Breast Cancer Workup

Updated: Jan 17, 2019
  • Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS  more...
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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 cancer−related 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. [85, 86] A review that used seven statistical models determined that the use of screening mammography reduced the rate of death from breast cancer by 28–65% (median, 46%). [85] A meta-analysis found that screening mammography reduces breast cancer mortality by about 20–35% in women 50–69 years old and slightly less in women 40–49 years old at 14 years of follow-up. [86]

In the UK Age trial, breast cancer mortality in the first 10 years after diagnosis was significantly lower (rate ratio [RR] 0.75) in women who received annual screening mammography from age 40-49 years than in those invited for screening at age 50 years and every 3 years thereafter. During the remainder of the 17-year follow-up period, however, reduction in breast cancer mortality was not evident (RR 1.02). [87]

In contrast, 25-year follow-up of 89,835 women in the Canadian National Breast Screening Study found that annual mammography in women aged 40-59 did not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Findings for women aged 40-49 and 50-59 were almost identical. Moreover, 22% (106/484) of invasive breast cancers detected by screening mammography were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial. [88]

A number of screening modalities exist for breast cancer, including clinical breast examination, mammography, ultrasonography, and MRI. (See Breast Cancer Screening.)

In December 2013, the US Food and Drug Administration (FDA) issued a warning that nipple aspirate tests are not an effective screening tool for breast cancer or other breast diseases and should not be used in place of mammography, other imaging tests, or biopsy. The agency is concerned that the test, which involves analysis of fluid aspirated from a woman's breast with a pump device, could lead to false-positive or -negative results if fluid analysis alone is used as a screen. [89]


Mammography is a low-dose x-ray−based modality used to image the breast. It is currently the best available population-based method for detecting breast cancer at an early stage. [86, 90, 91]

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 µm. 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. [92] 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). [93, 94]

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%. [95]

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 woman’s 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. [96, 97]

At present, the most widely accepted recommendations in the United States come from the American Cancer Society (ACS). In October 2015, the ACS updated its guidelines, which had previously recommended annual screening mammography, beginning at age 40 years for all women and continuing for as long as a woman is in good health, along with 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. [98]

The 2015 ACS recommendations for women at average risk of breast cancer are as follows [99] :

  • Women should begin regular screening mammography at age 45 years (strong recommendation)
  • Women aged 45-54 years should be screened annually (qualified recommendation)
  • Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation)
  • Women should have the opportunity to begin annual screening at 40-44 years of age (qualified recommendation)
  • Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation)
  • Clinical breast examination is not recommended for breast cancer screening in average-risk women at any age

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). [97]

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.

Similarly, a 2015 review by the American College of Physicians (ACP) recommends the following strategies as the least intensive and having the highest value for asymptomatic women at average risk and in good health [100] :

  • Women 40-49 years of age: Discuss benefits and harms; if the patient requests screening, order biennial mammography

  • Women 50-74 years of age: Encourage mammography every 2 years

For women of any age, the ACP does not recommend the following low-value screening strategies [100] :

  • Annual mammography

  • MRI

  • Tomosynthesis

  • Regular systematic breast examination

In contrast to the ACP recommendation against the use of tomosynthesis (3D mammography) in breast cancer screening, the American College of Radiology (ACR) states that, “breast tomosynthesis has shown to be an advance over digital mammography, with higher cancer detection rates and fewer patient recalls for additional testing.” The ACR notes that further studies will be needed to determine which subgroups of women are likely to benefit most from tomosynthesis screening. [101]

In the Screening with Tomosynthesis Or standard Mammography-2 (STORM-2) study—a prospective population-based screening study in 9672 women that compared integrated 3D mammography with 2D mammography—3D mammography detected more cases of breast cancer than 2D mammography but increased the percentage of false-positive recalls in sequential screen-reading. [102] Thus, the benefit of significantly increased breast cancer detection with tomosynthesis screening must be weighed against the possible risk of overdiagnosis.

For more discussion of tomosynthesis, see Mammography in Breast Cancer.

