Breast Cancer Evaluation: Introduction The aims of evaluation of a breast lesion are to judge whether Breast cancer incidence surgery is required and, if so, to plan the most appropriate Breast cancer is one of the most important diseases for women surgery. The ultimate goal of surgery is to achieve the most in the United States and constitutes one fourth of all cancers in appropriate degree of breast conservation while minimizing the females, making it the most common cancer in females. need for reoperation. Women in North America have the highest incidence of breast Triple assessment cancer in the world. The lifetime probability of developing In breast cancer, the general approach to evaluation has breast cancer in the United States is 1 in 8 for females. Breast become formalized as triple assessment, involving clinical cancer is 100 times less common in men. examination, imaging (usually mammography and/or Breast cancer accounts for approximately 15% of female cancer ultrasonography), and needle biopsy, but always perform this deaths. It is the leading cause of death in women aged 44-50 as part of a more general assessment beginning with clinical years. The incidence of breast cancer (number of new breast history. cancers per 100,000 women) increased during the 1980s but Clinical Assessment leveled off in the 1990s and declined between 2001 and 2003. Clinical history The current incidence is estimated at around 120 cases per Many early breast carcinomas may be asymptomatic, 100,000 women in the United States. The American Cancer particularly if they were discovered during a breast screening Society estimated that in 2007, approximately 178,480 women program. If the patient has not noticed a lump, then symptoms in the United States will be diagnosed with invasive breast indicating the possible presence of breast cancer may include cancer (Stages I-IV) and a further 62,030 will be diagnosed with the following: carcinoma in situ (CIS). Worldwide, the incidence of breast Change in breast size or shape cancer is highest in developed countries in North America and Skin dimpling Western Europe, with lowest incidences seen in South America, Recent nipple inversion or skin change Africa and parts of Asia. Within the United States, breast cancer Single-duct discharge, particularly if bloodstained incidence is highest in White women, lower in African American Axillary lump and Hispanic population and lowest in American Indian and Pain or discomfort is not usually a symptom of breast cancer. Alaskan native women. The clinician should be alert to symptoms of metastatic spread, The 5-year breast cancer survival rate ranges from 98% for such as the following: stage I cancer to approximately 16% for stage IV cancer. Death Breathing difficulties rates from breast cancer have steadily declined since the early Bone pain 1990s, with the largest decreases among younger women. Symptoms of hypercalcemia Nevertheless, it is estimated that about 40,460 women and 450 Abdominal distension men will die from breast cancer in the United States in 2007. Jaundice According to the American Cancer Society, the overall survival rate for breast cancer is as follows: Localizing neurological signs 85% after 5 years Altered cognitive function The clinical evaluation should include an assessment of specific 71% after 10 years risk factors for breast cancer, as follows: 57% after 15 years 1. Age 52% after 20 years Breast cancer is rare in women younger than 25 years. Approach to evaluation Incidence increases with age, with a plateau in women Breast cancer evaluation should be approached with an aged 50-55 years. ordered inquiry beginning with symptoms and general clinical history, followed by clinical examination and, finally, Age is the most significant risk factor. investigation, which may include imaging and biopsy. This 2. Genetics approach naturally lends itself to a gradually increasing degree Family history is a risk factor. The lifetime risk is up to 4 of invasiveness, so that when a diagnosis is obtained, the times higher if a mother and sister are affected. The family process can be stopped with the minimum amount of invasion history characteristics that suggest increased risk of cancer and, consequently, minimum discomfort to the patient. are as follows: Because the more invasive investigations also tend to be the Two or more relatives with breast or ovarian cancer most expensive, this approach is usually the most economical. Breast cancer occurring in an affected relative younger Evaluation goals than 50 years Relatives with both breast cancer and ovarian cancer One or more relative with 2 cancers (breast and ovarian 8. Other dietary, cultural, and/or geographic influences cancer or two independent breast cancers) High-risk regions include North America and northern Male relatives with breast cancer Europe. Individuals of Ashkenazi Jewish descent have a 2-times Low-risk regions include Japan and Hawaii; however, greater risk. descendants migrating to the United States take on the Japanese and Taiwanese woman have one fifth the risk higher US risk. when compared with US women. Clinical examination BRCA1 and BRCA2 mutations are associated with higher Outline the following features