Mary L. Gemignani
Breast cancer remains the most common cancer in women, and is second only to lung cancer as the leading cause of cancer-related death in the United States. It is estimated that in 2003 there will be 211,300 new cases of breast cancer diagnosed. The lifetime risk among women of developing breast cancer is 12.5% (1 in 8); the lifetime risk of dying from breast cancer is 3.6% (1 in 28). Although breast cancer remains a serious health concern in the United States as well as in other countries, breast cancer mortality is declining in the U.S. and in other industrialized countries. This decline is thought to be secondary to increased use of mammographic screening and early detection of breast cancer.
Obstetricians and gynecologists are commonly the primary care physicians for many women. According to the American College of Obstetricians and Gynecologists (ACOG), the diagnosis of breast disease, as well as the education of women on breast self-examination, and their referral for mammographic screening, is central to the obstetrician/gynecologist's role in women's health care.
This chapter presents an overview of breast cancer screening, benign and malignant conditions of the breast, and the role of the obstetrician/gynecologist in the diagnosis of and education of women about breast disease.
ANATOMY OF THE BREAST
The adult breast lies between the second and sixth ribs in the vertical plane and between the sternal edge (medially) and midaxillary line (laterally). The average breast measures 10 to 12 cm in diameter and is 5 to 7 cm in thickness. It is concentric, with a lateral projection into the axilla named the axillary tail of Spence.
The breast consists of three major structures: skin, subcutaneous fatty tissue, and breast tissue (parenchyma and stroma). The skin contains hair follicles, sebaceous glands, and eccrine sweat glands. The glandular breast is divided into 15 to 20 segments (lobes) that are separated by connective tissue and converge at the nipple in a radial arrangement. These lobes are made up of 20 to 40 lobules, which in turn consist of 10 to 100 alveoli (tubulosaccular secretory units). Five to ten major collecting milk ducts drain each segment and open at the nipple into subareolar lactiferous sinuses.
A superficial pectoral fascia envelops the breast; the undersurface of the breast lies on the deep pectoral fascia. Between these two fascial layers are fibrous bands, Cooper suspensory ligaments, which provide support for the breast. The space between the deep layers of the superficial fascia of the breast and the deep investing fascia of the pectoralis is the retromammary bursa.
The epidermis of the nipple (mammary papilla) and areola is pigmented and wrinkled and consists of keratinized, stratified squamous epithelium that contains smooth muscle fibers in dense connective tissue. These fibers are responsible for the erection of the nipple. Two receptor-type nerve endings (Ruffini-like bodies and end bulb of Krause) are present on the nipple and are associated with the tactile reception of stretch and pressure.
The areola has no hair follicles; it has sebaceous glands (at its margin), apocrine sweat glands, and accessory areolar glands (Montgomery glands) that open on the surface of the areola as small elevations called Morgagni tubercles.
The blood supply of the breast is mostly from superficial vessels. The principal blood supply is derived from the internal thoracic (mammary) and lateral thoracic artery and their tributaries. The posterior intercostal arteries of the second to fourth intercostal spaces also give off tributaries, the mammary branches.
The superficial veins follow the arteries and drain through perforating branches of the internal thoracic vein, tributaries of the axillary vein, and perforating branches of posterior intercostal veins. The veins anastomose circumferentially around the nipple, which is named the circulus venosus.
EPIDEMIOLOGY OF BREAST CANCER
Risk Factors and Assessment
Age
The incidence of breast cancer increases with age. Age is the most significant risk factor for breast cancer.
Family History
Hereditary breast cancers account for 5% to 10% of all breast cancers and are thought to be attributable to highly penetrant mutations in breast cancer–susceptibility genes. Two such tumor-suppressor genes, BRCA1 and BRCA2, have been well characterized. Breast cancer has also been noted to occur in association with other cancers such as in the Li-Fraumeni syndrome and Cowden syndrome.
Personal History
A patient's history of prior breast biopsy is important. Although the number of breast biopsies undergone does not increase a woman's risk of breast cancer, certain pathologic entities do play a role. Atypical ductal or lobular hyperplasia and lobular carcinoma in situ are considered markers of increased risk of developing invasive breast cancer. A personal history of breast cancer increases the risk for development of another breast cancer. Women treated for breast cancer are at risk for the development of a contralateral breast cancer. Various studies have shown this risk to be between 0.5% and 1% per year. In addition, patients treated with breast conservation (lumpectomy and radiation therapy) are at risk for an ipsilateral recurrence. In these women, this risk could be 10% or higher at 10 years post-treatment.
Reproductive History
Early menarche, late menopause, and nulliparity are thought to be risk factors for breast cancer. Age at first pregnancy is also thought to be a relative risk (RR) factor for breast cancer. Early age at first pregnancy is often associated with a lower risk for breast cancer; pregnancy by the age of 30 may reduce risk by up to 30%, and a full-term pregnancy by the age of 20 reduces risk by 50%. Breast-feeding has been reported to reduce risk of breast cancer, and the greatest effect is seen when cumulative times exceed 24 months. The effect of menopause as it relates to breast cancer risk has been examined. Late menopause poses an increase in risk of breast cancer. Bilateral oophorectomy before natural menopause has been reported to reduce risk of breast cancer.
Exogenous Hormone Use
The role of exogenous estrogens in the promotion of breast cancer is still controversial. Studies of oral contraceptives (OCP) and hormone replacement therapy (HRT) have yielded conflicting results. Studies of HRT and breast cancer risk indicate that women who are currently using HRT are at increased risk for breast cancer development. A meta-analysis of the largest studies, however, suggests that the increased risk is only about 10%. Women who have taken HRT in the past but are not currently using HRT are not at increased risk. Long-term use of HRT (>10 years) has been associated with relative increase in breast cancer risk, and the highest risk was noted in those patients using HRT with progestins (RR =1.41). Of note, multiple studies have shown that patients who develop breast cancer while on HRT have smaller, less aggressive cancers and a lower risk of death from breast cancer.
Recently, results from the Women's Health Initiative randomized controlled trial were reported. Between 1993 and 1998, 16,609 women with an intact uterus were randomized to receive combination HRT (0.625 mg/day conjugated equine estrogens and 2.5 mg/day medroxyprogesterone acetate) versus placebo. The planned duration of the trial was 8.5 years; however, the data and safety monitoring board of the committee recommended halting the trial because the incidence of invasive breast cancer had exceeded the stopping boundary that had been set at the initiation of the trial. This occurred after a mean of 5.2 years of follow-up. The increased risk of breast cancer reported hazard ratio was 1.25 (95% confidence interval [CI], 1.00-1.59). There was also a reported increased risk of coronary heart disease (HR 1.29; 95% CI, 1.02-1.63), stroke (HR, 1.41; 95% CI, 1.39-3.25). Beneficial effects included decreased risk in colorectal cancer (HR, 0.63; 95% CI, 0.43-0.92) and hip fracture (HR 0.66; 95% CI, 0.45-0.98). Based on the data and safety monitoring board did not recommend stopping the estrogen-alone arm in women who had had a hysterectomy. Results of this part of the study are anticipated in 2005.
The annual increased risk for an individual woman is still relatively small. The increased risk for breast cancer is apparent after four years of HRT use. The American College of Obstetricians and Gynecologists (ACOG) stresses the importance of addressing the reasons for initiating or continuing on HRT. It is no longer recommended to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention). In addition, it is no longer recommended solely for prevention of osteoporosis.
HRT is highly effective in treating vasomotor symptoms with limited effective alternative therapies. In this setting, short-term use (<5 years) can be considered as data on short-term use does not show an increased association with breast cancer.
In the past, most studies addressing OCP use and breast cancer risk concluded that there was a significant increase in risk associated with OCP use. However, the majority of studies regarding OCP use and breast cancer risk have demonstrated little association with breast cancer incidence rates. In women who have used OCP for extended periods of time (>10 years), a minimal, nonsignificant increase in breast cancer cases has been reported, seen most commonly in the group of women who began using OCP at a young age (<20 years). Past or present use of OCP at the time of diagnosis of breast cancer does not affect mortality from breast cancer. The presence of a family history of breast cancer does not appear to further increase the risk of breast cancer associated with either OCP or HRT use.
Prior Exposure to Radiation Therapy
Exposure to ionizing radiation such as occurs in treatment with mantle radiation for Hodgkin's disease poses a risk for breast cancer. This is noted 7 to 10 years after completion of radiation therapy. The cumulative probability of breast cancer at age 40 approaches 35% in these women. The risk of breast cancer associated with radiation exposure decreases with increasing age at exposure.
Other Factors
Breast cancer is more frequent in Jewish women than in non-Jewish women and in black women than in white women. Asian women have a low incidence of breast cancer. Japanese women show lower rates of breast cancer than white women. Although postmenopausal breast cancer is less common in Japanese women who have migrated to Western countries than among the general populations of these countries, after two or three generations, the incidences of breast cancer in these women approaches that of white women. The Western diet, with the increased intake of animal fat, has been implicated in these studies.
