pN1c - Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel node dissection but not clinically apparent
• pN2 - Four to nine axillary lymph nodes have metastases or in clinically apparent internal mammary lymph nodes in the absence of axillary lymph node metastases
• • pN2a - Metastases in 4-9 axillary lymph nodes
  • pN2b - Metastases in clinically apparent internal mammary lymph nodes in the absence of axillary lymph node metastases
• pN3 - Ten or more axillary lymph nodes have metastases, or infraclavicular lymph nodes, or clinically apparent ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary nodes, or more than 3 axillary lymph nodes with clinically negative microscopic metastases in internal mammary lymph nodes, or ipsilateral supraclavicular lymph nodes
• • pN3a - Metastases in 10 or more axillary lymph nodes or metastases in the infraclavicular lymph nodes
  • pN3b - Metastases in clinically apparent ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by SNL dissection but not clinically apparent
  • pN3c - Metastases in ipsilateral supraclavicular lymph nodes
• Distant metastases = M
• Mx - Cannot be assessed
• M0 - No metastases
• M1 - Distant metastases, including ipsilateral supraclavicular lymph nodes
• Stage groups are shown in Table 2.

Table 2. Stage Groups.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Medical Therapy

Medical therapy for breast cancer can be divided into 3 categories: chemoprevention, neo-adjuvant, and adjuvant therapy.

Chemoprevention

Several classes of drugs, including retinoids, cyclooxygenase (COX) inhibitors, and selective estrogen receptor modulators (SERM), have been studied in the chemoprevention of breast cancer. The NSABP-P1 trial has demonstrated the efficacy of tamoxifen, a SERM, in the prevention of invasive breast cancer. Treatment with tamoxifen reduced the risk of invasive breast cancer by 49%. Moreover, a 50% reduction in the risk of noninvasive cancers was demonstrated.

In terms of prevention, tamoxifen is approved by the US Food and Drug Administration (FDA) for use in healthy women at high risk for the development of invasive breast cancer and in patients with early invasive lesions at risk of secondary contralateral cancer. Dosing should be 20 mg/d for 5 years. Significant relative toxicity from tamoxifen use includes increased risk of endometrial cancer and pulmonary embolism in women older than 50 years. Currently, the NSABP P-2 trial (Study of Tamoxifen and Raloxifene [STAR] trial) is underway to compare the efficacy of tamoxifen with raloxifene, which is a SERM used for treatment of osteoporosis.

A relatively new class of drugs, aromatase inhibitors (AI), is being explored for efficacy in the chemoprevention of breast cancer. Three third-generation aromatase inhibitors (anastrozole, letrozole, exemestane) have already been approved by the FDA for use in adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer.

However, tamoxifen remains the standard of care for adjuvant endocrine therapy for premenopausal women. In select patients with small tumors and no nodal metastases, tamoxifen may provide a means for systemic treatment without the use of systemic chemotherapy. Conversely, ER(-) tumors are predictive of improved response to chemotherapy and minimal benefit from tamoxifen.

Trastuzumab is a relatively new chimerized mouse/human monoclonal antibody that targets the extracellular portion of the Her-2/neu membrane protein. Two major research studies, NSABP B-31 and North Central Cancer Treatment Group (NCCTG) trial N9831, were closed early because of clinically significant findings of improved disease-free and overall survival in women treated with trastuzumab in addition to chemotherapy. Trastuzumab, in combination with chemotherapy, is now recommended to all patients who have lymph node–positive Her-2–positive breast cancer, unless a clear contraindication exists to treatment. Consideration should be made for the significant cardiotoxicity associated with trastuzumab.

Neoadjuvant therapy for locally advanced breast cancer should involve anthracycline or taxane-based regimens.

Various chemotherapeutic regimens used following surgical treatment include anthracyclines, taxanes, and cyclophosphamide. Choice of the optimal adjuvant chemotherapeutic regimen should be made based on multiple factors including patient age, menopausal status, hormone receptor and Her-2/neu expression, lymph node involvement, and size of the primary lesion.

