Breast Cancer Evaluation: Introduction
Breast cancer incidence
Breast cancer is one of the most important diseases for women
in the United States and constitutes one fourth of all cancers in
females, making it the most common cancer in females.
Women in North America have the highest incidence of breast
cancer in the world. The lifetime probability of developing
breast cancer in the United States is 1 in 8 for females. Breast
cancer is 100 times less common in men.
Breast cancer accounts for approximately 15% of female cancer
deaths. It is the leading cause of death in women aged 44-50
years. The incidence of breast cancer (number of new breast
cancers per 100,000 women) increased during the 1980s but
leveled off in the 1990s and declined between 2001 and 2003.
The current incidence is estimated at around 120 cases per
100,000 women in the United States. The American Cancer
Society estimated that in 2007, approximately 178,480 women
in the United States will be diagnosed with invasive breast
cancer (Stages I-IV) and a further 62,030 will be diagnosed with
carcinoma in situ (CIS). Worldwide, the incidence of breast
cancer is highest in developed countries in North America and
Western Europe, with lowest incidences seen in South America,
Africa and parts of Asia. Within the United States, breast cancer
incidence is highest in White women, lower in African American
and Hispanic population and lowest in American Indian and
Alaskan native women.
The 5-year breast cancer survival rate ranges from 98% for
stage I cancer to approximately 16% for stage IV cancer. Death
rates from breast cancer have steadily declined since the early
1990s, with the largest decreases among younger women.
Nevertheless, it is estimated that about 40,460 women and 450
men will die from breast cancer in the United States in 2007.
According to the American Cancer Society, the overall survival
rate for breast cancer is as follows:
 85% after 5 years
 71% after 10 years
 57% after 15 years
 52% after 20 years
Approach to evaluation
Breast cancer evaluation should be approached with an
ordered inquiry beginning with symptoms and general clinical
history, followed by clinical examination and, finally,
investigation, which may include imaging and biopsy. This
approach naturally lends itself to a gradually increasing degree
of invasiveness, so that when a diagnosis is obtained, the
process can be stopped with the minimum amount of invasion
and, consequently, minimum discomfort to the patient.
Because the more invasive investigations also tend to be the
most expensive, this approach is usually the most economical.
Evaluation goals
The aims of evaluation of a breast lesion are to judge whether
surgery is required and, if so, to plan the most appropriate
surgery. The ultimate goal of surgery is to achieve the most
appropriate degree of breast conservation while minimizing the
need for reoperation.
Triple assessment
In breast cancer, the general approach to evaluation has
become formalized as triple assessment, involving clinical
examination, imaging (usually mammography and/or
ultrasonography), and needle biopsy, but always perform this
as part of a more general assessment beginning with clinical
history.
Clinical Assessment
Clinical history
Many early breast carcinomas may be asymptomatic,
particularly if they were discovered during a breast screening
program. If the patient has not noticed a lump, then symptoms
indicating the possible presence of breast cancer may include
the following:
 Change in breast size or shape
 Skin dimpling
 Recent nipple inversion or skin change
 Single-duct discharge, particularly if bloodstained
 Axillary lump
Pain or discomfort is not usually a symptom of breast cancer.
The clinician should be alert to symptoms of metastatic spread,
such as the following:
 Breathing difficulties
 Bone pain
 Symptoms of hypercalcemia
 Abdominal distension
 Jaundice
 Localizing neurological signs
 Altered cognitive function
The clinical evaluation should include an assessment of specific
risk factors for breast cancer, as follows:
1. Age
 Breast cancer is rare in women younger than 25 years.
 Incidence increases with age, with a plateau in women
aged 50-55 years.
 Age is the most significant risk factor.
2. Genetics
 Family history is a risk factor. The lifetime risk is up to 4
times higher if a mother and sister are affected. The family
history characteristics that suggest increased risk of cancer
are as follows:
 Two or more relatives with breast or ovarian cancer
 Breast cancer occurring in an affected relative younger
than 50 years
 Relatives with both breast cancer and ovarian cancer






3.


4.


5.
6.
7.







One or more relative with 2 cancers (breast and ovarian
cancer or two independent breast cancers)
Male relatives with breast cancer
Individuals of Ashkenazi Jewish descent have a 2-times
greater risk.
Japanese and Taiwanese woman have one fifth the risk
when compared with US women.
BRCA1 and BRCA2 mutations are associated with higher
risk. However, one study indicates that women with
the BRCA1 and BRCA2 mutationswho
undergo
riskreducing mastectomy have a lower risk of breast cancer.1
Ataxia telangiectasia heterozygotes are at 4-times
increased risk.
