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PREVENTION AND TREATMENT OF BREAST CANCER
GYNECOLOGIC ONCOLOGY FOR THE GENERALIST
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PREVENTION AND TREATMENT OF BREAST CANCER James Fiorica, MD
Breast carcinoma is the most common cancer in women, with 183,000 new cases and 41,000 deaths expected in the United States in the year 2000. In the new millennium, the incidence of breast cancer is expected to rise owing to better screening techniques and improved patient education. The American College of Obstetricians and Gynecologists (ACOG) requires all obstetrics and gynecology residency training programs in the United States to provide formal education in diagnosing and treating early breast cancer. Breast disease encompasses benign and malignant processes. Breast cancer is so prevalent that diagnosing only a small additional number of early breast cancers could save hundreds of lives per year. This article describes the techniques for early detection and treatment of this highly prevalent disease. Primary care providers must be able to perform a breast examination satisfactorily, understand the diagnostic screening modalities, and know when to refer patients to specialists. HISTORY AND PHYSICAL EXAMINATION
The degree of thoroughness of the history and physical examination often determine survival for women ultimately diagnosed with palpable breast cancers. In most cases, the patient will discover the breast lump herself. The physician must gather historical information from the patient, including the duration of the lump, the presence or absence of pain, the relation to menses, and the dimpling, if any, of the skin on the From the Gynecologic Oncology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, Florida
OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA VOLUME 28 NUMBER 4 * DECEMBER 2001
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breast. Cystic disease in women is most often associated with pain, whereas the contrary is true for breast disease. In postmenopausal women who are not taking estrogen, the presence of persistent unilateral pain should cause more concern and a closer look. In the premenopausal patient, tenderness with thickening is in all likelihood fibrocystic changes rather than a malignancy. In most instances, skin dimpling signals carcinoma because the dimpling is usually a result of the shortening of Cooper ligaments. The history is concentrated on the risk factors for breast cancer. Attention should be focused on the duration and onset of signs and symptoms, menstrual and reproductive history, hormone use, and dietary habits. Other factors that increase the risk for breast cancer include older age, a previous history of breast cancer, nulliparity, delayed childbearing (greater than 30 years of age), early menarche (before age 12), late menopause (after age 53), a family history of breast cancer (firstdegree paternal or maternal relative), biopsy-proven ductal or lobular hyperplasia, particularly with atypia, higher socioeconomic status, and obesity. Age is the most significant risk factor. The risk of breast cancer increases with age. The practitioner must recognize that only 12% of breast cancer patients have an identifiable risk factor. In 88% of female patients, no risk factor can be pinpointed, indicating that all patients should be considered at risk, which will enhance the thoroughness of the examination and the history. The most recognized epidemiologic risk factors are breast cancer in a first-degree relative or cancer in the opposite breast. The incidence of breast malignancy in the contralateral breast is approximately 1% annually. If there is a family history of breast cancer, the risk is increased by two or three times and can be as high as nine times when there has been bilateral premenopausal breast cancer in the relatives. Another component of the evaluation is nipple discharge. Usually, cancerous discharges are unilateral, bloody, or spontaneous in nature. If the discharge is postmenopausal, special evaluation must be done. Pertinent questions to ask the patient would include previous injury, inappropriate lactation, and surgery on the breast where the discharge is present. The clinical breast examination should be performed with the patient in the sitting and supine positions. Lack of proper training is widespread, and most primary care providers are uncomfortable with their ability to detect breast lumps. The best time to perform a breast examination is immediately after menstruation and before ovulation. The breasts are inspected in the upright position, looking for retractions, nipple inversion, and dermatologic disorders. A red scaly eruption around the areola suggests Paget’s disease. The breast should be inspected with the patient’s hands down at her sides and with her hands elevated. In addition, she should tense her arms at her hips, contracting the pectoralis muscles, possibly revealing subtle contours or skin retractions. In the sitting position, attention is also directed to the clavicle and axilla. Digital palpation is performed beneath the pectoralis muscles
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within the axilla in an upright patient, which is the most effective way of palpating clinically abnormal lymph nodes. With the patient in the supine position, the breast examination is repeated, paying particular attention to the chest wall, axilla, and entire breast. The breast is digitally palpated, first superficially at the skin, then intermediately within the breast stroma and subcutaneous tissue, and finally against the chest wall (triple-touch technique). Particular attention must be focused on the nipple-areolar complex because 18% of breast cancers occur at this location. This point is also the ideal time to instruct patients about the importance of breast self-examination. The physician has the opportunity to individualize and reinforce the monthly examination to the patient. Compliance is significantly improved when the patient is instructed by a physician or other health care provider in this manner (Figs. 1 and 2). Documentation of the physical breast examination is of utmost importance. If no lesions are noted, these pertinent negative findings can be summarized as “no dominant masses, no retractions, no nipple discharge or lymphadenopathy were noted in the sitting and supine positions.” It is also useful to record the date of the last mammogram, pertinent risk factors, and whether hormones were prescribed. One third of all breast malpractice cases involve inadequate chart documentation. Because 75% of all successful malpractice lawsuits involve family medi-
Figure 1. Upright position breast examination.
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Figure 2. Supine position breast examination.
cine, internal medicine, and obstetrics and gynecology, documentation is critical. FIBROCYSTIC CHANGES
The most common type of lesion in the female breast, when one considers cystic mastitis, chronic cystic mastopathy, mammary dysplasia, Schimmelbusch's disease, and Reclus's disease, is fibrocystic breast disease. On examination, it is imperative that the practitioner use precise and descriptive terminology to indicate physical findings because the broad diagnosis of fibrocystic breast disease is so vague. Often, fibrocystic breast disease has been mistaken for a breast malignancy, and the College of American Pathologists has abandoned the term in favor of fibrocystic changes. At least 50% of women have fibrocystic changes. The most common symptom of this condition is pain, which is also called mastodynia. The pain is often bilateral and premenstrual. The lumpiness can be localized or generalized. Fibrocystic changes can be divided into three categories: nonproliferative and proliferative with or without atypia. Seventy percent of changes are nonproliferative and show no increased for breast cancer. The remaining percentage are proliferative, but only 4% of these changes demonstrate atypia. Unless proliferative changes with atypia are present, fibrocystic changes are not a risk factor for cancer. Women with fibrocystic changes should have a careful examination.