Alcohol consumption has been reported to increase breast cancer risk in a dose-related manner. Women who drink approximately one drink per day have slightly elevated risk of breast cancer over nondrinkers. This risk is significantly higher with moderate to high alcohol consumption (two to five drinks per day).
Relative Risk
Relative risk (RR) is a ratio that depicts the likelihood over time of an event's occurrence in a study population relative to that in a reference population. It is often used to quantify risk factors for breast cancer. Absolute risk is a percentage that depicts the likelihood over time of the occurrence of an event. For rare events, these two are the same, but for common events they are not. It is best to discuss risk with patients in terms of absolute rather than relative risk.
Several models exist to estimate a woman's risk of breast cancer. The Gail model, developed for use in the National Surgical Adjuvant Breast and Bowel Project (NSABP P-1) Breast Cancer Prevention Trial, is available from the National Cancer Institute and provides a measurement of absolute risk over time for breast cancer. However, in familial-type hereditary cases, it underestimates the risk of breast cancer by overlooking age at onset, bilaterality of disease among affected family members, and breast cancer in nonfirst-degree relatives (Table 50.1).
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TABLE 50.1. Risk factors for breast cancer |
BRCA1 and BRCA2
BRCA1 and BRCA2 are breast cancer–susceptibility genes that have expanded our knowledge of familial breast cancer. Linkage studies done in 1990 in early-onset breast cancer families led to cloning of the BRCA1 gene at the University of Utah in Salt Lake City in 1994. The BRCA1 gene consists of 22 coding exons distributed over approximately 100 kb of genomic DNA on chromosome 17q21. It is thought to be responsible for approximately 45% of early-onset hereditary breast cancers, and nearly 90% of hereditary ovarian cancers in families with a high incidence of breast and ovarian cancers. Two specific mutations, 185delAGand 5382insC, are present in approximately 1% and 0.25% of the Ashkenazi Jewish population, respectively. They are thought to be founder mutations (i.e., an altered gene or genes seen with a high frequency in a population originating from a small ancestral group, one or more of the founders of which were carriers of the mutant gene).
BRCA2 was isolated on chromosome 13q12-13 in 1995. The BRCA2 gene is composed of 26 coding exons distributed over approximately 70 kb of genomic DNA. This gene appears to account for 35% of families with early-onset breast cancer. It confers a lower risk of ovarian cancer compared with breast cancer. A single mutation, 6174delT, is found in approximately 1.4% of the Ashkenazi Jewish population. Together, both BRCA1 and BRCA2 mutations are found in approximately 1 in 40 Ashkenazi Jewish individuals. For both genes, the estimated penetrance is 70% to 90% for breast cancer by age 70, but the risk of breast cancer by age 50 may be lower for BRCA2 mutations.
The likelihood of a patient having a BRCA1 or BRCA2 mutation is dependent on certain factors such as age at the time of diagnosis of breast or ovarian cancer and the number and age of first- and second-degree relatives in the same parental lineage and ethnicity with breast or ovarian cancer. The parental lineage can be either maternal or paternal. The American Society of Clinical Oncology issued guidelines for recommending genetic testing for families with high probability (>10%) of having a mutation for BRCA1 (Table 50.2).
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TABLE 50.2. American Society of Clinical Oncology (ASCO) guidelines for recommending genetic testing for families with high probablility (>10%) of having BRCA1 mutation |
Identification of patients with a high-risk family history should be referred for genetic counseling and testing. The decision to undergo genetic testing is a complex one, as it can affect an individual's personal, psychological, social, financial, and ethical well-being.
Women who have a negative genetic test should still be considered at risk on the basis of age, environment, or other genetic factors or unknown mutations.
HISTORY AND PHYSICAL EXAMINATION
Obtaining a thorough history, including a family history and information on menstrual status, pregnancies and lactation, hormone use, prior breast surgeries and trauma, is essential. In addition, ascertaining whether the patient performs breast self-examinations, as well as the presence and characterization of nipple discharge or a breast mass is important.
Bilateral breast examination is best performed right after menstruation and prior to ovulation. At this time, breast engorgement and tenderness is less likely to be present. A multipositional breast examination should be performed, including examination in the upright and supine positions (Fig. 50.1 and Fig. 50.2). Breast retraction and subtle changes in the skin and nipple may be missed if the patient is examined in only one position. Examination should be performed with hands at sides, elevated above the head, and finally, with the arms tensed at the waist (contracting the pectoralis muscles). Attention is directed toward the supraclavicular area and axilla. Digital palpation is performed beneath the lateral pectoralis muscles into the axilla itself.
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FIG. 50.1. A: Inspection of patient with arms at sides. B: Inspection of patient with both arms raised. C: Inspection of patient with hands at waist, pectoral muscles contracted. |
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FIG. 50.2. A: Palpation with patient upright, with support of ipsilateral elbow; axillary nodes and also supraclavicular nodes examined. B: Palpation of breast with patient in supine position. |
The second phase of the breast examination is conducted with the patient in the supine position. Digital palpation is carried out using the index and middle fingers and applying varying amounts of pressure with the flats or pads of the fingers. A thorough examination systemically covers the entire breast and chest wall. The examination can be done in a clockwise direction or by rows (stripwise). It is important to carefully examine beneath the nipple–areolar complex and within the axilla.
An inflammatory appearance of the breast should raise suspicion of an inflammatory carcinoma. The classic appearance of inflammatory breast cancer includes a red, swollen breast with skin edema (“peau d'orange”). The breast is generally not tender. If the inflammation persists following a short course of antibiotics to rule out cellulitis, biopsy of the breast and skin is warranted. Inflammatory breast cancer is often a clinical diagnosis, and a benign skin biopsy should not dissuade the clinician from undertaking further evaluation and treatment. Any asymmetric skin changes or changes of the nipple–areolar complex should arouse suspicion. Paget disease of the nipple is the presence of intraductal or invasive cancer involving the nipple and should be excluded by a nipple biopsy of the abnormal area following a mammogram.
It is important to instruct patients in the technique of breast self-examination. Physician-directed discussion on breast self-examination is the most effective approach. Physicians have the opportunity to reinforce what is normal versus abnormal to patients during the examination.
If no abnormal findings are noted on examination, it is critical to document negative findings. The date of the last mammogram, discussion of cancer screening, and plans for follow-up should also be recorded.
Hormones (HRT or OCP) should not be renewed without a documented annual breast examination or mammography if indicated. A great deal of litigation results from failure to diagnose breast cancer. The Physician Insurers Association of America's breast cancer claims study, conducted in 1988, determined that 75% of successful malpractice lawsuits involved primary care physicians with practices in family medicine, internal medicine, or obstetrics and gynecology. It is important that the medical chart include careful documentation, since approximately one third of the cases reported in the Physician Insurers Association of America's study resulted from inadequate documentation.
MAMMOGRAPHY
The primary goal of mammography is to screen asymptomatic women to help in detection of breast cancer at an early stage. In general, a routine screening mammogram consists of a mediolateral oblique (MLO) view and a craniocaudal (CC) view of each breast. With modern low-dose screening, the dose is less than 0.1 rad per study (for comparison, a chest x-ray delivers 0.025 rad per study). The effectiveness of screening also varies depending on the density of the breast.
Breast composition may be one of four patterns of increasing density:
1. almost entirely fat
2. scattered fibroglandular densities
3. heterogeneously dense
4. extremely dense.
The greater the breast density, the lower the sensitivity of the mammogram. Because some palpable cancers are invisible on mammography, a negative study cannot always exclude cancer. It is important to note that the false-negative rate for mammograms is 10% to 15% and that a normal mammogram does not eliminate the need for further evaluation of a dominant mass in the breast. If the clinical examination is suspicious, a negative mammogram should not delay further investigation.
Mammographic screening in women 40 years or older has reduced mortality by 20% to 30%. The efficacy of screening mammography in decreasing breast cancer mortality has been demonstrated in numerous studies. In the 1960s, the Health Insurance Plan of Greater New York performed a study of physical examination and mammography in a study group of 30,756 women and a control group of 30,239 women between the ages of 40 to 64 years. At 10-year follow-up, the study group had a 30% decrease in breast cancer mortality compared with the control group.
A total of eight large randomized trials on mammographic screening have been conducted. Six of the eight trials revealed a statistically significant reduction in mortality with mammographic screening. The reduction in mortality was not as evident among women between the ages of 40 and 49 compared with women over 50 years of age. The relative mortality reduction appears later in women between the ages of 40 and 49 at randomization compared with women 50 years of or older. It is also likely that the small numbers of women between 40 and 49 years of age in the existing randomized trials may have contributed to this difference.
In a meta-analysis of eight randomized, controlled trials of mammographic screening, a statistically significant 18% reduction in mortality in women aged 40 to 49 was noted. Combined data from five Swedish trials yielded a statistically significant mortality decrease of 29% (Table 50.3).
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TABLE 50.3. Randomized population-based mammography trials |
A re-analysis of the meta-analysis excluded six of the eight studies because of issues related to randomization methods used and other factors in these trials. This re-analysis questioned the risk reduction offered by mammography and resulted in much controversy. The risk reduction associated with mammography continues to be an area of debate within the medical community.