For women whose mammogram reveals dense breast tissue, 21 US states have laws requiring that the women be notified and be advised to discuss supplemental imaging with their provider. However, a prospective cohort study found that only a minority of women with dense breasts have high interval cancer rates. The authors concluded that supplemental imaging should not be justified on the basis of breast density alone . [103]

Kerlikowske et al reported that women at high risk can be identified by combining 5-year breast cancer risk, as determined with the Breast Cancer Surveillance Consortium (BCSC) risk calculator, with breast density as categorized with the Breast Imaging Reporting and Data System (BI-RADS). [103]

High interval cancer rates were observed for women with a 5-year BCSC risk of 1.67% or greater and extremely dense breasts or a 5-year risk of 2.50% or greater and heterogeneously dense breasts. However, study participants who met those criteria accounted for only 24% of all women with dense breasts. [103]

The highest rate of advanced-stage breast cancer, >0.4 case per 1000 examinations, was seen in women with 5-year BCSC risk of 2.50% or greater and heterogeneously or extremely dense breasts. Such patients comprised 21% of all women with dense breasts. [103]

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 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.)

In an observational study by Buist et al that included more than 2 million screenings in over 800,000 women, MRI screening for breast cancer was associated with higher rates of subsequent biopsy but a lower yield of cancer findings. In women with a breast cancer history, biopsy rates were more than twofold higher after MRI than after mammography alone; in women with no history of breast cancer, biopsy rates were more than fivefold higher. [104]

In women with a past history of breast cancer, ductal carcinoma in situ or invasive disease was found in 404.6 per 1000 biopsies  following mammography versus 267.7 per 1000 biopsies following MRI, a significant difference. Yield was nonsignificantly higher after mammography in women without a history of breast cancer: 279.3 versus 214.6 per 1000, respectively. [104]

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)

  • 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 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 [105]

  • 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 of99m 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 for99m Tc-tetrofosmin and99m 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)







63-95% (>95% palpable, 50% impalpable, 83-92% in women older than 50 y; decreases to 35% in dense breasts)

14-90% (90% palpable)


(94% palpable)

Initial investigation for symptomatic breast in women older than 35 y and for screening; investigation of choice for microcalcification


68-97% palpable

74-94% palpable

92% (palpable)

Initial investigation for palpable lesions in women younger than 35 y



21-97% (< 40% primary cancer)


Scarred breast, implants, multifocal lesions, and borderline lesions for breast conservation; may be useful in screening high-risk women


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


96% (90% axillary metastases)



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.



Breast cancers usually are epithelial tumors of ductal or lobular origin. For full discussion, see Breast Cancer Histology.

All of the following features are 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)





> 2

> 3

A. Tubule formation



< 10%

B. Mitotic count/HPF (microscope- and field-dependent)

< 7



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.

Ductal carcinoma in situ

Increased use of screening mammography has resulted in a dramatic increase in the detection of ductal carcinoma in situ (DCIS). Approximately 64,000 cases of DCIS are diagnosed annually in the United States. About 90% of DCIS cases are identified on mammography as suspicious calcifications: linear, clustered, segmental, focal, or mixed distribution.

DCIS is broadly divided into 2 subtypes: comedo (ie, cribriform, micropapillary, and solid; see the first image below) and noncomedo (see the second image below). The likelihood of progression or local recurrence, as well as the prognosis, varies in accordance with the DCIS subtype present (see Table 3 below).

Breast cancer. Intraductal carcinoma, comedo type. Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact basement membrane and central tumor necrosis.
Breast cancer. Intraductal carcinoma, noncomedo ty Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth pattern.

Table 3. Ductal Carcinoma in Situ Subtypes (Open Table in a new window)

DCIS Characteristic



Nuclear grade



Estrogen receptor

Often negative








Local recurrence






DCIS = ductal carcinoma in situ.

Lobular carcinoma in situ

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 images below). Over the past 25 years, the incidence of LCIS has doubled, currently standing at 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.

Breast cancer. Lobular carcinoma in situ. Enlargem Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.
Breast cancer. Lobular carcinoma in situ. Enlargem Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Infiltrating ductal carcinoma

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor (accounting for 75% of breast cancers) and has a tendency to metastasize via lymphatic vessels. This lesion has no specific histologic characteristics other than invasion through the basement membrane (see the image below). DCIS is a frequently associated finding on pathologic examination.

Breast cancer. Infiltrating ductal carcinoma. Low- Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.

Infiltrating lobular carcinoma

Infiltrating lobular carcinoma has a much lower incidence than infiltrating ductal carcinoma, accounting for 15-20% of invasive breast cancers. Histologically, it is characterized by the "single-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 multifocal and have discontinuous areas of involvement, making mammographic and even MRI staging imprecise.