Other pathology
Risk is increased with previous breast cancer, ovarian
cancer, endometrial cancer, ductal carcinoma in situ,
lobular carcinoma in situ, hyperplasia (unless mild),
complex fibroadenoma, radial scar, papillomatosis,
sclerosing adenosis, and microglandular adenosis.
Risk is decreased with cervical cancer.
Years menstruating
Factors increasing the number of menstrual cycles increase
the risk, probably due to increased endogenous estrogen
exposure.
Such factors include (1) nulliparity, (2) first full pregnancy
when older than 30 years, (3) menarche when younger
than 13 years (2 times the risk), (4) menopause when older
than 50 years, and (5) not breastfeeding.
Obesity: Increased risk is probably due to adipose
conversion of androgens to estrogens.
Socioeconomic class: Incidence is increased in individuals
in a higher socioeconomic class.
Exogenous factors
Hormone replacement therapy increases risk (1.35 times
for 5 or more years use, normalizing 5 years from
discontinuing).2
The use of oral contraceptive pills increases risk (1.24 times
for 10 years use, normalizing 10 years from discontinuing).
The progesterone-only pill is not associated with increased
risk.3
The use of diethylstilbestrol increases risk.
Alcohol consumption is associated with an increased risk,
probably through increasing estrogen levels.
Irradiation, particularly in first decade of life, is associated
with an increased risk of breast cancer.
Dichlorodiphenyldichloroethylene, a metabolite of the
insecticide
dichlorodiphenyltrichloroethane
(DDT),
exposure increases risk.
Exposure to some viral agents (e.g. mouse mammary
tumor virus) is associated with increased risk.
8.

Other dietary, cultural, and/or geographic influences
High-risk regions include North America and northern
Europe.
 Low-risk regions include Japan and Hawaii; however,
descendants migrating to the United States take on the
higher US risk.
Clinical examination
Outline the following features in nonmedical terms when
instructing a patient in breast self-examination. Explaining to
the patient that the axillary tail must be included in the
examination is important. Many patients are too anxious to
examine their own breasts or find it too difficult, possibly
because of generalized nodularity. In this situation, stressing
the need of the patient to simply alert a clinician to any change
in the breasts, particularly if the change persists through a
complete menstrual cycle, is often easier. The following
findings should raise concern:
 Lump or contour change
 Skin tethering
 Nipple inversion
 Dilated veins
 Ulceration
 Paget disease
 Edema or peau d'orange
The nature of palpable lumps is often difficult to determine
clinically, but the following features should raise concern:
 Hardness
 Irregularity
 Focal nodularity
 Asymmetry with the other breast
 Fixation to skin or muscle
To detect subtle changes in breast contour and skin tethering,
the examination must include an assessment of the breasts
with the patient upright with arms raised. Assess fixation to
muscle by moving the lump in the line of the pectoral muscle
fibers with the patient bracing her arms against her hips. A
complete examination includes assessment of the axillae and
supraclavicular fossae, examination of the chest and sites of
skeletal pain, and an abdominal and neurological examination.
Breast Cancer Imaging
After clinical assessment, the second part of triple assessment
involves imaging. Numerous imaging modalities are available
and the selection may be based on age, sensitivity, specificity,
local availability, and cost. Performing more than one imaging
modality to further improve diagnostic accuracy and to clarify
indeterminate findings is often appropriate. The different
imaging modalities are compared in Table 1.
Table 1. Accuracy of Breast Imaging Modalities
Moda Sensitivity
Specif Positive
lity
icity
Predictive
Value
Mam
63-95%
1410-50%
mogr
(>95%
90%
(94%
aphy
palpable,
(90%
palpable)
50%
palpa
impalpable,
ble)
83-92% in
women
older than
50
y)
(decreases
to 35% in
dense
breasts)
Ultras 68-97%
7492%
onogr (palpable)
94%
(palpable)
aphy
(palp
able)
MRI
86-100%
2197%
(<40
%
prima
ry
cance
r)
52%
Scinti
graph
y
76-95%
(palpable)
52-91%
(impalpable)
6294%
(94%
impal
pable
)
70-83%
(83%
palpable,
79%
impalpable
)
Positr
on
emissi
on
tomo
graph
y
(PET)
96%
(90% axillary
metastases)
100%
Indications
Initial
investigation
for
symptomatic
breast
in
women older
than 35 years
and
for
screening;
investigation of
choice
for
microcalcificati
on
Initial
investigation
for
palpable
lesions
in
women
younger than
35 years
Scarred breast,
implants,
multifocal
lesions,
and
borderline
lesions
for
breast
conservation;
may be useful
in
screening
high-risk
women
Lesions larger
than 1 cm and
axilla
assessment;
may
help
predict
drug
resistance
Axilla
assessment,
scarred breast,
and multifocal
lesions
In nonfatty breasts, ultrasonography and MRI are more
sensitive than mammography for invasive cancer but may
overestimate tumor extent. Combined mammography, clinical
examination, and MRI are more sensitive than any other
individual test or combination of tests.