in nonmedical terms when risk. However, one study indicates that women with instructing a patient in breast self-examination. Explaining to the BRCA1 and BRCA2 mutationswho undergo risk- the patient that the axillary tail must be included in the 1 reducing mastectomy have a lower risk of breast cancer. examination is important. Many patients are too anxious to Ataxia telangiectasia heterozygotes are at 4-times examine their own breasts or find it too difficult, possibly increased risk. because of generalized nodularity. In this situation, stressing 3. Other pathology the need of the patient to simply alert a clinician to any change Risk is increased with previous breast cancer, ovarian in the breasts, particularly if the change persists through a cancer, endometrial cancer, ductal carcinoma in situ, complete menstrual cycle, is often easier. The following lobular carcinoma in situ, hyperplasia (unless mild), findings should raise concern: complex fibroadenoma, radial scar, papillomatosis, Lump or contour change sclerosing adenosis, and microglandular adenosis. Skin tethering Risk is decreased with cervical cancer. Nipple inversion 4. Years menstruating Dilated veins Factors increasing the number of menstrual cycles increase Ulceration the risk, probably due to increased endogenous estrogen Paget disease exposure. Edema or peau d'orange Such factors include (1) nulliparity, (2) first full pregnancy The nature of palpable lumps is often difficult to determine when older than 30 years, (3) menarche when younger clinically, but the following features should raise concern: than 13 years (2 times the risk), (4) menopause when older Hardness than 50 years, and (5) not breastfeeding. Irregularity 5. Obesity: Increased risk is probably due to adipose Focal nodularity conversion of androgens to estrogens. Asymmetry with the other breast 6. Socioeconomic class: Incidence is increased in individuals Fixation to skin or muscle in a higher socioeconomic class. To detect subtle changes in breast contour and skin tethering, 7. Exogenous factors the examination must include an assessment of the breasts Hormone replacement therapy increases risk (1.35 times with the patient upright with arms raised. Assess fixation to for 5 or more years use, normalizing 5 years from muscle by moving the lump in the line of the pectoral muscle 2 discontinuing). fibers with the patient bracing her arms against her hips. A The use of oral contraceptive pills increases risk (1.24 times complete examination includes assessment of the axillae and for 10 years use, normalizing 10 years from discontinuing). supraclavicular fossae, examination of the chest and sites of The progesterone-only pill is not associated with increased skeletal pain, and an abdominal and neurological examination. 3 risk. Breast Cancer Imaging The use of diethylstilbestrol increases risk. After clinical assessment, the second part of triple assessment Alcohol consumption is associated with an increased risk, involves imaging. Numerous imaging modalities are available probably through increasing estrogen levels. and the selection may be based on age, sensitivity, specificity, Irradiation, particularly in first decade of life, is associated local availability, and cost. Performing more than one imaging with an increased risk of breast cancer. modality to further improve diagnostic accuracy and to clarify Dichlorodiphenyldichloroethylene, a metabolite of the indeterminate findings is often appropriate. The different insecticide dichlorodiphenyltrichloroethane (DDT), imaging modalities are compared in Table 1. exposure increases risk. Exposure to some viral agents (e.g. mouse mammary tumor virus) is associated with increased risk. Table 1. Accuracy of Breast Imaging Modalities In nonfatty breasts, ultrasonography and MRI are more Moda Sensitivity Specif Positive Indications sensitive than mammography for invasive cancer but may lity icity Predictive overestimate tumor extent. Combined mammography, clinical Value examination, and MRI are more sensitive than any other Mam 63-95% 14- 10-50% Initial individual test or combination of tests. mogr (>95% 90% (94% investigation Mammography aphy palpable, (90% palpable) for Two-view mammography (ie, craniocaudal and oblique) is the 4 50% palpa symptomatic imaging method of choice for breast screening. In the United impalpable, ble) breast in States, annual screening mammography has been recommend 83-92% in women older with clinical examination in women starting at age 40 5 women than 35 years years. However, in November 2009, the US Preventive Services older than and for Task Force (USPSTF) issued updated breast cancer screening 50 y) screening; guidelines that recommend against routine mammography (decreases investigation of before age 50 years. Instead, for women aged 40-49 years, the to 35% in choice for USPSTF suggests that the decision to start regular screening dense microcalcificati mammography be individualized and should include the breasts) on patient's values regarding specific benefits and harms (Grade C 6 Ultras 68-97% 74- 92% Initial recommendation). onogr (palpable) 94% (palpable) investigation In addition, rather than annual screening, the USPSTF aphy (palp for palpable guidelines recommend that screening mammography be able) lesions in performed biennially (Grade B recommendation). The USPSTF women concludes that there is currently insufficient evidence to assess younger than the additional benefits and harms of screening mammography 35 years in women aged 75 years or older and thus recommends 6 MRI 86-100% 21- 52% Scarred breast, stopping screening at age 74 years. 