Ultrasonography is performed chiefly to differentiate cystic from solid lesions and is not diagnostic of malignancy. Ultrasonography may show an irregular mass within a cyst in the rare case of intracystic carcinoma. If a tumor is palpable and clinically feels like a cyst, an 18-gauge needle can be used to aspirate the fluid and make the diagnosis of cyst. If a cyst is aspirated and the fluid is nonbloody, it does not have to be examined cytologically. If the mass does not recur, no further diagnostic test is necessary. Nonpalpable mammographic densities that appear benign should be investigated with ultrasound to determine whether the lesion is cystic or solid.
When a suspicious abnormality is identified by mammography alone and cannot be palpated by the clinician, the patient should undergo mammographic localization biopsy. This is performed by obtaining a mammogram in two perpendicular views and placing a needle or hook-wire near the abnormality so that the surgeon can use the metal needle or wire as a guide during operation to locate the lesion. After mammography confirms the position of the needle in relation to the lesion, an incision is made and the subcutaneous tissue is dissected until the needle is identified. Using the films as a guide, the abnormality can then be localized and excised. It often happens that the abnormality cannot even be palpated through the incision—this is the case with microcalcifications—and it is thus essential to obtain a mammogram of the specimen to document that the lesion was excised. At that time, a second marker needle can further localize the lesion for the pathologist.
Computerized stereotactic imaging can localize abnormalities and guide needle biopsy without surgery. Under mammographic guidance, a biopsy needle can be inserted into the lesion in the mammographer's suite, and a core of tissue for histologic examination or cells for cytology can be examined. Stereotactic core needle biopsies are as accurate as mammographic localization biopsies and are preferable to mammographic localization and surgical resection for accessible lesions.
Incidence & Risk Factors
The breast is the most common site of cancer in women, and cancer of the breast is second only to lung cancer as a cause of death from cancer among women. The probability of developing breast cancer increases throughout life. The mean and the median age of women with breast cancer is between 60 and 61 years.
There will be about 182,000 new cases of breast cancer and about 42,000 deaths from this disease in women in the USA in 2000. At the present rate of incidence, the American Cancer Society predicts that one of every eight or nine American women will develop breast cancer during her lifetime. Women whose mothers or sisters had breast cancer are more likely to develop the disease than others. Risk is increased in patients whose mothers' or sisters' breast cancers occurred before menopause or was bilateral and in those with a family history of breast cancer in two or more first-degree relatives. However, there is no history of breast cancer among female relatives in over 90% of breast cancer patients. Nulliparous women and women whose first full-term pregnancy was after age 35 have a slightly higher incidence of breast cancer than multiparous women. Late menarche and artificial menopause are associated with a lower incidence of breast cancer, whereas early menarche (under age 12) and late natural menopause (after age 50) are associated with a slight increase in risk of developing breast cancer. Mammary dysplasia (fibrocystic disease of the breast), when accompanied by proliferative changes, papillomatosis, or atypical epithelial hyperplasia, is associated with an increased incidence of cancer. A woman who has had cancer in one breast is at increased risk of developing cancer in the other breast. Women with cancer of the uterine corpus have a breast cancer risk significantly higher than that of the general population, and women with breast cancer have a comparably increased endometrial cancer risk. In the USA, breast cancer is more common in whites than in nonwhites. The incidence of the disease among nonwhites (mostly blacks), however, is increasing, especially in younger women. In general, rates reported from developing countries are low, whereas rates are high in developed countries, with the notable exception of Japan. Some of the variability may be due to underreporting in the developing countries, but a real difference probably exists. Dietary factors, particularly increased fat content, may account for some differences in incidence. Oral contraceptives do not appear to increase the risk of breast cancer. There is some evidence that administration of estrogens to postmenopausal women may result in a slightly increased risk of breast cancer, but only with higher, long-term doses of estrogens. Other studies suggest that women with a family history of breast cancer who take postmenopausal estrogens or those who take estradiol or unconjugated estrogens do slightly increase their risk of breast cancer. Alcohol consumption may increase the risk of breast cancer slightly.
Women who are at greater than normal risk of developing breast cancer (Table 18-1) should be identified by their physicians, taught the techniques of breast self-examination, and followed carefully. Screening programs involving periodic physical examination and mammography of asymptomatic high-risk women increase the detection rate of breast cancer and improve the survival rate by as much as 30%. Unfortunately, most women who develop breast cancer do not have significant identifiable risk factors, and analysis of epidemiologic data has failed to identify women who are not at significant risk and would not benefit from screening. Therefore, virtually all women over about age 35 are at sufficient risk of breast cancer so that they could benefit from screening. The cost-benefit ratio of screening programs to society as a whole is unclear. Less expensive screening techniques such as single-view mammography and the use of mobile vans are being investigated in an attempt to reduce the cost of widespread screenings. Recently, the National Surgical Adjuvant Breast Project (NSABP) compared tamoxifen with placebo for patients who show no evidence of breast cancer but who are at high risk for its occurrence. Women who received tamoxifen for 5 years had about a 50% reduction in noninvasive and invasive cancers compared with women taking placebo. However, women above the age of 50 who received the drug had an increased incidence of endometrial cancer and deep venous thrombosis. Unfortunately, no survival data will be produced from this trial. The estrogen replacement raloxifene, effective in preventing osteoporosis, may also prevent breast cancer. Several large studies to examine this hypothesis are under way.
