Approach Considerations

Breast cancer evaluation should be an ordered inquiry that begins with symptoms and a
general clinical history. This is followed by a sequence that has become formalized as triple
assessment, which includes the following components:
Clinical examination
Imaging (usually mammography, ultrasonography, or both)
Needle biopsy
This approach naturally lends itself to a gradually increasing degree of invasiveness, so that a
diagnosis can be obtained with the minimum degree of invasiveness and, consequently, the minimum
amount of discomfort to the patient. Because the more invasive investigations also tend to be the
most expensive, this approach is usually the most economical.
The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to
plan the most appropriate surgery. The ultimate goal of surgery is to achieve the most appropriate
degree of breast conservation while minimizing the need for reoperation.
Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the
patient or healthcare provider. Mammographic features suggestive of malignancy include asymmetry,
microcalcifications, and a mass or architectural distortion. If any of these features are identified,
diagnostic mammography along with breast ultrasonography should be performed before a biopsy is
obtained. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.
Breast Cancer Screening
Whereas early detection has been advocated as a primary defense against the development of
life-threatening breast cancer, questions have been raised in the past few years regarding the age at
which to initiate, the modality to use, the interval between screenings, whether to screen older
women, and even the impact on breast cancerrelated deaths. It is widely believed that breast
tumors that are smaller or nonpalpable and that present with a favorable tumor marker profile are
more treatable when detected early.
A survival benefit of early detection with mammography screening has been demonstrated.
[75,
76]
A number of screening modalities exist for breast cancer, including clinical breast examination,
mammography, ultrasonography, and MRI. (See Breast Cancer Screening.)
Mammography
Mammography is a low-dose x-raybased modality used to image the breast. It is currently
the best available population-based method for detecting breast cancer at an early stage.
[76, 77, 78]

Mammography is used both for screening to detect a cancer and for diagnostic workup of
patients after a tumor is detected. Screening mammography is performed in asymptomatic women,
whereas diagnostic mammography is performed in symptomatic women (ie, when a breast lump or
nipple discharge is present or when an abnormality is found during screening mammography).
Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity
at less than 100 m. Mammography often detects a lesion before it is palpable by clinical breast
examination and, on average, 1 to 2 years before noted by breast self-examination.
Recent advances in mammography include the development of digital mammography and the
increased use of computer-aided diagnosis (CAD) systems.
[79]
CAD systems have been developed to
help the radiologist identify mammographic abnormalities.
Digital mammography allows the image to be recorded and stored. With computer
technology, digital mammogram images can be magnified and the image modified to improve
evaluation of specific areas in question. Digital images can be transmitted electronically, decreasing
the time to second opinion without the risk of losing the film.
In a cohort study of women aged 50-74 years, which used data from the Ontario Breast
Screening Program, computed radiography (CR) was 21% less effective than digital direct
radiography (DR) for breast cancer detection; however, DR was equivalent to screen-film
mammography (SFM).
[80, 81]

The US Preventive Services Task Force (USPSTF) estimates the benefit of mammography in
women aged 50-74 years to be a 30% reduction in risk of death from breast cancer. For women aged
40-49 years, the risk of death is decreased by 17%.
[82]

Screening mammography
Although mammography guidelines have been in place for more than 30 years, 20-30% of
women still do not undergo screening as indicated. The 2 most significant factors governing a
womans decision to undergo mammography are physician recommendation and access to health
insurance. Nonwhite women and those of lower socioeconomic status remain less likely to obtain
mammography services and more likely to present with life-threatening, advanced stage disease.
[83,
84]

At present, the most widely accepted recommendations in the United States come from the
American Cancer Society (ACS), which recommends annual screening mammography, beginning at
age 40 years for all women and continuing for as long as a woman is in good health. The ACS
recommends clinical breast examinations about every 3 years for women in their 20s and 30s and
every year for women 40 and over, with monthly breast self-examination as an option for women
starting in their 20s.
[85]

In contrast, since 2009 the USPSTF has recommended biennial screening mammography for
women aged 50-74 years (grade B recommendation). The USPSTF recommends against routine
screening mammography in women aged 40-49 years because of high rates of false-negative
findings, perceived harm of unnecessary biopsy, and concern for the harm associated with
overdiagnosis and overtreatment (grade C recommendation).
[84]