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dedicated equipment. There is a definite difference between the two methods. When a screening mammogram is ordered, the radiologist frequently batch reads the films at the end of the day, whereas in the diagnostic mammography, the radiologist addresses the problem at the time of the mammogram before sending the patient home. The American College of Radiology has developed the breast imaging reporting and data system (BI-RADS)to help standardize mammogram reports. There are six essential categories ranging from 0 to 5, with 0 representing incomplete findings and 5 representing findings highly suspicious for malignancy. Table 2 delineates the specific nomenclature and recommendations that correlate with each category. Removal of clinically occult lesions requires radiologic assistance. Image-guided biopsies can be accomplished by stereotactic mammography, ultrasound-guided, or needle localization biopsy. Table 3 describes the advantages and disadvantages of each method. Although stereotactic biopsies are appropriate in most instances, 20% of all patients still require needle-localized biopsies in the operating room (Figs. 3 and 4). Atypical ductal hyperplasia on a stereotactic core biopsy is an indication for obtaining additional tissue by a needle-localized biopsy to rule out a more serious process. With advancements in computer technology, digital image mammography is now possible. A picture can be thought of as a twodimensional grid defined by pixels. Once the image is created as pixels, it can be displayed digitally and recorded on a computer. This digital image can be adjusted to make darker areas lighter without altering the visibility of structures in the lighter portion of the image. Digital image computers can analyze the image, store the image, and transfer it electronically to other radiology centers. This digital image technology offers enormous advantages over analog images. Magnetic resonance imaging may have diagnostic value as well in the separation of benign from malignant lesions. MR images of the breast have already been shown to be valuable in evaluating silicon implants. A variety of techniques are now applied to evaluate for breast Table 2. BREAST IMAGING REPORTING AND DATA SYSTEM NOMENCLATURE AND CLINICAL RECOMMENDATIONS Category 0 1 2 3 4
5
Assessment
Incomplete Negative Benign Probably benign Suspicious Highly suggestive of malignancy
Recommendations
Additional imaging Routine screening Routine screening Follow-up for stability Consider biopsy Biopsy and appropriate action
Likelihood of Malignancy of Atypia
-
Rare 9%
54%
From Bomalaski JJ,Tabano M, Hooper L, et a1 Mammography. Curr Opin Obstet Gynecol 1315-20, 2001; modified with permission.
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Table 3. CHARACTERISTICSOF IMAGE-GUIDED PROCEDURES Procedure
Needle localization excision
Advantages
Can be performed for all mammographic lesions (nodules, calcifications, and so forth) Allows complete excision for histologic evaluation Specimen mammogram confirms presence of lesion intraoperatively Location of lesion not a concern Most radiologists trained in technique Stereotactic core Relatively noninvasive, requires needle biopsy small skin incision All types of mammographic visible lesions, including calcifications, amenable to biopsy Outpatient procedure Diagnosis of malignancy allows planning of single procedure definitive surgery Extensive suspicious calcifications can be sampled at multiple sites, confirming multifocal/multicentric disease before attempting wide excision Ultrasound-guided Fastest, technically simplest, core biopsy procedure Minimally invasive Low cost Easy to biopsy multiple lesions if necessary
Disadvantages
Performed in operating room, increased cost, time Surgical scar Larger volume of breast tissue removed Second surgical procedure usually required if malignancy diagnosed
Requires dedicated equipment Requires radiologic training and expertise Some lesions (close to skin or chest wall) not amenable to stereotactic biopsy Nondiagnostic, discordant, or ADH biopsy requires needle localization excision Positioning on stereotactic table (usually prone) sometimes a physical problem for patients (extreme obesity, chronic obstructive pulmonary disease, anxiety disorders, and so forth) Lesion must be visible on ultrasound Not well suited for calcifications
ADH = atypical ductal hyperplasia. From Fakenberry S S Surgical procedures in the diagnosis and treatment of breast cancer. Operative techniques in Gynecologic Surgery 5142,2000; with permission.
carcinoma. Nearly all invasive breast malignancies enhance with gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA). Research has demonstrated that dynamic MR imaging techniques enhance malignancies more rapidly than benign lesions owing to tumor angiogenesis present in breast cancer. Malignant lesions are known to recruit large concentrations of tumor neovessels to permit their continued growth beyond a few millimeters. This increased concentration of vessels at the cancer site seems to account for the rapid accumulation of the Gd-DTPA. This initial rapid enhancement may allow MR imaging to be highly valuable in the future in determining a cancerous versus noncancerous lesion radiologically.
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Mic
Figure 3. Needle-localizedbreast biopsy. (From Marchant D: The diagnostic evaluation. ln Marchant D (ed): Breast Disease. Philadelphia, PA, Saunders, 1997, p 159; with permission.)
EVALUATION OF THE BREAST MASS
A dominant mass is defined as a discrete three-dimensional sphere within the breast. This mass must be differentiated from fibrocystic thickening. Once a discrete mass is identified, cancer should be ruled out histologically. The first step is to measure the mass adjacent to the surrounding structures in the breast. The next step is to determine whether the lesion is solid or cystic. A simple cyst aspiration can be accomplished with a 23-gauge needle and a 10-mL syringe. Once the needle is passed through the skin, cyst fluid can be evacuated, and the cystic lesion should disappear completely. The nonbloody serious fluid can be discarded and the patient asked to return for reevaluation in 4 to 6 weeks. If the dominant mass is noncystic, a fine-needle aspiration (FNA) may be performed by using the same technique, sending the tissue for cytologic evaluation (Fig. 5 ) . The sensitivity and specificity of FNA are only 82% and 97%, respectively; therefore, one must not rely on a
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Figure 4. A, The breast is positioned beneath the table, and the lesion is identified and localized. B, The radiologist positions the needle into the breast, and histologic core biopsies are obtained.
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1
4
6
5
0
.n.
