Disclosure Breast cancer incidence Breast cancer is one of the most important diseases for women in the United States and constitutes one fourth of all cancers in females, making it the most common cancer in females. The lifetime probability of developing breast cancer is 1 in 7 for females; breast cancer is 100 times less common in men than in women. Breast cancer accounts for approximately 15% of female cancer deaths. It is the leading cause of death in women aged 44-50 years. The incidence of breast cancer (number of new breast cancers per 100,000 women) increased by approximately 4% during the 1980s but leveled off to 100.6 cases per 100,000 women in the 1990s. The death rates from breast cancer also declined significantly between 1992 and 1996, with the largest decreases among younger women. The American Cancer Society estimates that in 2005, approximately 211,240 women in the United States will be diagnosed with invasive breast cancer (Stages I-IV). The 5-year breast cancer survival rate ranges from 98% for stage I cancer to approximately 16% for stage IV cancer. According to the American Cancer Society, the overall survival rate for breast cancer is as follows:
Approach to evaluation As with all clinical conditions, approach breast cancer evaluation in the systematic way learned at the start of clinical training, namely with an ordered inquiry beginning with symptoms and general clinical history, followed by clinical examination and, finally, investigation, which can include imaging and ultimately biopsy. This approach naturally lends itself to a gradually increasing degree of invasiveness, so that when a diagnosis is obtained, the process can be stopped with the minimum amount of invasion and, consequently, minimum discomfort to the patient. Because the more invasive investigations also tend to be the most expensive, this approach is usually the most economical. Evaluation goals The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan the most appropriate surgery. Therefore, the ultimate goal is to achieve the most appropriate degree of breast conservation while minimizing the need for reoperation. Triple assessment In breast cancer, the general approach to evaluation has become formalized as triple assessment, involving clinical examination, imaging (usually mammography and/or ultrasonography), and needle biopsy, but always perform this as part of a more general assessment beginning with clinical history.
Clinical history Many early breast carcinomas may be asymptomatic, particularly if they were discovered as part of a breast screening program. If the patient has not noticed a lump, then symptoms indicating the possible presence of breast cancer may include the following:
Pain or discomfort is not usually a symptom of breast cancer. The clinician should be alert to symptoms of metastatic spread, such as the following:
The clinical evaluation should include an assessment of specific risk factors for breast cancer, as follows:
Clinical examination Outline the following features in nonmedical terms when instructing a patient in breast self-examination. Explaining to the patient that the axillary tail must be included in the examination is important. Many patients are too anxious to examine their own breasts or find it too difficult, possibly because of generalized nodularity. In this situation, stressing the need of the patient to simply alert a clinician to any change in the breasts, particularly if the change persists through a complete menstrual cycle, is often easier. The following findings should raise concern:
The nature of palpable lumps is often difficult to determine clinically, but the following features should raise concern:
To detect subtle changes in breast contour and skin tethering, the examination must include an assessment of the breasts with the patient upright with arms raised. Assess fixation to muscle by moving the lump in the line of the pectoral muscle fibers with the patient bracing her arms against her hips. A complete examination includes assessment of the axillae and supraclavicular fossae, examination of the chest and sites of skeletal pain, and an abdominal and neurologic examination.