97% implants, In response, the American College of Obstetricians and (<40 multifocal Gynecologists (ACOG) has stated that while it is evaluating the % lesions, and USPSTF guidelines in detail, for the present it continues to prima borderline recommend adherence to current ACOG guidelines. These ry lesions for include screening mammography every 1-2 years for women cance breast aged 40-49 years and screening mammography every year for r) conservation; women age 50 or older. The ACOG notes, however, that may be useful because of the USPSTF downgrading, some insurers may no 7 in screening longer cover some of these studies. high-risk Despite its use as the tool of choice for breast screening, women mammography has significant limitations when used in Scinti 76-95% 62- 70-83% Lesions larger isolation. Although in general a highly sensitive investigation, 8 graph (palpable) 94% (83% than 1 cm and sensitivity is much reduced in younger or denser breasts ; y 52-91% (94% palpable, axilla therefore, mammography is considered inappropriate in (impalpable) impal 79% assessment; patients younger than 35 years. Evaluation of breast tissue is pable impalpable may help not possible when obscured by implants or in the presence of ) ) predict drug heavy scarring from previous surgery. resistance The positive predictive value of mammography can be as low as Positr 96% 100% Axilla 10%, demonstrating the need for other imaging modalities, on (90% axillary assessment, such as ultrasonography or magnetic resonance imaging, to emissi metastases) scarred breast, distinguish solid from cystic radiodensities. However, on and multifocal mammography remains the investigation of choice for tomo lesions detecting and classifying microcalcification. Benign graph microcalcification is characterized by diffuse scattering and y crescentic "tea-cupping." Malignant microcalcification is (PET) characterized by isolated clusters, punctate of varying sizes, and a branching or linear pattern. Mammography is also and structural noise relative to standard 2-dimensional images. efficient for helping detect larger patterns of calcification, such The dose of radiation is, however, the same. as the outlining of calcified arterioles or the coarse patchy Computer-aided detection uses an image checker computer calcification of long-standing fibroadenomata. that analyzes mammographic films that have been scanned and Other features that raise concern on mammography images digitized. This technology was approved by the FDA in 1998 and include (1) lesions with ill-defined edges, (2) areas of distortion, is able to highlight suspicious areas that may be indicative of 9 (3) asymmetry between breasts, and (4) spiculated lesions. cancer, thus acting as a pair of second eyes. Research has Indeterminate radiodensities can be assessed further suggested that the regular use of computer-aided detection mammographically using (1) additional angled views, (2) may oversight cases by 99%, particularly for patients with magnified images, (3) compression images, and (4) alterations dense breasts. However, a study of more than 200,000 women in exposure or contrast. concluded that computer-aided detection was associated with Recent advances in mammography include digital a reduction in diagnostic accuracy and a significant increase in 10 mammography, contrast-enhanced mammography, and biopsy rate. Further development and evolution of the computer-aided detection. Digital mammography uses technology may increase the use of computer-aided detection essentially the same mammographic system as conventional in the future. mammography, but it is equipped with digital receptors instead Ultrasonography of film cassettes. The digital detectors convert x-ray photons to Ultrasonographic evaluation in addition to mammography can digital signals for display on high-resolution monitors. The help distinguish between solid and cystic lesions, accurately processes of acquisition, storage, and display of images can be determine the size of a spiculated lesion and guide accurate separated and individually optimized, thus allowing alteration biopsy of a suspicious area. Ultrasonography is therefore of the magnification, brightness, contrast, and orientation of considered an indispensable adjunct to mammography and is the mammogram. one of the most useful investigations to perform on a patient The diagnostic accuracy of digital mammography has been with a palpable breast lump. shown to be similar overall to traditional film mammography. Ultrasonography is becoming ever more sophisticated. Higher However, digital mammography is more accurate in younger or resolutions are being achieved, and the introduction of Doppler premenopausal women and women with radiographically enables accurate definition of characteristic blood flow dense breasts. Digital