0
Figure 5. Fine-needle aspiration. The breast mass is stabilized with one hand while the needle is passed into the lesion. The needle is then passed back and forth through the mass while applying negative pressure. (From Hindle WM: The diagnostic evaluation. In Marchant D (ed): Breast Disease. Philadelphia, PA, Saunders, 1997, p 77; with permission.)
negative FNA. An open biopsy is required on all noncystic masses that are nondiagnostic by FNA. Mammography should be performed before an open biopsy to better delineate or define the lesion and possibly identify other lesions within the breast (Fig. 6). MANAGEMENT OF EARLY BREAST CARCINOMA
It is imperative that the physician or health care provider undertake the important task of counseling the patient when a mammogram or FNA shows the possible presence of cancer. Histologically, breast cancer is either infiltrating ductal or invasive lobular (Figs. 7 and 8). Infiltrating ductal cancer accounts for most cases (72%)and is often unilateral and discrete. Invasive lobular carcinoma occurs in 10% to 15% of cases, is bilateral in 20% of instances, and often presents as nonspecific parenchymal thickening on a mammogram or breast examination. The two noninvasive categories are ductal carcinoma in situ and lobular carcinoma in
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Incision indicated
i
-
\
Figure 6. Open biopsy. Once the dominant mass is isolated, an incision is made directly over the lesion. (From Marchant D: The diagnostic evaluation. In Marchant D (ed): Breast Disease. Philadelphia, PA, Saunders, 1997, p 156; with permission.)
Figure 7. Histologic appearance of infiltrating ductal carcinoma ( x 40).
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Figure 8. Histologic appearance of invasive lobular carcinoma. (x40)
situ. Ductal carcinoma in situ can be either focal or multicentric/diffuse. Lobular carcinoma in situ is believed to be a precursor marker for future ductal or lobular cancer. Breast cancer occurs in the upper outer quadrant 50% of the time, followed by infra-areolar area in 18% of cases, and the upper inner quadrant in 15% of cases. The American Joint Commission on Cancer uses the TNM classification (T = size of primary tumor; N = status of regional lymph nodes; M = presence or absence of distant metastasis) for staging. The stage depends on the combination of these factors as assessed by the practitioner, but, as a general rule, stage I cancers are 2 cm or smaller with no axillary or distant metastasis, stage I1 cancers are larger than 2 cm but smaller than or equal to 5 cm without metastasis, stage I11 cancers are tumors of any size with nodal involvement or chest wall extension, and stage IV cancers have distant metastasis. Once a histologic diagnosis of cancer is attained, the appropriate treatment is ideally accomplished by a multidisciplinary team incorporating a pathologist, surgeon, radiation oncologist, and medical oncologist. The tumor location, histologic subtype, grade, margin status, tumor distribution, and breast size are factors that must be considered when planning surgical treatment. A breast conservation procedure, including quadrantectomy or lumpectomy with axillary node dissection, or modified radical mastectomy are the most common treatments. A lumpectomy or quadrantectomy involves resection of the tumor with the overlying skin in the involved quadrant of the breast. The resection of the tumor is performed with removal of 1 to 2 cm of adjacent normal breast tissue. These procedures are coupled with an axillary lymph node
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dissection of the level I and I1 lymph nodes (Fig. 9). A modified radical mastectomy involves complete removal of the breast, pectoralis major fascia, and the level I and I1 axillary lymph nodes. It preserves the pectoralis muscles. Both surgical methods have identical cure rates as long as whole breast radiation therapy is administered after breast-preserving surgery; therefore, breast preservation is the preferred treatment modality in patients with early cancers and normal breast sizes. Age should not be considered a contraindication to breast conservation. When mastectomy is chosen, all patients should be offered breast reconstruction either at the time of surgery or at the completion of adjuvant therapy. The patient must ultimately make the decision because of the psychologic impact of the breast cancer process. Lymph node dissection has been used to evaluate for regional metastasis. A complete lymph node dissection is associated with morbidity, including numbness, lymphadema, weakness, and arm pain. The technique of intraoperative lymphatic mapping and sentinel lymph node identification may decrease this morbidity significantly yet still achieve important prognostic information regarding the lymph node status. This technique involves a peritumor injection of 450 uCi of filtered (0.2 km filter) technetium, sulphur colloid, and 5 mL of 1%blue dye. A handheld gamma detector is used intraoperatively to identify the primary sentinel lymph node, which can be immediately removed and evaluated
Figure 9. Axillary lymph node anatomy. Level I are in the lateral axilla, level II are beneath the pectoralis minor muscle, and level 111 are medial to the pectoralis major muscle. (From Falkenberry SS: Surgical procedures in the diagnosis and treatment of breast cancer. Operative Techniques in Gynecologic Surgery 3148, 2000; with permission.)
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for cancer. If this sentinel lymph node does not contain cancer, further dissection is not necessary. In a study of 167 patients at the author’s center, a false-negative rate of 2% was achieved. As of December 1999, more than 1500 women underwent lymphatic mapping at the same cancer facility, with a resultant success rate of 96% in locating the axillary sentinel lymph node. These preliminary data support the concept that sentinel lymph node biopsy may be a viable alternative to level I and level I1 axillary node dissection. Further investigations are underway. The skill and experience of the physician performing the lymphatic mapping have a direct impact on the accuracy of the results. There are two critical prognostic factors for breast cancer patients: (1) nodal involvement and (2) tumor size. If a patient has no nodal involvement, there is a 78% 5-year survival rate and a 65% 10-year survival rate, with an 82% 5-year, disease-free survival rate. In the event that nodes are involved, the survival decreases to a 5-year rate of 46% and a 10-year rate of 25%, with a 35% 5-year disease-free survival. Adjuvant therapy is recommended for all patients with nodal involvement. Adjuvant therapy includes chemotherapy, immunotherapy, tamoxifen, or ovarian ablation. In premenopausal patients, chemotherapy should be administered. In postmenopausal patients with nodal involvement who are positive for estrogen receptor, tamoxifen citrate is recommended. When the patient is estrogen receptor-negative and postmenopausal, patients should be offered chemotherapy as an option, and tamoxifen may be beneficial. Node-negative patients may benefit from adjuvant therapy as well. If the node-negative patient is at minimal or low risk, there is no need for additional treatment. If the risk is moderate, tamoxifen is recommended. For high-risk patients, the division is between premenopausal and postmenopausal disease. Premenopausal patients should receive chemotherapy regardless of the estrogen receptor status. Postmenopausal patients should receive chemotherapy