Mammography
Two-view mammography (ie, craniocaudal and oblique) is the
imaging method of choice for breast screening. 4 In the United
States, annual screening mammography has been recommend
with clinical examination in women starting at age 40
years.5 However, in November 2009, the US Preventive Services
Task Force (USPSTF) issued updated breast cancer screening
guidelines that recommend against routine mammography
before age 50 years. Instead, for women aged 40-49 years, the
USPSTF suggests that the decision to start regular screening
mammography be individualized and should include the
patient's values regarding specific benefits and harms (Grade C
recommendation).6
In addition, rather than annual screening, the USPSTF
guidelines recommend that screening mammography be
performed biennially (Grade B recommendation). The USPSTF
concludes that there is currently insufficient evidence to assess
the additional benefits and harms of screening mammography
in women aged 75 years or older and thus recommends
stopping screening at age 74 years.6
In response, the American College of Obstetricians and
Gynecologists (ACOG) has stated that while it is evaluating the
USPSTF guidelines in detail, for the present it continues to
recommend adherence to current ACOG guidelines. These
include screening mammography every 1-2 years for women
aged 40-49 years and screening mammography every year for
women age 50 or older. The ACOG notes, however, that
because of the USPSTF downgrading, some insurers may no
longer cover some of these studies.7
Despite its use as the tool of choice for breast screening,
mammography has significant limitations when used in
isolation. Although in general a highly sensitive investigation,
sensitivity is much reduced in younger or denser breasts 8 ;
therefore, mammography is considered inappropriate in
patients younger than 35 years. Evaluation of breast tissue is
not possible when obscured by implants or in the presence of
heavy scarring from previous surgery.
The positive predictive value of mammography can be as low as
10%, demonstrating the need for other imaging modalities,
such as ultrasonography or magnetic resonance imaging, to
distinguish solid from cystic radiodensities. However,
mammography remains the investigation of choice for
detecting
and
classifying
microcalcification.
Benign
microcalcification is characterized by diffuse scattering and
crescentic "tea-cupping." Malignant microcalcification is
characterized by isolated clusters, punctate of varying sizes,
and a branching or linear pattern. Mammography is also
efficient for helping detect larger patterns of calcification, such
as the outlining of calcified arterioles or the coarse patchy
calcification of long-standing fibroadenomata.
Other features that raise concern on mammography images
include (1) lesions with ill-defined edges, (2) areas of distortion,
(3) asymmetry between breasts, and (4) spiculated lesions.
Indeterminate radiodensities can be assessed further
mammographically using (1) additional angled views, (2)
magnified images, (3) compression images, and (4) alterations
in exposure or contrast.
Recent advances in mammography include digital
mammography, contrast-enhanced mammography, and
computer-aided detection. Digital mammography uses
essentially the same mammographic system as conventional
mammography, but it is equipped with digital receptors instead
of film cassettes. The digital detectors convert x-ray photons to
digital signals for display on high-resolution monitors. The
processes of acquisition, storage, and display of images can be
separated and individually optimized, thus allowing alteration
of the magnification, brightness, contrast, and orientation of
the mammogram.
The diagnostic accuracy of digital mammography has been
shown to be similar overall to traditional film mammography.
However, digital mammography is more accurate in younger or
premenopausal women and women with radiographically
dense breasts. Digital spot view mammography allows faster
and more accurate stereotactic biopsy, whereas full-field digital
mammography (FFDM) is being promoted as the future
modality for the screening and diagnosis of breast cancer. In
2006, around 10% of mammography units in the United Stated
used digital mammography, although this is likely to become
more prevalent in the future.
The benefits of digital mammography include the following:
1. Faster image acquisition with shorter exposure and
examination time
2. Ability to correct under- or overexposed images, thus
preventing the need for repeat mammography
3. Improved diagnostic accuracy in some patient groups
4. Improved contrast between dense and nondense breasts
5. Enables the easy storage of images and their sharing
between health professionals (including remote
consultation)
Contrast-enhanced mammography uses the principle that
aggressive cancers are associated with increased vascularity.
Iodinated contrast agents are administered, they distribute
throughout the circulation, and x-ray imaging shows increased
contrast where they concentrate. Individual images are
obtained and then reconstructed into 3-dimensional series of
thin high-resolution slices. These slices reduce tissue overlap
and structural noise relative to standard 2-dimensional images.
The dose of radiation is, however, the same.
