Breast Cancer Workup

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 a diagnosis can be obtained 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.

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.

The general approach to evaluation of breast cancer has become formalized as triple assessment: clinical examination, imaging (usually mammography and/or ultrasonography), and needle biopsy. However, this should always be performed as part of a more general assessment beginning with clinical history.

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, a mass, or architectural distortion. If any of these features are identified, a diagnostic mammogram along with a breast ultrasound should be performed before obtaining a biopsy. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.

Early detection remains the primary defense available to patients in preventing the development of life-threatening breast cancer. Breast tumors that are smaller or nonpalpable are more treatable when detected and thus have a more favorable prognosis.

Screening modalities for breast cancer include breast self-examination, clinical breast examination, mammography, ultrasonography, and magnetic resonance imaging. Go to Breast Cancer Screening for more information on this topic.

Mammography is a special type of low-dose x-ray imaging used to create detailed images of the breast. Mammography can demonstrate microcalcifications smaller than 100 µm; it often reveals a lesion before it is palpable by CBE and, on average, 1-2 years before noted by BSE.

There are 2 types of mammography examinations: screening and diagnostic. Screening mammography is done in asymptomatic women.

Diagnostic mammography is performed in symptomatic women (eg, when a breast lump or nipple discharge is found during self-examination or an abnormality is found during screening mammography). This examination is more involved, time-consuming, and expensive than screening mammography and 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 will usually require the additional views used in diagnostic mammography.

Other uses of mammography in breast cancer

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 has become a widely available and useful adjunct to mammography in the clinical setting. Ultrasound is generally used to assist the clinical examination of a suspicious lesion detected on mammography or physical examination. As a screening device, ultrasound is limited by a number of factors, most notably by the failure to detect microcalcifications and by 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 that 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.

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.

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 be highly sensitive (approximating 99% when combined with mammogram and CBE) to malignant changes in the breast. Go to Magnetic Resonance Mammography for more information on this topic.

Indications for MRI

The high cost and limited availability of MRI, as well as the difficulties inherent in performing and interpreting the studies, require careful recommendations for its use. The following are common agreed-upon and useful 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 to MRI

Conversely, in a number of situations, MRI is essentially contraindicated, usually because of physical constraints that prevent adequate patient positioning. These constraints include the following:

• Contraindication to gadolinium-based contrast media (eg, allergy, pregnancy)
• Patient's 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
• Assessment of mammographically detected microcalcifications

Three radiotracers are commonly used for breast imaging or scintimammography in either clinical practice or research: technetium-99m (^99m Tc)-sestamibi and^99m Tc-tetrofosmin (both used for myocardial perfusion imaging), as well as^99m Tc-methylene diphosphonate (MDP) (used for bone scintigraphy).^99m Tc-sestamibi was the first radiopharmaceutical agent to be approved by the FDA for use in scintimammography.^[4]

Although not indicated as a screening procedure for the detection of breast cancer, scintimammography may play a useful and significant 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]

PET scanning 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 [¹⁸ FDG]), changes in metabolic activity, vascularization, oxygen consumption, and tumor receptor status can be detected. At present, its main use may be to help detect recurrences in scarred breasts, but it is also useful in multifocal disease, in detecting axillary involvement, and in equivocal cases of systemic metastases.^[5]

PET/computed tomography (CT) scans may be appropriate to assist in identification of nonaxillary lymph node metastasis (ie, internal mammary or supraclavicular lymph nodes) for staging locally advanced and inflammatory breast cancer before starting neoadjuvant therapy.

Table 2, below, summarizes the accuracy of various techniques used in breast imaging. 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. Table 2. Accuracy of Breast Imaging Modalities (Open Table in a new window)

Percutaneous vacuum-assisted large-gauge core biopsy (VACNB) with image guidance is the recommended diagnostic approach for newly diagnosed breast cancers. Core biopsies spare the need for operative intervention (and subsequent scarring), often providing pathologic results more quickly than surgical excisions.

Additionally, excisional biopsy, as the initial operative approach, has been shown to increase the rate of positive margins. Thus, core biopsies for diagnosing breast cancer can eliminate the need for additional surgeries for definitive margin control and assessment of nodal status.