spot view mammography allows faster patterns. This can aid in differentiating benign and malignant and more accurate stereotactic biopsy, whereas full-field digital lesions and distinguishing lymph node metastases from normal mammography (FFDM) is being promoted as the future or reactive lymph nodes. With evolving ultrasonographic modality for the screening and diagnosis of breast cancer. In technology, image resolution and quality is likely to improve, 2006, around 10% of mammography units in the United Stated confirming the place of ultrasonography as an essential used digital mammography, although this is likely to become modality for the investigation of patients with suspected breast more prevalent in the future. cancer. The benefits of digital mammography include the following: Ultrasonographic features of malignancy include the following: 1. Faster image acquisition with shorter exposure and 1. Poorly defined borders examination time 2. Heterogeneous internal echoes 2. Ability to correct under- or overexposed images, thus 3. Disruption of the tissue layers preventing the need for repeat mammography 4. Irregular shadowing 3. Improved diagnostic accuracy in some patient groups 5. Superficial echo enhancement 4. Improved contrast between dense and nondense breasts 6. Depth greater than height 5. Enables the easy storage of images and their sharing 7. High vascular density and flow rates on Doppler images between health professionals (including remote Features of benign lesions include the following: consultation) 1. Cyst - Absence of internal echoes, marked deep Contrast-enhanced mammography uses the principle that enhancement aggressive cancers are associated with increased vascularity. 2. Fibroadenoma - Well-defined borders, well-defined Iodinated contrast agents are administered, they distribute internal echoes, and displacement of tissue planes throughout the circulation, and x-ray imaging shows increased 3. Lymph node - Well-defined peripheral blood flow on contrast where they concentrate. Individual images are Doppler images obtained and then reconstructed into 3-dimensional series of MRI thin high-resolution slices. These slices reduce tissue overlap 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 to annual mammography and clinical breast examination in 15 the tumor and in detecting multifocal disease. This may be of women in the following situations: particular importance when assessing whether borderline case 1. BRCA1 or BRCA2 mutation are suitable for breast-conserving surgery. 2. Have not undergone genetic testing but have a first-degree MRI allows for the construction of 3-dimensional images, and relative with a BRCA1 or BRCA2 mutation its versatility is enhanced by the use of different sequences, 3. Lifetime risk greater than 20% based on models that are including high-resolution, rapid-imaging, fat-suppression, highly dependent on family history subtraction, and dynamic sequences. 4. History of lobular carcinoma in situ Dynamic imaging is the most specific sequence and can help 5. Underwent radiation treatment to the chest between age distinguish between benign and malignant lesions, and is 10 and 30 years particularly useful in the assessment of the scarred breast 6. Carry or have a first-degree relative who carries a genetic when looking for tumor recurrence. Dynamic imaging relies on mutation in the TP53 or PTEN genes (Li-Fraumeni, Cowden, the shape of the time-signal curves using gadolinium- and Bannahyan-Riley-Ruvalcaba syndromes) diethylenetriamine penta-acetic acid enhancement; According to the NCCN, MRI is specifically not recommended malignancies typically show rapid, strong enhancement for screening women at average risk for breast cancer. because of high vascularity. Scintimammography The American Cancer Society published guidelines for the use This radioisotope study typically uses technetium Tc 99m 11 of MRI for screening high-risk women. Screening MRI is Sestamibi, a compound that concentrates in mitochondria. The recommended for women with an approximate lifetime risk of efflux of this label is related to expression of the multidrug 20% or greater. However, data to support the use of screening resistance protein. Therefore, the size of the signal MRI in women at intermediate or low risk are insufficient. distinguishes the high metabolic rate of a malignant tumor and Advantages of MRI compared with conventional imaging may help predict resistance to chemotherapy. techniques to detect breast cancer include the following: Scintimammography, while less sensitive than MRI for lesions Improved staging and treatment planning smaller than 1 cm, is more specific for palpable lesions and is Enhanced evaluation of enhanced breast useful for detecting axillary involvement. Better detection of recurrence Single-photon emission computed tomography promises to Improved screening in high-risk patients 12 advance scintimammography in the same way that CT scans Wasif et al found that MRI was more accurate than have advanced plain radiographs. ultrasonography or mammography for determination of the Positron emission tomography size of a breast cancer mass. They compared 61 breast cancers PET is the most sensitive and specific of all