Instead of routine screening for women 40-49 years old, the USPSTF recommends that
clinicians provide screening to selected patients in this age range, depending on individual
circumstances and patient preferences. The USPSTF further concluded that for most individuals
without signs or symptoms, there is likely to be only a small benefit from screening.
Finally, the USPSTF recommends against teaching breast self-examination and concludes that
the current evidence is insufficient to assess the benefits and harms of clinical breast examination in
women aged 40 years or older or the benefits and harms of screening mammography in women
aged 75 years or older.
Diagnostic mammography
Diagnostic mammography is more expensive than screening mammography. It is used to
determine the exact size and location of breast abnormalities and to image the surrounding tissue
and lymph nodes. Women with breast implants or a personal history of breast cancer may require
the additional views used in diagnostic mammography as part of their routine screening
examination.
A ductogram (or galactogram) is sometimes helpful for determining the cause of nipple
discharge. In this specialized examination, a fine plastic tube is placed into the opening of the duct in
the nipple. A small amount of contrast medium is injected, which outlines the shape of the duct on a
mammogram and shows whether a mass is present inside the duct.
Ultrasonography
Ultrasonography has become a widely available and useful adjunct to mammography in the
clinical setting. It is generally employed to assist the clinical examination of a suspicious lesion
detected on mammography or physical examination. As a screening tool, ultrasonography is limited
by a number of factors, most notably its failure to detect microcalcifications and its poor specificity
(34%).
Originally, ultrasonography was used primarily as a relatively inexpensive and effective
method of differentiating cystic breast masses, which did not require sampling, from solid breast
masses, which were usually examined with biopsy; in many cases, the results of these biopsies were
benign. However, it is now well established that ultrasonography also provides valuable information
about the nature and extent of solid masses and other breast lesions and can often provide useful
information regarding the staging of the axilla.
This imaging technique is also useful in the guidance of biopsies and therapeutic procedures;
research is currently under way to evaluate its role in cancer screening.
Magnetic resonance imaging
In an effort to overcome the limitations of mammography and ultrasonography, MRI has been
explored as a modality for detecting breast cancer in women at high risk and in younger women. A
combination of T1, T2, and 3-D contrast-enhanced MRI techniques has been found to possess high
sensitivity (approximating 86-100% in combination with mammography and clinical breast
examination) to malignant changes in the breast. (See Magnetic Resonance Mammography.)
Indications for MRI
The high cost and limited availability of MRI, as well as the difficulties inherent in performing
and interpreting the studies with high false-positive rates, necessitate that the use of this modality
be carefully considered before it is recommended in a patient. The following are current indications
for MRI:
Characterization of an indeterminate lesion after a full assessment with physical
examination, mammography, and ultrasonography
Detection of occult breast carcinoma in a patient with carcinoma in an axillary lymph node
Evaluation of suspected multifocal or bilateral tumor
Evaluation of invasive lobular carcinoma, which has a high incidence of multifocality
Evaluation of suspected extensive high-grade intraductal carcinoma
Detection of occult primary breast carcinoma in the presence of metastatic adenocarcinoma
of unknown origin
Monitoring of the response to neoadjuvant chemotherapy
Detection of recurrent breast cancer
Contraindications for MRI
Conversely, in a number of situations, MRI is contraindicated, usually because of physical
constraints that prevent adequate patient positioning. Additional contraindications include the
following:
Contraindication to gadolinium-based contrast media (eg, allergy or pregnancy)
Patients inability to lie prone
Marked kyphosis or kyphoscoliosis
Marked obesity
Extremely large breasts
Severe claustrophobia
Relative contraindications also exist. These are essentially based on the high sensitivity but
limited specificity of the technique. MRI may not be useful for the following:
Cancer-phobic patients at average or low risk of disease for breast cancer, because of the
psychological stress associated with false-positive findings
Assessment of mammographically detected microcalcifications
Nuclear imaging
The following 3 radiotracers are commonly used for breast imaging or scintimammography in
either clinical practice or research:
Technetium-99m (
99m
Tc)-sestamibi (for myocardial perfusion imaging); this was the first
radiopharmaceutical agent to be approved by the US Food and Drug Administration (FDA) for use in
scintimammography
[86]


99m
Tc-tetrofosmin (also for myocardial perfusion imaging)

99m
Tc-methylene diphosphonate (MDP; for bone scintigraphy)
Scintimammography is not indicated as a screening procedure for the detection of breast
cancer. However, it may play a role in various specific clinical indications, as in cases of
nondiagnostic or difficult mammography and in the evaluation of high-risk patients, tumor response
to chemotherapy, and metastatic involvement of axillary lymph nodes.
In several prospective studies, overall sensitivity of
99m
Tc-sestamibi scintimammography in the
detection of breast cancer was 85%, specificity was 89%, and positive and negative predictive values
were 89% and 84%, respectively. Similar numbers have been demonstrated for
99m
Tc-tetrofosmin
and
99m
Tc-MDP scintimammography.
[4]

