Carcinoma of the Female Breast

Essentials of Diagnosis

• Risk factors include delayed childbearing, positive family history of breast cancer or genetic mutations (BRCA1, BRCA2), and personal history of breast cancer or some types of mammary dysplasia.
• Most women with breast cancer do not have identifiable risk factors.
• Early findings: Single, nontender, firm to hard mass with ill-defined margins; mammographic abnormalities and no palpable mass.
• Later findings: Skin or nipple retraction; axillary lymphadenopathy; breast enlargement, redness, edema, pain; fixation of mass to skin or chest wall.

Incidence & Risk Factors

Aside from skin cancer, 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 217,500 new cases of breast cancer and about 40,200 deaths from this disease in women in the United States in the year 2004. An additional 59,000 cases of ductal carcinoma in situ will be detected, principally by screening mammography. One out of every eight or nine American women will develop breast cancer during her lifetime. The incidence of breast cancer continues to increase, but recently mortality has appeared to decrease slightly. This reflects both early detection and increased use of systemic therapy. Women whose mothers or sisters had breast cancer are three to four times more likely to develop the disease. Risk is further increased in patients whose mothers' or sisters' breast cancers occurred before menopause or were 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 75% of patients. Nulliparous women and women whose first full-term pregnancy was after age 35 have a 1.5 times higher incidence of breast cancer than multiparous women. Late menarche and artificial menopause are associated with a lower incidence, whereas early menarche (under age 12) and late natural menopause (after age 50) are associated with a slight increase in risk. Fibrocystic disease, when accompanied by proliferative changes, papillomatosis, or atypical epithelial hyperplasia, is associated with an increased incidence. A woman who has had cancer in one breast is at increased risk of developing cancer in the other breast. Such women develop a contralateral cancer at the rate of 1% or 2% per year. 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 United States, breast cancer is more common in whites. The incidence of the disease among nonwhites (mostly blacks) 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 consumption, may account for some differences in incidence. Oral contraceptives do not appear to increase the risk of breast cancer. There is 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. Concomitant administration of progesterone and estrogen may markedly increase the incidence of breast cancer compared with the use of estrogen alone. The Women's Health Initiative prospective randomized study of hormone replacement therapy stopped treatment with estrogen and progesterone early because of an increased risk of breast cancer compared with untreated controls or women treated with estrogen alone. Alcohol consumption increases the risk slightly. Some inherited breast cancers have been found to be associated with a gene on chromosome 17. This gene, BRCA1, is mutated in families with early-onset breast cancer and ovarian cancer. As many as 85% of women with BRCA1 gene mutations will develop breast cancer in their lifetime. Other genes are associated with increased risk of breast and other cancers, such as BRCA2, ataxia-telangiectasia mutation, and p53, the tumor suppressor gene. p53 mutations have been found in approximately 1% of breast cancers in women under 40 years of age. Genetic testing is now commercially available for women at high risk of breast cancer. Women with genetic mutations who develop breast cancer may be treated in the same way as women who do not have mutations (ie, lumpectomy), though data are emerging to suggest an increased recurrence rate for these women. Such women with mutations often elect bilateral mastectomy as treatment. Some states have enacted legislation to prevent insurance companies from considering mutations as "preexisting conditions," preventing insurability.

Women at greater than normal risk of developing breast cancer (Table 16–1) should be identified by their physicians, taught the techniques of breast self-examination, and followed carefully. Those with an exceptional family history should be counseled and given the option of genetic testing. Some of these high-risk women may consider prophylactic mastectomy or tamoxifen.

The National Surgical Adjuvant Breast Project (NSABP) conducted the Breast Cancer Prevention Trial (BCPT), which studied the efficacy of tamoxifen as a preventive agent in women who had never had breast cancer but were at high risk for developing the disease. 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.

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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 about 10 cancers per 1000 women older than age 50 and about two cancers per 1000 women younger than age 50. About 80% of these women have negative axillary lymph nodes at the time of surgery, whereas only 50% of nonscreened women 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. The probability of cancer on a screening mammogram is directly related to the BIRADS assessment, and work-up should be performed based on this classification. 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 at least 90% of malignancies (see x-ray); (see x-ray). Smaller tumors, particularly those without calcifications, are more difficult to detect, especially in dense breasts. The lack of sensitivity and the low incidence of breast cancer in young women have led to questions concerning the value of mammography for screening in women 40–50 years of age. The specificity of mammography in women under 50 varies from about 30% to 40% for nonpalpable mammographic abnormalities to 85% to 90% for clinically evident malignancies.

Fig. Fatty breast. (Courtesy of K Kerlikowske.)

Fig. Extremely dense breast. (Courtesy of K Kerlikowske.)