Medullary carcinoma

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

  • Sheets of anaplastic tumor cells with scant stroma

  • Moderate or marked stromal lymphoid infiltrate

  • Histologic circumscription or a pushing border

DCIS may be observed in the surrounding normal tissues. Medullary carcinomas are typically high-grade lesions that are negative for ER, PR, and HER2 and that commonly demonstrate mutation of TP53.

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. There are 2 main types of lesions, 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 image below), whereas type B is a distinct variant with endocrine differentiation.

Breast cancer. Colloid (mucinous) carcinoma. Nests Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells in pool of extracellular mucin.

DCIS is not a frequent occurrence in this setting, though 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.

Tubular carcinoma

Tubular carcinoma of the breast is an uncommon histologic type, accounting for only 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 make up 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 (see the image below) encompasses a spectrum of histologic subtypes. 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.

Breast cancer. Papillary carcinoma. Solid papillar Breast cancer. Papillary carcinoma. Solid papillary growth pattern with early cribriform and well-developed thin papillary fronds.

Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and a good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype similar to that of infiltrating ductal carcinoma, even though about 70% of cases are ER-positive. A retrospective review of 1400 cases of invasive carcinoma identified 83 cases (6%) with at least 1 component of invasive micropapillary ductal carcinoma. Additionally, lymph node metastasis is seen frequently in this subtype (70-90% of cases). [106]

Metaplastic breast cancer

Metaplastic breast cancer (MBC) accounts for fewer than 1% of breast cancer cases. It 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 on the basis of a similarity in clinical behavior. Compared with infiltrating ductal carcinoma, MBC tumors are larger, faster-growing, commonly node-negative, and typically negative for ER, PR, and HER2.

Mammary Paget disease

Mammary Paget disease is relatively rare, accounting for 1-4% of all breast cancers. The peak incidence is seen in the sixth decade of life. This adenocarcinoma is localized within the epidermis of the nipple-areola complex and is 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. In situ or invasive breast cancer is found in approximately 85% of patients with Paget disease. Thus, all diagnosed patients require a careful breast examination and mammographic evaluation, with additional imaging, including breast MRI, if the mammogram is negative.


Breast Cancer Staging

The American Joint Committee on Cancer (AJCC) staging system groups patients into four stages according to the TNM system, which is based on tumor size (T), lymph node status (N), and distant metastasis (M). (See Table 4 below.) The forthcoming eighth edition of the AJCC staging system, which will take effect on January 1, 2018, will have changes that include the following [107] :

  • Incorporation of immunohistochemically detected tumor markers, to refine prognosis
  • Use of genomic assays when available to downstage some estrogen receptor–positive, lymph node–negative tumors
  • Removal of lobular carcinoma in situ, because it is not a malignancy but a risk factor

Table 4. TNM Staging System for Breast Cancer (Open Table in a new window)





Stage 0




Stage I




Stage IIA










Stage IIB







Stage IIIA













Stage IIIB










Stage IIIC

Any T



Stage IV

Any T

Any N


Primary tumor (T)

Tumor size definitions are as follows:

  • Tx – Primary tumor cannot be assessed

  • T0 – No evidence of primary tumor

  • Tis – DCIS

  • Tis – LCIS

  • 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 in greatest diameter

  • T1mic – Microinvasion ≤0.1 cm in greatest diameter

  • 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

  • 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)

Clinical 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

The 5-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 histologic grade—along with determination of ER, PR, and HER2 status—is necessary for determining prognosis.

Lymph node assessment

Evaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node dissection (ALND) has also been considered necessary for staging and prognosis.