Multiple guidelines are available to assist clinicians in selecting the most appropriate regimen. They include the National Comprehensive Cancer Network's Breast Cancer Guidelines v 2.2006 and Adjuvant! Online.

Surgical Therapy

Definitions and Techniques

• Ductal excision: Ductal excision may be indicated for suggestive nipple discharge without an associated palpable or radiographic lesion. Bloody discharge and spontaneous clear discharge from a single duct are findings with an increased risk of malignancy. Ductal excision can be performed using a small (4.0) lacrimal duct probe to localize the draining duct. A cone-shaped sample of tissue then should be excised around the probe. The most common histologic findings in this setting are intraductal papilloma or ductal ectasia (approximately 80%). Most of the remaining lesions demonstrate intraductal or infiltrating carcinoma.
• Excisional biopsy or lumpectomy: This should be performed for palpable lesions with suggestive or malignant findings on needle biopsy. Benign or inconclusive findings on needle biopsy also may prompt excisional biopsy in the presence of high clinical suspicion (eg, large mass fixed to the chest wall, atypical epithelial hyperplasia). In general, circumareolar incisions should be made for lesions close to the nipple and radial incisions for lower outer quadrant lesions. All incisions should be made with consideration of potential need for incorporation into subsequent mastectomy incisions. The surgeon should carefully orient specimens with suture for histologic assessment of individual margins. The procedure may be performed safely with local anesthesia and/or monitored intravenous sedation. The need for open biopsy can usually be obviated by the use of CNB as described in Diagnostic Procedures.
• Lumpectomy or wide local excision: Most often performed along with some form of lymph node dissection as part of a breast conservation procedure, lumpectomy involves excision of a palpable malignant breast lesion with adequate margins. In the case of nonpalpable lesions, a needle-localization procedure may precede lumpectomy. This is performed with ultrasonographic or mammographic assistance for nonpalpable, radiographically identified lesions. Following placement of a fine J wire under radiographic guidance, the lesion can be excised surgically. Care must be taken to obtain a solid core of breast tissue around the tip of the wire with margins of at least 1 cm. The specimen should be reevaluated radiographically to confirm excision of the intended lesion prior to completion of the operation.
• Quadrantectomy: This is removal of an entire quadrant of the breast, which is less cosmetically satisfactory than lumpectomy.
• Sentinel lymph node biopsy (SLNB): The sentinel lymph nodes (SLN) are the first nodes that receive drainage from tumors. The technique involves injecting radiocolloid, blue dye, or both in the tissues of the breast. Several techniques of injection are available, including subareolar, peritumoral, intradermal, or intraparenchymal. After injection, an incision is made with consideration of the potential need for subsequent completion lymph node dissection (see next paragraph). Therefore, the incision can be elongated easily if the SLN is positive for metastasis.
• Completion Lymph Node Dissection (CLND): If an SLN is found to be positive on histologic evaluation, a CLND is indicated to assess the degree of lymph node involvement. This can have a significant impact on staging as well as adjuvant treatment.
• Axillary Lymph Node Dissection (AxLND): This procedure is equivalent to SLNB combined with CLND. Axillary lymph node staging provides prognostic information to both the patient and the treating physicians. A formal level I and II axillary lymph node dissection has historically been the standard of care in surgical therapy for the axilla. However, AxLND can result in significant morbidity. Complications of AxLND include pain, paresthesia, seroma, infection, limitation of shoulder motion, and lymphedema.
• Breast conservation therapy: This term is used to describe lumpectomy, quadrantectomy, or segmental mastectomy with or without axillary dissection and adjuvant radiation therapy.
• Total or simple mastectomy: This describes removal of breast parenchyma, including nipple-areolar complex, with no node dissection. It may be performed as a therapeutic or a prophylactic procedure in select patients at high risk.
• Modified radical mastectomy: This procedure involves resection of the breast parenchyma and axillary nodes lateral to and behind the medial border of the pectoralis minor (levels I and II).
• Subcutaneous/skin-sparing mastectomy: This procedure involves subcutaneous removal of breast parenchymal tissue and the nipple-areolar complex and may be accompanied by level I and II axillary dissection; it also is referred to as prophylactic mastectomy when performed in healthy patients with strong risk factors such as LCIS or multiple affected family members.
• Patey modified radical mastectomy: Primarily of historical significance, this involves modified radial mastectomy (MRM) with additional removal of level III nodes requiring division or resection of the pectoralis minor; compared to MRM, this procedure increases lymphedema from 3-10% in the arm.
• Radical (Halsted) mastectomy: This procedure entails removal of all breast, axillary nodes through level III, and both the pectoralis minor and pectoralis major muscles; historically, this was the most commonly performed procedure for breast cancer.

