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					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
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         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
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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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