Early Detection of Breast Cancer
Screening Programs
A number of mass screening programs consisting of physical and mammographic examination of the breasts of asymptomatic women have been conducted. Such programs frequently identify more than six asymptomatic cancers per 1000 women. About 80% of these women have negative axillary lymph nodes at the time of surgery, whereas only about 50% of patients found in the course of usual medical practice have uninvolved axillary nodes. Detecting breast cancer before it has spread to the axillary nodes greatly increases the chance of survival, and about 85% of such women will survive at least 5 years.
Both physical examination and mammography are necessary for maximum yield in screening programs, since about 35–50% of early breast cancers can be discovered only by mammography and another 40% can be detected only by palpation. About one-third of the abnormalities detected on screening mammograms will be found to be malignant when biopsy is performed. Women 20–40 years of age should have a breast examination as part of routine medical care every 2–3 years. Women over age 40 should have yearly breast examinations. The sensitivity of mammography varies from approximately 60% to 90%. This sensitivity depends on several factors, including patient age (breast density), tumor size, location, and mammographic appearance. In young women with dense breasts, mammography is less sensitive than in older woman with fatty breasts, in whom mammography can detect nearly 90% of malignancies. Smaller tumors, particularly those without calcifications, are more difficult to detect, especially in dense breasts. The lack of sensitivity in young women is leading to questions concerning the value of mammography for screening in women 40–50 years of age. The specificity of mammography varies from about 30% to 40% for nonpalpable mammographic abnormalities to 85% to 90% for clinically evident malignancies.
In February 1993, the National Cancer Institute held an international workshop on screening for breast cancer. The purpose was to review recent clinical screening trials. The conference examined only randomized studies and focused on clinical evidence related to the efficacy of breast cancer screening in various age groups. Of eight randomized trials considered, only the Health Insurance Plan Project (HIP) demonstrated a benefit of screening in women between 40 and 49 years of age. This was seen between 10 and 18 years after entry into the study and resulted in a 25% decrease in breast cancer deaths. Several other trials showed a 13% decrease in the mortality rate of breast cancer in this age group after 12 years of follow-up, but the differences were not statistically significant. In a meta-analysis of five trials, the breast cancer death rates in women aged 40–49 were the same whether the women screened or not. The value of screening in women aged 50–69 is undisputed. The evidence for those older than 70 is inconclusive, partly because few women over 70 have been screened. Therefore, doubt exists about screening in women under 50 because of concerns about the potentially harmful effects of x-rays in a large population of young women. Nevertheless, in practice screening among younger women is popular.
Currently, the National Cancer Institute states that there is no agreement on the role of screening mammography for women aged 40–49. The American College of Radiology and the American Cancer Society continue to recommend a screening mammogram by age 40 and then every 1–2 years until age 50, whereupon the study should be performed every year. They no longer urge a baseline examination at age 35. These recommendations seem reasonable, but such a policy may be too costly to justify.
Large trials will be required to determine conclusively the value of mammography in young women. Screening should be performed in those over age 70 after consideration of the patient's overall health. Women under 50 should be counseled individually.
Ductography is useful to evaluate the cause of nipple discharge. In this study, the radiologist injects contrast medium into the discharging duct and obtains a mammogram. The injected duct may contain a filling defect (most commonly an intraductal papilloma) or may have a dilated or cystic appearance in patients with duct ectasia or fibrocystic disease. Malignancy may appear as an abrupt obstruction or filling defect.
Other modalities of breast imaging have been investigated. Automated breast ultrasonography is very useful in distinguishing cystic from solid lesions but should be used only as a supplement to physical examination and mammography in screening for breast cancer. Diaphanography (transillumination of the breasts) and thermography are of no proved screening value and should not be performed.
Self-Examination
All women over age 20 should be advised to examine their breasts monthly. Premenopausal women should perform the examination 7–8 days after the menstrual period. The breasts should be inspected initially while standing before a mirror with the hands at the sides, overhead, and pressed firmly on the hips to contract the pectoralis muscles. Masses, asymmetry of breasts, and slight dimpling of the skin may become apparent as a result of these maneuvers. Next, in a supine position, each breast should be carefully palpated with the fingers of the opposite hand. Physicians should instruct women in the technique of self-examination and advise them to report at once for medical evaluation if a mass or other abnormality is noted.
Some women discover small breast lumps more readily when their skin is moist while bathing or showering.
Most women do not practice self-examination, and its value is controversial. Clearly, however, it is not harmful and may be beneficial.
Mammography
Mammography is the most useful technique for the detection of early breast cancer. The two methods of mammography in common use are ordinary film screen radiography and xeroradiography. From the standpoint of diagnosing breast cancer, the two methods give comparable results. Using film screen techniques, it is now possible to perform a high-quality mammogram while delivering less than 0.4 cGy to the mid breast per view, and for this reason film screen mammography has largely replaced the xeromammographic technique, which delivers more radiation.
Mammography is the only reliable means of detecting breast cancer before a mass can be palpated in the breast. Slowly growing breast cancers can be identified by mammography at least 2 years before reaching a size detectable by palpation.
Calcifications are the most easily recognized mammographic abnormality. The most common mammographic abnormalities associated with carcinoma of the breast are clustered polymorphic microcalcifications. Such calcifications are usually at least five to eight in number, aggregated in one part of the breast and differing from each other in size and shape, often including branched or V- or Y-shaped configurations. There may be an associated mammographic mass density or, at times, only a mass density with no calcifications. Such a density usually has irregular or ill-defined borders and may lead to architectural distortion within the breast. A small mass or architectural distortion, particularly in a dense breast, may be subtle and difficult to detect.