Screening Interval
For several years, there has been a significant debate about the appropriate age at which to commence mammographic screening. In 1997, the American Cancer Society (ACS) and the National Cancer Institute (NCI) modified the guidelines for mammographic screening for women between the ages of 40 and 49, recommending regular mammograms for women in this age group. The recommended intervals differ: the ACS recommends a yearly mammogram starting at age 40, while the NCI recommends a mammogram every 1 or 2 years. The ACOG recommendations on mammography are similar to the NCI guidelines.
Annual screening mammography may commence earlier than age 40 in a few special circumstances (Table 50.4).
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TABLE 50.4. Screening guidelines for women under age 40 |
BI-RADS
In the past, a lack of uniformity in mammography terminology and reporting often led to confusion as to the malignant nature of a lesion. In 1994, the Mammography Quality Standards Act was passed by Congress and is administered by the Food and Drug Administration (FDA). It requires that mammography facilities monitor the results of their breast cancer–detection programs, including the number of recommended biopsies, and the size, number, and stage of cancers detected. The American College of Radiology (ACR) Breast Imaging Reporting and Data System uses a terminology and lexicon system called BI-RADSfor reporting abnormalities seen on mammography (Table 50.5). This standardized reporting system—the Breast Imaging Reporting and Data System—was developed in 1995. Each category leads to a fixed assessment and specific management recommendations.
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TABLE 50.5. American College of Radiology (ACR) BI-RADS assessment categories |
In addition, associated findings such as skin or nipple retraction, skin thickening, skin lesions, axillary adenopathy, and the presence of architectural distortion should also be reported.
The predictors of malignancy for the BI-RADS categories are 0% to 2% for category 3 and approximately 98% or greater for category 5.
Category 4 is less predictable. Liberman and colleagues and Orel and colleagues have placed the risk of malignancy for this category around 30%.
The ACR is working on a new edition of the BI-RADS classification system that, in particular, will attempt to provide data on category 4 in terms of risk of malignancy. According to the ACR, in the forthcoming edition of BI-RADS, category 4 will be divided into three subdivisions—low, medium, and high—in an effort to better guide clinicians and to get meaningful data about this category (personal communication, July 2002).
Diagnostic Mammography
Abnormalities found on mammographic screening may need further evaluation with additional mammography views or other imaging modalities such as ultrasound or magnetic resonance imaging (MRI). In some screening programs, the mammograms are reviewed by the radiologist as they are performed, and if additional views are needed, they are performed on the same day. In other programs, if additional studies are required, the patient is called back for them at a later date. In several studies, the frequency of “call-backs” has ranged from 5% to 11%.
Mammographic Lesions
A “mass” is defined as a space-occupying lesion seen in two different projections. If a possible mass is seen on only one view, it is called a “density” until its three-dimensionality is confirmed. A description of the shape and the margins of the lesion are also necessary. The highest frequency of carcinoma is noted in masses that have an irregular shape or spiculated borders. These lesions are associated with pleomorphic calcifications that appear discontinuous and linear in distribution. This discontinuous linear pattern suggests irregular filling of a duct with abnormal cells.
Microcalcifications
The BI-RADS lexicon describes calcification morphology (shape) and distribution. Calcifications may be scattered or clustered, coarse or fine, old or new. Comparison with prior mammograms is often necessary (Table 50.6).
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TABLE 50.6. Morphology of microcalcifications and associated lesions |
Breast Ultrasound and MRI
Breast ultrasonography can be used to distinguish between solid and cystic masses in the breast. It can be used to evaluate a focal mass identified on a mammogram or a palpable mass. It is also used as an adjuvant for biopsy. Because of its low specificity, it is not thought to be a good modality for screening. It cannot replace mammography, as it has no ability to detect microcalcifications. Ultrasound can complement mammography in young women with dense breasts (which limits the accuracy of the mammogram).
Presently, MRI has no role in breast cancer screening. MRI has a high sensitivity in the diagnosis of breast cancer, ranging from 86% to 100%, but a low specificity 37% to 97%. Because of this low specificity it is of limited value in screening. It is an expensive test that requires intravenous contrast and the technology for performing biopsy under MRI guidance is not widely available. Current uses include evaluation of breast implants for rupture, evaluation of pectoralis involvement with extensive breast cancer, and evaluation of post-lumpectomy bed fibrosis. Research into the use of MRI for screening of patients with dense breasts is under investigation. Future uses may include evaluation of occult breast cancers and evaluation of multifocal disease in those patients who are considering breast conservation.
DIAGNOSTIC EVALUATION
Palpable Mass
The workup of a patient with a dominant mass should include a bilateral mammogram. In addition to gaining valuable information about the characteristics of the mass, a secondary purpose in this setting is to screen the normal surrounding breast and the contralateral breast for nonpalpable mammographic abnormalities (densities or calcifications). Evaluation of a palpable mass is important to determine whether the mass is cancerous even if the mammogram is negative.
Fine-Needle Aspiration or Biopsy
Fine-needle aspiration (FNA) can be extremely useful in providing a cytologic analysis of a palpable breast mass. Many palpable thickenings and all dominant masses should be considered for FNA as it can differentiate between solid and cystic masses. In addition, FNA can diagnose and treat simple cysts and provide cellular material for cytologic analysis. The FNA should be performed after radiologic examination because the resultant hematoma could mask an underlying abnormality.
The breast is prepped with alcohol; with the physician facing the patient, the lesion is stabilized with the physician's opposite hand. Usually, a 21-gauge or 25-gauge needle on a 10-cc syringe is used. Approximately 3 cc of air is aspirated into the syringe to facilitate expulsion of the contents onto the slide following the procedure. The needle is introduced into the lesion, and suction is applied on the syringe (Fig. 50.3A, Fig. 50.3B and Fig. 50.3C). If the mass is cystic, the fluid is completely evacuated and the lesion should completely disappear. The syringe is withdrawn and the fluid is discarded if it is serous and nonbloody. The patient should return in 4 to 6 weeks for reexamination.
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FIG. 50.3. Aspiration biopsy. A: Mass. B: Stabilizing the lesion. C: Aspirating. |
If the lesion encountered is not cystic or suspected to be solid, an FNA biopsy can be performed in the same manner. After insertion into the lesion, multiple passes (10–15) through the lesion with changes in direction allow extensive sampling and create a “feel” for the mass (carcinomas are usually hard and gritty). The goal of sampling is to obtain material in the hub of the needle, not to fill the syringe. Care should be taken to release the suction before withdrawing the needle to prevent aspiration into the syringe. The sample is then ejected onto a glass slide, gently smeared with another slide and placed in sterile jars containing 95% ethanol for transport to the cytology lab. Alternatively, it can be placed in a specimen jar containing cytofixative. The needle should be removed from the syringe, the medium aspirated into the syringe, the needle replaced, and the medium then ejected into the jar.
An FNA requires a cytopathologist experienced in breast pathology. The false-negative rate can range from 3% to 35% depending on the expertise of the aspirator and the cytopathologist, the size of the lesion, the location within the breast and the cellular composition of the lesion. Negative findings of an FNA in the presence of a suspicious mass should not preclude further diagnostic evaluation. A diagnosis of atypical cells following an FNA warrants a surgical biopsy. Any mass remaining after aspiration of a cyst should be excised. Similarly, a cyst that recurs in the same location after one or two aspirations should be excised.
The false-positive rate of an FNA is less than 1%, but in the United States most surgeons will not perform definitive surgery (i.e., a mastectomy or axillary dissection) without a prior surgical biopsy, core-needle biopsy, or frozen-section diagnosis at the time of surgery. An FNA that is positive for adenocarcinoma could, however, provide a preliminary diagnosis and guide subsequent management.
Patients with palpable solid masses can have a biopsy of the mass in the office with use of a Tru-cut 14-gauge biopsy device. The breast is prepped sterilely and a local anesthetic is used to infiltrate the skin. A small nick is made in the skin with a scalpel to accommodate the biopsy instrument. A core biopsy of the solid mass is obtained. The instrument has a “firing” range and therefore should be kept parallel to the chest wall to avoid penetrating trauma. The specimen is placed in formalin and sent to pathology. It is believed that if the specimen “floats” in the solution, it is likely nondiagnostic fat. Tumor specimens will have a grayish appearance and will typically “sink” in the solution.
Needle-Localization and Excision
Needle localization is a technique that allows surgical excision of a lesion that is nonpalpable. The technique uses a hook-wire system to target the lesion, and image guidance can be provided by mammogram, ultrasound, and in some cases MRI. In mammography-guided needle localization, coordinates of the lesion are obtained by placing the breast in an alphanumeric grid. The needle is inserted and, when adequate placement is noted, the hook wire is deployed and the needle removed. Two mammographic views are then obtained.