Computer-aided detection uses an image checker computer
that analyzes mammographic films that have been scanned and
digitized. This technology was approved by the FDA in 1998 and
is able to highlight suspicious areas that may be indicative of
cancer, thus acting as a pair of second eyes. 9 Research has
suggested that the regular use of computer-aided detection
may oversight cases by 99%, particularly for patients with
dense breasts. However, a study of more than 200,000 women
concluded that computer-aided detection was associated with
a reduction in diagnostic accuracy and a significant increase in
biopsy rate.10 Further development and evolution of the
technology may increase the use of computer-aided detection
in the future.
Ultrasonography
Ultrasonographic evaluation in addition to mammography can
help distinguish between solid and cystic lesions, accurately
determine the size of a spiculated lesion and guide accurate
biopsy of a suspicious area. Ultrasonography is therefore
considered an indispensable adjunct to mammography and is
one of the most useful investigations to perform on a patient
with a palpable breast lump.
Ultrasonography is becoming ever more sophisticated. Higher
resolutions are being achieved, and the introduction of Doppler
enables accurate definition of characteristic blood flow
patterns. This can aid in differentiating benign and malignant
lesions and distinguishing lymph node metastases from normal
or reactive lymph nodes. With evolving ultrasonographic
technology, image resolution and quality is likely to improve,
confirming the place of ultrasonography as an essential
modality for the investigation of patients with suspected breast
cancer.
Ultrasonographic features of malignancy include the following:
1. Poorly defined borders
2. Heterogeneous internal echoes
3. Disruption of the tissue layers
4. Irregular shadowing
5. Superficial echo enhancement
6. Depth greater than height
7. High vascular density and flow rates on Doppler images
Features of benign lesions include the following:
1. Cyst - Absence of internal echoes, marked deep
enhancement
2. Fibroadenoma - Well-defined borders, well-defined
internal echoes, and displacement of tissue planes
3. Lymph node - Well-defined peripheral blood flow on
Doppler images
MRI
MRI is a particularly useful modality for detailing architectural
abnormalities in the breast and can help detect lesions as small
as 2-3 mm. In cancers, it is useful in defining the precise size of
the tumor and in detecting multifocal disease. This may be of
particular importance when assessing whether borderline case
are suitable for breast-conserving surgery.
MRI allows for the construction of 3-dimensional images, and
its versatility is enhanced by the use of different sequences,
including high-resolution, rapid-imaging, fat-suppression,
subtraction, and dynamic sequences.
Dynamic imaging is the most specific sequence and can help
distinguish between benign and malignant lesions, and is
particularly useful in the assessment of the scarred breast
when looking for tumor recurrence. Dynamic imaging relies on
the shape of the time-signal curves using gadoliniumdiethylenetriamine
penta-acetic
acid
enhancement;
malignancies typically show rapid, strong enhancement
because of high vascularity.
The American Cancer Society published guidelines for the use
of MRI for screening high-risk women.11 Screening MRI is
recommended for women with an approximate lifetime risk of
20% or greater. However, data to support the use of screening
MRI in women at intermediate or low risk are insufficient.
Advantages of MRI compared with conventional imaging
techniques to detect breast cancer include the following:
 Improved staging and treatment planning
 Enhanced evaluation of enhanced breast
 Better detection of recurrence
 Improved screening in high-risk patients12
Wasif et al found that MRI was more accurate than
ultrasonography or mammography for determination of the
size of a breast cancer mass. They compared 61 breast cancers
using the 3 modalities; the Pearson correlation coefficient was
0.80 for MRI, 0.57 for ultrasonography, and 0.26 for
mammography. Mean tumor size was 2.1 cm by
mammography, 1.73 cm by ultrasonography, 2.65 cm by MRI,
and 2.76 cm by pathology. MRI-based tumor size was within 1
cm of pathologic size in 44 tumors (72%), more than 1 cm
above pathologic size in 6 tumors, and more than 1 cm below
pathologic size in 11 tumors.13
According to Dang et al, breast MRI has been shown to have
greater sensitivity than both mammography and
ultrasonography, but there have been concerns that increased
use of MRI for breast cancer screening will result in an
increased rate of mastectomy in women with early-stage
breast cancer. However, the authors found that from 20032007, although the number of breast MRIs ordered by their
institution rose from 68 annually to 358 annually, the
percentage of women who underwent mastectomy did not
change over that period.14
The 2009 National Comprehensive Cancer Network (NCCN)
Clinical Practice Guidelines in Oncology for Breast Cancer
Screening and Diagnosis include using breast MRI as an adjunct
to annual mammography and clinical breast examination in
women in the following situations:15
1. BRCA1 or BRCA2 mutation
2. Have not undergone genetic testing but have a first-degree
relative with a BRCA1 or BRCA2 mutation
3. Lifetime risk greater than 20% based on models that are
highly dependent on family history
4. History of lobular carcinoma in situ
5. Underwent radiation treatment to the chest between age
10 and 30 years
6. Carry or have a first-degree relative who carries a genetic
mutation in the TP53 or PTEN genes (Li-Fraumeni, Cowden,
and Bannahyan-Riley-Ruvalcaba syndromes)
According to the NCCN, MRI is specifically not recommended
for screening women at average risk for breast cancer.