Indications for mammography are as follows: (1) to evaluate each breast when a diagnosis of potentially curable breast cancer has been made, and at yearly intervals thereafter; (2) to evaluate a questionable or ill-defined breast mass or other suspicious change in the breast; (3) to search for an occult breast cancer in a woman with metastatic disease in axillary nodes or elsewhere from an unknown primary; (4) to screen women prior to cosmetic operations or prior to biopsy of a mass, to examine for an unsuspected cancer; (5) to screen at regular intervals women who are at high risk for developing breast cancer (see below); and (6) to follow those women with breast cancer who have been treated with breast-conserving surgery and radiation.
Patients with a dominant or suspicious mass must undergo biopsy despite mammographic findings. The mammogram should be obtained prior to biopsy so that other suspicious areas can be noted and the contralateral breast can be checked. Mammography is never a substitute for biopsy, because it may not reveal clinical cancer in a very dense breast, as may be seen in young women with mammary dysplasia, and may not reveal medullary type cancers.
Clinical Findings & Diagnosis
The patient with breast cancer usually presents with a lump in the breast. When the history is taken, special note should be made of breast cancer risk factors, the temporal relationship of mass to menstrual cycle, and previous breast problems. Clinical evaluation should include assessment of the local lesion and a search for evidence of metastases in regional nodes or distant sites. After the diagnosis of breast cancer has been confirmed by biopsy, additional studies are often needed to complete the search for distant metastases or an occult primary in the other breast. Then, before any decision is made about treatment, all the available clinical data are used to determine the extent or stage of the patient's disease.
Symptoms
The presenting complaint in about 70% of patients with breast cancer is a lump (usually painless) in the breast. About 90% of breast masses are discovered by the patient herself. Less frequent symptoms are breast pain; nipple discharge; erosion, retraction, enlargement, or itching of the nipple; and redness, generalized hardness, enlargement, or shrinking of the breast. Rarely, an axillary mass or swelling of the arm may be the first symptom. Back or bone pain, jaundice, or weight loss may be the result of systemic metastases, but these symptoms are rarely seen on initial presentation.
Signs
The relative frequency of carcinoma in various anatomic sites in the breast is shown in Figure 18-1.
| Figure 18–1. Frequency of breast carcinoma at various anatomic sites. |
Inspection of the breast is the first step in physical examination and should be carried out with the patient sitting, arms at sides and then overhead. Abnormal variations in breast size and contour, minimal nipple retraction, and slight edema, redness, or retraction of the skin can be identified. Asymmetry of the breasts and retraction or dimpling of the skin can often be accentuated by having the patient raise her arms overhead or press her hands on her hips in order to contract the pectoralis muscles. Axillary and supraclavicular areas should be thoroughly palpated for enlarged nodes with the patient sitting (Figure 18-2). Palpation of the breast for masses or other changes should be performed with the patient both seated and supine with the arm abducted (Figure 18-3). Some authorities recommend palpation with a rotary motion of the examiner's fingers as well as a horizontal stripping motion.
| Figure 18–2. Palpation of axillary region for enlarged lymph nodes. |
| Figure 18–3. Palpation of breasts. Palpation is performed with the patient supine and arm abducted. |
Breast cancer usually consists of a nontender, firm or hard lump with poorly delineated margins (caused by local infiltration). Slight skin or nipple retraction is an important sign. Minimal asymmetry of the breast may be noted. Very small (1–2 mm) erosions of the nipple epithelium may be the only manifestation of Paget's carcinoma. Watery, serous, or bloody discharge from the nipple is an occasional early sign but is more often associated with benign disease.
A lesion smaller than 1 cm in diameter may be difficult or impossible for the examiner to feel and yet may be discovered by the patient. She should always be asked to demonstrate the location of the mass; if the physician fails to confirm the patient's suspicions, the examination should be repeated in several months, preferably 1–2 weeks after the onset of menses. During the premenstrual phase of the cycle, increased innocuous nodularity may suggest neoplasm or may obscure an underlying lesion. If there is any question regarding the nature of an abnormality under these circumstances, the patient should be asked to return after her period. Thirty-five to 50 percent of women with cancers detected during organized screening programs have them detected by mammography only and not physical examination.
The following are characteristic of advanced carcinoma: edema, redness, nodularity, or ulceration of the skin; the presence of a large primary tumor; fixation to the chest wall; enlargement, shrinkage, or retraction of the breast; marked axillary lymphadenopathy; supraclavicular lymphadenopathy; edema of the ipsilateral arm; and distant metastases.
Metastases tend to involve regional lymph nodes, which may be clinically palpable. With regard to the axilla, one or two movable, nontender, not particularly firm lymph nodes 5 mm or less in diameter are frequently present and are generally of no significance. Firm or hard nodes larger than 5 mm in diameter usually contain metastases. Axillary nodes that are matted or fixed to skin or deep structures indicate advanced disease (at least stage III). Histologic studies show that microscopic metastases are present in about 30% of patients with clinically negative nodes. On the other hand, if the examiner thinks that the axillary nodes are involved, that impression will be borne out by histologic section in about 85% of cases. The incidence of positive axillary nodes increases with the size of the primary tumor. Noninvasive cancers do not metastasize.