the imaging using the 3 modalities; the Pearson correlation coefficient was modalities for breast disease, but it is also one of the most 0.80 for MRI, 0.57 for ultrasonography, and 0.26 for expensive and least widely available. Using a wide range of mammography. Mean tumor size was 2.1 cm by labeled metabolites (eg, fluorinated glucose [18FDG]), changes mammography, 1.73 cm by ultrasonography, 2.65 cm by MRI, in metabolic activity, vascularization, oxygen consumption, and and 2.76 cm by pathology. MRI-based tumor size was within 1 tumor receptor status can be detected. At present, its main use cm of pathologic size in 44 tumors (72%), more than 1 cm may be for helping detect recurrences in scarred breasts, but it above pathologic size in 6 tumors, and more than 1 cm below is also useful in multifocal disease, detecting axillary 13 16 pathologic size in 11 tumors. involvement and in equivocal cases of systemic metastases. According to Dang et al, breast MRI has been shown to have Biopsy greater sensitivity than both mammography and Pathologic diagnosis of a breast lesion can be achieved using a ultrasonography, but there have been concerns that increased number of biopsy techniques. The use of image guidance use of MRI for breast cancer screening will result in an (usually ultrasonography) significantly increases biopsy success increased rate of mastectomy in women with early-stage rates, irrespective of needle size. Visualization of postfire breast cancer. However, the authors found that from 2003- needle tip position can help verify the accuracy of biopsy for 2007, although the number of breast MRIs ordered by their discrete mass lesions. With a larger biopsy sample, greater institution rose from 68 annually to 358 annually, the accuracy and more information are obtained, but at the percentage of women who underwent mastectomy did not expense of increased invasiveness. Ideally, needle biopsies 14 change over that period. should be performed after imaging to help prevent distortions The 2009 National Comprehensive Cancer Network (NCCN) of imaging due to tissue trauma and hematoma. Table 2 Clinical Practice Guidelines in Oncology for Breast Cancer compares the accuracy of needle biopsy techniques. Screening and Diagnosis include using breast MRI as an adjunct Table 2. Accuracy of Needle Biopsy Techniques Needle type Sensitivity Specificity Mammotome biopsy Fine-needle aspiration (FNA) 52-95% 95-100% The mammotome is an instrument for taking breast tissue Tru-Cut 68-84% 100% biopsies using vacuum-assistance. The 11-gauge needle is Biopty cut 18G 93-96% 100% positioned using ultrasonography or mammographic guidance Biopty cut 14G 88-98% 100% (under local anesthetic) and targeted breast tissue is drawn, Mammotome 100% cut, and saved in a collecting chamber. This apparatus is Fine-needle aspiration relatively expensive, but may be an alternative to open surgery The least invasive method of biopsy is FNA. The technique of for the therapeutic excision of benign lesions <15 mm or FNA is determined largely by individual preference, which may, additional tissue biopsy in patients with microcalcification or in part, reflect hand size and strength. A 21-gauge (green) borderline breast lesions. needle is used most commonly, although in expert hands, a 23- Excision biopsy gauge (blue) needle can yield as much information, with less The ultimate diagnostic biopsy is open excision biopsy of a discomfort and bruising. Some clinicians opt for a hand-held lesion, normally performed under general anesthetic. Open 10-mL syringe, while others prefer a 20-mL syringe used with a excision biopsy should be reserved for lesions where the syringe holder. Syringe holders allow a vacuum to be diagnosis remains equivocal despite imaging and less invasive maintained easily but can make control of the needle tip less assessment or for benign lesions that the patient chooses to precise. have removed. A wide clearance of the lesion is usually not the To perform a fine needle aspiration, the skin should be goal in diagnostic biopsies, thus avoiding unnecessary disinfected with an alcohol wipe, and the needle passed distortion of the breast. Ongoing audit is essential to help through the lesion a number of times, while maintaining reduce an excessive benign-to-malignant biopsy ratio. suction and steadying the breast tissue with the other hand. Evaluation of Screen-detected Lesions Appreciating the potential risk of pneumothorax is Criteria for screening important when performing needle biopsies of the breast, and In women older than 40 years, breast screening in the United wherever possible, the needle should be angled tangentially to States occurs annually by clinical examination and 2-view the chest wall. Continue sampling until aspirate is observed at mammography (ie, oblique and craniocaudal). In patients aged the bottom of the plastic portion of the needle. 