Surgical Indications

Ductal carcinoma in situ

Histologic appearance is one of the most important factors in determining an appropriate treatment plan. Specific cellular characteristics in both noninvasive and invasive breast cancer have significant prognostic value. In DCIS, the presence of various pathologic criteria, such as high nuclear grade and comedo necrosis, have been suggested as risk factors for local recurrence of breast cancer. Lagios et al found that patients with both of these characteristics had 4 times the local failure rate of patients without chemotherapy.

In 1995, Silverstein et al described the Van Nuys classification, which stratified 238 patients into 3 groups based on these 2 factors. Group 1 had low nuclear grade and no comedo necrosis, group 2 also had low nuclear grade but positive comedo necrosis, and group 3 had high nuclear grade with or without comedo necrosis. All patients had been treated with lumpectomy with or without radiation. Retrospective analysis indicated that Groups 1 and 2 were treatable with excision alone. Only Group 3 had significant survival benefit from the addition of XRT.

The Van Nuys Prognostic Index is based on the Van Nuys histologic classification scheme, tumor size, and width of surgical margins. Retrospective analysis of 333 patients, using this index, suggested that local excision alone could be used for definitive treatment of favorable lesions. Conversely, patients with higher scores had high (60%) local recurrence rates despite the addition of XRT. Based on these findings, traditional treatment with mastectomy was recommended for patients with unfavorable histology.

The NSABP B-17 trial prospectively randomized more than 700 women with DCIS to lumpectomy versus lumpectomy and XRT. At the 8-year follow-up point, the Van Nuys classification was applied to their data to determine its role in the assessment for subsequent ipsilateral (recurrent) breast tumors.

First of all, only comedo necrosis independently showed strong predictive value. Surprisingly, other criteria, such as tumor-free margins, multifocality, and nuclear grade, did not prove to be significant independent risk factors.

Secondly, patients in all 3 Van Nuys groups demonstrated a survival benefit from the addition of XRT according to the NSABP B-17 study. Even in Group 1, with favorable histology, a 59% relative risk reduction was observed after treatment with XRT.

Finally, despite a high incidence of subsequent invasive carcinoma, overall mortality of patients treated with lumpectomy and radiation remains less than 2% at 8 years of follow-up study. This is comparable to accepted long-term mortality rates following mastectomy for DCIS. Therefore, the NSABP B-17 investigators emphatically reject the need for mastectomy in patients with DCIS equal to or less than 1 cm. Total mastectomy in the treatment of DCIS greater than 1 cm remains controversial.

Axillary dissection routinely was performed on all patients early in the NSABP-B17 trial. When no nodal involvement was found, the procedure was removed from the protocol. However, the sizes of lesions in this trial were uniformly less than 1 cm. Therefore, the role of axillary dissection in larger lesions requires further study. In general, axillary dissection is not indicated in the treatment of noninvasive lesions but current studies of lymph node morphology may change this recommendation.

Nearly all patients with truly noninvasive ductal carcinoma are candidates for breast conservation surgery and radiation treatment. Additional treatment, including total mastectomy, should be individualized. Tamoxifen should be considered.