In most cases no nodes are palpable in the supraclavicular fossa. Firm or hard nodes of any size in this location or just beneath the clavicle (infraclavicular nodes) are suggestive of metastatic cancer and should be biopsied. Ipsilateral supraclavicular or infraclavicular nodes containing cancer indicate that the tumor is in an advanced stage (stage IV). Edema of the ipsilateral arm, commonly caused by metastatic infiltration of regional lymphatics, is also a sign of advanced (stage IV) cancer.
Laboratory Findings
A consistently elevated sedimentation rate may be the result of disseminated cancer. Liver or bone metastases may be associated with elevation of serum alkaline phosphatase. Hypercalcemia is an occasional important finding in advanced cancer of the breast. Carcinoembryonic antigen (CEA) and CA 15-3 or CA 27-29 may be used as markers for recurrent breast cancer.
Imaging for Metastases
Chest radiographs may show pulmonary metastases. Computed tomography (CT) scanning of the liver and brain is of value only when metastases are suspected in these areas. Bone scans utilizing technetium Tc 99m-labeled phosphates or phosphonates are more sensitive than skeletal x-rays in detecting metastatic breast cancer. Bone scanning has not proved to be of clinical value as a routine preoperative test in the absence of symptoms, physical findings, or abnormal calcium or alkaline phosphatase levels. The frequency of abnormal findings on bone scan parallels the status of the axillary lymph nodes on pathologic examination. Bone scan should be performed for patients with symptoms and for those with elevated calcium or alkaline phosphatase levels. Positron emission tomography (PET) may prove to be an effective single scan for bone and soft tissue or visceral metastases in patients with signs or symptoms of metastatic disease.
Biopsy
The diagnosis of breast cancer depends ultimately upon examination of tissue or cells removed by biopsy. Treatment should never be undertaken without an unequivocal histologic or cytologic diagnosis of cancer. The safest course is biopsy examination of all suspicious masses found on physical examination and, in the absence of a mass, of suspicious lesions demonstrated by mammography. About 60% of lesions thought to be definitely cancer prove on biopsy to be benign, and about 30% of lesions believed to be benign are found to be malignant. These findings demonstrate the fallibility of clinical judgment and the necessity for biopsy. Dominant masses or suspicious nonpalpable mammographic findings must be biopsied. A breast mass should not be followed without histologic diagnosis, except perhaps in the premenopausal woman with a nonsuspicious mass presumed to be fibrocystic disease. A lesion such as this could be observed through one or two menstrual cycles. However, if the mass does not completely resolve during this time, it must be biopsied. Figures 18-4 and 18-5 present algorithms for management of breast masses in pre- and postmenopausal patients.
| Figure 18–4. Evaluation of breast masses in premenopausal women. (Modified from Giuliano AE: Breast disease. In: Practical Gynecologic Oncology, 2nd ed. Berek JS, Hacker NF [editors]. Lippincott Williams & Wilkins, 1994.) |
| Figure 18–5. Evaluation of breast masses in postmenopausal women. (Modified from Giuliano AE: Breast disease. In: Practical Gynecologic Oncology, 2nd ed. Berek JS, Hacker NF [editors]. Lippincott Williams & Wilkins, 1994 |
The simplest method is needle biopsy, either by aspiration of tumor cells (fine-needle aspiration cytology) or by obtaining a small core of tissue with a Vim-Silverman or other special needle. A nondiagnostic needle biopsy or fine-needle aspiration should be followed by open biopsy, because false-negative needle biopsies may occur in 5–10% of cancers. False-positive results occur rarely (< 1%).
Open biopsy under local anesthesia as a separate procedure prior to deciding upon definitive treatment is the most reliable means of diagnosis. Needle biopsy or aspiration, when positive for malignancy, offers a more rapid approach with less morbidity, but when nondiagnostic it must be followed by excisional biopsy.
Decisions on additional workup for metastatic disease and on definitive therapy can be made and discussed with the patient after the histologic or cytologic diagnosis of cancer has been established. This approach has the advantage of avoiding unnecessary hospitalization and diagnostic procedures in many patients, since cancer is found in the minority of patients who require biopsy for diagnosis of a breast lump. In addition, in situ cancers are not easily diagnosed cytologically.
As an alternative in highly suspicious circumstances, the patient may be admitted directly to the hospital, where the diagnosis is made on frozen section of tissue obtained by open biopsy under general anesthesia. If the frozen section is positive, the surgeon could proceed immediately with operation. This one-step method should rarely be used today except perhaps when cytologic study has already suggested the presence of cancer.
In general, the two-step approach—outpatient biopsy followed by definitive operation at a later date—is preferred in the diagnosis and treatment of breast cancer, because patients can be given time to adjust to the diagnosis of cancer, can carefully consider alternative forms of therapy, and can seek a second opinion if they wish. Studies have shown no adverse effect from the short (1–2 weeks) delay of the two-step procedure, and this is the current recommendation of the National Cancer Institute.
At the time of the initial biopsy of breast cancer, it is important for the physician to preserve a portion of the specimen for determination of estrogen and progesterone receptors.
Other Cytology
Cytologic examination of nipple discharge or cyst fluid may be helpful on rare occasions. As a rule, mammography (or ductography) and breast biopsy are required when nipple discharge or cyst fluid is bloody or cytologically questionable.
Differential Diagnosis
The lesions to be considered most often in the differential diagnosis of breast cancer are the following, in descending order of frequency: mammary dysplasia (cystic disease of the breast), fibroadenoma, intraductal papilloma, lipoma, and fat necrosis. The differential diagnosis of a breast lump should be established without delay by biopsy, by aspiration of a cyst, or by observing the patient until disappearance of the lump within a period of a few weeks.