Doubt exists about the beneficial effect of screening, especially in women under age 50. Questions such as the potential harmful effects of x-rays in a large population of young women and the general value of early detection were raised and largely ignored as various groups supported screening between ages 40 and 50. Although the Health Insurance Plan Project study did show a beneficial effect of screening in such women, reducing breast cancer mortality 25% between 10 and 18 years after entry into the study, a Canadian trial demonstrated an unexplained shortening of survival from time of random assignment to death in the screening group. The small number of patients in this study experienced no beneficial effect, but the 95% confidence interval included a potential lifesaving effect as well as a potential harmful effect. A very large number of patients is necessary to show a beneficial effect of screening among patients aged 40–49, where the incidence of breast cancer is low. In addition, the problems of crossover of patients in the control group with women undergoing physician examination and nonscreening mammograms, problems with mammography quality, and problems in recruitment, randomization, and compliance make the interpretation of such trials difficult. The beneficial effect of screening in women aged 50–69 is undisputed and has been confirmed by all clinical trials. The efficacy of screening in older women—those older than 70—is inconclusive and is difficult to determine because of the few women screened.

More recent studies showing a beneficial effect of screening young women and the recommendation of a Swedish consensus panel led the National Cancer Institute (NCI) to reconsider its position on screening mammography for women in their 40s. Two Swedish trials that had shown a 13% decrease in breast cancer mortality (not statistically significant) now showed a statistical advantage for screening women in their 40s, and a meta-analysis similarly revealed a statistical survival advantage for screened women with longer follow-up. In March 1997, the National Cancer Advisory Board recommended that women with average risk factors should have screening mammography every 1–2 years in their 40s and that women at higher risk should seek medical advice on when to begin screening. The American Cancer Society then recommended screening every year for asymptomatic women starting at age 40. Studies continue to support the value of screening mammography.

Self-Examination

Breast self-examination has not been shown to improve survival. Despite this and despite possible increased biopsy rates, it is a useful technique since many patients do detect their own cancer, and women often feel more in control and proactive by using the procedure. 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. Some women discover small breast lumps more readily when their skin is moist while bathing or showering. Physicians should instruct women in the technique of self-examination and advise them to report a mass or other abnormality.

Mammography

Mammography is the most useful technique for the detection of early breast cancer. Film screen mammography delivers less than 0.4 cGy to the mid breast per view and has largely replaced the older xeromammographic technique, which delivers more radiation.

Mammography is the only reliable means of detecting breast cancer before a mass can be palpated. Slowly growing cancers can be identified by mammography at least 2 years before reaching a size detectable by palpation. New computer-assisted film reading may aid in diagnosis but is not routinely performed at centers with experienced mammographers.

Calcifications are the most easily recognized mammographic abnormality. The most common findings 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 (see x-ray). A small mass or architectural distortion, particularly in a dense breast, may be subtle and difficult to detect.

Fig. Cancer in a fatty breast. (Courtesy of K Kerlikowske.)

Indications for mammography are as follows: (1) to screen at regular intervals women at high risk for developing breast cancer (see above); (2) to evaluate each breast when a diagnosis of potentially curable breast cancer has been made, and at yearly intervals thereafter; (3) to evaluate a questionable or ill-defined breast mass or other suspicious change in the breast; (4) to search for an occult breast cancer in a woman with metastatic disease in axillary nodes or elsewhere from an unknown primary; (5) to screen women prior to cosmetic operations or prior to biopsy of a mass, to examine for an unsuspected cancer; 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 fibrocystic changes, and may not reveal medullary cancers (see x-ray).

Fig. Heterogeneously dense tissue. (Courtesy of K Kerlikowske.)

Communication and documentation between the patient, the referring physician, and the interpreting physician are critical for high-quality screening and diagnostic mammography. The patient should be told about how she will receive timely results of her mammogram; that mammography does not "rule out" cancer; and that she may receive a correlative examination such as ultrasound at the mammography facility if referred for a suspicious lesion. She should also be aware of the technique and need for breast compression and that this may be uncomfortable. The mammography facility should be informed in writing of abnormal physical examination findings. It is strongly recommended in the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines that all mammography reports be communicated with the patient as well as the health care provider in writing. Additional phone communication about any abnormal findings should take place between the interpreting and referring physicians. Magnetic resonance imaging (MRI) and positron emission tomography (PET) may play a role in imaging atypical lesions but only after diagnostic mammography has been performed.

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Stoutjesdijk MJ et al: Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 2001;93:1095. [PMID: 11459871]

Clinical Clues to Early Detection of Breast Cancer

Symptoms and Signs

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.

The relative frequency of carcinoma in various anatomic sites in the breast is shown in Figure 16–1: illustration.