After clinical assessment, the second part of triple assessment involves imaging. Many modalities of imaging can be applied, and the selection is based on age, sensitivity, specificity, local availability, and cost. Performing more than one imaging modality to further improve diagnostic accuracy and to clarify indeterminate findings is often appropriate. The different modalities are compared in Table 1. Table 1. Accuracy of Breast Imaging Modalities
In nonfatty breasts, ultrasonography and MRI are more sensitive than mammography for invasive cancer but involve risk of overestimation of tumor extent. Combined mammography, clinical examination, and MRI are more sensitive than any other individual test or combination of tests. Mammography Two-view mammography (ie, craniocaudal and oblique) is the imaging method of choice for breast screening. In the United States, annual screening mammography is recommended with clinical examination in women aged 40 years. Despite its use as the tool of choice for breast screening, mammography has significant limitations when used in isolation. Although in general a highly sensitive investigation, sensitivity is much reduced in younger or denser breasts; therefore, mammography is considered inappropriate in patients younger than 35 years. However, many centers are now using mammography in patients aged 30 years and older who are in high-risk groups. Evaluation of breast tissue is not possible when obscured by implants or in the presence of heavy scarring from previous surgery. The positive predictive value of mammography can be as low as 10%, demonstrating the need for other imaging modalities, such as ultrasonography, to distinguish solid from cystic radiodensities. However, mammography remains the investigation of choice for detecting and classifying microcalcification. Benign microcalcification is characterized by diffuse scattering and crescentic "tea-cupping." Malignant microcalcification is characterized by isolated clusters, punctate of varying sizes, and a branching or linear pattern. Mammography is also efficient for helping detect larger patterns of calcification, such as the outlining of calcified arterioles or the coarse patchy calcification of long-standing fibroadenomata. Other features that raise concern on mammography images include (1) lesions with ill-defined edges, (2) areas of distortion, (3) asymmetry between breasts, and (4) spiculated lesions. Indeterminate radiodensities can be assessed further mammographically using (1) additional angled views, (2) magnified images, (3) compression images, and (4) alterations in exposure or contrast. Recent advances in mammography include digital mammography, contrast-enhanced mammography, and computer-aided detection (CAD). Digital mammography uses essentially the same mammographic system as conventional mammography, but it is equipped with digital receptors instead of film cassettes. The digital detectors convert x-ray photons to digital signals for display on high-resolution monitors. The processes of acquisition, storage, and display of images can be separated and individually optimized, thus allowing alteration of the magnification, brightness, contrast, and orientation of the mammogram. Digital spot view mammography allows faster and more accurate stereotactic biopsy, whereas full-field digital mammography (FFDM) is being promoted as the future modality for the screening and diagnosis of breast cancer. The benefits of FFDM include the following:
Contrast-enhanced mammography uses the principle that aggressive cancers are associated with increased vascularity. Iodinated contrast agents are administered, they distribute throughout the blood system, and x-ray imaging shows increased contrast where they concentrate. Individual images are obtained and then reconstructed into 3-dimensional series of thin high-resolution slices. These slices reduce tissue overlap and structural noise relative to standard 2-dimensional images. The dose of radiation is, however, the same. CAD uses an image checker computer that analyzes mammographic films that have been scanned and digitized. It then highlights suspicious areas that may be indicative of cancer, thus acting as a pair of second eyes. Studies have shown that for every 100 cancers detected on screening, 22 remain undiagnosed by the radiologist. Use of CAD along with the regular evaluation reduces oversight cases by 99%. CAD is particularly good for dense breasts. Ultrasonography Mammographic features often require further ultrasonographic evaluation, for example to distinguish between solid and cystic lesions or to accurately determine the size of a spiculated lesion. Therefore, ultrasonography is an indispensable adjunct to mammography and is one of the most useful investigations to perform on a patient with a palpable breast lump. Ultrasonography is becoming ever more sophisticated. Higher resolutions are being achieved, and the introduction of Doppler enables definition of characteristic blood flow patterns. This can aid in separating benign and malignant lesions and distinguishing lymph node metastases from normal or reactive lymph nodes. Tridimensional images may also be useful in the future. Ultrasonographic features of malignancy include the following:
Features of benign lesions include the following:
MRI MRI is a particularly useful modality for detailing architectural abnormalities in the breast and can help detect lesions as small as 2-3 mm. In cancers, it is useful in defining the precise size of the tumor and in detecting multifocal disease. This is particularly helpful when deciding whether borderline cases are appropriate for breast-conserving surgery. MRI allows for the construction of tridimensional images, and its versatility is enhanced by the use of different sequences, including high-resolution, rapid-imaging, fat-suppression, subtraction, and dynamic sequences. Dynamic imaging is the most specific sequence and can help distinguish between benign and malignant lesions, which is particularly useful in the scarred breast when looking for tumor recurrence. Dynamic imaging relies on the shape of the time-signal curves using gadolinium-diethylenetriamine pentaacetic acid enhancement; malignancies typically show rapid, strong enhancement because of high vascularity. Advantages of MRI compared with conventional imaging techniques to detect breast cancer include the following:
Scintimammography Scintimammography, while less sensitive than MRI for lesions smaller than 1 cm, is more specific for palpable lesions and is useful for detecting axillary involvement. The label typically used is technetium Tc 99m Sestamibi, a compound that concentrates in mitochondria. The efflux of this label is related to expression of the multidrug resistance protein. Therefore, the size of the signal distinguishes the high metabolic rate of a malignant tumor and may help predict resistance to chemotherapy. Single-photon emission computed tomography promises to advance scintimammography in the same way that CT scans have advanced plain radiographs. Positron emission tomography PET is the most sensitive and specific of all the imaging modalities for breast disease, but it is also one of the most expensive and least widely available. Using a wide range of labeled metabolites (eg, fluorinated glucose [18FDG]), changes in metabolic activity, vascularization, oxygen consumption, and tumor receptor status can be detected. At present, its main use may be for helping detect recurrences in scarred breasts, but it is also useful in multifocal disease and in helping detect axillary involvement. |
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Pathologic diagnosis of a breast lesion can be achieved using a number of biopsy techniques. With a larger biopsy sample, greater accuracy and more information are obtained, but this is at the expense of increased invasiveness. Ideally, needle biopsies should be performed after imaging to help prevent distortions of imaging due to hematoma. Table 2 compares the accuracy of needle biopsy techniques. Table 2. Accuracy of Needle Biopsy Techniques
Fine-needle aspiration The least invasive method of biopsy is FNA. The technique of FNA is determined largely by individual preference, which may, in part, reflect hand size and strength. A 21-gauge (green) needle is used most commonly, although a 23-gauge (blue) needle can yield as much information in some people's hands, with less discomfort and bruising. Some clinicians opt for a hand-held 10-mL syringe, while others prefer a 20-mL syringe used with a syringe holder. Syringe holders allow a vacuum to be maintained easily but can make control of the needle tip less precise. Disinfect the skin with an alcohol wipe, and pass the needle through the lesion a number of times, while maintaining suction and steadying the breast tissue with the other hand. With all needle biopsies of the breast, appreciating the risk of causing a pneumothorax is important; wherever possible, angle the needle tangentially to the chest wall. Continue sampling until aspirate is observed at the bottom of the plastic portion of the needle. Transfer the aspirate to the slides. Spread the aspirate thin enough to visualize individual cells. The slides may be air-dried or fixed according to the preference of the local laboratory. Cytospin preparations of the aspirate may allow a greater number of slides to be made. Wide-bore needle biopsy A Tru-Cut needle, ideally 14-gauge, is used for core biopsy. Because of the fibrous nature of much breast tissue, adequate samples are best obtained using a spring-loaded firing device, such as the Biopty-Cut system. The procedure is often less painful than FNA despite the wider-bore needle. Inject local anesthetic beneath the skin. The cores from a few passes of the needle are fixed immediately in formalin. If the lesion contains calcification based on the mammogram findings, x-ray films of the cores are taken to confirm presence of calcification and, therefore, are representative. The risk of bruising is higher than with FNA, and typically a pressure dressing is applied for at least 24 hours. Often, the samples are large enough to allow detailed histologic assessment, including the type and grade of the tumor and hormone receptor status, but sampling error may occur if the cores are not representative of the entire lesion. Some centers now provide even wider-bore core biopsies, up to 11-gauge, using the Mammotome vacuum system. This apparatus is relatively expensive, but the technology may lead to new methods of therapeutic excision biopsy without resorting to open surgery. Excision biopsy The ultimate diagnostic biopsy is open excision biopsy of a lesion, normally performed under general anesthetic. Open excision biopsy should be reserved for lesions for which some doubt remains regarding diagnosis after less invasive assessment or for benign lesions that the patient wants removed. A wide clearance of the lesion is usually not the goal in diagnostic biopsies, thus avoiding unnecessary distortion of the breast. Ongoing audit is essential to help reduce an excessive benign-to-malignant biopsy ratio.