Lobular carcinoma in situ

As first described in 1941 by Foote and Stewart, LCIS remains "a rare form of mammary cancer." Most cases of LCIS are discovered incidentally on biopsy for other clinical findings. In 1978, in one of the largest histologic review series, Haagensen et al described LCIS as having no associated palpable mass, higher incidence in premenopausal women, absence of nodal metastases, tendency for multifocal or bilateral disease, and predisposition to carcinoma in either breast. More recently, most of the subsequent breast cancers in these women have been demonstrated to be invasive ductal carcinomas. As a result, LCIS is regarded primarily as a risk factor for malignancy. The NSABP P-1 trial prospectively studied the efficacy of tamoxifen in the prevention of breast cancer and included patients with LCIS. The researchers found a 55% risk reduction in women treated with tamoxifen.

Overall treatment options include observation and close follow-up care with or without tamoxifen and bilateral mastectomy with or without reconstruction. No evidence exists of therapeutic benefit from local excision, axillary dissection, radiation, or chemotherapy. The presence of LCIS in the breast of a woman with ductal or lobular cancer does not require further immediate surgery on the opposite breast. Mirror biopsy of the contralateral breast, once advocated in the treatment of LCIS, is a procedure mainly of historic interest.

Invasive ductal carcinoma

Once the diagnosis of invasive breast cancer has been made, the next step is resection, if clinically feasible. The only exception is locally advanced breast cancer, in which neoadjuvant therapy may precede surgery. The choice of surgical procedure depends on multiple factors, including patient risk factors for contralateral or metachronous cancer, histology, mammographic findings, evidence of nodal or extramammary metastases, comorbidities, and the patient's understanding of the surgical options.

Veronesi et al at the National Cancer Institute in Milan, Italy, evaluated patients with small primary tumors (<2 cm) and showed no benefit to radical mastectomy over quadrantectomy, axillary dissection, and radiation. Similarly, in the US NSABP-B6 trial, nearly 2000 women with tumors up to 4 cm were randomized to lumpectomy, lumpectomy with radiation, and total mastectomy. This study demonstrated no difference in disease-free or overall survival of patients in any category. However, researchers found a significant beneficial effect of radiation therapy on the local recurrence rate.

Breast conservation therapy is applicable in most patients with stage I and II invasive carcinomas. Relative contraindications include small breast size, large tumor size (>5 cm), and collagen vascular disease. Absolute contraindications include multifocal disease, history of prior radiation to the area of treatment, first or second trimester of pregnancy, and persistent positive margins following attempts at conservation. Factors that often are considered but should not be deterrents include axillary node involvement and tumor location. Consideration of cosmesis, while important, never should outweigh the clinical priority of obtaining negative surgical margins. For instance, lesions involving Paget disease of the nipple may be treated with excision of the nipple-areolar complex and reconstruction. Larger lesions in patients with concerns regarding cosmesis may be better served by standard modified radical mastectomy and concurrent reconstruction.

The primary route of dissemination of breast cancer is via the axillary lymphatics. Therefore, axillary dissection plays an important role in the staging of breast cancer. Guidelines for the use of axillary dissection are somewhat controversial. Current standard of care mandates assessment of the axilla in all cases of invasive breast cancer. The NSABP B-4 trial has demonstrated that axillary dissection improves rates of local control when compared to radiation. Nevertheless, it has failed to have a significant effect on overall survival.

The technique of axillary dissection has evolved on the basis of high morbidity observed following removal of all axillary lymphatic tissue. The significant increase in lymphedema with dissection of level III nodes outweighs the potential benefit of detecting microscopic invasion in them. Invasion into level III nodes without involvement of levels I and II is exceedingly rare and supports the limitation of dissection to the more easily accessible nodes. Randomized controlled trials have confirmed that no improvement in overall survival occurs with complete excision versus axillary sampling.

The sentinel lymph node biopsy (SLNB) is an alternative procedure that allows patients without nodal metastases to avoid axillary dissection. In addition to decreasing morbidity associated with the procedure and being a more cost-effective modality for nodal staging, another advantage of SLNB is that it allows a more focused examination of the lymph node most at risk for metastatic disease.

The technique of injection may not be as important as the skill and experience of the surgeon with the chosen technique and with SLN identification in general. In their initial series, Krag et al demonstrated mapping failure rates of 18% and 35% based on the solitary use of radiocolloid and blue dye, respectively. Subsequent reports by Giuliano have demonstrated a failure rate of 5%. In the initial series of Cox et al, an initial failure rate of 6.6% was noted with a combination technique, which subsequently decreased to 5%.