Staging
The extent of disease evident from physical findings and special preoperative studies is used to determine its clinical stage. Currently, the American Joint Committee on Cancer and the International Union Against Cancer have agreed on a TNM (Tumor, Regional Lymph Nodes, Distant Metastases) staging system for breast cancer. The use of this uniform TNM staging system will enhance communication among investigators and clinicians. Table 18-2 sets forth the TNM classification.
Pathologic Types
Numerous pathologic subtypes of breast cancer can be identified histologically (Table 18-3). These types are distinguished by the histologic appearance and growth pattern of the tumor. In general, breast cancer arises either from the epithelial lining of the large or intermediate-sized ducts (ductal) or from the epithelium of the terminal ducts of the lobules (lobular). The cancer may be invasive or in situ. Most breast cancers arise from the intermediate ducts and are invasive (invasive ductal, infiltrating ductal), and most histologic types are merely subtypes of invasive ductal cancer with unusual growth patterns (colloid, medullary, scirrhous, etc). Ductal carcinoma that has not invaded the extraductal tissue is intraductal or in situ ductal. Lobular carcinoma may be either invasive or in situ.
Except for the in situ cancers, the histologic subtypes have only a slight bearing on prognosis when outcomes are compared after accurate staging. Various histologic parameters, such as invasion of blood vessels, tumor differentiation, invasion of breast lymphatics, and tumor necrosis have been examined, but they too seem to have little prognostic value.
The noninvasive cancers by definition lack the ability to spread. However, in patients whose biopsies show noninvasive intraductal cancer, associated invasive ductal cancers are present in about 1–3% of cases. Some clinicians consider lobular carcinoma in situ to be a premalignant lesion that is not a true cancer. It lacks the ability to spread but is associated with subsequent development of invasive cancer in at least 20% of cases. The subsequent cancer may occur in either breast regardless of the side of the original biopsy.
Special Clinical Forms of Breast Cancer
Paget's Carcinoma
The basic lesion is usually an infiltrating ductal carcinoma, usually well differentiated. The nipple epithelium is infiltrated, but gross nipple changes are often minimal, and a tumor mass may not be palpable. The first symptom is often itching or burning of the nipple, with superficial erosion or ulceration. The diagnosis is established by biopsy of the erosion.
Paget's carcinoma is not common (about 1% of all breast cancers), but it is important because it appears innocuous. It is frequently diagnosed and treated as dermatitis or bacterial infection, leading to unfortunate delay in detection. When the lesion consists of nipple changes only, the incidence of axillary metastases is about 5%, and the prognosis is excellent. When a breast tumor is also present, the incidence of axillary metastases rises, with an associated marked decrease in prospects for cure by surgical or other treatment.
Inflammatory Carcinoma
This is the most malignant form of breast cancer and constitutes less than 3% of all cases. The clinical findings consist of a rapidly growing, sometimes painful mass that enlarges the breast. The overlying skin becomes erythematous, edematous, and warm. Often there is no distinct mass, since the tumor infiltrates the involved breast diffusely. The diagnosis should be made when the redness involves more than one-third of the skin over the breast and biopsy shows invasion of the subdermal lymphatics. The inflammatory changes, often mistaken for an infectious process, are caused by carcinomatous invasion of the dermal lymphatics, with resulting edema and hyperemia. If the physician suspects infection but the lesion does not respond rapidly (1–2 weeks) to antibiotics, biopsy examination must be performed. Metastases tend to occur early and widely, and for this reason inflammatory carcinoma is rarely curable. Mastectomy is seldom, if ever, indicated. Radiation, hormone therapy, and anticancer chemotherapy are the measures most likely to be of value.
Breast Cancer Occurring during Pregnancy or Lactation
Only 1–2% of breast cancers occur during pregnancy or lactation. Breast cancer complicates approximately one in 3000 pregnancies. The diagnosis is frequently delayed, because physiologic changes in the breast may obscure the true nature of the lesion. This results in a tendency of both patients and physicians to misinterpret the findings and to procrastinate in deciding on biopsy. When the neoplasm is confined to the breast, the 5-year survival rate after mastectomy is about 70%. Axillary metastases are already present in 60–70% of patients, and for them the 5-year survival rate after mastectomy is only 30–40%. Pregnancy (or lactation) is not a contraindication to operation, and treatment should be based on the stage of the disease as in the nonpregnant (or nonlactating) woman. Overall survival rates have improved, since cancers are now diagnosed in pregnant women earlier than in the past. Pregnant women with breast cancer may undergo breast-conserving surgery, radiation, and chemotherapy.
Bilateral Breast Cancer
Clinically evident simultaneous bilateral breast cancer occurs in less than 1% of cases, but there is a 5–8% incidence of later occurrence of cancer in the second breast. Bilaterality occurs more often in women under age 50 and is more frequent when the tumor in the primary breast is lobular. The incidence of second breast cancers increases directly with the length of time the patient is alive after her first cancer—about 1% per year.
In patients with breast cancer, mammography should be performed before primary treatment and at regular intervals thereafter, to search for occult cancer in the opposite breast. Routine biopsy of the opposite breast is usually not warranted.