The mammography films are available intraoperatively and show the relationship between the lesion and localizing hook. Excision with needle localization allows the surgeon to minimize the amount of breast tissue removed by following the needle to the targeted lesion. After removal, a specimen radiograph is obtained to ensure that successful removal of the lesion has been performed. Radiologists and surgeons experienced in needle localization and excisions report only 0.2% to 0.3% of lesions missed with this approach. The specimen radiograph helps to ascertain the lesion was not missed.
Image-Guided Percutaneous Breast Biopsy
With the current advancements available in breast imaging, percutaneous image-guided breast biopsy is increasingly being used as an alternative to surgical biopsy. Percutaneous biopsy methods differ with respect to the method of imaging guidance and the tissue-acquisition device used. The use of image-guided percutaneous biopsy has advantages over surgical excision for the diagnosis of breast lesions. It is less invasive and because less tissue is removed, it will result in less scarring on subsequent mammograms. Regardless of whether the diagnosis is benign or malignant, the patients who have percutaneous biopsies will undergo fewer operations. In addition, in cases of malignancy, the discussion and surgical treatment plan can be streamlined. The choice of which image-guided modality to use depends on the lesion. Stereotactic biopsy is best for calcifications. If a lesion is seen on ultrasound, it is best to use that modality, since it is easier to use and has been reported to be less costly.
Stereotactic Biopsy
Stereotactic biopsy uses specialized mammography equipment to calculate the location of a lesion in three dimensions. Stereotactic biopsy can be performed with the patient prone on a dedicated table or with the patient sitting in an upright unit. An automated core needle or directional vacuum-assisted biopsy probe is used to obtain the tissue specimens. Multiple tissue specimens are obtained for pathologic analysis. Many reports in the medical literature state the procedure has a sensitivity of 70% to 100% and a specificity of 85% to 100%. The greatest success is noted in reports using 14-gauge core needles, as well as in those with increased numbers of specimens obtained. In mass lesions, it is likely that five core samples may be adequate for accurate diagnosis; however, ten or more core specimens may be required in cases of calcifications.
Ultrasound-Guided Biopsy
The use of ultrasound imaging for percutaneous biopsy of lesions seen on ultrasound has certain advantages. For example, it requires no specialized equipment, no radiation exposure, and has the ability to sample areas that may be inaccessible with stereotactic biopsy (such as the axilla). A 14-gauge automated needle is used, and real-time imaging allows accurate positioning. Multiple tissue core samples are sent for pathologic analysis.
Tissue-Acquisition Devices
Available tissue-acquisition devices include fine needles, automated core needles, directional vacuum-assisted probes, and biopsy cannulas. Excellent results have been obtained using the 14-gauge automated needle for biopsy of masses under ultrasound or stereotactic guidance. Most centers use larger tissue-acquisition devices instead of fine needles, because of accuracy of tissue diagnosis when a larger volume of tissue is obtained. Compared with the automated needle, the vacuum device acquires larger samples of tissue, has a higher frequency of retrieval of calcifications, and may provide more accurate lesion characterization. Accurate placement of a localizing clip through the biopsy probe is necessary to facilitate subsequent localization if needed.
Surgical Excision/Breast Biopsy
The ACOG has stopped short of recommending that open biopsy be performed by every obstetrician and gynecologist.
A biopsy can be performed on an outpatient basis under local anesthesia in the majority of patients. It is important to choose the appropriate incision and location (Fig. 50.4). Unless the lesion is close to the nipple or suspected to be a fibroadenoma, the incision should be made in close proximity to the mass and not circumareolar. The surgeon should keep in mind the possibility of subsequent mastectomy when placing the incision. Many times, the biopsy is part of the treatment. The specimen should be adequately oriented for margin analysis by the pathologist and also sent for the appropriate markers such as estrogen-receptor (ER) and progesterone-receptor (PR) status and HER2/neu. Orientation of the specimen is important, as a reexcision of a close or involved margin may need to be performed.
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FIG. 50.4. Optimal orientation of biopsy incisions. |
The incision should be closed with fine suture material, with a subcuticular closure. Hemostasis needs to be ascertained prior to closing and is usually achieved with electrocautery. Weck clips can be placed in the cavity bed if a diagnosis of breast cancer is known and breast conservation is planned. No particular immobilization is required but a good support bra is recommended to minimize hematoma and induration.
BENIGN BREAST CONDITIONS
Fibrocystic Changes
Fibrocystic change is the most common benign breast condition in women. It is a result of fluctuating hormone levels, and most common in premenopausal women between the ages of 20 and 50. It is often associated with pain and tenderness (mastodynia) and tends to be bilateral. Most women will report symptoms during the premenstrual phase of the cycle.
Pain is due to breast stromal edema, ductal dilation, and associated inflammatory response. An increase in breast size is also frequently reported. The differential diagnosis for breast pain includes other conditions affecting the anterior chest wall such as intercostal neuralgia, myalgia, and chronic costochondritis. Women with large pendulous breasts will have associated stretching of Cooper ligaments and associated breast pain.
Etiologic factors are still inconclusive. The ingestion of foods and medications containing methylxanthines has been implicated through an inhibition of 3′5′-cyclic adenosine monophosphate (cAMP) phosphodiesterase and 3′5′-cyclic guanosine monophosphate (cGMP) phosphodiesterase. This inhibition will lead to accumulation of increased amounts of cAMP and cGMP. High levels of cAMP and cGMP have been detected in patients with fibrocystic change. In some studies, reduction of dietary methylxanthines has been associated with symptomatic subjective reduction in pain, tenderness, and palpable nodularity. Other studies, however, have failed to show an effect from decreased consumption of dietary methylxanthines.
Fibrocystic change is not a risk factor for cancer in the majority of women. Histologically, there are two changes noted with fibrocystic change: nonproliferative changes and proliferative changes. The nonproliferative changes include cystic changes with formation of microcysts (2 mm or less in size), macrocysts, and fibrosis.
Proliferative Changes
Proliferative changes include hyperplasia and adenosis. Hyperplasia is proliferation of ductal epithelium, which results in layering of the cells. Atypia may be associated with this proliferation. If atypia is noted, this confers a five fold increase in breast cancer risk for the patient. Hyperplasia with atypia is the only fibrocystic change associated with an increased risk factor for breast cancer. If atypia is noted on a core biopsy, a surgical excision of the area is recommended, as it is thought that there is a 50% chance of finding a coexistent carcinoma.
Adenosis is also a proliferative lesion, caused by changes in the acini in the distal mammary lobule. Sclerosing adenosis refers to the dense, fibrotic tissue surrounding these small ducts. These lesions may present as a palpable mass in women in their 30s and 40s.
A papilloma can result from this ductal proliferation. Papillomas are papillary lesions with a branching fibrovascular core surrounded by epithelium. These lesions are associated with serosanguineous nipple discharge in 25% to 50% of presentations. Ninety percent of the time, there is a small palpable mass adjacent to the areola. Intraductal papillomas are rarely associated with carcinoma, but require surgical excision to rule out the possibility of misdiagnosis of a malignancy.
Management of fibrocystic changes includes regular physical examinations, appropriate imaging, and supportive measures. Recommendations for use of a good support bra may be helpful, especially in physically active women. Dietary restrictions of methylxanthines may produce subjective improvement in 65% of patients. The use of vitamins A and E has been reported in some studies to be helpful. Diuretic therapy during the premenstrual period has been reported to provide temporary relief, and requires cyclical use. Fluid retention is a result of cyclical hormonal stimulation.
Oral contraceptives suppress symptoms of fibrocystic changes in the majority of patients (70%–90%). Symptoms often recur after discontinuation. Other medications such as danazol (17α-norethisterone) in doses of 100 to 400 mg per day should be reserved for patients in whom other agents have been ineffective. Their side-effect profile can lead to poor compliance. A 3- to 6-month course can provide significant reduction in symptoms, and its effect can last several months after its discontinuation.
Fibroadenoma
Fibroadenomas are benign fibroepithelial tumors and are the second most common benign lesion of the breast. They are the most common lesion found in women under the age of 25. They will persist during the menstrual years of a woman's life, but regression after menopause has been reported. Patients typically present with a mobile, smooth, painless, palpable mass. Ultrasound examination, along with physical examination, can help in making the diagnosis. Mammographically, fibroadenomas may appear as round, oval, or lobulated masses with circumscribed margins. In older women, they can have a rim of coarse calcifications. FNA will reveal benign ductal epithelial cells and elongated dense stromal cells. Microscopically fibrous tissue composes most of the fibroadenoma. Carcinoma arising in fibroadenomas is rare.
Fibroadenomas can be followed without the need for complete surgical excision. This can be achieved with physical examination or ultrasound examination if they are not palpable. However, surgical excision should be performed if:
· the mass continues to enlarge
· the results of FNA or core biopsy are inconclusive or yield atypia
· the patient desires surgical excision.
Phyllodes Tumor
Phyllodes tumors are uncommon, slow-growing fibroepithelial tumors. Previously referred to as cystosarcoma phyllodes, this name contributed to confusion in understanding this entity. Although very similar to a fibroadenoma, the stromal component is hypercellular with increased pleomorphism and mitotic activity. Phyllodes tumors can occur in women of any age, but more commonly occur in premenopausal women.