Scintimammography
This radioisotope study typically uses technetium Tc 99m
Sestamibi, a compound that concentrates in mitochondria. The
efflux of this label is related to expression of the multidrug
resistance protein. Therefore, the size of the signal
distinguishes the high metabolic rate of a malignant tumor and
may help predict resistance to chemotherapy.
Scintimammography, while less sensitive than MRI for lesions
smaller than 1 cm, is more specific for palpable lesions and is
useful for detecting axillary involvement.
Single-photon emission computed tomography promises to
advance scintimammography in the same way that CT scans
have advanced plain radiographs.
Positron emission tomography
PET is the most sensitive and specific of all the imaging
modalities for breast disease, but it is also one of the most
expensive and least widely available. Using a wide range of
labeled metabolites (eg, fluorinated glucose [18FDG]), changes
in metabolic activity, vascularization, oxygen consumption, and
tumor receptor status can be detected. At present, its main use
may be for helping detect recurrences in scarred breasts, but it
is also useful in multifocal disease, detecting axillary
involvement and in equivocal cases of systemic metastases. 16
Biopsy
Pathologic diagnosis of a breast lesion can be achieved using a
number of biopsy techniques. The use of image guidance
(usually ultrasonography) significantly increases biopsy success
rates, irrespective of needle size. Visualization of postfire
needle tip position can help verify the accuracy of biopsy for
discrete mass lesions. With a larger biopsy sample, greater
accuracy and more information are obtained, but at the
expense of increased invasiveness. Ideally, needle biopsies
should be performed after imaging to help prevent distortions
of imaging due to tissue trauma and hematoma. Table 2
compares the accuracy of needle biopsy techniques.
Table 2. Accuracy of Needle Biopsy Techniques
Needle type
Sensitivity Specificity
Fine-needle aspiration (FNA) 52-95%
95-100%
Tru-Cut
68-84%
100%
Biopty cut 18G
93-96%
100%
Biopty cut 14G
88-98%
100%
Mammotome
100%
Fine-needle aspiration
The least invasive method of biopsy is FNA. The technique of
FNA is determined largely by individual preference, which may,
in part, reflect hand size and strength. A 21-gauge (green)
needle is used most commonly, although in expert hands, a 23gauge (blue) needle can yield as much information, with less
discomfort and bruising. Some clinicians opt for a hand-held
10-mL syringe, while others prefer a 20-mL syringe used with a
syringe holder. Syringe holders allow a vacuum to be
maintained easily but can make control of the needle tip less
precise.
To perform a fine needle aspiration, the skin should be
disinfected with an alcohol wipe, and the needle passed
through the lesion a number of times, while maintaining
suction and steadying the breast tissue with the other hand.
Appreciating the potential risk of pneumothorax is
important when performing needle biopsies of the breast, and
wherever possible, the needle should be angled tangentially to
the chest wall. Continue sampling until aspirate is observed at
the bottom of the plastic portion of the needle.
Transfer the aspirate to the slides. Spread the aspirate thin
enough to visualize individual cells. The slides may be air-dried
or fixed according to the preference of the local laboratory.
Cytospin preparations of the aspirate may allow a greater
number of slides to be made.
Wide-bore needle biopsy
A Tru-Cut needle, ideally 14-gauge, is used for core biopsy.
Because of the fibrous nature of much breast tissue, adequate
samples are best obtained using a spring-loaded firing device,
such as the Biopty-Cut system. The procedure is often less
painful than FNA despite the wider-bore needle.
After local anesthetic subcutaneous injection, cores of tissue
can be taken and should be immediately fixed in formalin. If
the lesion contains calcification based on the mammogram
findings, radiographs of the cores are taken to confirm
presence of calcification and, therefore, are representative. The
risk of bruising is higher than with FNA. For this reason,
anticoagulants should be stopped, where possible prior to
biopsy and a pressure dressing is applied usually for at least 24
hours.
Often, the samples are large enough to allow detailed
histological assessment, including tumor type and grade and
hormone receptor status, but sampling error may occur if the
cores are not representative of the entire lesion.
Mammotome biopsy
The mammotome is an instrument for taking breast tissue
biopsies using vacuum-assistance. The 11-gauge needle is
positioned using ultrasonography or mammographic guidance
(under local anesthetic) and targeted breast tissue is drawn,
cut, and saved in a collecting chamber. This apparatus is
relatively expensive, but may be an alternative to open surgery
for the therapeutic excision of benign lesions <15 mm or
additional tissue biopsy in patients with microcalcification or
borderline breast lesions.