Noninvasive Cancer
Noninvasive cancer can occur within the ducts (ductal carcinoma in situ) or lobules (lobular carcinoma in situ). While ductal carcinoma in situ behaves as an early malignancy, lobular carcinoma in situ would perhaps be better called lobular neoplasia. Ductal carcinoma in situ tends to be unilateral and most likely progresses to invasive cancer. Approximately 40–60% of women who have ductal carcinoma in situ treated with biopsy alone will develop invasive cancer within the same breast. Lobular carcinoma in situ, however, appears to be more of a risk factor calling attention to the probability of developing invasive cancer in either breast. Approximately 20% of women with lobular carcinoma in situ will develop invasive cancer (usually ductal). This invasive cancer occurs with equal frequency in either breast.
The treatment of intraductal lesions is controversial. Ductal carcinoma can be treated with total mastectomy or breast conservation with wide excision with or without radiation therapy. Lobular carcinoma in situ is probably best managed with careful observation. However, patients who are unwilling to accept the increased risk of breast cancer may be offered bilateral total mastectomy. tamoxifen is effective in preventing invasive breast cancer in patients with lobular or ductal carcinoma in situ. Axillary metastases are rare.
Hormone Receptor Sites
The presence or absence of estrogen and progesterone receptors in the cytoplasm of tumor cells is of paramount importance in managing all patients with breast cancer, especially those with recurrent or metastatic disease. They are of proved value in determining adjuvant therapy and therapy for patients with advanced disease. Up to 60% of patients with metastatic breast cancer will respond to hormonal manipulation if their tumors contain estrogen receptors. However, fewer than 5% of patients with metastatic, estrogen receptor (ER)-negative tumors can be successfully treated with hormonal manipulation.
Progesterone receptors may be an even more sensitive indicator than estrogen receptors of patients who may respond to hormonal manipulation. Up to 80% of patients with metastatic progesterone receptor-positive tumors seem to respond to hormonal manipulation. Receptors have no relationship to response to chemotherapy.
Some studies suggest that estrogen receptors are of prognostic significance. Patients whose primary tumors are receptor-positive have a more favorable course than those whose tumors are receptor-negative.
Receptor status is valuable not only for the management of metastatic disease but also for the selection of patients for adjuvant therapy. Adjuvant hormonal therapy (tamoxifen) for patients with receptor-positive tumors and adjuvant chemotherapy for patients with receptor-negative tumors improve survival rates even in the absence of lymph node metastases (see Adjuvant Therapy).
Estrogen and progesterone receptor assays should be done routinely for every breast cancer at the time of initial diagnosis. Tumors are examined by immunohistochemistry or paraffin sections. The value of this assay technique remains to be proved. Receptor status may change after hormonal therapy, radiotherapy, or chemotherapy. The specimen requires special handling, and the laboratory should be prepared to process the specimen correctly.
Curative Treatment
Treatment may be curative or palliative. Curative treatment is advised for clinical stage I and stage II disease (Table 18-2). Patients with locally advanced (stage III) and even inflammatory tumors may be cured with multimodality therapy, but in most cases palliation is all that can be expected. Palliative treatment is appropriate for all patients with stage IV disease and for previously treated patients who develop distant metastases or who have unresectable local cancers.
The growth potential of tumors and host resistance factors vary over a wide range from patient to patient and may be altered during the course of the disease. The doubling time of breast cancer cells ranges from several weeks in a rapidly growing lesion to nearly a year in a slowly growing one. Assuming that the rate of doubling is constant and that the neoplasm originates in one cell, a carcinoma with a doubling time of 100 days may not reach clinically detectable size (1 cm) for about 8 years. On the other hand, rapidly growing cancers have a much shorter preclinical course and a greater tendency to metastasize to regional nodes or more distant sites by the time a breast mass is discovered.
The relatively long preclinical growth phase and the tendency of breast cancers to metastasize have led many clinicians to believe that breast cancer is a systemic disease at the time of diagnosis. Although it may be true that breast cancer cells are released from the tumor prior to diagnosis, variations in the host-tumor relationship may prohibit the growth of disseminated disease in many patients. For this reason, a pessimistic attitude concerning the management of localized breast cancer is not warranted, and many patients can be cured with proper treatment.
Choice of Primary Therapy
The extent of disease and its biologic aggressiveness are the principal determinants of the outcome of primary therapy. Clinical and pathologic staging help in assessing extent of disease (Table 18-2), but each is to some extent imprecise. Other factors such as deoxyribonucleic acid (DNA) flow cytometry, tumor grade, hormone receptor assays, and oncogene amplification may be of prognostic value but are not important in determining the type of local therapy. Since about two-thirds of patients eventually manifest distant disease regardless of the form of primary therapy, there is a tendency to think of breast carcinoma as being systemic in most patients at the time they first present for treatment.
There is a great deal of controversy regarding the optimal method of primary therapy of stage I, II, and III breast carcinoma, and opinions on this subject have changed considerably in the past decade. Legislation initiated in California and Massachusetts and now adopted in numerous states requires physicians to inform patients of alternative treatment methods in the management of breast cancer.
Breast-Conserving Therapy
The results of the Milan trial and a large randomized trial conducted by the National Surgical Adjuvant Breast Project (NSABP) in the USA showed that disease-free survival rates were similar for patients treated by partial mastectomy plus axillary dissection followed by radiation therapy and for those treated by modified radical mastectomy (total mastectomy plus axillary dissection). All patients whose axillary nodes contained tumor received adjuvant chemotherapy.
