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BREAST CANCER REVIEW

Diagnosis and Staging

Introduction

Evaluation of a breast symptom or abnormal finding begins with a thorough medical history and physical examination, followed by imaging tests. Breast biopsy is used for subsequent investigation of suspicious lesions and for definitive diagnosis. The process reflects a gradually increasing degree of invasiveness so that diagnosis is obtained with a minimum amount of patient discomfort and cost. Abnormalities found to be cancer are staged and further characterized in order to estimate prognosis and determine appropriate treatment.

Medical History and Physical Examination

The first step in the evaluation of a patient with suspected breast cancer begins with a complete medical history. In addition to obtaining detailed information about the breast finding, including any changes over time, the provider should inquire about any new localized or constitutional symptoms; take note of known breast cancer risk factors; and elicit a detailed family history of cancer, with special attention given to breast and ovarian cancers. Also important, the provider should ask about or observe any signs of emotional distress that may be related to the discovery of the breast lesion. While most cases will prove to be benign, the process of evaluation can be a difficult time for a patient. The provider can help by facilitating any needed emotional counseling or support.¹

In addition to a general exam, a complete physical examination includes a full pelvic exam and Pap smears. A visual and manual inspection of the breasts will search for the presence of lumps or masses; asymmetry; changes to the skin or to the nipples; and tenderness. Regional lymph nodes will be palpated for swelling or firmness. Other areas of the body will be checked for obvious spread of breast cancer and to help evaluate the general condition of the patient's health.²

The Breast Cancer Diagnostic Algorithms for Primary Care Providers (Cancer Detection Section, California Department of Health Services, 2005) provides detailed guidance for the work-up of a new palpable mass; abnormal screening mammogram with normal CBE; spontaneous unilateral nipple discharge; breast skin changes; and breast pain. There is also a risk assessment algorithm, and, in the case of breast biopsy, an algorithm for the management of pathologic findings. The algorithms have been developed by an expert panel of California providers and are available for viewing on this web site.

Primary care providers are responsible for assessing a patient's risk for breast cancer, performing CBE, recommending appropriate screening techniques, and ensuring that the patient receives complete and timely follow-up of any abnormal findings. Primary care records should contain all relevant imaging and biopsy results, documenting a complete and timely follow-up. California's Cancer Detection Programs: Every Woman Counts expects this complete follow-up of abnormal findings within 60 days.

Imaging Tests

The most common imaging tests used for the evaluation of an abnormal breast finding are diagnostic mammogram and breast ultrasound. Other imaging tests may be used to improve diagnostic accuracy and to clarify indeterminate findings. A final BI-RADS category should be assigned based on the results of all imaging procedures.

Diagnostic Mammogram is similar to a screening mammogram but includes additional views focused on the area of concern. In addition to the standard craniocaudal and mediolateral oblique views, diagnostic mammogram may include lateromedial, mediolateral, and exaggerated craniocaudal views, and other special views, such as spot compression and magnification. Mammography is the imaging method of choice for investigating microcalcifications.

The additional views of a diagnostic mammogram can be a source of concern for women who are not properly informed about the procedure. The primary care provider can help alleviate potential anxiety by explaining that the need for additional images does not imply that a malignancy has been found on screening mammography. In fact, a majority of cases where extra views are obtained do not result in recommendations for biopsy.

Breast Ultrasound is a common and indispensable adjunct to diagnostic mammography Using high-frequency sound waves for examining tissues, breast ultrasound is especially helpful for distinguishing between a solid mass and a fluid filled cyst. Structures with certain characteristics can be confidently diagnosed as benign. Ultrasound is also used for evaluating masses in women whose mammograms are difficult to interpret, such as women with dense breast tissue.

Magnetic Resonance Imaging (MRI) may be used for viewing palpable abnormalities that are not visible with mammography or ultrasound. Using magnets and radio waves to produce very detailed, cross-sectional images, MRI is especially helpful for discriminating between cancer and scar tissue. Like ultrasound, it is also useful in evaluating dense breast tissue. Breast MRI may also be used to help define the size and extent of cancer within breast tissue and to help spot multifocal disease. In known cases of breast cancer, MRI can be used to scan other regions of the body for signs of metastasis.