Most groups would agree that improvement comes with learning and experience. Several factors are thought to contribute to mapping failure, including medial lesions that map to the intramammary nodes without concomitant drainage to the ipsilateral axillary lymph nodes, injection into a cavity with a mature lining, inflammation around a biopsy site that occludes lymphatic channels, obstruction of lymphatic channels by tumor cells, and complete replacement of lymph nodes by tumor. Inaddition, in older patients, the capacity of lymph nodes to retain the radioactive colloid or dye may be reduced because lymph nodes in the elderly tend to be replaced by fat. If physicians fail to identify the SLN, a complete AxLND should be performed. Importantly, SLNB is contraindicated in patients with palpable axillary adenopathy.

The standard of care for breast cancer patients with SLN metastases remains completion axillary lymph node dissection (CLND). Many people have questioned the need for CLND in every patient with detectable SLN metastases, particularly in those with a perceived low additional disease risk. Proponents of CLND argue that the total number of involved nodes is important prognostic information and can guide decisions regarding adjuvant chemotherapy. Proponents also cite the meta-analysis by Orr showing a 5.4% survival benefit associated with CLND.

Opponents of CLND argue that therapeutic benefit is minimal and that half of patients have no further axillary metastases. NSABP Z-11 was designed to answer the question regarding the necessity of CLND after positive SLNB, but the study closed early because of poor accrual. Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) have developed a nomogram to assist the clinician and patient in determining the likelihood of further axillary metastases before deciding whether or not to proceed with CLND.

Locally advanced breast cancer

Locally advanced breast cancer is, by definition, stage III, thus includes large lesions, with or without lymph node involvement, that have no evidence of distant metastases. Clinically, these lesions frequently involve the skin, are fixed to the chest wall, and/or have palpable gross lymphadenopathy. Core needle biopsy easily can be performed and provides adequate tissue for diagnosis and treatment planning. Standard of care includes neo-adjuvant chemotherapy with a doxorubicin-based regimen, surgical resection, and adjuvant chemotherapy followed by radiation.

Metastatic breast cancer

The prognosis of metastatic breast cancer is dismal, and treatment is aimed primarily at palliation. Surgical palliation may include mastectomy in patients with large and/or erosive breast masses. The role of reconstructive surgery in metastatic breast cancer remains controversial.

Preoperative Details

Preoperative preparation of the patient for breast surgery should include attention to psychosocial as well as surgical issues. Patients may have unexpressed concerns regarding risk of recurrence, need for adjuvant radiation or chemotherapy, surveillance, length of rehabilitation, and particularly cosmesis. In discussing treatment options, it is important not to neglect the options of immediate versus delayed reconstruction and/or augmentation.

From a surgical standpoint, routine preoperative lab testing should be performed based on the patient's age, presence of symptoms, and comorbid conditions. Preoperative administration of a first-generation cephalosporin is a common practice, albeit with no proven benefit.

Intraoperative Details

The keys to successful surgery of the breast include a thorough knowledge of anatomy, accurate assessment of the extent of disease, and recognition of the potential for future operations.

All biopsy incisions should be placed carefully with consideration for the placement of a future mastectomy incision. For instance, a radial incision in the upper inner quadrant does not incorporate into an elliptical mastectomy scar with the same ease as a horizontal or curvilinear incision. However, clearly, adequate surgical margins never should be compromised for the sake of cosmesis. Circumareolar incisions are cosmetically favorable and generally adequate for most central parenchymal lesions.

The axillary incision, if done separately, can be made in a curvilinear or S-shaped fashion based on surgeon preference. Dissection begins with incision of the clavipectoral fascia and identification of the lateral border of the pectoralis minor and the inferior border of the axillary vein. The vein then is traced laterally to the thoracodorsal complex. Once this has been identified with careful preservation of the nerve, attention is turned directly medially to the chest wall where the long thoracic nerve descends to the serratus.