for estrogen receptor-negative tumors only, with the possible addition of tamoxifen. Tamoxifen has been used for estrogen receptor-negative, node-negative, high-risk menopausal patients. Recurrence is reduced by 25% with the use of tamoxifen and mortality by 17% The US Food and Drug Administration (FDA) advisory committee emphasizes that the effects of long-term treatment with tamoxifen are unknown because follow-up data are limited to 5 years. Tamoxifen-treated patients have been shown statistically to have a lower incidence of contralateral breast cancer. These observations resulted in a large prospective breast cancer prevention trial involving 13,388 women. This placebo-controlled, double-blinded, randomized study showed a 49% risk reduction in the incidence of breast carcinoma in high-risk individuals. The high-risk population was composed of women with a 5-year predicted risk of breast cancer of at least 1.67%as calculated by the Gail statistical model. This model uses a combination of variables, including first-degree relatives with breast cancer, age at first delivery, the number of breast biopsies, age at menarche, and the
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history of atypical ductal hyperplasia. The FDA has approved tamoxifen for breast cancer prevention, contralateral breast cancer prevention, and use in the adjuvant setting. Patients should be informed of the adverse effects of tamoxifen use, including deep vein thrombosis, pulmonary emboli, cataracts, and endometrial cancer, along with the substantial benefit of breast cancer prevention. The association of tamoxifen and the development of endometrial cancer has been scrutinized over the past few years. In the National Surgical Adjuvant Breast and Bowel Project prevention trial, the risk ratio for developing endometrial cancer was 2.53 in the tamoxifen-treated women. Several approaches have been explored for screening asymptomatic women taking tamoxifen. Screening for endometrial cancer with routine transvaginal ultrasounds, endometrial biopsies, or both has not been effective. The ACOG Committee on Gynecologic Practice recommends that women taking tamoxifen be educated about the risks of endometrial cancer and symptoms. These women should have an annual gynecologic examination. Any abnormal vaginal bleeding, bloody vaginal discharge, or spotting should be investigated. G ENETlCS
An estimated 6% to 19% of all patients with breast cancer have a family history of breast carcinoma. Approximately 5% to 10% of this group may have a single, dominantly inherited gene mutation that confers a high risk for breast cancer. In the general population, 1 in 800 individuals carry a mutation. Mutations in the BRCAl and BRCA2 tumor suppressor genes account for the majority of these inherited breast cases. A woman who inherits a mutation has an estimated 50% to 80% lifetime risk of breast cancer. Hallmarks of hereditary breast cancer include premenopausal early-onset breast cancer; three or more relatives with breast, ovarian cancer, or both in the same lineage; and individuals with two early onset primary cancers or male breast cancers. These individuals should be referred to a clinical geneticist for evaluation and counseling. Individuals should be counseled before and after testing to ensure they understand the potential impact on themselves, other family members, and potential employers or health care companies. Currently, clinical management includes increased surveillance, prophylactic surgery, and chemoprevention. Genetic testing will undoubtedly have an important role in future health care. Individual care and decision making must be provided for individuals with mutations. Ideally, patients should be entered into a clinical trial so future information may be gathered. SUMMARY
In the new millennium, practitioners who provide primary care for women of all ages must be well educated in the diagnosis and treatment
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modalities for breast carcinoma. This disease strikes one of eight women. That statistic alone should encourage diligent and persistent efforts to detect this disease early enough to prevent the large number of deaths annually. Early detection will reduce the morbidity associated with breast cancer. Strong efforts are ongoing in the fields of genetics and breast cancer research to achieve earlier detection of breast cancer and a reduction in morbidity regardless of the stage of the breast carcinoma. As results of ongoing studies materialize and new studies are funded, it is hoped that more answers will emerge to combat the devastating effects of breast cancer. References 1. American Cancer Society: Cancer Facts and Figures-2000. Atlanta, American Cancer Society, 2000 2. American College of Obstetricians and Gynecologist (ACOG): Breast-ovarian cancer screening. ACOG Committee Opinion No. 247. Washington, DC, ACOG, 2000 3. American College of Obstetricians and Gynecologists (ACOG): Nonmalignant conditions of the breast. ACOG Technical Bulletin No. 156. Washington, DC, ACOG, 1991 4. American College of Obstetricians and Gynecologists (ACOG): Routine cancer screening. ACOG Committee Opinion No. 247. Washington, DC, ACOG, 2000 5. American College of Obstetricians and Gynecologists (ACOG): Tamoxifen and the prevention of breast cancer in high risk women. ACOG Committee Opinion No. 224. Washington, DC, ACOG, 1999 6. Berube M, Cupen B, Ugolini P, et d.Level of suspicion of a mammographic lesion: Use of features defined by BI-RAE lexicon and correlation with large core biopsy. Can Assoc Radio1 J 49:223-228, 1998 7. Bomalaski JJ, Tabano M, Hooper L, et al: Mammography. Curr Opin Obstet Gynecol 13:15-20, 2001 8. Consensus Statement: Treatment of early-stage breast cancer: National Institutes of Health Consensus Development Panel. J Natl Cancer Inst Monogr 11:l-5, 1992 9. DOrsi CJ (ed): The American College of Radiology Breast Imaging Reporting and Data System, ed 2. Reston, VA, American College of Radiology, 1995 10. Dolan JR, Wierda A Breast biopsy: Indications and techniques. Operative Techniques in Gynecologic Surgery 5:128-137, 2000 11. Ferlita TM, Sutphen R, Tabano M, et a 1 Introduction to hereditary breast and ovarian cancer. Operative Techniques in Gynecologic Surgery 5:183-189,2000 12. Fisher B, Costantino JP, Wickerman DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 901371-1388, 1998 13. Fleming ID, Cooper JS, Henson DE, et al: Manual for Staging of Cancer: American Joint Committee on Cancer. Philadelphia, Lippincott-Raven, 1997, pp 171-180 14. Fobben ES, Rubin CZ, Kalisher L, et al: Breast MRI techniques with commercially available techniques: Radiologic-pathologic correlation. Radiology 196:143-52, 1995 15. Greenblatt RB, Samaras C , Vasquez JM, et al: Fibrocystic disease of the breast. Clin Obstet Gynecol25370,1982 16. Henderson IC, Canellos Gl? Cancer of the breast The past decade. N Engl J Med 30217-30, 1980
Address reprint requests to James Fiorica, MD Gynecologic Oncology Program H. Lee Moffitt Cancer Center 12902 Magnolia Drive Tampa, FL 33612 e-mail: [email protected]
0889-8545/01 $15.00
+
.OO
PREVENTION AND TREATMENT OF BREAST CANCER James Fiorica, MD