Malignant behavior in phyllodes tumors is rare in premenopausal women. Malignant phyllodes tumors are noted when there is a combination of increased mitotic activity, invasive borders, or marked pleomorphism. Incomplete excision is a major determinant for local recurrence. Treatment is total surgical excision with a wide margin of healthy tissue.
Superficial Thrombophlebitis
Superficial thrombophlebitis is also known as Mondor disease of the breast. It is an uncommon benign inflammatory process. It can occur spontaneously, but usually is associated with breast trauma, breast surgery, or pregnancy. It is a thrombophlebitis of the thoracoepigastric vein, which drains the upper-outer quadrant of the breast. Patients present with acute pain and a linear, tender fibrotic band with skin retraction over the distribution of the thoracoepigastric vein.
Treatment is conservative, with analgesics and application of heat. The condition resolves in 1 to 3 weeks. Skin retraction superficial to the area of inflammation can remain if the inflammation is extensive. Biopsy is not necessary.
Mastitis
Mastitis usually occurs in relation to lactation. It can occur in nonpuerperal periods in association with galac-torrhea. Skin organisms, Staphylococcus aureus, and Streptococcus species may cause infection of the nipple and breast ducts. Presence of milk in the ducts is an excellent medium for infection.
Women with mastitis may continue to breast-feed. Antibiotic therapy with dicloxacillin sodium (250 mg q.i.d.) or penicillin G is indicated. If there is no response, an abscess that may require surgical drainage must be excluded. Inflammatory carcinomas can mimic mastitis, and if no resolution of infection is noted despite continued antibiotics, a skin biopsy may be indicated.
Galactoceles are milk-filled cysts. They are usually tender and present after the abrupt termination of breast-feeding. Aspiration of the cyst is often necessary for symptomatic relief. If reaccumulation occurs, however, surgical excision may be required to avoid infection.
Duct Ectasia
Duct ectasia is a condition usually occurring in perimenopausal or postmenopausal women. Patients present with a tender, hard erythematous mass adjacent to the areola in association with burning, itching, or a sensation of pulling in the nipple area. A thick greenish-black discharge may be present. Histologic evaluation of the area shows dilate, distended terminal collecting ducts obstructed with inspissated lipid-containing epithelial cells and phagocytic histiocytes. This process tends to occur in a segmental fashion extending from the involved nipple area to adjacent ducts. Occasionally, as a result of this infection, a small abscess forms at the base of the nipple. Treatment is excisional biopsy.
Younger women can present with inflammation of the ducts in the region of the nipple, which may produce fissures and fistulae with connection from the nipple ducts to the skin at the edges of the areola. Prior periductal mastitis leads to the squamous epithelium of the terminal dilated portion of the collecting ducts to undergo squamous metaplasia. Keratin is formed in the duct, accumulates, and can cause an abscess at the base of the nipple. Excision of the area usually is necessary.
Fat Necrosis
Fat necrosis is a relatively uncommon benign condition occurring as a response to breast trauma. Patients present with a hard mass that can mimic a carcinoma. The irregular mass is palpable and may involve skin retraction. Multiple calcifications can be seen on mammography.
The histology is active chronic inflammatory cells, with lymphocytes and histiocytes predominating. In the later stages, a collagenous scar is noted, with “oil cysts” or free lipid material released by lipocyte necrosis. Fat necrosis does not increase the risk of carcinoma, and its clinical importance is in the differential diagnosis of a carcinoma.
Nipple Discharge
Nipple discharge has been reported in 10% to 15% of women with benign breast disease and in 2.5% to 3.0% of those with carcinoma. The discharge is classified according to its appearance as milky, green, bloody, serous, cloudy, or purulent. The drainage should be classified according to whether it is unilateral, bilateral, or spontaneous, or recurrent. This information is obtained at the time of a thorough history and physical examination. For example, if the drainage first appeared in the patient's bra or nightgown on awakening, this finding is significant. The presence of a mass should also be investigated. The risk of cancer is increased when the discharge is unilateral from a single duct, occurs in a postmenopausal patient, or when a mass is present.
Unilateral, Spontaneous Nipple Discharge
In cases of unilateral, spontaneous nipple discharge, several causes are included in the differential. The most common cause of nipple discharge is mammary-duct ectasia, which produces a multicolored (green, yellow, white, brown, gray, or reddish brown) nipple discharge. The reddish-brown discharge is often mistaken for a blood discharge. It is thought to be due to an increase in glandular secretions, with the production of an irritating lipid fluid that can produce a nipple discharge. Guaiac of the discharge can help to diagnose whether it is bloody.
The next most common cause of a multicolored, sticky nipple discharge is nonpuerperal mastitis. The persistent type involves inflammation in deeper portions of the breast; the transient types are associated with periareolar inflammation. If the inflammation develops into an inflammatory mass, surgical excision and drainage are necessary. Medical management with local care, avoidance of all nipple manipulation, and nonsteroidal antiinflammatory agents and an antistaphylococcal antibiotic is often successful when infection is suspected.
Bloody nipple discharge warrants surgical evaluation. Intraductal papillomas are the most common cause of bloody nipple discharge. During the breast examination, physicians should look for an associated periareolar mass. The examination consists of gently and carefully palpating the subareolar region to identify the pressure point that produces the discharge. It is important to reproduce the discharge and demonstrate the breast quadrant from which it emanates. All significant nipple discharges warrant referral for tissue biopsy. Although a mass is usually present when the discharge is due to cancer, there is no palpable mass in 13% of cancers with nipple secretions. Bloody discharge occurring in the third trimester of pregnancy however may be regarded as physiologic and does not require intervention unless persistent for several months after delivery. There are no contraindications to breast-feeding in these patients.
In addition, physicians should not rely solely on the cytology of the discharge because there is an 18% false-negative rate and a 2.6% false-positive rate with standard cytology alone.
Galactography (injecting radiopaque contrast into the discharging duct and then performing mammography) offers better visualization of small intraductal papillomas but cannot differentiate between benign and malignant lesions. A surgical procedure is still necessary. Mammography has a 9.5% false-negative rate and a 1.6% false-positive rate for detecting cancer in patients with a nipple discharge.
BREAST CANCER
Natural History
The most common site of origin of breast cancer is the upper-outer quadrant (38.5%), central area (29%), upper-inner quadrant (14.2%), lower-outer quadrant (8.8%), and the lower-inner quadrant (5%). These percentages correlate with the amount of tissue that is present in these quadrants. Metachronous bilateral carcinoma of the breast has been observed in 5% to 8% of patients.
Metastasis to the ipsilateral axilla is the most common route of spread. Metastasis to the internal mammary nodes is more frequent with inner-quadrant lesions and is more likely to occur when involvement of the axillary nodes is also present.
Pathology
Ductal Carcinoma in Situ
Ductal carcinoma in situ (DCIS) is an abnormal proliferation of malignant epithelial cells within the mammary ductal–lobular system without invasion into the surrounding stroma. It is classified as a heterogenous group of lesions with different growth patterns and cytologic features. Classification of DCIS has traditionally been based on architectural pattern. The most common types are comedo, cribriform, micropapillary, papillary, and solid.
Paget's Disease
Paget's disease is involvement of the nipple with intraductal carcinoma. In absence of a palpable mass, invasive carcinoma occurs in less than 40% of cases. The malignant cells are large and pale-staining and are seen in the basal layer and upper portions of the epidermis. Diagnosis is made through a nipple biopsy.
Lobular Carcinoma in Situ
Foote and Stewart initially described lobular carcinoma in situ (LCIS) in 1941 as a noninvasive lesion arising from the lobules and terminal ducts of the breast. LCIS is characterized by a solid proliferation of small cells with round to oval nuclei that distort the involved spaces in the terminal duct–lobular units. Three important features of LCIS are:
1. It is usually an incidental microscopic finding that is not detected clinically or by gross pathologic examination.
2. It is multicentric, and the associated cancer may be ductal or lobular.
3. The risk for subsequent cancer is the same for both breasts.
It is unfortunate that Foote and Stewart chose the name they did, as it has led to a great deal of confusion over the past several decades. LCIS is a marker for breast cancer risk and is not a malignant finding.
Invasive Duct Carcinoma
Invasive duct carcinoma is the most common group of malignant mammary tumors and comprises 65% to 80% of all mammary carcinomas. Included in this group are special subtypes: Tubular, medullary, metaplastic, mucinous (colloid) papillary, and adenoid cystic carcinoma. Each subtype constitutes only 1% to 2% of all invasive breast cancers, except medullary carcinoma, which constitutes 7%, and the rare adenoid cystic carcinomas, at less than 0.1%.
Many of these subtypes, such as tubular and medullary carcinomas, carry an excellent prognosis. Metaplastic carcinomas, however, often have an aggressive behavior. These tumors are characterized by the presence of homologous (epithelial) or heterologous (mesenchymal) elements. Two types have been described: Squamous and pseudosarcomatous metaplasia.