Often, several branches of the intercostobrachial nerve can be identified superficially during axillary dissection. These can be divided if preservation means compromise of the extent of dissection. Level I and II lymphatic tissue is resected with a combination of blunt and careful sharp dissection. Use of electrocautery should be avoided during deep dissection. Hemoclips or sutures are used to divide small vessels or lymphatics to reduce the risk of seroma and/or hematoma formation. Next, an axillary drain, if placed, is brought through a separate stab incision inferiorly.

For a mastectomy, the standard elliptical incision includes the nipple-areolar complex and extends from the lateral border of the sternum to the latissimus dorsi. An umbilical tape or suture may be helpful in measuring the upper and lower sides of the ellipse to ensure even lengths and avoid dog ears, particularly at the lateral corner. Cat's paw retractors or rakes are used to elevate the skin edges, and flaps are raised superiorly and inferiorly using electrocautery. The thickness of the flaps ideally should be approximately 1.0 cm. This relatively avascular plane is readily identifiable with adequate flap traction perpendicular to the chest wall. The breast parenchyma is removed from medial to lateral either sharply or with electrocautery in continuity with the pectoral fascia. Care should be taken to ligate or cauterize any major perforating vessels. The axillary dissection then should proceed as described above through the same incision.

The authors routinely place two drains through separate stab incisions inferior and lateral just above the inframammary fold. One is placed in the axilla and the other in the parenchymal defect. Fine subcuticular suture is used to close the skin.

Postoperative Details

Immediate postoperative care involves assessment for appropriate wound healing and evaluation and treatment of postoperative complications such as seroma, wound infection, bleeding, and nerve damage. Drains are routinely removed when output is less than 30 mL/d. Seromas that develop following drain removal are usually best managed with repeat aspiration. Follow-up of the pathologic specimen should be routine to determine adequacy of margins in the resection of the primary tumor.

Early patient mobility and range of motion exercises should be encouraged postoperatively, although the timing and degree should be tailored to the extent of the procedure performed (ie, lumpectomy vs skin-sparing mastectomy with immediate reconstruction).

Follow-up

Surveillance

Recommendations for surveillance include baseline postoperative mammography of both breasts or of the remaining breast at 6 months and tapered clinical visits. Suggested frequency of clinical assessment during the first 2 years is every 4 months; every 6 months up to the fifth year; then annually for the remainder of the patient's lifetime. Mammography and chest radiographs also should be performed annually. Further workup is not indicated in the absence of suggestive symptoms such as bone pain, headache, or findings on annual routine laboratory chemistry panels.

COMPLICATIONS

Section 7 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Complications of all of the described procedures include wound infection, cosmetic disfiguration, and bleeding.

Although the incidence of wound infection is relatively low, the rate may be decreased further with the administration of appropriate prophylactic antibiotics.

Bleeding and hematoma formation should be avoided easily with meticulous hemostasis prior to skin closure. However, seroma formation, usually an adverse postoperative finding, is both expected and cosmetically beneficial after excisional breast biopsies. Inappropriate closure of "dead space" following lumpectomy may prevent accumulation of serous fluid and result in dimpling or distortion of the breast contour. In contrast, placement of drains for modified radical mastectomy prevents accumulation of serous/lymphatic fluid underneath the breast flaps and in the axilla and may decrease the likelihood of wound infection and dehiscence.

Unfortunately, lymphedema is one of the more common and debilitating complications of axillary node dissection. The incidence of lymphedema, using current techniques for axillary dissection, has decreased significantly. Removal of level III axillary nodes can increase the incidence from 3-10% when compared with limited level I and II dissection.

Neurologic injuries vary widely from mild traction neuralgias to major brachial plexus injuries. The brachial plexus may be spared by keeping dissection inferior to the axillary vein. The most common neurologic complaint postoperatively is numbness of the axillary skin and upper medial arm. This is secondary to transection of the intercostobrachial nerve as it crosses the axilla.

Necrosis of the skin flaps is an uncommon complication following mastectomy. Simple use of the standard horizontal incision for mastectomy, careful attention to flap thickness, and tension-free closure of the wound can prevent this unpleasant complication.