Excision biopsy
The ultimate diagnostic biopsy is open excision biopsy of a
lesion, normally performed under general anesthetic. Open
excision biopsy should be reserved for lesions where the
diagnosis remains equivocal despite imaging and less invasive
assessment or for benign lesions that the patient chooses to
have removed. A wide clearance of the lesion is usually not the
goal in diagnostic biopsies, thus avoiding unnecessary
distortion of the breast. Ongoing audit is essential to help
reduce an excessive benign-to-malignant biopsy ratio.
Evaluation of Screen-detected Lesions
Criteria for screening
In women older than 40 years, breast screening in the United
States occurs annually by clinical examination and 2-view
mammography (ie, oblique and craniocaudal). In patients aged
20-39 years, clinical examination is advised every 3 years,
supplemented by breast self-examination every month.
The American Cancer Society guidelines for breast cancer
screening are as follows:
1. Average-risk women
 Clinical breast examination performed annually for women
older than 40 years
 Yearly mammogram starting at age 40 years
 Clinical breast examination every 3 years for women aged
20-30 years
2. Older women: Individualize screening decisions
considering potential benefits and risks of mammography
in context of current health status and estimated life
expectancy.
3. Women at >20% lifetime risk offered annual MRI in
addition to mammography
4. Women at 15-20% lifetime risk advised to discuss the
benefits and limitations of MRI in addition to annual
mammography
5. Other strategies for women at increased risk
o Early initiation of screening
o Shorter screening intervals
Recall
Any abnormalities detected through screening are observed by
recall of the patient to the assessment clinic, where further
imaging may be undertaken. This is usually in the form of
ultrasonography or further mammographic views, such as
lateral, magnified, or compression views, or alterations in
exposure.
Biopsy
Because most of the lesions detected during screening are
early impalpable abnormalities, subsequent needle biopsy
must be image-guided. Ultrasound-guided biopsy is usually the
most straightforward approach, but lesions better seen on
mammography images, particularly microcalcifications, require
stereotactic localization. More modern stereotactic imagers
allow the use of core biopsy or the Mammotome. Radiographs
of these larger samples then may be obtained to ensure that
they contain evidence representative of microcalcification.
Ultimately, open biopsy may be required, if necessary aided by
ultrasonographic
guidance,
skin
marking
by
the
ultrasonographer or stereotactic wire localization. If the
procedure is intended for diagnosis rather than therapy, a
maximum biopsy size of 20 g is desirable to reduce unnecessary
cosmetic distortion. To avoid too many unnecessary biopsies,
the benign biopsy rate in a breast unit should not greatly
exceed the malignant rate.
Staging
Before deciding on definitive treatment for a newly diagnosed
breast cancer, staging the disease is necessary to plan optimum
treatment. Lymph node involvement makes a full axillary
clearance more appropriate, whereas distant spread of disease
may indicate primary chemotherapy.
The most common method of denoting the stage of the disease
is the TNM (tumor, node, metastases) system. The TNM
classification of breast cancer is as follows:
1. Tumor
 Stage TX - Tumor not assessable
 Stage T0 - No primary tumor
 Stage Tis - Carcinoma in situ
 Stage T1a - Tumor diameter greater than 0.1 cm but not
greater than 0.5 cm
 Stage T1b - Tumor diameter greater than 0.5 cm but not
greater than 1 cm
 Stage T1c - Tumor diameter greater than 1 cm but not
greater than 2 cm
 Stage T2 - Tumor diameter greater than 2 cm but not
greater than 5 cm
 Stage T3 - Tumor larger than 5 cm
 Stage T4a - Involvement of chest wall
 Stage T4b - Involvement of skin
 Stage T4c - Stages T4a and T4b
 Stage T4d - Inflammatory cancer
2. Node
 Stage NX - Node not assessable
 Stage N0 - No regional lymph node metastases



3.



Stage N1 - Palpable ipsilateral axillary lymph nodes
Stage N2 - Fixed ipsilateral axillary lymph nodes
Stage N3 - Ipsilateral internal mammary nodes
Metastasis
Stage - Metastasis not assessable
Stage M0 - No evidence of metastasis
Stage M1 - Distant metastasis, including ipsilateral
supraclavicular nodes
Evaluation of the Axilla
Clinical
Clinical evaluation of the axilla for lymph node metastases is
not particularly sensitive, although some use it to select
patients for preoperative staging investigations.
Imaging
Conventional mammography does not adequately image all of
the axillary contents, whereas other modalities including
ultrasonography, MRI, scintimammography, and PET scans can
reliably detect abnormalities in the axilla because of their wider
field.