In the NSABP trial, patients were randomized to three treatment types: (1) "lumpectomy" (removal of the tumor with confirmedtumor-free margins) plus whole breast irradiation, (2) lumpectomy alone, and (3) total mastectomy. All patients underwent axillary lymph node dissection. Some patients in this study had tumors as large as 4 cm with (or without) palpable axillary lymph nodes. The lowest local recurrence rate was among patients treated with lumpectomy and postoperative irradiation; the highest was among patients treated with lumpectomy alone. However, no statistically significant differences were observed in overall or disease-free survival among the three treatment groups. This study shows that lumpectomy and axillary dissection with postoperative radiation therapy is as effective as modified radical mastectomy for the management of patients with stage I and stage II breast cancer. A high local failure rate (nearly 40% at 8 years) was seen for lumpectomy without radiation therapy.
The results of these and other trials have demonstrated that much less aggressive surgical treatment of the primary lesion than has previously been thought necessary gives equivalent therapeutic results and may preserve an acceptable cosmetic appearance.
Tumor size is a major consideration in determining the feasibility of breast conservation. The lumpectomy trial of the NSABP randomized patients with tumors as large as 4 cm. To achieve an acceptable cosmetic result, the patient must have a breast of sufficient size to enable excision of a 4 cm tumor without considerable deformity. Therefore, large size is only a relative contraindication. Subareolar tumors are also difficult to excise without considerable deformity. Clinically detectable multifocality is a relative contraindication to breast-conserving surgery, as is fixation to the chest wall or skin or involvement of the nipple or overlying skin. However, the patient and not the surgeon should be the judge of what is cosmetically acceptable; some patients would prefer breast deformity rather than complete absence of the breast or even reconstruction.
It is important to recognize that axillary dissection is valuable in planning therapy, staging cancer, and preventing axillary recurrences. Intraoperative lymphatic mapping and excision of the sentinel lymph node draining a primary breast carcinoma is a less invasive but highly accurate alternative for identifying patients with clinically occult axillary nodal metastases. Because the sentinel node is the first regional lymph node to receive tumor cells that metastasize along the lymphatic pathway from a primary breast cancer, its tumor status should reflect the status of the entire axillary basin. Sentinel lymphadenectomy holds promise as a staging technique to replace formal level I and level II axillary lymph node dissection in selected patients with breast carcinoma, thus avoiding an unnecessary procedure that has no role in many patients with tumor-free axillae. Two large randomized trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the American College of Surgeons Oncology Group (ACSOG) are examining intraoperative lymphatic mapping and sentinel lymphadenectomy for the management of patients with invasive breast carcinoma. Even when tumor is detected in the sentinel node, immunohistochemical examination of multiple sections of this node may indicate whether or not complete axillary lymph node dissection is necessary.
Biopsy and immunocytochemical examination of bone marrow may be as sensitive a staging procedure as axillary dissection and may identify patients at high risk of disseminated disease.
Current Recommendations
A National Institutes of Health (NIH) consensus statement argues that breast-conserving surgery with radiation is the preferred form of treatment for patients with early-stage breast cancer. However, this technique has still not gained wide acceptance by physicians or patients. Despite the numerous randomized trials comparing breast conserving surgery and radiation therapy to mastectomy, breast-conserving surgery appears underutilized and mastectomy remains the more common treatment. In a recent survey, only 25% of patients in the United States with stage I or II breast cancer were treated with breast-conserving surgery and radiation therapy, compared with 75% treated with mastectomy. Use of breast-conserving surgery and radiation therapy seems to vary by region of the country, ranging from 15% in the South Central United States to approximately 30% in the Pacific Region.
Modified radical mastectomy (total mastectomy plus axillary lymph node dissection) has been the standard therapy for most patients with breast cancer. This operation removes the entire breast, overlying skin, nipple, and areolar complex as well as the underlying pectoralis fascia with the axillary lymph nodes in continuity. It offers the same overall survival and local control rates as does lumpectomy with axillary dissection and postoperative radiation therapy. The major advantage of modified radical mastectomy is that radiation therapy is usually not necessary. The disadvantage, of course, is the psychologic trauma associated with breast loss. Radical mastectomy, which removes the underlying pectoralis muscle, should be performed rarely if at all. Axillary node dissection is not indicated for noninfiltrating cancers, because nodal metastases are rarely present. Radiotherapy consists of 5–6 weeks of five daily fractions to a total dose of 5000–6000 cGy. Most radiotherapists use a boost dose, but its value is uncertain.
Preoperatively, full discussion with the patient regarding the rationale for operation and various alternative forms of treatment is essential. Breast-conserving surgery and radiation should be offered whenever possible, since most patients would prefer to save the breast. Breast reconstruction should be discussed with patients who choose or require mastectomy, and the option of simultaneous mastectomy with immediate reconstruction should be discussed. Time spent preoperatively in educating the patient and her family about these matters is time well spent.
Adjuvant Therapy
Following surgery and radiation therapy, chemotherapy or hormonal therapy is advocated for most patients with curable breast cancer (Tables 18-4 and 18-5). The objective of adjuvant therapy is to eliminate the occult metastases responsible for late recurrences while they are microscopic and theoretically most vulnerable to anticancer agents.