Breast carcinoma is the most common cancer in women, with 183,000 new cases and 41,000 deaths expected in the United States in the year 2000. In the new millennium, the incidence of breast cancer is expected to rise owing to better screening techniques and improved patient education. The American College of Obstetricians and Gynecologists (ACOG) requires all obstetrics and gynecology residency training programs in the United States to provide formal education in diagnosing and treating early breast cancer. Breast disease encompasses benign and malignant processes. Breast cancer is so prevalent that diagnosing only a small additional number of early breast cancers could save hundreds of lives per year. This article describes the techniques for early detection and treatment of this highly prevalent disease. Primary care providers must be able to perform a breast examination satisfactorily, understand the diagnostic screening modalities, and know when to refer patients to specialists. HISTORY AND PHYSICAL EXAMINATION
The degree of thoroughness of the history and physical examination often determine survival for women ultimately diagnosed with palpable breast cancers. In most cases, the patient will discover the breast lump herself. The physician must gather historical information from the patient, including the duration of the lump, the presence or absence of pain, the relation to menses, and the dimpling, if any, of the skin on the From the Gynecologic Oncology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, Florida
OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA VOLUME 28 NUMBER 4 * DECEMBER 2001
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breast. Cystic disease in women is most often associated with pain, whereas the contrary is true for breast disease. In postmenopausal women who are not taking estrogen, the presence of persistent unilateral pain should cause more concern and a closer look. In the premenopausal patient, tenderness with thickening is in all likelihood fibrocystic changes rather than a malignancy. In most instances, skin dimpling signals carcinoma because the dimpling is usually a result of the shortening of Cooper ligaments. The history is concentrated on the risk factors for breast cancer. Attention should be focused on the duration and onset of signs and symptoms, menstrual and reproductive history, hormone use, and dietary habits. Other factors that increase the risk for breast cancer include older age, a previous history of breast cancer, nulliparity, delayed childbearing (greater than 30 years of age), early menarche (before age 12), late menopause (after age 53), a family history of breast cancer (firstdegree paternal or maternal relative), biopsy-proven ductal or lobular hyperplasia, particularly with atypia, higher socioeconomic status, and obesity. Age is the most significant risk factor. The risk of breast cancer increases with age. The practitioner must recognize that only 12% of breast cancer patients have an identifiable risk factor. In 88% of female patients, no risk factor can be pinpointed, indicating that all patients should be considered at risk, which will enhance the thoroughness of the examination and the history. The most recognized epidemiologic risk factors are breast cancer in a first-degree relative or cancer in the opposite breast. The incidence of breast malignancy in the contralateral breast is approximately 1% annually. If there is a family history of breast cancer, the risk is increased by two or three times and can be as high as nine times when there has been bilateral premenopausal breast cancer in the relatives. Another component of the evaluation is nipple discharge. Usually, cancerous discharges are unilateral, bloody, or spontaneous in nature. If the discharge is postmenopausal, special evaluation must be done. Pertinent questions to ask the patient would include previous injury, inappropriate lactation, and surgery on the breast where the discharge is present. The clinical breast examination should be performed with the patient in the sitting and supine positions. Lack of proper training is widespread, and most primary care providers are uncomfortable with their ability to detect breast lumps. The best time to perform a breast examination is immediately after menstruation and before ovulation. The breasts are inspected in the upright position, looking for retractions, nipple inversion, and dermatologic disorders. A red scaly eruption around the areola suggests Paget’s disease. The breast should be inspected with the patient’s hands down at her sides and with her hands elevated. In addition, she should tense her arms at her hips, contracting the pectoralis muscles, possibly revealing subtle contours or skin retractions. In the sitting position, attention is also directed to the clavicle and axilla. Digital palpation is performed beneath the pectoralis muscles
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within the axilla in an upright patient, which is the most effective way of palpating clinically abnormal lymph nodes. With the patient in the supine position, the breast examination is repeated, paying particular attention to the chest wall, axilla, and entire breast. The breast is digitally palpated, first superficially at the skin, then intermediately within the breast stroma and subcutaneous tissue, and finally against the chest wall (triple-touch technique). Particular attention must be focused on the nipple-areolar complex because 18% of breast cancers occur at this location. This point is also the ideal time to instruct patients about the importance of breast self-examination. The physician has the opportunity to individualize and reinforce the monthly examination to the patient. Compliance is significantly improved when the patient is instructed by a physician or other health care provider in this manner (Figs. 1 and 2). Documentation of the physical breast examination is of utmost importance. If no lesions are noted, these pertinent negative findings can be summarized as “no dominant masses, no retractions, no nipple discharge or lymphadenopathy were noted in the sitting and supine positions.” It is also useful to record the date of the last mammogram, pertinent risk factors, and whether hormones were prescribed. One third of all breast malpractice cases involve inadequate chart documentation. Because 75% of all successful malpractice lawsuits involve family medi-
Figure 1. Upright position breast examination.
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Figure 2. Supine position breast examination.
cine, internal medicine, and obstetrics and gynecology, documentation is critical. FIBROCYSTIC CHANGES
The most common type of lesion in the female breast, when one considers cystic mastitis, chronic cystic mastopathy, mammary dysplasia, Schimmelbusch's disease, and Reclus's disease, is fibrocystic breast disease. On examination, it is imperative that the practitioner use precise and descriptive terminology to indicate physical findings because the broad diagnosis of fibrocystic breast disease is so vague. Often, fibrocystic breast disease has been mistaken for a breast malignancy, and the College of American Pathologists has abandoned the term in favor of fibrocystic changes. At least 50% of women have fibrocystic changes. The most common symptom of this condition is pain, which is also called mastodynia. The pain is often bilateral and premenstrual. The lumpiness can be localized or generalized. Fibrocystic changes can be divided into three categories: nonproliferative and proliferative with or without atypia. Seventy percent of changes are nonproliferative and show no increased for breast cancer. The remaining percentage are proliferative, but only 4% of these changes demonstrate atypia. Unless proliferative changes with atypia are present, fibrocystic changes are not a risk factor for cancer. Women with fibrocystic changes should have a careful examination.