In recent years, axillary ultrasonography has been highlighted
as an important tool for axillary staging. The reported
sensitivity of axillary ultrasonography (with FNA or core biopsy
of suspicious nodes) for the detection of positive nodes has
ranged from 21-33%, suggesting that sentinel node biopsy may
be unnecessary in a significant proportion of node-positive
patients. Increased operator experience and greater
understanding of ultrasonographic criteria for lymph node
biopsy are likely to improve the sensitivity for the detection of
involved lymph nodes using this technique.
Intraoperative assessment
Intraoperative assessment of axillary samples helps to
determine whether to continue on to a full axillary clearance
during the same operation. Techniques include the following:
1. Four-node sampling by feel
2. Sentinel node biopsy (using dye and/or radioactive tracer)
3. Imprint cytology
4. Frozen section
Laboratory evaluation of specimen
Depending on the level of axillary clearance, as many as 45-48
lymph nodes may be present. These are identified and assessed
by a number of techniques, as follows:
1. Palpation and bench-top dissection
2. En bloc sectioning
3. Fat clearance techniques
4. Single or multiple sectioning (eg, at 5-mm intervals)
5. Immunohistochemistry - Cytokeratin markers
6. Reverse transcriptase polymerase chain reaction (RT-PCR)
for micrometastases
Serologic tests
Serologic tests provide general information on the patient's
overall health in the face of disseminated disease, but, more
specifically, results can indicate sites of possible metastases or,
in the case of tumor markers, can help estimate the disease
load.
1. Liver involvement - Levels of bilirubin, alkaline
phosphatase, alanine and aspartate transaminases,
gamma-glutamyltransferase, 5-nucleotidase, albumin, and
prothrombin time
2. Pulmonary involvement - Arterial blood gas values
3. Bone involvement - Hypercalcemia, alkaline phosphatase
isoenzyme levels (usually normal as osteolytic)
4. Tumor markers - Cancer antigen 15-3, cancer antigen 72-4,
cancer antigen 27.29, and carcinoembryonic antigen
Imaging
Imaging is a useful noninvasive form of assessment, with the
simplest staging scans being plain chest radiograph and liver
ultrasonic scan. Often, technical difficulties with the liver scan
(eg, due to patient body habitus) necessitate CT scans. With
contrast, CT scans can help specify lesions with high vascularity.
CT scan is also useful for helping detect lung and brain
metastases and high axillary and intrathoracic lymph
adenopathy.
Bone scans, for example using technetium Tc 99m methylene
diphosphonate, are sensitive for increased osteoclastic activity,
but their specificity relies on the pattern of distribution of the
tracer in the body in view of the frequent detection of
degenerative disease. Attention must be given to a history of
old fractures or arthritis. Ultimately, the whole body scan can
be used to direct further, more localized, corroborative imaging
such as plain radiographs or CT scan and/or MRI of the spine.
Suggestive characteristics of tracer distribution include single
high-signal areas in the spine, asymmetric distribution, and
occurrence away from joints and tendon insertions (ie, not
arthritis).
Biopsy
Biopsy may be needed for final confirmation of suspected
metastases, which may involve cytologic analysis of pleural or
ascitic tap fluid or direct image-guided needle biopsy into
lymph nodes, liver, or bone.
Micrometastases in bone marrow aspirates or lymph node
biopsy specimens can be determined based on findings from
immunocytochemistry (ie, cytokeratins CK19 and CAM 5.2),
PCR, and RT-PCR.
Prognostic Indicators
Criteria for Prognostic Indicators
For a prognostic indicator to be accepted as clinically useful,
ideally it must have the following criteria:
1. Proven biological relevance (level I evidence)
2. Ability to identify high-risk and low-risk patients
3. Appropriate cut-off point
4. Inexpensive
5. Significant treatment implications
One of the most successful indices of prognosis in breast cancer
is the Nottingham Prognostic Index (NPI)17 , which can be used
to select patients for adjuvant treatment and which makes use
of the following 3 proven prognostic indicators:
NPI = [0.2 X tumor size in cm] + tumor grade [1-3] + lymph node
stage [1-3]
The addition of the progesterone receptor status, angiogenesis,
and VEGF status to the classic parameters from which NPI is
derived makes it possible to increase prognostic capacity of this
index further.
Prognostic Indicators
Tumor size
Prognosis deteriorates with increasing tumor size, which is an
independent predictor of survival in node-negative patients
and correlates with the incidence of nodal metastases.
Staging
The status of the axillary lymph nodes is one of the most useful
prognostic indicators for breast cancer, with average 10-year
survival rates of 60-70% for node-negative patients, dropping
to 20-30% in node-positive patients. Metastatic spread in other
parts of the body invariably indicates axillary node
involvement.
Histopathology
1. Histological type18
 Because it is a preinvasive condition, carcinoma in situ is
curable if completely removed, although 16% of patients
with carcinoma in situ develop invasive recurrence after
local excision of ductal carcinoma in situ, usually high
grade. Similarly, 18% of patients develop invasive
recurrence after lobular carcinoma in situ excision.