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 16–2: illustration). Palpation of the breast for masses or other changes should be performed with the patient both seated and supine with the arm abducted (Figure 16–3: illustration). Some authorities recommend palpation with a rotary motion of the examiner's fingers as well as a horizontal stripping motion.

Palpation of axillary region for enlarged lymph nodes.

Palpation of breasts. Palpation is performed with the patient supine and arm abducted.

Breast cancer usually consists of a nontender, firm or hard mass 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 2–3 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 (see x-ray). If there is any question regarding the nature of an abnormality under these circumstances, the patient should be asked to return after her period. Ultrasound is often valuable and mammography essential when an area is felt by the patient to be abnormal but the physician feels no mass.

Fig. Scattered fibroglandular tissue. (Courtesy of K Kerlikowske.)

Metastases tend to involve regional lymph nodes, which may be palpable. One or two movable, nontender, not particularly firm axillary lymph nodes 5 mm or less in diameter are frequently present and are generally of no significance. Firm or hard nodes larger than 1 cm are typical of metastases. Axillary nodes that are matted or fixed to skin or deep structures indicate advanced disease (at least stage III). 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 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 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 but are not helpful in diagnosis of early lesions.

Imaging for Metastases

Chest x-ray may show pulmonary metastases. CT scanning of the liver and brain is of value only when metastases are suspected in these areas. Bone scans utilizing ^99mTc-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 alkaline phosphatase or calcium levels. The frequency of abnormal findings on bone scan parallels the status of the axillary lymph nodes on pathologic examination. PET may prove to be an effective single scan for bone and soft tissue or visceral metastases in patients with symptoms or signs of metastatic disease.

Diagnostic Tests

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 of suspicious lesions demonstrated by mammography. About 60% of lesions clinically thought to be 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. 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 16-4: illustration and 16-5: illustration present algorithms for management of breast masses in pre- and postmenopausal patients.

Evaluation of breast masses in premenopausal women. (Modified from Giuliano AE: Breast disease. In: Practical Gynecologic Oncology, 3rd ed. Berek JS, Hacker NF [editors]. Williams & Wilkins, 2000.)

Evaluation of breast masses in postmenopausal women. (Modified from Giuliano AE: Breast disease. In: Practical Gynecologic Oncology, 3rd ed. Berek JS, Hacker NF [editors]. Williams & Wilkins, 2000.)

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 hollow needle.

Fine-needle aspiration cytology is a useful technique whereby cells are aspirated with a small needle and examined by the pathologist. This technique can be performed easily with no morbidity and is much less expensive than excisional or open biopsy. The main disadvantages are that it requires a pathologist skilled in the cytologic diagnosis of breast cancer and that it is subject to sampling problems, particularly because deep lesions may be missed. Furthermore, noninvasive cancers usually cannot be distinguished from invasive cancers. The incidence of false-positive diagnoses is extremely low, perhaps 1–2%. The false-negative rate is as high as 10%. Most experienced clinicians would not leave a suspicious dominant mass in the breast even when fine-needle aspiration cytology is negative unless the clinical diagnosis, breast imaging studies, and cytologic studies were all in agreement.

Large-needle (core needle) biopsy removes a core of tissue with a large cutting needle. Hand-held biopsy devices make large-core needle biopsy of a palpable mass easy and cost effective in the office with local anesthesia. As in the case of any needle biopsy, the main problem is sampling error due to improper positioning of the needle, giving rise to a false-negative test result.

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, offers a more rapid approach with less expense and morbidity, but when nondiagnostic it must be followed by excisional biopsy.

Additional evaluation for metastatic disease and therapeutic options can be discussed with the patient after the histologic or cytologic diagnosis of cancer has been established. This approach has the advantage of avoiding unnecessary procedures, since cancer is found in the minority of patients biopsied for a breast lump. In situ cancers are not easily diagnosed cytologically and usually require excisional biopsy.

As an alternative in highly suspicious circumstances, the patient may be admitted 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 can proceed immediately with operation. This one-step method is rarely used today except when cytologic study has suggested cancer but is not diagnostic and there is a high clinical suspicion of malignancy.

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 consider alternative forms of therapy, and can seek a second opinion if they wish. There is no adverse effect from the short (1–2 weeks) delay of the two-step procedure, and this is the current recommendation of the NCI.

Ultrasonography

Ultrasonography is performed chiefly to differentiate cystic from solid lesions. Though not diagnostic, ultrasound may reveal features highly suggestive of malignancy such as irregular margins on a new solid mass. Ultrasonography may show an irregular mass within a cyst in the rare case of intracystic carcinoma. If a tumor is palpable and 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. These may even be needle-biopsied with ultrasound guidance.