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dedicated equipment. There is a definite difference between the two methods. When a screening mammogram is ordered, the radiologist frequently batch reads the films at the end of the day, whereas in the diagnostic mammography, the radiologist addresses the problem at the time of the mammogram before sending the patient home. The American College of Radiology has developed the breast imaging reporting and data system (BI-RADS)to help standardize mammogram reports. There are six essential categories ranging from 0 to 5, with 0 representing incomplete findings and 5 representing findings highly suspicious for malignancy. Table 2 delineates the specific nomenclature and recommendations that correlate with each category. Removal of clinically occult lesions requires radiologic assistance. Image-guided biopsies can be accomplished by stereotactic mammography, ultrasound-guided, or needle localization biopsy. Table 3 describes the advantages and disadvantages of each method. Although stereotactic biopsies are appropriate in most instances, 20% of all patients still require needle-localized biopsies in the operating room (Figs. 3 and 4). Atypical ductal hyperplasia on a stereotactic core biopsy is an indication for obtaining additional tissue by a needle-localized biopsy to rule out a more serious process. With advancements in computer technology, digital image mammography is now possible. A picture can be thought of as a twodimensional grid defined by pixels. Once the image is created as pixels, it can be displayed digitally and recorded on a computer. This digital image can be adjusted to make darker areas lighter without altering the visibility of structures in the lighter portion of the image. Digital image computers can analyze the image, store the image, and transfer it electronically to other radiology centers. This digital image technology offers enormous advantages over analog images. Magnetic resonance imaging may have diagnostic value as well in the separation of benign from malignant lesions. MR images of the breast have already been shown to be valuable in evaluating silicon implants. A variety of techniques are now applied to evaluate for breast Table 2. BREAST IMAGING REPORTING AND DATA SYSTEM NOMENCLATURE AND CLINICAL RECOMMENDATIONS Category 0 1 2 3 4
5
Assessment
Incomplete Negative Benign Probably benign Suspicious Highly suggestive of malignancy
Recommendations
Additional imaging Routine screening Routine screening Follow-up for stability Consider biopsy Biopsy and appropriate action
Likelihood of Malignancy of Atypia
-
Rare 9%
54%
From Bomalaski JJ,Tabano M, Hooper L, et a1 Mammography. Curr Opin Obstet Gynecol 1315-20, 2001; modified with permission.
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Table 3. CHARACTERISTICSOF IMAGE-GUIDED PROCEDURES Procedure
Needle localization excision
Advantages
Can be performed for all mammographic lesions (nodules, calcifications, and so forth) Allows complete excision for histologic evaluation Specimen mammogram confirms presence of lesion intraoperatively Location of lesion not a concern Most radiologists trained in technique Stereotactic core Relatively noninvasive, requires needle biopsy small skin incision All types of mammographic visible lesions, including calcifications, amenable to biopsy Outpatient procedure Diagnosis of malignancy allows planning of single procedure definitive surgery Extensive suspicious calcifications can be sampled at multiple sites, confirming multifocal/multicentric disease before attempting wide excision Ultrasound-guided Fastest, technically simplest, core biopsy procedure Minimally invasive Low cost Easy to biopsy multiple lesions if necessary
Disadvantages
Performed in operating room, increased cost, time Surgical scar Larger volume of breast tissue removed Second surgical procedure usually required if malignancy diagnosed
Requires dedicated equipment Requires radiologic training and expertise Some lesions (close to skin or chest wall) not amenable to stereotactic biopsy Nondiagnostic, discordant, or ADH biopsy requires needle localization excision Positioning on stereotactic table (usually prone) sometimes a physical problem for patients (extreme obesity, chronic obstructive pulmonary disease, anxiety disorders, and so forth) Lesion must be visible on ultrasound Not well suited for calcifications
ADH = atypical ductal hyperplasia. From Fakenberry S S Surgical procedures in the diagnosis and treatment of breast cancer. Operative techniques in Gynecologic Surgery 5142,2000; with permission.
carcinoma. Nearly all invasive breast malignancies enhance with gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA). Research has demonstrated that dynamic MR imaging techniques enhance malignancies more rapidly than benign lesions owing to tumor angiogenesis present in breast cancer. Malignant lesions are known to recruit large concentrations of tumor neovessels to permit their continued growth beyond a few millimeters. This increased concentration of vessels at the cancer site seems to account for the rapid accumulation of the Gd-DTPA. This initial rapid enhancement may allow MR imaging to be highly valuable in the future in determining a cancerous versus noncancerous lesion radiologically.
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Mic
Figure 3. Needle-localizedbreast biopsy. (From Marchant D: The diagnostic evaluation. ln Marchant D (ed): Breast Disease. Philadelphia, PA, Saunders, 1997, p 159; with permission.)
EVALUATION OF THE BREAST MASS
A dominant mass is defined as a discrete three-dimensional sphere within the breast. This mass must be differentiated from fibrocystic thickening. Once a discrete mass is identified, cancer should be ruled out histologically. The first step is to measure the mass adjacent to the surrounding structures in the breast. The next step is to determine whether the lesion is solid or cystic. A simple cyst aspiration can be accomplished with a 23-gauge needle and a 10-mL syringe. Once the needle is passed through the skin, cyst fluid can be evacuated, and the cystic lesion should disappear completely. The nonbloody serious fluid can be discarded and the patient asked to return for reevaluation in 4 to 6 weeks. If the dominant mass is noncystic, a fine-needle aspiration (FNA) may be performed by using the same technique, sending the tissue for cytologic evaluation (Fig. 5 ) . The sensitivity and specificity of FNA are only 82% and 97%, respectively; therefore, one must not rely on a
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Figure 4. A, The breast is positioned beneath the table, and the lesion is identified and localized. B, The radiologist positions the needle into the breast, and histologic core biopsies are obtained.
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1
4
6
5
0
.n.