Criteria for screening In women older than 40 years, breast screening in the United States occurs annually by clinical examination and 2-view mammography (ie, oblique and craniocaudal). In patients aged 20-39 years, clinical examination is advised every 3 years, supplemented by breast self-examination every month. The 2003 American Cancer Society guidelines for breast cancer screening are as follows:
Recall Any abnormalities detected through screening are observed by recall of the patient to the assessment clinic, where further imaging may be undertaken. This is usually in the form of ultrasonography or further mammographic views, such as lateral, magnified, or compression views, or alterations in exposure. Biopsy Because most of the lesions detected during screening are early impalpable abnormalities, subsequent needle biopsy must be image-guided. Ultrasonographic-guided biopsy is the most straightforward approach, but lesions better seen on mammography images, particularly microcalcifications, require stereotactic localization. More modern stereotactic imagers allow the use of core biopsy or the Mammotome. Radiographs of these larger samples then may be obtained to ensure that they contain evidence representative of microcalcification. Ultimately, open biopsy, which may be aided by skin marking by the ultrasonographer or by ultrasonographic-guided or stereotactic wire localization, may be necessary. If the procedure is intended for diagnosis rather than therapy, a maximum biopsy size of 20 g is desired to reduce unnecessary cosmetic distortion. To avoid too many unnecessary biopsies, a breast unit's benign biopsy rate should not greatly exceed the malignant rate.
Before deciding on definitive treatment for a newly diagnosed breast cancer, staging the disease is necessary because results may affect the choice of first-line treatment. Lymph node involvement makes a full axillary clearance more appropriate, whereas distant spread of disease may indicate primary chemotherapy. The most common method of denoting the stage of the disease is the TNM (tumor, node, metastases) system. The TNM classification of breast cancer is as follows:
Evaluation of the axillaClinical Clinical evaluation of the axilla for lymph node metastases is not particularly sensitive, although some use it for selecting patients for preoperative staging investigations. Imaging Conventional 2-view mammography does not adequately cover all of the axillary contents, whereas ultrasonography and Doppler studies can be directed to cover all of the axilla. Similarly, MRI, scintimammography, and PET scans can help reliably detect abnormalities in the axilla because of their wider field. Intraoperative assessment Intraoperative assessment of axillary samples helps to determine whether to continue on to a full axillary clearance during the same operation. Techniques include the following:
Laboratory evaluation of specimen As many as 45-48 lymph nodes can be present according to the level of axillary clearance. These are identified and assessed by a number of techniques, as follows:
Serologic testsSerological tests provide general information on the patient's overall health in the face of disseminated disease, but, more specifically, results can indicate sites of possible metastases or, in the case of tumor markers, can help estimate the disease load.