The ultimate diagnostic biopsy is open excisional biopsy of a lesion, normally performed under general anesthesia. Open excisional biopsy should be reserved for lesions where the diagnosis remains equivocal despite imaging and less invasive assessment, or the procedure should be used 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.

Breast cancers usually are epithelial tumors of ductal or lobular origin (see the images below). 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 receptors and progesterone receptors
• Nuclear and histologic grade
• DNA content
• S-phase fraction
• Vascular invasion
• Tumor necrosis
• Quantity of intraductal component

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. Grade I tumors are associated with a 10-year survival rate of 85%, whereas the survival rate falls to 45% for grade III tumors. Microscopic criteria for grading are shown in Table 3, below.

Table 3. Grading System in Invasive Breast Cancer (Modified Bloom and Richardson) (Open Table in a new window)

Ductal carcinoma in situ

Increased use of screening mammography has resulted in a dramatic increase in the detection of DCIS. Approximately 64,000 cases of DCIS are diagnosed annually in the US. Ninety percent of DCIS cases are identified on mammography as suspicious calcifications, linear, clustered, segmental, focal, or mixed distribution. DCIS is divided into comedo (ie, cribriform, micropapillary, solid) and noncomedo subtypes, which provides additional prognostic information on the likelihood of progression or local recurrence (see the images and Table 4 below).

Table 4. Ductal Carcinoma in Situ Subtypes (Open Table in a new window)

Lobular carcinoma in situ

LCIS arises from the terminal duct apparatus and shows a rather diffuse distribution throughout the breast, which explains its presentation as a nonpalpable mass in most cases (see the 2 images below). Over the last 25 years, LCIS incidence has doubled and is currently 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.

Infiltrating ductal carcinoma

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a tendency to metastasize via lymphatics. This lesion, which accounts for 75% of breast cancers, has no specific histologic characteristics other than invasion through the basement membrane, as seen in the image below. DCIS is a frequently associated finding on pathologic examination.

Infiltrating lobular carcinoma

Infiltrating lobular carcinoma has a much lower incidence and comprises less than 15% of invasive breast cancer. It is characterized histologically by the “Indian file” arrangement of small tumor cells. Like ductal carcinoma, infiltrating lobular carcinoma typically metastasizes to axillary lymph nodes first. However, it also has a tendency to be more multifocal. Despite this, the prognosis is comparable to that of ductal carcinoma.

Medullary carcinoma

Medullary carcinoma is relatively uncommon (5%) and generally occurs in younger women. Most patients present with a bulky palpable mass with axillary lymphadenopathy. Diagnosis of this type of breast cancer depends on the following histologic triad:

1. Sheets of anaplastic tumor cells with scant stroma

2. Moderate or marked stromal lymphoid infiltrate

3. Histologic circumscription or a pushing border

DCIS may be observed in the surrounding normal tissues. ER, PR, and HER2 are typically negative, and TP53 is commonly mutated.

Mucinous carcinoma

Mucinous (colloid) carcinoma is another rare histologic type seen in fewer than 5% of invasive breast cancer cases. It usually presents during the seventh decade of life as a palpable mass or appears mammographically as a poorly defined tumor with rare calcifications.

Mucin production is the histologic hallmark with 2 main forms, type A and B, with AB lesions possessing features of both. Type A mucinous carcinoma represents the classic variety with larger quantities of extracellular mucin (see the following image), whereas type B is a distinct variant with endocrine differentiation.

DCIS is not a frequent occurrence, although it may be found. Most cases are ER- and PR-positive, but HER2 overexpression is rare. Additionally, these carcinomas predominantly express glycoproteins MUC2 and MUC6. Overall, patients with mucinous carcinoma have an excellent prognosis (>80% 10-year survival).

Tubular carcinoma

Tubular carcinoma of the breast is an uncommon histologic type involving 1-2% of all breast cancers. Characteristic features of this type include a single layer of epithelial cells with low-grade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands.

Tubular components comprise more than 90% of pure tubular carcinomas and at least 75% of mixed tubular carcinomas. This type of breast cancer has a low incidence of lymph node involvement and a very high overall survival rate. Because of its favorable prognosis, patients are often treated with only breast-conserving surgery and local radiation therapy.