20-39 years, clinical examination is advised every 3 years, Transfer the aspirate to the slides. Spread the aspirate thin supplemented by breast self-examination every month. enough to visualize individual cells. The slides may be air-dried The American Cancer Society guidelines for breast cancer or fixed according to the preference of the local laboratory. screening are as follows: Cytospin preparations of the aspirate may allow a greater 1. Average-risk women number of slides to be made. Clinical breast examination performed annually for women Wide-bore needle biopsy older than 40 years A Tru-Cut needle, ideally 14-gauge, is used for core biopsy. Yearly mammogram starting at age 40 years Because of the fibrous nature of much breast tissue, adequate Clinical breast examination every 3 years for women aged samples are best obtained using a spring-loaded firing device, 20-30 years such as the Biopty-Cut system. The procedure is often less 2. Older women: Individualize screening decisions painful than FNA despite the wider-bore needle. considering potential benefits and risks of mammography After local anesthetic subcutaneous injection, cores of tissue in context of current health status and estimated life can be taken and should be immediately fixed in formalin. If expectancy. the lesion contains calcification based on the mammogram 3. Women at >20% lifetime risk offered annual MRI in findings, radiographs of the cores are taken to confirm addition to mammography presence of calcification and, therefore, are representative. The 4. Women at 15-20% lifetime risk advised to discuss the risk of bruising is higher than with FNA. For this reason, benefits and limitations of MRI in addition to annual anticoagulants should be stopped, where possible prior to mammography biopsy and a pressure dressing is applied usually for at least 24 5. Other strategies for women at increased risk hours. o Early initiation of screening Often, the samples are large enough to allow detailed o Shorter screening intervals histological assessment, including tumor type and grade and Recall hormone receptor status, but sampling error may occur if the Any abnormalities detected through screening are observed by cores are not representative of the entire lesion. 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 Stage N1 - Palpable ipsilateral axillary lymph nodes lateral, magnified, or compression views, or alterations in Stage N2 - Fixed ipsilateral axillary lymph nodes exposure. Stage N3 - Ipsilateral internal mammary nodes Biopsy 3. Metastasis Because most of the lesions detected during screening are Stage - Metastasis not assessable early impalpable abnormalities, subsequent needle biopsy Stage M0 - No evidence of metastasis must be image-guided. Ultrasound-guided biopsy is usually the Stage M1 - Distant metastasis, including ipsilateral most straightforward approach, but lesions better seen on supraclavicular nodes mammography images, particularly microcalcifications, require Evaluation of the Axilla stereotactic localization. More modern stereotactic imagers Clinical allow the use of core biopsy or the Mammotome. Radiographs Clinical evaluation of the axilla for lymph node metastases is of these larger samples then may be obtained to ensure that not particularly sensitive, although some use it to select they contain evidence representative of microcalcification. patients for preoperative staging investigations. Ultimately, open biopsy may be required, if necessary aided by Imaging ultrasonographic guidance, skin marking by the Conventional mammography does not adequately image all of ultrasonographer or stereotactic wire localization. If the the axillary contents, whereas other modalities including procedure is intended for diagnosis rather than therapy, a ultrasonography, MRI, scintimammography, and PET scans can maximum biopsy size of 20 g is desirable to reduce unnecessary reliably detect abnormalities in the axilla because of their wider cosmetic distortion. To avoid too many unnecessary biopsies, field. the benign biopsy rate in a breast unit should not greatly In recent years, axillary ultrasonography has been highlighted exceed the malignant rate. as an important tool for axillary staging. The reported Staging sensitivity of axillary ultrasonography (with FNA or core biopsy Before deciding on definitive treatment for a newly diagnosed of suspicious nodes) for the detection of positive nodes has breast cancer, staging the disease is necessary to plan optimum ranged from 21-33%, suggesting that sentinel node biopsy may treatment. Lymph node involvement makes a full axillary be unnecessary in a significant proportion of node-positive clearance more appropriate, whereas distant spread of disease patients. Increased operator experience and greater may indicate primary chemotherapy. understanding of ultrasonographic criteria for lymph node The most common method of denoting the stage of the disease biopsy are likely to improve the sensitivity for the detection of is the TNM (tumor, node, metastases) system. The TNM involved lymph nodes using this technique. classification of breast cancer is as follows: Intraoperative assessment 1. Tumor Intraoperative assessment of axillary samples helps to Stage TX - Tumor not assessable determine whether to continue on to a full axillary clearance Stage T0 - No primary tumor during the same operation. Techniques include the following: Stage Tis - Carcinoma in situ 1. Four-node sampling by feel Stage T1a - Tumor diameter greater than 0.1 cm but not 2. Sentinel node