Invasive duct carcinoma not otherwise specified (NOS) is a generic term that includes tumors that may express more than one element of the specific forms of duct carcinoma.
Infiltrating Lobular Carcinoma
Infiltrating lobular carcinoma has been reported to constitute 10% to 14% of invasive carcinomas. These carcinomas are characterized by uniform cells with small, round nuclei and limited cytoplasm. The presence of intracytoplasmic mucin vacuoles often gives the cells the appearance of signet-ring cells. The cells tend to grow circumferentially around ducts and lobules with a linear arrangement. This pattern is referred to as “Indian-file” or targetoid growth. There is often an associated desmoplastic stromal reaction.
Inflammatory Carcinoma
Inflammatory carcinoma is characterized by cutaneous findings present with an underlying invasive carcinoma. Usually the invasive tumor is a poorly differentiated infiltrating duct carcinoma. Upon microscopic evaluation, skin involvement often reveals tumor emboli in dermal lymphatics with an associated lymphocytic reaction in the dermis.
Metastases from Extramammary Tumors
The most common primary site of an occult extramammary tumor is the lung. Other primary sites include the ovaries, uterus, kidneys, and stomach. In those previously diagnosed, melanoma, prostate, cervix, uterus, and urinary bladder are the most common sites. Metastatic ovarian cancer may simulate papillary or mucinous carcinoma of the breast. A workup and history are often helpful in difficult cases. Often, identification of an in situ component helps to provide definitive evidence of a mammary origin.
Biologic Markers/Prognostic Factors
Axillary Lymph Node Status
The most important prognostic factor is nodal status. The presence of metastasis, as well as the number of lymph nodes involved, is significant and correlates with local failure and distant metastases. It is predictive of overall survival.
Tumor Size
Tumor size correlates with the incidence of lymph node metastases. The size of the tumor is also important, even in the absence of lymph node involvement. Patients with tumors less than 1 cm in size, or with good histologic types measuring less than 3 cm, do very well.
Histologic Grade
Histologic grade also correlates with breast cancer outcome. Poorly differentiated tumors have been associated with more aggressive behavior.
Estrogen Receptors/Progesterone Receptors
The hormone receptors can be measured by immunohistochemical (IHC) studies using monoclonal antibodies directed against the receptors. Positivity correlates with response to antihormonal agents as well as better prognosis.
HER2/neu
HER2/neu is an oncogene whose protein product may function as a growth factor receptor. It can be detected by IHC demonstration of the protein product or by gene amplifications. Overexpression or amplification has been shown to correlate with a poor prognosis; however, the studies differ with regard to the method of detection used, as well as the interpretation of results. HER2/neu has been used as a predictor of response to certain chemotherapeutic agents. Particularly, increased-response, doxorubicin-based therapy has been reported in the treatment of patients with positive nodes and overexpression of HER2/neu. Herceptin (trastuzumab) is a humanized anti-HER2 antibody against the extracellular domain of the 2-neu oncoprotein. Its use in the metastatic setting has been reported to demonstrate an increase in response rate and prolongation of disease-free and overall survival.
p53
A tumor-suppressor gene, p53 has a protein product that is a nuclear transcription factor with many functions, including regulation of the cell cycle and apoptosis. Most clinical studies have used IHC to study protein expression. Accumulation of p53 protein has been reported to correlate with reduced survival in some studies.
STAGING OF BREAST CANCER
Staging of Breast Cancer Using the Tumor–Node–Metastasis (TNM) System
The American Joint Committee on Cancer (AJCC) determines staging of breast cancer. The AJCC staging system is a clinical and pathologic staging system based on the tumor–node–metastasis (TNM) system. The new updated AJCC staging system (2002) incorporates sentinel node staging. It distinguishes micrometastasis from isolated tumor cells on the basis of size and histologic evidence of malignant activity. In the current AJCC staging system, supraclavicular lymph node metastasis is now classified as N3 disease, rather than M1 disease, as in the old system (Table 50.7, Table 50.8).
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TABLE 50.7. American Joint Committee on Cancer Staging for breast cancer |
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TABLE 50.8. Stage by tumor, node, metastasis (TNM) |
TREATMENT OF BREAST CANCER
Mastectomy
William Halsted performed a radical mastectomy in 1894. The guiding principle at this time was centered on the belief that cancer originates in the breast and spreads in a stepwise fashion first to the regional lymph nodes, and then to distant sites. Removal of all the breast tissue, pectoral muscles, and axillary contents was the standard surgical treatment. Over the next several decades, two simultaneous trends existed. One involved less-radical surgery, which included removal of the breast and axillary contents, but preserved the pectoral muscles and more skin. This was described by Patey and Dyson in 1948, and is the modern-day modified radical mastectomy. The other trend involved more extensive surgery, the extended radical mastectomy, which included en-bloc removal of the internal mammary chain at the time of radical mastectomy. Subsequent randomized trials failed to show a survival advantage with the extended radical mastectomy when compared with the radical mastectomy.
Breast-Conservation Therapy
The shift toward less radical surgery at the time of mastectomy occurred for several reasons. As earlier diagnosis of breast cancer with smaller tumors and less involvement of pectoral muscles occurred, the need for radical procedures decreased. In addition, even with radical mastectomy not all patients were cured, and although regional recurrences were low, patients died of distant disease. The morbidity of the radical mastectomy was well documented, including lymphedema, immobility of the shoulder, and disfigurement. A shift to breast conservation followed the same trends. The initial trials with radiation therapy using radium implants at the Princess Margaret Hospital in Toronto had promising results.
This led to randomization studies comparing breast-conservation therapy with mastectomy. Table 50.9 lists randomized trials that compared radical and modified radical mastectomy in stage I and stage II carcinoma of the breast.
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TABLE 50.9. Conservation surgery and irradiation in Stage I and II carcinoma of the breast: Results of randomized comparisons with radical or modified mastectomy |
In breast-conserving surgery, a wide local excision is performed with excision of the tumor and a 1- to 2-cm rim of normal tissue. This excision is referred to as “lumpectomy” or a “tumorectomy.” This differs from a quadrantectomy, in which a resection of the tumor with the overlying skin and the involved quadrant of the breast is performed. The six randomized trials differed with respect to the type of wide local excision performed as well as tumor size in the patients who were randomized. In the Milan trial, a quadrantectomy was performed. In the Insitut Gustave Roussy trial, the “tumorectomy” performed was removal of the tumor and a 2-cm margin of normal tissue. In the United States, the NSABP B-06 trial did not specify the margins on the lumpectomy specimen, providing they were grossly free of tumor.
In all trials, the authors noted comparable disease-free survival in both arms. The only difference noted was in local recurrence. In addition to the randomized trials, there are many nonrandomized reports published with similar results in survival between breast conservation and mastectomy.
Radiation therapy is an important component of breast conservation. Adequate surgical margins are required to be negative on pathologic inspection. After healing, the radiation therapy is planned. Treatment to the entire breast should be at a dose of 1.8 to 2.0 Gy per day for a total of 45 to 50 Gy. A 10- to 15-Gy electron-therapy boost is often given to the lumpectomy bed.
Breast conservation depends on the use of radiation. The question of whether lumpectomy alone would yield similar results has been addressed through randomized trials. Local recurrence rates of 18% to 40% with lumpectomy alone have been reported compared with 2% to 14% with lumpectomy and radiation. In these studies, a significant reduction in relapse was noted in the lumpectomy-and-radiation arm.
The NSABP B-17 trial is the only randomized trial of lumpectomy alone versus lumpectomy and radiation in patients with DCIS. Ipsilateral relapse was 7% in the radiation arm versus 16.4% in the lumpectomy-alone arm. Actuarial 5-year survival showed an ipsilateral recurrence rate of 7.5% for noninvasive and 2.9% for invasive recurrence in the lumpectomy-plus-radiation arm. By comparison, the rates were 10.4% and 10.5%, respectively, in the lumpectomy-alone arm. The overall survival was excellent and comparable to that seen with mastectomy. In cases of invasive recurrence, patients in the lumpectomy-plus-radiation arm can be salvaged with mastectomy.
Patient Selection
Possible contraindications can interfere with offering a patient breast-conservation therapy. Cosmetic result should be considered when deciding whether to offer breast-conserving surgery; tumor size in relation to breast size is an important consideration. In addition, other factors that may affect the ability to receive irradiation must be considered (i.e., history of prior breast or chest irradiation, concurrent pregnancy, autoimmune connective-tissue disease). Particularly with a history of systemic lupus erythematosis, radiation may not be a possibility. Women with multiple cancers in the breast are not candidates for this approach and require a mastectomy. In addition, in patients with extensive calcifications on a mammogram suggesting a diffuse process may be better treated with mastectomy.