Papillary carcinoma

Papillary carcinoma of the breast encompasses a spectrum of histologic subtypes (see the image below). There are 2 common types: cystic (noninvasive form) and micropapillary ductal carcinoma (invasive form). This form of breast cancer is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers. Papillary carcinomas are centrally located in the breast and can present as bloody nipple discharge. They are strongly ER- and PR-positive.

Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype, even though approximately 70% of cases are ER-positive. A retrospective review of 1,400 cases of invasive carcinoma identified 83 cases (6%) with at least one component of invasive micropapillary ductal carcinoma.

Additionally, lymph node metastasis is seen frequently in this subtype (70-90% incidence), and the number of lymph nodes involved appears to correlate with survival.

Metaplastic breast cancer

MBC accounts for less than 1% of breast cancer cases, tends to occur in older women (average age of onset in the sixth decade), and has a higher incidence in blacks. It is characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components.

A wide variety of histologic patterns includes the following:

• Spindle-cell carcinoma
• Carcinosarcoma
• Squamous cell carcinoma of ductal origin
• Adenosquamous carcinoma
• Carcinoma with pseudosarcomatous metaplasia
• Matrix-producing carcinoma

This diverse group of malignancies is identified as a single entity based on a similarity in clinical behavior. When compared with infiltrating ductal carcinoma, MBC tumors are larger; more rapidly growing; commonly node-negative; and typically ER-, PR-, and HER2-negative.

Mammary Paget disease

MPD is relatively rare, comprising 1-4% of all breast cancers. Peak incidence is seen in the sixth decade of life (mean age, 57 y).

This adenocarcinoma is localized within the epidermis of the nipple-areola complex and composed of the histologic hallmark Paget cells within the basement membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nuclei, dispersed between the keratinocytes singly or as a cluster of cells.

Lesions are predominantly unilateral, developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with symptoms of itching, tingling, burning, or pain.

The American Joint Committee on Cancer (AJCC) staging system groups patients into 4 stages based on tumor size (T), lymph node status (N), and distant metastasis (M). See Table 5, below.

Primary tumor (T)

Tumor size definitions are as follows:

• Tx: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: (DCIS) Carcinoma in situ
• Tis: (LCIS) Carcinoma in situ
• Tis: Paget disease of the nipple with no tumor (Paget disease associated with a tumor is classified according to the size of the tumor.)
• T1: Tumor 2 cm or smaller in greatest diameter
• T1mic: Microinvasion 0.1 cm or less in greatest dimension
• T1a: Tumor >0.1 but not >0.5 cm in greatest diameter
• T1b: Tumor >0.5 but not >1 cm in greatest diameter
• T1c: Tumor >1 cm but not >2 cm in greatest diameter
• T2: Tumor >2 cm but not >5 cm in greatest diameter
• T3: Tumor >5 cm in greatest diameter
• T4: Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as described below
• T4a: Extension to the chest wall, not including the pectoralis muscle
• T4b: Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast
• T4c: Both T4a and T4b
• T4d: Inflammatory disease

Regional lymph nodes (N)

Regional lymph node definitions are as follows:

• Nx: Regional lymph nodes cannot be assessed (eg, previously removed)
• N0: No regional lymph node metastasis
• N1: Metastasis in movable ipsilateral axillary lymph node(s)
• N2: Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis
• N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures
• N2b: Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes
• N3: Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of axillary lymph node
• N3a: Metastasis in ipsilateral infraclavicular lymph node(s)
• N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
• N3c: Metastasis in ipsilateral supraclavicular lymph node(s)

Distant metastasis

Metastases are defined as follows:

• Mx: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

Table 5. TNM Staging System for Breast Cancer (Open Table in a new window)

Five-year survival rates are highly correlated with tumor stage, as follows:

• Stage 0: 99-100%
• Stage I: 95-100%
• Stage II: 86%
• Stage III: 57%
• Stage IV: 20%

This prognostic information can guide physicians in making therapeutic decisions. Pathologic review of the tumor tissue for histological grade along with the determination of estrogen/progesterone receptor status and HER2 status is necessary for determining prognosis.