biopsy (using dye and/or radioactive tracer) greater than 0.5 cm 3. Imprint cytology Stage T1b - Tumor diameter greater than 0.5 cm but not 4. Frozen section greater than 1 cm Laboratory evaluation of specimen Stage T1c - Tumor diameter greater than 1 cm but not Depending on the level of axillary clearance, as many as 45-48 greater than 2 cm lymph nodes may be present. These are identified and assessed Stage T2 - Tumor diameter greater than 2 cm but not by a number of techniques, as follows: greater than 5 cm 1. Palpation and bench-top dissection Stage T3 - Tumor larger than 5 cm 2. En bloc sectioning Stage T4a - Involvement of chest wall 3. Fat clearance techniques 4. Single or multiple sectioning (eg, at 5-mm intervals) Stage T4b - Involvement of skin 5. Immunohistochemistry - Cytokeratin markers Stage T4c - Stages T4a and T4b 6. Reverse transcriptase polymerase chain reaction (RT-PCR) Stage T4d - Inflammatory cancer for micrometastases 2. Node Serologic tests Stage NX - Node not assessable Serologic tests provide general information on the patient's Stage N0 - No regional lymph node metastases overall health in the face of disseminated disease, but, more specifically, results can indicate sites of possible metastases or, One of the most successful indices of prognosis in breast cancer 17 in the case of tumor markers, can help estimate the disease is the Nottingham Prognostic Index (NPI) , which can be used load. to select patients for adjuvant treatment and which makes use 1. Liver involvement - Levels of bilirubin, alkaline of the following 3 proven prognostic indicators: phosphatase, alanine and aspartate transaminases, gamma-glutamyltransferase, 5-nucleotidase, albumin, and NPI = [0.2 X tumor size in cm] + tumor grade [1-3] + lymph node prothrombin time stage [1-3] 2. Pulmonary involvement - Arterial blood gas values 3. Bone involvement - Hypercalcemia, alkaline phosphatase The addition of the progesterone receptor status, angiogenesis, isoenzyme levels (usually normal as osteolytic) and VEGF status to the classic parameters from which NPI is 4. Tumor markers - Cancer antigen 15-3, cancer antigen 72-4, derived makes it possible to increase prognostic capacity of this cancer antigen 27.29, and carcinoembryonic antigen index further. Imaging Prognostic Indicators Imaging is a useful noninvasive form of assessment, with the Tumor size simplest staging scans being plain chest radiograph and liver Prognosis deteriorates with increasing tumor size, which is an ultrasonic scan. Often, technical difficulties with the liver scan independent predictor of survival in node-negative patients (eg, due to patient body habitus) necessitate CT scans. With and correlates with the incidence of nodal metastases. contrast, CT scans can help specify lesions with high vascularity. Staging CT scan is also useful for helping detect lung and brain The status of the axillary lymph nodes is one of the most useful metastases and high axillary and intrathoracic lymph prognostic indicators for breast cancer, with average 10-year adenopathy. survival rates of 60-70% for node-negative patients, dropping Bone scans, for example using technetium Tc 99m methylene to 20-30% in node-positive patients. Metastatic spread in other diphosphonate, are sensitive for increased osteoclastic activity, parts of the body invariably indicates axillary node but their specificity relies on the pattern of distribution of the involvement. tracer in the body in view of the frequent detection of Histopathology 18 degenerative disease. Attention must be given to a history of 1. Histological type old fractures or arthritis. Ultimately, the whole body scan can Because it is a preinvasive condition, carcinoma in situ is be used to direct further, more localized, corroborative imaging curable if completely removed, although 16% of patients such as plain radiographs or CT scan and/or MRI of the spine. with carcinoma in situ develop invasive recurrence after Suggestive characteristics of tracer distribution include single local excision of ductal carcinoma in situ, usually high high-signal areas in the spine, asymmetric distribution, and grade. Similarly, 18% of patients develop invasive occurrence away from joints and tendon insertions (ie, not recurrence after lobular carcinoma in situ excision. arthritis). Well-differentiated invasive cancers have a relatively good Biopsy prognosis if they are tubular, mucinous, cribriform, or Biopsy may be needed for final confirmation of suspected secretory. metastases, which may involve cytologic analysis of pleural or Medullary carcinoma is probably of intermediate ascitic tap fluid or direct image-guided needle biopsy into prognosis, but different studies have used different criteria lymph nodes, liver, or bone. for its definition. Micrometastases in bone marrow aspirates or lymph node Invasive ductal and invasive lobular carcinomas have a less biopsy specimens can be determined based on findings from favorable prognosis but are influenced heavily by other immunocytochemistry (ie, cytokeratins CK19 and CAM 5.2), factors. PCR, and RT-PCR. 2. Cytologic grade Prognostic Indicators Cytologic grade is the best predictor of disease prognosis in Criteria for Prognostic Indicators carcinoma in situ but is dependent on the grading system For a prognostic indicator to be accepted as clinically useful, used, such as the Van Nuys classification (high-grade, low- ideally it must have the following criteria: grade comedo, low-grade noncomedo). 