ImagingImaging is a useful noninvasive form of assessment, with the simplest staging scans being plain chest radiograph and liver ultrasonic scan. Often, technical difficulties with the liver scan (eg, due to patient body habitus) necessitate CT scans. With contrast, CT scans can help specify lesions with high vascularity. CT scan is also useful for helping detect lung and brain metastases and high axillary and intrathoracic lymphadenopathy. Bone scans, for example using technetium Tc 99m methylene diphosphonate, are sensitive for increased osteoclastic activity, but their specificity relies on the pattern of distribution of the tracer in the body in view of the frequent detection of degenerative disease. Attention must be given to a history of old fractures or arthritis. Ultimately, the whole body scan can be used to direct further, more localized, corroborative imaging such as plain radiographs or CT scan and/or MRI of the spine. Suggestive characteristics of tracer distribution include single high-signal areas in the spine, asymmetric distribution, and occurrence away from joints and tendon insertions (ie, not arthritis). BiopsyBiopsy may be needed for final confirmation of suggested metastases, which may involve cytologic analysis of pleural or ascitic tap fluid or direct image-guided needle biopsy into lymph nodes, liver, or bone. Micrometastases in bone marrow aspirates or lymph node biopsy specimens can be determined based on findings from immunocytochemistry (ie, cytokeratins CK19 and CAM 5.2), PCR, and RT-PCR.
Criteria for prognostic indicatorsFor a prognostic indicator to be accepted as clinically useful, ideally it must have the following criteria:
One of the most successful indices of prognosis in breast cancer is the Nottingham Prognostic Index (NPI), which can be used to select patients for adjuvant treatment and which makes use of the following 3 proven prognostic indicators: NPI = [0.2 X tumor size in cm] + tumor grade [1-3] + lymph node stage [1-3] The addition of the progesterone receptor status, angiogenesis, and VEGF status to the classic parameters from which NPI is derived makes it possible to increase prognostic capacity of this index further. Prognostic indicatorsTumor size Prognosis deteriorates with increasing tumor size, which is an independent predictor of survival in node-negative patients and correlates with the incidence of nodal metastases. Staging The status of the axillary lymph nodes is one of the most useful prognostic indicators for breast cancer, with average 10-year survival rates of 60-70% for node-negative patients, dropping to 20-30% in node-positive patients. Metastatic spread in other parts of the body invariably indicates axillary node positivity. Histopathology
Other prognostic indicators Advances in the knowledge of the molecular mechanisms that influence normal and aberrant cell growth has led to the identification of an increasing number of surrogate biomarkers, which have been correlated with prognosis or used as predictors of response to specific treatments. These novel prognostic markers can be classified as follows:
Need for follow-up care Whether regular follow-up care affects overall or disease-free survival is debatable, as is whether significantly more recurrences are detected than would be otherwise by the patients themselves or their general practitioners. However, a number of reasons support continuing evaluation of patients with breast cancer following their initial treatment plan, as follows:
Frequency of follow-up care Different centers vary in the precise scheduling of hospital follow-up appointments, but the general trend is to reduce the frequency of clinic visits until final discharge to the breast screening service after 10 years if no new disease has occurred. Following is a suggested schedule for the hospital follow-up care for patients who have undergone curative resection:
Types of follow-up evaluation Clinical assessment at each visit is mandatory, paying special attention to symptoms and signs of local or distant recurrence. Mammography every year for patients who have had breast-conservation surgery is standard, although other modalities of imaging may be appropriate, such as MRI in the scarred breast or for patients in whom the primary tumor was not detected on mammography images. For patients postmastectomy, twice-yearly mammograms of the other breast may be sufficient. Special investigations may be indicated if new symptoms or signs suggestive of local or distant recurrence develop, encompassing all imaging, serologic, and biopsy evaluations covered in the previous sections. Patient education For excellent patient education resources, visit eMedicine's Imaging Center, Cancer and Tumors Center, and Women's Health Center . Also, see eMedicine's patient education articles Mammogram, Breast Cancer, Breast Lumps and Pain, and Breast Self-Exam. Future of breast cancer evaluation Newer imaging technologies that are being developed include optical imaging, electrical potential measurements, dedicated breast CT, thermography, and microwave imaging. Newer treatment modalities include immunotherapy and modeling treatment. Immunotherapy involving specific active cancer vaccines or nonspecific immunostimulation with cytokines is available. Modeling treatment to the genotype of individual cancers is currently being used.
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