Ductogram (also called a galactogram) is a type of contrast enhanced mammography used for helping to determine the cause of abnormal nipple discharge. The procedure involves the insertion of a cannula (a very fine plastic tube) into the breast duct into which a small amount of contrast medium (dye) is injected. The breast is then imaged with mammography. A ductogram may be valuable for diagnosing benign tumors, such as papillomas, and for evaluating suspected cancer, such as ductal carcinoma in situ. Fluid from a nipple discharge might also be collected and examined under a microscope (nipple smear).

Scintimammography is a nuclear medicine imaging test that uses a radioactive tracer (Tc 99m Sestamibi) to help detect breast cancer. The procedure involves injecting small amounts of slightly radioactive substances into the body. Most generally, malignancies show increased uptake of the radioactive tracer as compared to benign lesions. Although considered still experimental by some experts, scintimammography is sometimes used as a supplemental imaging method for certain patients. Like MRI, it is most useful for women with dense breast tissue and for women with breast implants. It is also useful with large, palpable abnormalities that cannot be imaged well with mammography or ultrasound, and for detecting axillary involvement.

Positron Emission Tomography (PET) is another type of nuclear medicine imaging that may play a role in determining whether a breast mass is cancerous. As with scintimammography, PET imaging requires an injection of a small amount of radioactive substance into the body. A series of detailed computer images record metabolic activity that help distinguish normal cells from cancer. Higher metabolic rates suggest cancer. An NCI-sponsored clinical trial is evaluating the usefulness of PET scans in women with breast cancer compared with other imaging techniques. This trial is also studying the effectiveness of PET scans in tracking the response of a tumor to treatment.

Electrical Impedance Imaging (also known as Transscan, or T-scan) consists of a hand-held probe that scans the breast for electrical conductivity, sending two-dimensional images of breast tissue to a computer screen. Because breast cancer cells tend to have lower electrical impedance causing them to appear different (bright white) from normal cells, electrical impedance imaging can help evaluate tumors detected by mammography. While the device is not approved as a screening method, it does have FDA approval for use as a diagnostic aid. According to the National Cancer Institute (NCI), electrical impedence imaging may reduce the number of biopsies needed to determine whether a breast mass is cancerous and also improve the identification of women for whom a biopsy is appropriate.³

Breast Biopsy

In some cases, breast imaging can determine that an abnormality is not cancer, however, imaging tests alone cannot prove that a lesion is malignant. The only definitive method for diagnosing breast cancer is with a breast biopsy. Biopsy involves the removal of tissue or cells for microscopic examination. The specimen can be obtained from a symptomatic area or from an area identified with breast imaging. There are several different types of breast biopsies.

Needle Biopsy

Two types of needle biopsies are used to diagnose breast cancer. The most common is core needle biopsy. A less commonly used needle procedure is fine needle aspiration biopsy.

Core Needle Biopsy (CNB) uses a larger needle than FNAB and instead of cells, CNB removes a small cylinder of tissue (a core) about the size of a grain of rice. About 3 to 5 cores are usually removed, although more may be taken. The core tissue samples are then analyzed by a pathologist for malignant cells.

Image Guided Biopsy is often used to facilitate the sampling of cells or tissue from abnormalities that can be seen on one or more imaging tests but cannot be felt. If an abnormality is better seen on a mammogram, guidance with mammography is usually preferred. If better seen by ultrasound, then the method of choice may be ultrasound. Similarly, MRI may be used for enabling the biopsy of a lesion that cannot be seen by either mammogram or ultrasound. The mammogram guided technique, called stereotactic needle biopsy, creates pairs of x-ray images of the breast biopsy path from two slightly angled directions to help guide the needle. Ultrasound, which does not use x-ray, provides the flexibility of real-time display while guiding the needle to the precise location. A marker clip is usually placed to aid in future identification of the area biopsied.

To increase diagnostic accuracy and eliminate as many false-negative results as possible, the triple assessment principle is applied. Also known as triple test, this refers to the correlation of findings from 1) clinical breast examination, 2) breast imaging, and 3) biopsy. The triple test seeks concordance of findings using different screening and diagnostic techniques and ensures comprehensive follow-up of abnormal findings. For example, abnormal clinical breast exam (CBE) findings with a normal mammography result requires additional follow-up to further investigate the abnormal findings from the CBE.

Surgical Biopsy

Surgical biopsy, also called open biopsy, may be used for a lesion that is not accessible by needle biopsy. There are two types of surgical biopsy: incisional and excisional. Incisional biopsy removes a small portion of the lesion.  Excisional biopsy removes the entire lesion as well as a surrounding margin of normal appearing breast tissue. If the lesion is nonpalpable, or otherwise difficult to locate, a wire localization technique may be used to direct the surgeon to its precise location.