An area of controversy remains over the status of negative margins at the time of lumpectomy. Generally a reexcision should be performed. Extensive intraductal component (EIC) is a condition that exists when greater than 25% of the tumor is associated with DCIS. In these cases, the invasive component may be outside the area of the intraductal carcinoma. This has been reported to have a higher relapse rate with breast conservation; however, it is thought to be secondary to margin status, since margin involvement may be an indication of residual intraductal carcinoma. In DCIS, Silverstein and associates developed the Van Nuys prognostic index (VNPI). The system combines the scores for histologic grade, tumor size, and margin status of a lesion in order to obtain an overall score. It considers margins of 1 cm to indicate a decreased rate of local relapse, even with no radiation.
Management of the Axilla
The axilla is a pyramidal space between the arm and thoracic wall. It contains the axillary vessels and their branches, the brachial plexus and its branches, and lymph nodes embedded in fatty tissue. The primary route of lymphatic drainage of the breast is through the axillary lymph nodes. The lymph nodes are also divided into levels based on location relative to the pectoralis minor. Level 1 lymph nodes lie lateral to the lateral border of the pectoralis minor muscle. Level 2 nodes lie behind the pectoralis minor muscle, and level 3 nodes are medial to the medial border of this muscle.
In an axillary dissection, nerve branches of the brachial plexus are encountered. The lateral and medial pectoral nerves supply the pectoralis muscles. The thoracodorsal nerve runs downward, and innervates the latissimus dorsi. The long thoracic nerve is located on the medial wall of the axilla on the serratus anterior. It arises from the C5 to C7 roots, and injury to these nerves results in paralysis to part or all of the serratus anterior. The functional deficit is inability to raise the arm above the level of the shoulder.
At the time of Halsted's radical mastectomy procedure, a complete axillary dissection was performed. The status of the axilla is the most important prognostic factor for breast cancer. The use of axillary dissection has, in the past, been demonstrated to significantly decrease local recurrence, which may ultimately translate to a survival advantage.
Clinical examination of the axilla is inaccurate, since even in patients with a T1 lesion, there is a 10% risk of lymph node metastasis. Prior to the use of sentinel lymph node biopsy, there was no accurate method to adequately stage the axilla without an axillary dissection. Axillary lymph node sampling (i.e., removal of only a few lymph nodes) was inadequate.
Metastatic involvement of lymph nodes usually occurs in a stepwise manner. Rosen and co-workers demonstrated the incidence of ″skip metastasis″ to be less than 2%. A complete level 1 and 2 lymph node dissection provides excellent local control, and local recurrence after this procedure has been shown to be less than 1%. The NSABP B-04 trial randomized patients with clinically negative nodes to one of three groups: radical mastectomy, total mastectomy with nodal irradiation, or total mastectomy alone. The patients who had no axillary nodal therapy had an overall worse survival if recurrence occurred.
The morbidity associated with axillary lymphadenectomy is not inconsequential. About 10% to 15% of patients will develop lymphedema. In addition, numbness, pain, or weakness contribute to a significant decrease in the quality of life in these patients.
Sentinel Lymph Node Biopsy
Sentinel lymph node (SLN) biopsy in breast cancer evolved out of efforts to minimize the morbidity associated with axillary lymph node dissection while still providing important staging information. Initial studies in melanoma, by Morton and colleagues in 1992, demonstrated the feasibility of the concept. Methods employed include use of blue dye or radioisotope (Fig. 50.5).
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FIG. 50.5. Intraoperative identification of the sentinel lymph node. |
Several studies have confirmed the accuracy of SLN biopsy. In the majority of the studies, successful identification of the SLN occurs between 92% and 98% of the time. The combination of blue dye and isotope has been reported to be better for identification of the SLN; when used in combination, the positive predictive value of the technique approaches 100%, with a negative predictive value close to 95%. The false-negative rate is about 5% to 10% in most studies.
The validity of the SLN concept lies in the ability of the SLN to predict the status of the regional lymphatic basin. Turner and colleagues performed IHC staining of all lymph nodes, sentinel and nonsentinel, in a series of patients undergoing standard axillary dissection with negative nodes. Of 157 SLNs, 10 (6%) demonstrated IHC positivity compared with 1 of 1,087 (0.09%) of the non-SLNs. This provided validity of the SLN concept.
Overall, greater scrutiny is paid to SLNs through serial sectioning and IHC stains. This is possible because only a few SLNs are obtained at the time of the procedure, and would not be cost-effective in a standard axillary dissection that yields an average of 20 nodes.
The use of the SLN biopsy procedure is widely employed in invasive breast cancer. In certain situations, however, a standard axillary dissection should still be considered. These include:
· in cases of palpable suspicious nodes
· in cases of large lesions (the majority of reports indicate that the procedure is reliable if there are no suspicious nodes in the axilla)
· in cases of prior radiation, of a large excisional cavity close to the axilla, or any condition in which disruption of the lymphatics is suspected.
Systemic Treatment
Adjuvant treatment in breast cancer was first used over 100 years ago. In 1894, Beatson reported on the results of oophorectomy and response rate in the metastatic breast cancer setting. Initially, the use of systemic therapy involved the use of single-agent chemotherapy; later, multi-agent chemotherapy was employed. As in most breast cancer trials, the initial reports were of patients with metastatic disease.
Multiple randomized studies have demonstrated that the addition of chemotherapy improves overall survival in patients with breast cancer. The decision to use adjuvant chemotherapy or hormonal therapy depends on certain factors such as the size of the primary tumor, lymph node status, and the presence or absence of metastatic disease. In addition, the expression or lack of expression of ER or PR (ER/PR status) is also an important factor.
Adjuvant chemotherapy is standard treatment for patients with positive nodes or large tumors. The combination of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil [5-FU]) has been used for many years in the treatment of patients with breast cancer. An anthracycline-based regimen such as FAC (5-FU, adriamycin, and cyclophosphamide) has been used in patients with high risk factors for recurrence. The use of paclitaxel is also considered in this setting. For patients with intermediate risk factors, such as ER-negative tumors (>1 cm in size) and negative nodes, chemotherapy is considered.
The Early Breast Cancer Trialists' Collaborative Group was formed in 1985 to analyze all available, properly conducted, randomized trials. A second overview was done in 1990, and a third in 1995. In women under the age of 50, administration of multi-agent chemotherapy decreased the annual risk of relapse by 35% and mortality by 27%. With 10 years of follow-up, this translates into absolute gains of 7% in patients with node-negative tumors and 11% in those with node-positive tumors. For women over the age of 50 years, the benefits of chemotherapy were smaller but still significant. Annual risk reduction was 20% for recurrence and 11% for mortality. At 10 years of follow-up, this risk reduction translated into absolute gains of 2% in patients with node-negative tumors and 3% in patients with node-positive tumors. It is important to note that in the overview, different regimens of CMF were used; but the greatest benefit was seen in those using CMF for 6 months or longer.
The question of whether to use CMF or FAC in high-risk patients (tumors = 2 cm in size or ER/PR-negative with negative nodes) has been addressed. While the anthracycline regimen is more toxic than CMF, trials have shown superiority with this regimen. Presently, other factors are used to determine which regimen to recommend in this subgroup. The most promising candidate factor is HER2/neu overexpression because increased response rates with an anthracycline-based therapy have been reported in cases where there is overexpression of HER2/neu.
The use of taxanes such as docetaxel and paclitaxel as adjuvant treatment in combination with anthracycline-based chemotherapy is being investigated. Postmenopausal women with negative nodes and ER-negative tumors greater than 1 cm in size are also considered for chemotherapy. In these patients, CMF is usually the treatment of choice.
Metastatic Disease
The goal of therapy in metastatic disease is palliation of symptoms, as cure is unlikely. The majority of patients with metastatic disease receive antihormonal therapy. First-line agents include tamoxifen, or aromatase inhibitors such as letrozole or anastrozole. These agents offer a 20% response with in ER/PR-positive tumors. Disease stabilization is the goal of therapy, and because these therapies are less toxic than chemotherapy, most patients will remain on them for prolonged periods of time. Upon failure of these agents, however, chemotherapy is the next step.
High-Dose Chemotherapy
Five large randomized trials have been conducted addressing the use of high-dose chemotherapy with bone-marrow or stem-cell rescue in metastatic breast cancer. Only one trial, conducted in South Africa, showed a lower rate of relapse. The other four trials showed no increase in overall survival. The investigators of the trial conducted in South Africa subsequently admitted to fraud. Thus, it is felt that high-dose chemotherapy offers no survival advantage over conventional treatment approaches.
Neoadjuvant Chemotherapy
Preoperative or neoadjuvant chemotherapy is attractive, as it may reduce the amount of disease present and thereby facilitate in obtaining clean surgical margins when the disease is still confined to the breast. This is often the case in inflammatory breast cancer, or in N2 disease, in which neoadjuvant chemotherapy may improve surgical resectability. A significant response of 50% to 90% has been seen with this approach.
Down-staging of the tumor, as well as the axillary lymph nodes, has been reported.