1. Proven biological relevance (level I evidence) The grading of invasive carcinoma is also important as a 2. Ability to identify high-risk and low-risk patients prognostic indicator, with higher grades indicating a worse 3. Appropriate cut-off point prognosis. Microscopic criteria for grading are shown in 4. Inexpensive Table 3. 5. Significant treatment implications 3. Table 3. Grading System in Invasive Breast Cancer o Cyclin D1 (Modified Bloom and Richardson) o Nm23 Score 2. Proteases 1 2 3 o uPA and PA1 A. Tubule >75% 10-75% <10% o Cathepsin D formation o Tenascin C B. Mitotic count <7 7-12 >12 3. Markers of proliferation - Ki-67 per high-power HER-2/neu identifies patients with a poor prognosis. These field (microscope- patients are likely to respond to treatment with trastuzumab and field- (Herceptin). dependent) Tumors positive for Ki-67 have a high metastatic potential and C. Nuclear size Near normal Slightly Markedly warrant the possible use of early aggressive therapy. and Little enlarged enlarged uPA and cathepsin D identify poor prognosis node-negative pleomorphism variation Moderate Marked tumors. High levels of these markers can guide the decision to variation variation offer chemotherapy. The use of gene expression profiling to detect breast carcinoma 1. Cancer is considered grade I if the total score (A + B + C) is has already shown that the differential expression of specific 3-5. genes is a more powerful prognostic indicator than traditional 2. Cancer is considered grade II if the total score (A + B + C) is determinants such as tumor size and lymph node status. 6 or 7. Profiling of specific genes in patients with proven breast cancer 3. Cancer is considered grade III if the total score (A + B + C) is may help identify those most likely to benefit from specific 8 or 9. adjuvant treatments such as chemotherapy. Early studies 4. Grade I tumors are associated with a 10-year survival rate demonstrate that these genetic techniques have great of 85%, whereas the survival rate falls to 45% for grade III potential and are likely to become more prevalent in future tumors. breast cancer management. 5. Lymphovascular: Lymphatic invasion, vascular invasion, Follow-up microvessel quantification, and lymphoplasmacytic Need for follow-up care infiltration are associated with a worse prognosis. Whether regular follow-up care affects overall or disease-free 6. Immunohistochemistry survival is debatable, as is the question of whether significantly The most widely used tests are for the estrogen receptors more recurrences are detected than would be otherwise by the (ER) and progesterone receptors (PR). patients themselves or their general practitioners. However, a Immunohistochemistry analysis of heat-treated paraffin number of reasons support continuing evaluation of patients sections has largely superseded the enzyme-linked with breast cancer following their initial treatment plan. immunosorbent assay (ELISA) ligand-binding assay. ER- and 1. Managing adverse effects of treatment PR-positive status (i.e., >10 fmol on ELISA; >15 H-score on 2. Monitoring response of metastatic disease to treatment immunohistochemistry) predict improved response to 3. Psychological support endocrine treatment, time to relapse, and overall survival. 4. Detection and early treatment of recurrences Immunohistochemical positivity for c-erb-B2 and p53 is 5. Screening of high-risk groups for new disease associated with a worse prognosis. 6. Palliative care Other prognostic indicators 7. Audit of short- and long-term outcome of treatment Advances in the knowledge of the molecular mechanisms that 8. Clinical trials influence normal and aberrant cell growth, has led to the Frequency of follow-up care identification of an increasing number of surrogate Different centers vary in the precise scheduling of hospital 19 biomarkers. follow-up appointments, but the general trend is to reduce the Currently for breast cancer, the existing markers are of little frequency of clinic visits until final discharge to the breast value for screening or aiding early diagnosis. screening service after 10 years if no new disease has occurred. These novel prognostic markers can be classified as follows: Following is a suggested schedule for the hospital follow-up 1. Oncogene products care for patients who have undergone curative resection: o Bcl-2 1. Visits every 3 months for 1 year (plus adjuvant treatment) o p53 2. Visits every 6 months for 4 years o HER-2/neu 3. Yearly visits for 5 years 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. In patients treated with mastectomy, twice-yearly mammograms of the other breast may be sufficient. If new symptoms or signs suggestive of local or distant recurrence develop, special investigations may be indicated, including imaging, serologic, and biopsy evaluations covered in the previous sections. 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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