Positron Emission Tomography
Using a wide range of labeled metabolites (eg, fluorinated glucose [
18
FDG]), positron emission
tomography (PET) can detect changes in metabolic activity, vascularization, oxygen consumption,
and tumor receptor status.
When PET is combined with computed tomography (CT) to assist in anatomic localization
(PET-CT), scans can identify axillary and nonaxillary (eg, internal mammary or supraclavicular) lymph
node metastasis for the purposes of staging locally advanced and inflammatory breast cancer before
initiation of neoadjuvant therapy and restaging high-risk patients for local or distant recurrences.
Accuracy of Breast Imaging Modalities
The different techniques used in breast imaging vary with respect to sensitivity, specificity,
and positive predictive value (see Table 1 below).
Table 1. Accuracy of Breast Imaging Modalities (Open Table in a new window)

Modality Sensitivity Specificity PPV Indications
Mammography 63-95% (>95%
palpable, 50%
impalpable, 83-92%
in women older than
50 y; decreases to
35% in dense
breasts)
14-90% (90%
palpable)
10-50%

(94%
palpable)
Initial investigation for
symptomatic breast in
women older than 35 y and
for screening; investigation
of choice for
microcalcification
Ultrasonography 68-97% palpable 74-94%
palpable
92%
(palpable)
Initial investigation for
palpable lesions in women
younger than 35 y
MRI 86-100% 21-97% (<
40% primary
cancer)
52% Scarred breast, implants,
multifocal lesions, and
borderline lesions for breast
conservation; may be useful
in screening high-risk
women
Scintigraphy 76-95% palpable, 52-
91% impalpable
62-94% (94%
impalpable)
70-83% (83%
palpable, 79%
impalpable)
Lesions >1 cm and axilla
assessment; may help
predict drug resistance
PET 96% (90% axillary
metastases)
100% Axilla assessment, scarred
breast, and multifocal
lesions
MRI = magnetic resonance imaging; PET = positron emission tomography; PPV = positive predictive
value.
Breast Biopsy
Percutaneous vacuum-assisted large-gauge core-needle biopsy (VACNB) with image guidance
is the recommended diagnostic approach for newly diagnosed breast tumors. Core biopsies can
minimize the need for operative intervention (and subsequent scarring, and provide accurate
pathologic diagnosis for appropriate management.
Excisional biopsy, as the initial operative approach, has been shown to increase the rate of
positive margins. Open excisional biopsy is reserved for lesions where the diagnosis remains
equivocal despite imaging and core biopsy assessment or for benign lesions that the patient chooses
to have removed. Because wide clearance of the lesion is usually not the goal in diagnostic biopsies,
unnecessary distortion of the breast is thereby avoided. Ongoing audit is essential to help reduce an
excessive benign-to-malignant biopsy ratio.

Histology
Breast cancers usually are epithelial tumors of ductal or lobular origin. The following features are all
important in deciding on a course of treatment for any breast tumor:
Size
Status of surgical margin
Presence or absence of estrogen receptor (ER) and progesterone receptor (PR)
Nuclear and histologic grade
Proliferation
Vascular invasion
Tumor necrosis
Quantity of intraductal component
HER2 status
Histologic grade
Histologic grade is the best predictor of disease prognosis in carcinoma in situ, but it is
dependent on the grading system used, such as the Van Nuys classification (high-grade, low-grade
comedo, low-grade noncomedo). The grading of invasive carcinoma is also important as a prognostic
indicator, with higher grades indicating a worse prognosis (see Table 2 below).
Table 2. Grading System in Invasive Breast Cancer (Modified Bloom and Richardson) (Open
Table in a new window)

Score
1 > 2 > 3
A. Tubule formation >75% 10-75% < 10%
B. Mitotic count/HPF
(microscope- and field-
dependent)
< 7 7-12 >12
C. Nuclear size and
pleomorphism
Near normal;
little variation
Slightly enlarged;
moderate variation
Markedly enlarged;
marked variation
Grade I cancer if total score (A + B + C) is 3-5
Grade II cancer if total score (A + B + C) is 6 or 7
Grade III cancer if total score (A + B + C) is 8 or 9
HPF = high-power field.