Evaluation of lymph node involvement by sentinel lymph node biopsy or axillary lymph node dissection has also been considered necessary for staging and prognosis, as recommended in the 2009 edition of the National Comprehensive Cancer Network (NCCN) breast cancer guidelines, but the 2011 update modifies this recommendation. The 2011 NCCN breast cancer guidelines state that lymph node evaluation is optional in the following cases:

• Strongly favorable tumors
• When no result would affect the choice of adjuvant systemic therapy
• Elderly patients
• Patients with comorbid conditions

The 2011 NCCN guidelines state that for staging, sentinel lymph node biopsy is preferred over axillary lymph node dissection.^{[6, 18]} .

The 2011 NCCN guidelines, like the 2009 version, recommends the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I and II):

• Complete blood cell (CBC) count with differential
• Liver function tests (LFTs)
• Renal function tests
• Serum calcium

In addition, women with stage III (locally advanced or inflammatory breast cancer) or symptomatic disease should have a chest x-ray or CT scan of the chest, CT scan of the abdomen and pelvis, and bone scan for evaluation of distant metastasis. Tumor markers (carcinoembryonic antigen [CEA] and CA15.3 or CA27.29) may also be obtained in these patients.^{[6, 18]}

Genetic testing for BRCA1 and BRCA2 can be performed in selected high-risk patients with a strong family history of breast or ovarian carcinoma. However, genetic counseling and discussion of subsequent management and treatment options should be performed before testing.

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate; therefore, the American Society of Clinical Oncology (ASCO) and CAP have recommended guidelines in HER2 testing to ensure accuracy. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (ie, HercepTest, Dako, Glostrup, Denmark) for HER2 protein expression.^[7] The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

• 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells
• 2+: Equivocal for HER2 protein expression - Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells
• 0 or 1+: Negative for HER2 protein expression

Breast cancer specimens with equivocal IHC should undergo validation using a HER2 gene amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on FISH alone for determining HER2 status.

In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 FISH results are seen in less than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC less than 3+/FISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.

Newer methodologies for establishing HER2 status, including reverse transcriptase–polymerase chain reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have not yet been validated. The interpretation for HER2 FISH testing (HER2/CEP17 ratio and gene copy number) is given below:

• Positive HER2 amplification: FISH ratio is greater than 2.2 or HER2 gene copy is greater than 6.0
• Equivocal HER2 amplification: FISH ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0
• Negative HER2 amplification: FISH ratio is less than 1.8 or HER2 gene copy of less than 4.0

Go to Breast Cancer and HER2 for complete information on this topic.

Oncotype Dx assay

The Onco type Dx assay (Genomic Health, Inc, Redwood City, Calif) has been validated in and approved by the FDA for women with early-stage, ER-positive, node-negative breast cancer treated with tamoxifen, where the recurrence score (RS) correlated with both relapse-free interval and overall survival. This assay is an RT-PCR-based assay of 21 genes (16 cancer genes and 5 reference genes) performed on paraffin-embedded breast tumor tissue.

Using a formula based on the expression of these genes, a recurrence score can be calculated that correlates with the likelihood of distant recurrence at 10 years. Breast tumors with a recurrence score of less than 18 are considered low risk; a score of 18-30 is considered intermediate risk; and a score greater than 30 is considered high risk.

Furthermore, the Onco type Dx assay has been shown retrospectively in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors.

Women with a low recurrence score showed a significantly greater improvement in disease-free survival (DFS) with the addition of tamoxifen versus chemotherapy, whereas women with a high recurrence score had a significant improvement in disease-free survival with the addition of chemotherapy. Among women with 1-3 node-positive, hormone receptor-positive disease, the Onco type Dx recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in the recurrence score.

In general, results from these studies would indicate that a select group of node-positive, hormone receptor-positive patients with a low recurrence score would not benefit from an anthracycline-based regimen. The benefit of adding chemotherapy to hormonal therapy in tumors with an intermediate score is still controversial; The Trial Assigning Individualized Options for Treatment [TAILORx] Trial, a large, prospective, randomized phase III study sponsored by the National Cancer Institute (NCI), is addressing this important question.