A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the American Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be offered to the following patients [108] :

  • Women with operable breast cancer and multicentric tumors

  • Women with DCIS who will be undergoing mastectomy

  • Women who previously underwent breast and/or axillary surgery

  • Women who received preoperative/neoadjuvant systemic therapy

According to the ASCO guidelines, sentinel lymph node biopsy should not be performed in patients with any of the following:

  • Large or locally advanced invasive breast cancer (tumor size T3/T4)

  • Inflammatory breast cancer

  • DCIS (when breast-conserving surgery is planned)

  • Pregnancy

ASCO recommendations regarding ALND in patients who have undergone sentinel lymph node biopsy are as follows:

  • ALND should not be performed in women with no sentinel lymph node (SLN) metastases

  • In most cases, ALND should not be performed in women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy

  • ALND should be offered to women with SLN metastases who will be undergoing mastectomy

National Comprehensive Cancer Network (NCCN) recommendations differ from those of ASCO in that the NCCN considers that women with clinical stage as high as IIIA T3, N1, M0 may be candidates for SLN biopsy. In addition, the NCCN concluded that there is insufficient evidence to make recommendations for or against SLN biopsy in pregnant patients; the NCCN recommends that decisions regarding use of SLN biopsy in pregnancy be individualized. However, isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy; radiolabeled sulfur colloid appears to be safe. [75]

The NCCN breast cancer guidelines state that lymph node dissection is optional in the following cases [75] :

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

Also see Breast Cancer Staging for summarized information.


Additional Testing

The 2017 NCCN guidelines [75] recommend the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I–IIB):

  • Complete blood count (CBC) with differential
  • Comprehensive metabolic panel, with liver function tests (LFTs) and alkaline phosphatase

Additional studies indicated in specific settings include the following:

  • Bone scan, in patients with localized bone pain or alkaline phosphatase elevation
  •  Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast, in patients with elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis
  • Chest diagnostic CT with contrast, in patients with pulmonary symptoms

For women with clinical stage lllA (T3, N1, M0) disease, tests to consider are as follows:

  • CBC
  • Comprehensive metabolic panel, including LFTs and alkaline phosphatase
  • Chest diagnostic CT with contrast
  • Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast
  • Bone scan or sodium fluoride PET/CT (category 2B)
  • FDG PET/CT (optional)

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO) and CAP have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (eg, HercepTest; Dako, Glostrup, Denmark) for HER2 protein expression. [109] (See Breast Cancer and HER2.)

The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

  • 3+ – Positive for HER2 protein 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, or uniform intense membrane staining in 30% or less of tumor cells

  • 1+ – Weak or incomplete membrane staining in any tumor cells

  • 0 – Negative for HER2 protein expression; no staining

Breast cancer specimens with equivocal IHC results should undergo validation with 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 fewer than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC < 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 been developed. The HER2 CISH PharmDX Kit (Dako Denmark A/S, Glostrup, Denmark) was approved by the FDA in November 2011. The interpretation for HER2 FISH testing (ratio of HER2 to chromosome 17 centromere [HER2/CEP17] and gene copy number) is as follows:

  • Positive HER2 amplification – HER2:CEP17 ratio is greater than 2.2 or HER2 gene copy is greater than 6.0

  • Equivocal HER2 amplification – HER2:CEP17 ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0

  • Negative HER2 amplification – HER2:CEP17 ratio is less than 1.8 or HER2 gene copy of less than 4.0

Molecular profiling assays

The Onco type Dx assay (Genomic Health, Inc, Redwood City, CA) has been approved by the US Food and Drug Administration (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.

By using a formula based on the expression of these genes, an RS can be calculated that correlates with the likelihood of distant recurrence at 10 years. Breast tumor RSs and risk levels are as follows:

  • < 18, low risk

  • 18-30, intermediate risk

  • >30, high risk

Furthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies, the Onco type Dx assay was shown retrospectively to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors. [110] Similarly, among women with 1- to 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 RS.

Women with a low RS showed a significantly greater improvement in disease-free survival (DFS) with the addition of tamoxifen; no additional benefit was derived from the addition of chemotherapy. In contrast, women with a high RS had a significant improvement in DFS with the addition of chemotherapy to hormonal therapy (tamoxifen).

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], a large, prospective, randomized phase III study sponsored by the National Cancer Institute (NCI), is addressing this important question.

The MammaPrint assay (Agendia, The Netherlands) is a genetic test that measures the activity of 70 genes to determine the 5- to 10-year relapse risk for women diagnosed with early breast cancer. It was approved for use by the FDA in 2007 and is an alternative platform to Oncotype DX. MammaPrint test results are reported as either a low-risk or a high-risk RS:

  • A low-risk score means that the cancer has a 10% risk of coming back within 10 years without any additional treatments after surgery

  • A high-risk score means that the cancer has a 29% risk of coming back within 10 years without any additional treatments after surgery