0
Figure 5. Fine-needle aspiration. The breast mass is stabilized with one hand while the needle is passed into the lesion. The needle is then passed back and forth through the mass while applying negative pressure. (From Hindle WM: The diagnostic evaluation. In Marchant D (ed): Breast Disease. Philadelphia, PA, Saunders, 1997, p 77; with permission.)
negative FNA. An open biopsy is required on all noncystic masses that are nondiagnostic by FNA. Mammography should be performed before an open biopsy to better delineate or define the lesion and possibly identify other lesions within the breast (Fig. 6). MANAGEMENT OF EARLY BREAST CARCINOMA
It is imperative that the physician or health care provider undertake the important task of counseling the patient when a mammogram or FNA shows the possible presence of cancer. Histologically, breast cancer is either infiltrating ductal or invasive lobular (Figs. 7 and 8). Infiltrating ductal cancer accounts for most cases (72%)and is often unilateral and discrete. Invasive lobular carcinoma occurs in 10% to 15% of cases, is bilateral in 20% of instances, and often presents as nonspecific parenchymal thickening on a mammogram or breast examination. The two noninvasive categories are ductal carcinoma in situ and lobular carcinoma in
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Incision indicated
i
-
\
Figure 6. Open biopsy. Once the dominant mass is isolated, an incision is made directly over the lesion. (From Marchant D: The diagnostic evaluation. In Marchant D (ed): Breast Disease. Philadelphia, PA, Saunders, 1997, p 156; with permission.)
Figure 7. Histologic appearance of infiltrating ductal carcinoma ( x 40).
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Figure 8. Histologic appearance of invasive lobular carcinoma. (x40)
situ. Ductal carcinoma in situ can be either focal or multicentric/diffuse. Lobular carcinoma in situ is believed to be a precursor marker for future ductal or lobular cancer. Breast cancer occurs in the upper outer quadrant 50% of the time, followed by infra-areolar area in 18% of cases, and the upper inner quadrant in 15% of cases. The American Joint Commission on Cancer uses the TNM classification (T = size of primary tumor; N = status of regional lymph nodes; M = presence or absence of distant metastasis) for staging. The stage depends on the combination of these factors as assessed by the practitioner, but, as a general rule, stage I cancers are 2 cm or smaller with no axillary or distant metastasis, stage I1 cancers are larger than 2 cm but smaller than or equal to 5 cm without metastasis, stage I11 cancers are tumors of any size with nodal involvement or chest wall extension, and stage IV cancers have distant metastasis. Once a histologic diagnosis of cancer is attained, the appropriate treatment is ideally accomplished by a multidisciplinary team incorporating a pathologist, surgeon, radiation oncologist, and medical oncologist. The tumor location, histologic subtype, grade, margin status, tumor distribution, and breast size are factors that must be considered when planning surgical treatment. A breast conservation procedure, including quadrantectomy or lumpectomy with axillary node dissection, or modified radical mastectomy are the most common treatments. A lumpectomy or quadrantectomy involves resection of the tumor with the overlying skin in the involved quadrant of the breast. The resection of the tumor is performed with removal of 1 to 2 cm of adjacent normal breast tissue. These procedures are coupled with an axillary lymph node
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dissection of the level I and I1 lymph nodes (Fig. 9). A modified radical mastectomy involves complete removal of the breast, pectoralis major fascia, and the level I and I1 axillary lymph nodes. It preserves the pectoralis muscles. Both surgical methods have identical cure rates as long as whole breast radiation therapy is administered after breast-preserving surgery; therefore, breast preservation is the preferred treatment modality in patients with early cancers and normal breast sizes. Age should not be considered a contraindication to breast conservation. When mastectomy is chosen, all patients should be offered breast reconstruction either at the time of surgery or at the completion of adjuvant therapy. The patient must ultimately make the decision because of the psychologic impact of the breast cancer process. Lymph node dissection has been used to evaluate for regional metastasis. A complete lymph node dissection is associated with morbidity, including numbness, lymphadema, weakness, and arm pain. The technique of intraoperative lymphatic mapping and sentinel lymph node identification may decrease this morbidity significantly yet still achieve important prognostic information regarding the lymph node status. This technique involves a peritumor injection of 450 uCi of filtered (0.2 km filter) technetium, sulphur colloid, and 5 mL of 1%blue dye. A handheld gamma detector is used intraoperatively to identify the primary sentinel lymph node, which can be immediately removed and evaluated
Figure 9. Axillary lymph node anatomy. Level I are in the lateral axilla, level II are beneath the pectoralis minor muscle, and level 111 are medial to the pectoralis major muscle. (From Falkenberry SS: Surgical procedures in the diagnosis and treatment of breast cancer. Operative Techniques in Gynecologic Surgery 3148, 2000; with permission.)
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for cancer. If this sentinel lymph node does not contain cancer, further dissection is not necessary. In a study of 167 patients at the author’s center, a false-negative rate of 2% was achieved. As of December 1999, more than 1500 women underwent lymphatic mapping at the same cancer facility, with a resultant success rate of 96% in locating the axillary sentinel lymph node. These preliminary data support the concept that sentinel lymph node biopsy may be a viable alternative to level I and level I1 axillary node dissection. Further investigations are underway. The skill and experience of the physician performing the lymphatic mapping have a direct impact on the accuracy of the results. There are two critical prognostic factors for breast cancer patients: (1) nodal involvement and (2) tumor size. If a patient has no nodal involvement, there is a 78% 5-year survival rate and a 65% 10-year survival rate, with an 82% 5-year, disease-free survival rate. In the event that nodes are involved, the survival decreases to a 5-year rate of 46% and a 10-year rate of 25%, with a 35% 5-year disease-free survival. Adjuvant therapy is recommended for all patients with nodal involvement. Adjuvant therapy includes chemotherapy, immunotherapy, tamoxifen, or ovarian ablation. In premenopausal patients, chemotherapy should be administered. In postmenopausal patients with nodal involvement who are positive for estrogen receptor, tamoxifen citrate is recommended. When the patient is estrogen receptor-negative and postmenopausal, patients should be offered chemotherapy as an option, and tamoxifen may be beneficial. Node-negative patients may benefit from adjuvant therapy as well. If the node-negative patient is at minimal or low risk, there is no need for additional treatment. If the risk is moderate, tamoxifen is recommended. For