OUTCOME AND PROGNOSIS

Section 8 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Survival in breast cancer depends on multiple social, biologic, and independent patient factors.

Accessibility to medical care, compliance with screening, level of education, and socioeconomic status all can impact the stage at which breast cancer first is diagnosed, which therefore influences survival.

Race has been associated with mortality from breast cancer in American women. The National Cancer Institute reported a 57% survival for black women versus 71% for white women.

Genetic predisposition also can influence outcome. Once diagnosis has been achieved, tumor size, receptor status, and axillary node involvement can affect prognosis.

A 20-year follow-up study from the BCDDP found overall 20-year survival rates regardless of age, stage, or treatment to be greater than 78%. For women aged 40-49 years, survival rate was 80% without accounting for stage and treatment. Older women (60-69 y) had a lower overall survival rate of 76%.

Tumor size clearly is associated with higher mortality. Lesions greater than 5.0 cm were associated with a 50-60% 20-year survival rate compared to those less than 1 cm, which had a 93-98% 20-year survival rate. The BCDDP also found, predictably, that nodal involvement also negatively influenced survival rates.

Choice of treatment modality also has significance with respect to survival. As discussed above, no statistically significant difference in survival was noted for patients with stage I and II breast cancers treated with breast conservation versus mastectomy.

For 2006, the 5-year survival rates for women in the United States have improved to 98% for disease localized to the breast. With nodal involvement, this decreases to 81%, and with distant metastases, the 5-year survival is only 26%.

Metastatic disease

Median survival for metastatic breast cancer is approximately 2 years. Post-menopausal patients are candidates for treatment with endocrine therapy with an AI, SERM, or agents such as fulvestrant, megestrol acetate, fluoxymesterone, or ethinyl estradiol. Chemotherapy regimens for all patients may include anthracyclines and taxanes similar to the recommended regimens for adjuvant treatment. Trastuzumab, when used in combination with chemotherapy, has been shown to improve overall survival time as well as time to disease progression.

Preliminary data had indicated potential benefit from stem cell rescue, cytotoxic chemotherapy, and autologous bone marrow transplant; however, currently no conclusive results support routine use of these therapies.

The standards of preoperative, operative, and adjuvant treatment require continuous reassessment in randomized controlled clinical trials.

FUTURE AND CONTROVERSIES

Section 9 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

The revolution in breast cancer treatment is well underway. Developments in radiology, surgery, and oncology are dramatically changing the diagnosis, treatment, and prognosis for patients with breast cancer. New imaging modalities, including magnetic resonance mammography, are being assessed for application in the detection and treatment of breast cancer. Magnetic resonance-guided biopsy is one application of this technology that has been rapidly expanding its use.

With recent growth in acceptance of breast conservation surgery, the door has been opened for even less invasive techniques such as sentinel node biopsy. Although these procedures carry a significant learning curve, informed patients and surgeons increasingly are noticing the obvious advantages of decreased morbidity and rapid patient recovery.

Laboratory milestones, such as the development of selective ER antagonists and specific monoclonal antibodies directed against cell membrane proteins, are changing the face of medical therapy for breast cancer. The Multiple Outcomes of Raloxifene Trial already has shown a decreased incidence of breast cancer in postmenopausal patients taking raloxifene. The STAR trial, described above, currently is comparing raloxifene with tamoxifen. Other studies, such as the NCCTG N9831 and the Herceptin Adjuvant (HERA) trial, are underway in hopes of defining the optimal therapeutic regimen for trastuzumab in combination with chemotherapy. Bevacizumab is a newer human monoclonal antibody that inhibits vascular endothelial growth factor and has had dramatic results in the treatment of metastatic colon cancer. Studies in progress show some promise that bevacizumab may improve overall survival in patients with metastatic breast cancer, as well.

Gene therapy and improvements in patient education and screening tools may hold further promise in the prevention of breast cancer.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Media file 1:  Inflammatory breast cancer
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Media file 2:  Advanced breast cancer
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Media file 3:  Nipple retraction due to breast cancer
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Media file 4:  Metastatic breast cancer to the back
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