Numerous clinical trials with various adjuvant chemotherapeutic regimens have been completed. The most extensive clinical experience to date is with the CMF regimen (cyclophosphamide, methotrexate, and fluorouracil). Cyclophosphamide can be given either orally, in a dose of 100 mg/m2 daily for 14 days; or intravenously, in a dose of 600 mg/m2 on days 1 and 8. Methotrexate is given intravenously, 40 mg/m2 on days 1 and 8; and fluorouracil is given intravenously, 600 mg/m2 on days 1 and 8. This cycle is repeated every 4 weeks. Some clinicians prefer to give the drugs on 1 day only every 3 weeks. There appears to be no obvious advantage except that patient compliance is assured when the Cyclophosphamide is give intravenously. The regimen should be continued for 6 months in patients with axillary metastases. Premenopausal women with positive axillary nodes definitely benefit from adjuvant chemotherapy. The recurrence rate in premenopausal patients who received no adjuvant chemotherapy was more than 11/2 times that of those who received such therapy. No therapeutic effect with CMF has been shown in postmenopausal women with positive nodes, perhaps because therapy was modified so often in response to side effects that the total amount of drugs administered was less than planned. It has recently been suggested that anthracycline combination chemotherapy (usually doxorubicin and Cyclophosphamide) appears superior to CMF. Despite the early findings, postmenopausal women benefit as well from systemic chemotherapy.
Tamoxifen can be given with few side effects even in the elderly. tamoxifen appears to increase bone density and favorably affect lipid and lipoprotein profiles, which may explain the observed decreased mortality rate from coronary artery disease seen in patients taking tamoxifen.
The addition of hormones improves the results of adjuvant therapy. For example, tamoxifen has been shown to enhance the beneficial effects of melphalan and fluorouracil in postmenopausal women whose tumors are ER-positive. tamoxifen alone in a dosage of 10 mg orally twice a day has been the recommended treatment for postmenopausal women with ER-positive tumors. However, a recent NSABP trial showed that tamoxifen plus chemotherapy (Adriamycin [doxorubicin] plus Cyclophosphamide (AC) or prednisone plus Adriamycin plus fluorouracil (PAF)) lowered recurrence rates more than tamoxifen alone in postmenopausal women with ER-positive tumors.
The length of time adjuvant therapy must be administered remains uncertain. Several studies suggest that shorter treatment periods may be as effective as longer ones. For example, one study compared 6 versus 12 cycles of postoperative CMF and found 5-year disease-free survival rates to be comparable. One of the earliest adjuvant trials used a 6-day perioperative regimen of intravenous Cyclophosphamide alone; follow-up at 15 years shows a 15% improvement in disease-free survival rates for treated patients, suggesting that short-term therapy may be effective.
Patients with negative nodes have not been treated with adjuvant therapy until recently. Several studies of adjuvant therapy in node-negative women have now been published and show a beneficial effect of adjuvant chemotherapy or tamoxifen in delaying recurrence and improving survival. A number of protocols, including CMF—cyclophosphamide, methotrexate, and fluorouracil—with leucovorin rescue as well as tamoxifen alone have increased disease-free survival times. The magnitude of this improvement is about one-third, ie, a group of women with an estimated 30% recurrence rate would have a 20% recurrence rate after adjuvant systemic therapy. Quality of life while receiving chemotherapy does not appear to be greatly altered.
A recent NIH consensus conference reexamined the standards for adjuvant therapy of breast cancer. Since the last conference on this topic in 1990, the long-term advantage of systemic therapy has been more firmly established. The panel acknowledged that in the last 10 years no new prognostic factors have been validated to aid in the selection of patients for adjuvant treatment. The use of adjuvant systemic therapy should be based on the patient's age; on the size, histopathologic grade, and hormone receptor status of the breast tumor; and on the status of the regional lymph nodes. The use of HER2-neu, P53, angiogenesis factors, and vascular invasion are of interest but as yet are not proved prognostic factors. The panel concluded that adjuvant systemic chemotherapy with drug combinations improves survival and should be used for most women who have potentially curable breast cancer regardless of other factors. The use of anthracyclines is superior to combinations without anthracyclines. tamoxifen should be used as a systemic agent in all women whose tumors are hormone receptor-positive regardless of age, menopausal status, or other prognostic factors. HER2-neu status should not affect the choice of agents or the use of hormone therapy. The panelists note that ovarian ablation in premenopausal patients with estrogen receptor-positive tumors may produce a benefit similar to what can be achieved with adjuvant systemic chemotherapy. Taxanes have demonstrated benefit in patients with metastatic cancer but have not yet proved to be of value in node-negative patients. Adjuvant systemic therapy should not be given to women who have small, node-negative breast cancers with favorable histologic subtypes, such as mucinous or tubular carcinoma.
Important questions remaining to be answered are the timing and duration of adjuvant chemotherapy, which chemotherapeutic agents should be applied for which subgroups of patients, how best to coordinate adjuvant chemotherapy with postoperative radiation therapy, the use of combinations of hormonal therapy and chemotherapy, and the value of prognostic factors other than hormone receptors in predicting response to adjuvant therapy. Adjuvant systemic therapy is not currently indicated for patients with small tumors and those with negative lymph nodes who have favorable DNA studies and hormone receptor assays.
Palliative Treatment
This section covers palliative therapy of disseminated disease incurable by surgery (stage IV).
Radiotherapy
Palliative radiotherapy may be advised for locally advanced cancers with distant metastases in order to control ulceration, pain, and other manifestations in the breast and regional nodes. Irradiation of the breast and chest wall and the axillary, internal mammary, and supraclavicular nodes should be undertaken in an attempt to cure locally advanced and inoperable lesions when there is no evidence of distant metastases. A small number of patients in this group are cured in spite of extensive breast and regional node involvement. Adjuvant chemot