high-risk patients, the division is between premenopausal and postmenopausal disease. Premenopausal patients should receive chemotherapy regardless of the estrogen receptor status. Postmenopausal patients should receive chemotherapy for estrogen receptor-negative tumors only, with the possible addition of tamoxifen. Tamoxifen has been used for estrogen receptor-negative, node-negative, high-risk menopausal patients. Recurrence is reduced by 25% with the use of tamoxifen and mortality by 17% The US Food and Drug Administration (FDA) advisory committee emphasizes that the effects of long-term treatment with tamoxifen are unknown because follow-up data are limited to 5 years. Tamoxifen-treated patients have been shown statistically to have a lower incidence of contralateral breast cancer. These observations resulted in a large prospective breast cancer prevention trial involving 13,388 women. This placebo-controlled, double-blinded, randomized study showed a 49% risk reduction in the incidence of breast carcinoma in high-risk individuals. The high-risk population was composed of women with a 5-year predicted risk of breast cancer of at least 1.67%as calculated by the Gail statistical model. This model uses a combination of variables, including first-degree relatives with breast cancer, age at first delivery, the number of breast biopsies, age at menarche, and the
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history of atypical ductal hyperplasia. The FDA has approved tamoxifen for breast cancer prevention, contralateral breast cancer prevention, and use in the adjuvant setting. Patients should be informed of the adverse effects of tamoxifen use, including deep vein thrombosis, pulmonary emboli, cataracts, and endometrial cancer, along with the substantial benefit of breast cancer prevention. The association of tamoxifen and the development of endometrial cancer has been scrutinized over the past few years. In the National Surgical Adjuvant Breast and Bowel Project prevention trial, the risk ratio for developing endometrial cancer was 2.53 in the tamoxifen-treated women. Several approaches have been explored for screening asymptomatic women taking tamoxifen. Screening for endometrial cancer with routine transvaginal ultrasounds, endometrial biopsies, or both has not been effective. The ACOG Committee on Gynecologic Practice recommends that women taking tamoxifen be educated about the risks of endometrial cancer and symptoms. These women should have an annual gynecologic examination. Any abnormal vaginal bleeding, bloody vaginal discharge, or spotting should be investigated. G ENETlCS
An estimated 6% to 19% of all patients with breast cancer have a family history of breast carcinoma. Approximately 5% to 10% of this group may have a single, dominantly inherited gene mutation that confers a high risk for breast cancer. In the general population, 1 in 800 individuals carry a mutation. Mutations in the BRCAl and BRCA2 tumor suppressor genes account for the majority of these inherited breast cases. A woman who inherits a mutation has an estimated 50% to 80% lifetime risk of breast cancer. Hallmarks of hereditary breast cancer include premenopausal early-onset breast cancer; three or more relatives with breast, ovarian cancer, or both in the same lineage; and individuals with two early onset primary cancers or male breast cancers. These individuals should be referred to a clinical geneticist for evaluation and counseling. Individuals should be counseled before and after testing to ensure they understand the potential impact on themselves, other family members, and potential employers or health care companies. Currently, clinical management includes increased surveillance, prophylactic surgery, and chemoprevention. Genetic testing will undoubtedly have an important role in future health care. Individual care and decision making must be provided for individuals with mutations. Ideally, patients should be entered into a clinical trial so future information may be gathered. SUMMARY
In the new millennium, practitioners who provide primary care for women of all ages must be well educated in the diagnosis and treatment
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modalities for breast carcinoma. This disease strikes one of eight women. That statistic alone should encourage diligent and persistent efforts to detect this disease early enough to prevent the large number of deaths annually. Early detection will reduce the morbidity associated with breast cancer. Strong efforts are ongoing in the fields of genetics and breast cancer research to achieve earlier detection of breast cancer and a reduction in morbidity regardless of the stage of the breast carcinoma. As results of ongoing studies materialize and new studies are funded, it is hoped that more answers will emerge to combat the devastating effects of breast cancer. References 1. American Cancer Society: Cancer Facts and Figures-2000. Atlanta, American Cancer Society, 2000 2. American College of Obstetricians and Gynecologist (ACOG): Breast-ovarian cancer screening. ACOG Committee Opinion No. 247. Washington, DC, ACOG, 2000 3. American College of Obstetricians and Gynecologists (ACOG): Nonmalignant conditions of the breast. ACOG Technical Bulletin No. 156. Washington, DC, ACOG, 1991 4. American College of Obstetricians and Gynecologists (ACOG): Routine cancer screening. ACOG Committee Opinion No. 247. Washington, DC, ACOG, 2000 5. American College of Obstetricians and Gynecologists (ACOG): Tamoxifen and the prevention of breast cancer in high risk women. ACOG Committee Opinion No. 224. Washington, DC, ACOG, 1999 6. Berube M, Cupen B, Ugolini P, et d.Level of suspicion of a mammographic lesion: Use of features defined by BI-RAE lexicon and correlation with large core biopsy. Can Assoc Radio1 J 49:223-228, 1998 7. Bomalaski JJ, Tabano M, Hooper L, et al: Mammography. Curr Opin Obstet Gynecol 13:15-20, 2001 8. Consensus Statement: Treatment of early-stage breast cancer: National Institutes of Health Consensus Development Panel. J Natl Cancer Inst Monogr 11:l-5, 1992 9. DOrsi CJ (ed): The American College of Radiology Breast Imaging Reporting and Data System, ed 2. Reston, VA, American College of Radiology, 1995 10. Dolan JR, Wierda A Breast biopsy: Indications and techniques. Operative Techniques in Gynecologic Surgery 5:128-137, 2000 11. Ferlita TM, Sutphen R, Tabano M, et a 1 Introduction to hereditary breast and ovarian cancer. Operative Techniques in Gynecologic Surgery 5:183-189,2000 12. Fisher B, Costantino JP, Wickerman DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 901371-1388, 1998 13. Fleming ID, Cooper JS, Henson DE, et al: Manual for Staging of Cancer: American Joint Committee on Cancer. Philadelphia, Lippincott-Raven, 1997, pp 171-180 14. Fobben ES, Rubin CZ, Kalisher L, et al: Breast MRI techniques with commercially available techniques: Radiologic-pathologic correlation. Radiology 196:143-52, 1995 15. Greenblatt RB, Samaras C , Vasquez JM, et al: Fibrocystic disease of the breast. Clin Obstet Gynecol25370,1982 16. Henderson IC, Canellos Gl? Cancer of the breast The past decade. N Engl J Med 30217-30, 1980
Address reprint requests to James Fiorica, MD Gynecologic Oncology Program H. Lee Moffitt Cancer Center 12902 Magnolia Drive Tampa, FL 33612 e-mail: [email protected]