The NSABP B-18 trial randomized patients with operable breast cancer to receive adjuvant chemotherapy preoperatively for four cycles followed by reevaluation for surgical treatment. Results for this group were compared with those for patients who received surgery followed by adjuvant chemotherapy. Preoperative chemotherapy was associated with a higher incidence of breast conservation. Also, a significant reduction in the number of positive axillary nodes was noted in the preoperative chemotherapy group. There was, however, no difference in overall survival between those patients who received preoperative chemotherapy and those who received postoperative chemotherapy. Several subsequent trials have reported a higher local recurrence rate for patients treated with neoadjuvant chemotherapy and breast-conservation therapy.
Radiation Therapy
Radiation therapy is used in conjunction with lumpectomy for patients opting for breast conservation. The dose used is 1.8 to 2.0 Gy per day for a total of 45 to 50 Gy to the entire breast. A 10- to 15-Gy electron-therapy boost is often given to the lumpectomy bed.
Postmastectomy chest-wall irradiation is used with increasing frequency. Patients with large tumors (T3 lesions) and more than four positive nodes are offered chest-wall radiation because they are at risk for local–regional failure. Chest-wall radiation is 50 Gy over 5 weeks, with a 10-Gy boost to the mastectomy scar. For patients with a chest-wall recurrence, the option of surgical debulking followed by chest-wall irradiation is employed.
Radiation therapy can also be used in the palliative setting. It can be used for metastatic lesions to the bone or brain and can help to alleviate the patient's symptoms.
Stage-Directed Therapy
Patients with intraductal carcinoma and stage I and stage II breast cancer have the options of breast-conservation therapy and mastectomy.
For patients with invasive breast cancer, the axillary nodes can be addressed with an SLN biopsy and, possibly, an axillary dissection.
In intraductal carcinoma, an SLN biopsy or axillary dissection is generally not indicated. There are special circumstances of intraductal carcinoma such as high-grade DCIS or extensive DCIS in which a microinvasive component may be associated with the intraductal carcinoma. In these circumstances, particularly if a mastectomy is being performed, an SLN biopsy may be considered.
For patients with more extensive disease, a mastectomy may be necessary. The use of postmastectomy chest-wall irradiation in these patients may also be considered.
Breast Reconstruction
Breast reconstruction represents a major advance in cancer rehabilitation for patients undergoing a mastectomy. Previously, a 2-year surveillance period was recommended prior to reconstruction for detection of local disease recurrence. Immediate reconstruction has not interfered with disease detection, however, and it has the advantage of combining the two procedures into one. In addition, a greater amount of skin can be saved with planned immediate reconstruction, and the scar tissue that would be encountered with delayed procedure can be avoided.
A delayed reconstruction can be performed if the patient is ambiguous about the reconstruction, or if operative risk is increased with prolonged anesthesia. It is also considered in those patients with locally advanced disease if a delay in adjuvant irradiation or chemotherapy is anticipated because of the reconstruction.
Reconstruction options include expandable breast prosthesis (implant) and autologous tissue transfer. Tissue-transfer operations may yield the greatest symmetry between breasts, especially with larger breasts; however, they take longer, require greater surgical expertise, involve a longer recovery, and result in another scar at the donor site. The donor site may be the latissimus dorsi, transverse rectus abdominus, or gluteal muscle.
SPECIAL ISSUES
Hereditary Breast Cancer
One of the most characteristic features of hereditary breast cancer is its tendency to manifest at a young age. In the Breast Cancer Consortium's study of BRCA1-linked families that transmit BRCA1 mutations, more than 80% of breast cancers occurred in women under 50 years of age.
Pathologic Features
Most BRCA1-associated breast cancers have been reported to be of an infiltrating ductal type with an over-representation of poorly differentiated high-grade types. The tumors tend to be ER/PR-negative. Less than 20% of these cancers are ER/PR-positive, even when age matched with non–BRCA1-associated controls. In BRCA2 there is less of this over-representation of aggressive histology. Overall, BRCA2-associated breast cancers tend to be ER/PR-positive.
Stage
Most studies demonstrate that BRCA-associated breast cancers are seen at a stage comparable to non–BRCA-associated breast cancers. The incidence of axillary metastasis does not appear to be significantly different in patients with BRCA-associated breast cancers. In the literature, conflicting study data exist regarding the prognosis of patients with BRCA-associated breast cancer. Some studies have conferred a worse prognosis in patients with certain mutations in BRCA1. Some of these reports have been of highly selected groups of women, and thus further study is necessary in larger series of women with BRCA1 and BRCA2 mutations.
Treatment
Although some researchers have questioned the role of breast-conservation therapy in women with hereditary predisposition, there is no reason to suspect a unique survival advantage for mastectomy in these women.
Studies that have examined the outcomes of breast-conservation therapy in women with BRCA mutations are small with variable follow-up. Local ipsilateral recurrence appears to be about 15% at 5 years. Although this is higher than would be expected for patients treated with breast-conservation therapy, it is within the range observed for treatment of young women with breast cancer. It is likely to be an influence of the age at diagnosis and not because of radiation resistance.
After breast-conservation therapy, however, the breast tissue remains at risk for developing a second primary. Women with BRCA mutations may be at risk for a late ipsilateral recurrence because of the development of a second primary breast cancer.
The degree of contralateral risk needs to also be addressed with patients. Some studies have reported an estimated average risk of 2.5% to 5% per year in BRCA1 mutation carriers, and this risk may be higher with younger age at diagnosis. In patients with BRCA2, the risk appears lower, estimated at 1.8% per year. Unlike the BRCA1-associated risk, in BRCA2 the age dependence is unknown.
Chemoprevention
Chemoprevention is the principle that cancer prevention can be achieved through pharmacologic intervention. It refers to the use of a medication in a healthy patient to reduce the risk of a particular cancer. It is an option for all women with significant risk for future breast cancer development. Currently, the only FDA-approved medication for prevention of breast cancer is tamoxifen. Tamoxifen is a selective estrogen-receptor modulator that acts as an antiestrogen in breast tissue. It has been used in the adjuvant setting in breast cancer since 1972 for both metastatic and early breast cancers. A reduction of 40% to 50% in contralateral breast cancer was seen in the adjuvant setting; thus, it was thought to be an ideal agent to use in a chemopreventive setting.
The trial to determine the role of tamoxifen in chemoprevention was performed by the NSABP. In this randomized, double-blinded trial, women with a projected risk of breast cancer of greater than 1.66% over a 5-year period received either tamoxifen or a placebo for a period of 5 years. The Gail model was used to assess the risk. When an independent reviewing agency verified a 50% reduction in both invasive and noninvasive breast cancer cases in the population taking tamoxifen, the trial results were unblinded earlier than expected. Shortly thereafter, the use of tamoxifen was approved for chemoprevention.
Two other chemoprevention trials using tamoxifen have been reported: the Italian tamoxifen-prevention study and the Royal Marsden Hospital tamoxifen trial in the United Kingdom. These two trials did not reveal a statistically significant reduction in breast cancer risk in women randomized to tamoxifen. However, the studies differed in respect to subject numbers, median age, eligibility criteria, risk, and use of HRT.
Raloxifene is also a selective estrogen-receptor modulator (SERM) and is FDA-approved for use in osteoporosis. In studies in which raloxifene was used for treatment of osteoporosis, a secondary finding was a noted reduction of breast cancer risk of 50% to 70% in the population taking the medication. The women in those trials were at fairly low risk of breast cancer development. A randomized, double-blinded trial to compare raloxifene with tamoxifen in a population of postmenopausal women at increased risk for breast cancer development is currently open, the Study of Tamoxifen and Raloxifene (STAR) trial/P-2 study. In the NASBP P-1 study there was an increased risk of developing endometrial cancer with tamoxifen use (annual risk 2.3/1,000 women vs. 0.9/1,000 women in the placebo group). All cases of endometrial cancer in the patients taking tamoxifen were early stage. Another important side effect noted was a higher incidence of thromboembolic phenomena. Raloxifene does not increase the risk of endometrial cancer and thus may prove to be an alternative to tamoxifen in a chemopreventive role. An ideal SERM would have an antiestrogenic activity on breast and uterine tissues, but estrogenic effects on bone and the cardiovascular system among others. Current investigations into other SERMs are being conducted.
CONCLUSIONS
Screening for breast cancer is clearly indicated for all women at the appropriate age. Determining a woman's unique risk factors will help to determine both the age at which that screening should begin and also the intensity of that screening. It will also help to identify those women who need to be counseled regarding options for prevention of breast cancer. The hope is that, by correctly identifying high-risk populations and then applying appropriate screening schedules and chemopreventive agents, many cases of breast cancers will be averted completely and that those that still occur will be found at the earliest stages. The role of the obstetrician and gynecologist in providing information on breast cancer diagnosis and screening is very important.
In addition, the understanding of breast disease, benign and malignant, is crucial not only in the diagnosis of disease, but also in helping to guide women in their treatment and follow-up.
SUGGESTED READINGS
Introduction
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Benign Breast Conditions
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Breast Cancer
Pathology, Biologic Markers and Prognostic Factors
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Treatment of Breast Cancer
Breast-conservation Therapy
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Sentinel Lymphnode Biopsy
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Special Issues
Hereditary Breast Cancer
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Chemoprevention
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