 Well-differentiated invasive cancers have a relatively good
prognosis if they are tubular, mucinous, cribriform, or
secretory.
 Medullary carcinoma is probably of intermediate
prognosis, but different studies have used different criteria
for its definition.
 Invasive ductal and invasive lobular carcinomas have a less
favorable prognosis but are influenced heavily by other
factors.
2. Cytologic grade
 Cytologic grade is the best predictor of disease prognosis in
carcinoma in situ but is dependent on the grading system
used, such as the Van Nuys classification (high-grade, lowgrade comedo, low-grade noncomedo).
 The grading of invasive carcinoma is also important as a
prognostic indicator, with higher grades indicating a worse
prognosis. Microscopic criteria for grading are shown in
Table 3.
3.
Table 3. Grading System in Invasive Breast Cancer
(Modified Bloom and Richardson)
Score
1
2
3
A.
Tubule >75%
10-75%
<10%
formation
B. Mitotic count <7
7-12
>12
per
high-power
field (microscopeand
fielddependent)
C. Nuclear size Near normal Slightly
Markedly
and
Little
enlarged
enlarged
pleomorphism
variation
Moderate
Marked
variation
variation
1.
Cancer is considered grade I if the total score (A + B + C) is
3-5.
2. Cancer is considered grade II if the total score (A + B + C) is
6 or 7.
3. Cancer is considered grade III if the total score (A + B + C) is
8 or 9.
4. Grade I tumors are associated with a 10-year survival rate
of 85%, whereas the survival rate falls to 45% for grade III
tumors.
5. Lymphovascular: Lymphatic invasion, vascular invasion,
microvessel quantification, and lymphoplasmacytic
infiltration are associated with a worse prognosis.
6. Immunohistochemistry
 The most widely used tests are for the estrogen receptors
(ER)
and
progesterone
receptors
(PR).
Immunohistochemistry analysis of heat-treated paraffin
sections has largely superseded the enzyme-linked
immunosorbent assay (ELISA) ligand-binding assay. ER- and
PR-positive status (i.e., >10 fmol on ELISA; >15 H-score on
immunohistochemistry) predict improved response to
endocrine treatment, time to relapse, and overall survival.
 Immunohistochemical positivity for c-erb-B2 and p53 is
associated with a worse prognosis.
Other prognostic indicators
Advances in the knowledge of the molecular mechanisms that
influence normal and aberrant cell growth, has led to the
identification of an increasing number of surrogate
biomarkers.19
Currently for breast cancer, the existing markers are of little
value for screening or aiding early diagnosis.
These novel prognostic markers can be classified as follows:
1. Oncogene products
o Bcl-2
o p53
o HER-2/neu
o Cyclin D1
o Nm23
2. Proteases
o uPA and PA1
o Cathepsin D
o Tenascin C
3. Markers of proliferation - Ki-67
HER-2/neu identifies patients with a poor prognosis. These
patients are likely to respond to treatment with trastuzumab
(Herceptin).
Tumors positive for Ki-67 have a high metastatic potential and
warrant the possible use of early aggressive therapy.
uPA and cathepsin D identify poor prognosis node-negative
tumors. High levels of these markers can guide the decision to
offer chemotherapy.
The use of gene expression profiling to detect breast carcinoma
has already shown that the differential expression of specific
genes is a more powerful prognostic indicator than traditional
determinants such as tumor size and lymph node status.
Profiling of specific genes in patients with proven breast cancer
may help identify those most likely to benefit from specific
adjuvant treatments such as chemotherapy. Early studies
demonstrate that these genetic techniques have great
potential and are likely to become more prevalent in future
breast cancer management.
Follow-up
Need for follow-up care
Whether regular follow-up care affects overall or disease-free
survival is debatable, as is the question of whether significantly
more recurrences are detected than would be otherwise by the
patients themselves or their general practitioners. However, a
number of reasons support continuing evaluation of patients
with breast cancer following their initial treatment plan.
1. Managing adverse effects of treatment
2. Monitoring response of metastatic disease to treatment
3. Psychological support
4. Detection and early treatment of recurrences
5. Screening of high-risk groups for new disease
6. Palliative care
7. Audit of short- and long-term outcome of treatment
8. Clinical trials
Frequency of follow-up care
Different centers vary in the precise scheduling of hospital
follow-up appointments, but the general trend is to reduce the
frequency of clinic visits until final discharge to the breast
screening service after 10 years if no new disease has occurred.
Following is a suggested schedule for the hospital follow-up
care for patients who have undergone curative resection:
1. Visits every 3 months for 1 year (plus adjuvant treatment)
2. Visits every 6 months for 4 years
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 breastconservation 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.