Mammography

When a suspicious abnormality is identified by mammography alone and cannot be palpated by the clinician, the lesion should be biopsied by computerized stereotactic guided core needle technique. These units have been added to mammographic suites in order to localize abnormalities and perform needle biopsy without surgery. Under mammographic guidance, a biopsy needle can be inserted into the lesion by the mammographer, and a core of tissue for histologic examination or cells for cytology can then be examined. Vacuum assistance increases the amount of tissue obtained and improves diagnosis.

Mammographic localization biopsy 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 thus it is 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. Stereotactic core needle biopsies have proved equivalent to mammographic localization biopsies. Core biopsy is preferable to mammographic localization for accessible lesions.

Other imaging modalities

Other modalities of breast imaging have been investigated. Automated breast ultrasonography is useful in distinguishing cystic from solid lesions but should be used only as a supplement to physical examination and mammography. Ductography may be useful to define the site of a lesion causing a bloody discharge, but since biopsy is always indicated, ductography may be omitted and the blood-filled nipple system excised. MRI is highly sensitive but not specific and should not be used for screening, but it may be of value in highly selective cases. It is useful, for example, in differentiating scar from recurrence postlumpectomy and may be valuable to screen high-risk women (eg, women with BRCA mutations) and to examine for multicentricity when there is a known primary cancer or to examine the contralateral breast in women with cancer. PET scanning does not appear useful in evaluating the breast but may prove to be of value in examining regional lymphatics.

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. Ductal lavage, a technique that washes individual duct systems with saline and loosens epithelial cells for cytologic evaluation, is being evaluated as a risk assessment tool but appears to be of little value.

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Dooley WC: Routine operative breast endoscopy during lumpectomy. Ann Surg Oncol 2003;10:38. [PMID: 12513958]

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van der Hoeven JJ et al: Determinants of diagnostic performance of [F-18] fluorodeoxyglucose positron emission tomography for axillary staging in breast cancer. Ann Surg 2002;236: 619. [PMID: 12409668]

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.

Staging

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 between investigators and clinicians. Table 16–2 sets forth the TNM classification.

Pathologic Types

Numerous pathologic subtypes of breast cancer can be identified histologically (Table 16–3). 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) (see micrograph). Ductal carcinoma that has not invaded the extraductal tissue is intraductal or in situ ductal (see micrograph). Lobular carcinoma may be either invasive or in situ (see micrograph).

Fig. Intraductal carcinoma, cribriform type, showing the duct to be distended by a uniform population of cells. The basement membrane is intact. (Reproduced, with permission, from Chandrasoma P, Taylor CR: Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)

Fig. Infiltrating lobular carcinoma of the breast, showing tumor cells arranged in single rows and fibrosis. (Reproduced, with permission, from Chandrasoma P, Taylor CR: Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)

Fig. Lobular carcinoma in situ. The involved lobule (arrow) shows complete filling and distention of all constituent acini by small round cells. Compare with normal breast lobule at top left (labeled N). (Reproduced, with permission, from Chandrasoma P, Taylor CR: Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)

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 are confined by the basement membrane of the ducts and lack the ability to spread. However, in patients whose biopsies show noninvasive intraductal cancer, associated invasive ductal cancers metastasize to lymph nodes in about 1–3% of cases. Lobular carcinoma in situ (LCIS) is a premalignant lesion that is not a true cancer but is a risk factor associated with subsequent development of invasive cancer in at least 20% of cases, and the cancer may be in either breast.

Special Clinical Forms of Breast Cancer

Paget's Carcinoma

The basic lesion is usually an infiltrating ductal carcinoma, usually well differentiated, or a ductal carcinoma in situ (DCIS). The ducts of the nipple epithelium are 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 the nipple changes appear innocuous. These are frequently diagnosed and treated as dermatitis or bacterial infection, leading to delay in detection. When the lesion consists of nipple changes only, the incidence of axillary metastases is less than 5%, and the prognosis is excellent. When a breast mass 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 infiltrating carcinoma with invasion of the subdermal lymphatics (see photograph). The inflammatory changes, often mistaken for an infection, are caused by carcinomatous invasion of the subdermal lymphatics, with resulting edema and hyperemia (see micrograph). If the physician suspects infection but the lesion does not respond rapidly (1–2 weeks) to antibiotics, biopsy is performed. Metastases tend to occur early and widely, and for this reason inflammatory carcinoma is rarely curable. Mastectomy is seldom indicated unless chemotherapy and radiation have resulted in clinical remission with no evidence of distant metastases. In these cases, residual disease in the breast may be eradicated. Radiation, hormone therapy, and chemotherapy are the measures most likely to be of value rather than operation.

Fig. Inflammatory breast carcinoma, showing dermal lymphatic containing carcinoma cells (arrows). (Reproduced, with permission, from Chandrasoma P, Taylor CR: Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)

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