As with needle biopsy, tissue removed by surgical biopsy is sent to a pathology lab for microscopic examination. In the case of positive findings, blood tests will be taken and one or more imaging procedures may be used for helping to screen for evidence of cancer spread, including chest chest x-ray, bone scan, CT-scan, MRI and/or PET.

Staging of Breast Cancer

Staging is the process of determining the growth and extent of cancer in the body.  The stage of cancer is one of the most important factors for planning treatment and offers insight into prognosis. Staging also provides a standardized means by which medical providers may communicate with one another about an individual case and a method by which cancer researchers may compare case outcomes.

The stage of a breast cancer is determined by information gathered from tests on tumor tissue, lymph nodes, and distant organs. There are two assessment points. Clinical staging occurs prior to surgery and is based upon information obtained from physical examination and imaging tests. Pathological staging occurs after biopsy, and includes both clinical information and findings from microscopically examined tissue. The latter is the more definitive for planning treatment and estimating prognosis.

TNM System

The system most widely used for breast cancer staging is the TNM system. This system has been accepted by the American Joint Committee on Cancer (AJCC) and is the main method used by most medical facilities for cancer reporting. The letters stand for tumor (T), lymph nodes (N), and metastasis (M). Each letter is followed by a number, or additional letters, that describes what is known about the growth and extent of disease at diagnosis. (Both information for clinical and pathological staging is gathered during the period prior to first course of therapy.) The T component designates the size and invasiveness of the primary tumor, with the numeric value increasing with tumor size and extent of invasiveness. The N component designates the presence or absence of regional node involvement, with the numeric value based on the number or location of involved lymph nodes. The M component identifies the presence or absence of distant metastasis, including lymph nodes that are not regional. Once the values for the T, N, and M components have been determined, the information is grouped and expressed as one of five possible stages, represented by Roman numerals from Stage 0 (carcinoma in situ) to Stage IV (distant metastasis). Stages II and III are further refined into subsets, represented by capital letters (IIB, IIC, etc.). In practice, most clinicians simply use Stages 0-IV. See Table I.⁴

Table I

Further information about TNM Definitions and AJCC Stage Groupings is available on the National Cancer Institute web site. Additionally, the American Joint Committee on Cancer web site offers a variety of publications and other staging resources for healthcare professionals. 

5-Year Survival Rates

Five-year survival rates refer to the percentage of patients who live at least 5 years from diagnosis. Relative survival compares the observed survival of people with breast cancer with that expected for people without breast cancer. (Mortality due to others causes is excluded from the rate.) The following is an approximate 5-year relative survival rate for each stage of breast cancer based on data from patients diagnosed from 1995 to 1998. Current survival rates may be higher due to improvements in treatment and modifications to the TNM staging system made in 2002. The figures are derived from the American College of Surgeons National Cancer Data Base, as reported by the American Cancer Society.⁵

5-Year Relative Survival Rate by Stage:

Stage 0	100%
Stage I	100%
Stage IIA	92%
Stage IIB	81%
Stage IIIA	67%
Stage IIIB	54%
Stage IIIC	rate not available
Stage IV	20%

After seven years, the relative survival rates decrease for each stage. As with all averages, however, it should be noted that individual outcomes may vary depending upon a woman's personal characteristics, such as age, general health and menopausal status, and upon additional prognostic factors related to tumor features.

Additional Prognostic Factors

In addition to those described for TNM staging, factors that affect prognosis include type of cancer, tumor grade, hormone receptor status (estrogen and progesterone), HER-2/neu expression, DNA content (ploidy) and cell proliferation rate (S-phase fraction).

Type of cancer may be in situ or invasive, ductal or lobular, or a rarer form, such a Phylloides tumor which develops in the breast stroma. The many variations of ductal and lobular carcinoma have differing implications for prognosis. (For more information, please see Anatomy and Pathology: Types of Breast Cancer )

Tumor grade classifies breast cancer cells on the basis of three features: rate of cell division (mitotic rate), percent of cancer composed of tubular structures (tubule formation), and change in cell size and uniformity (nuclear grade). Each feature is assigned a score ranging from 1 to 3, based upon microscopic observations of the cells. The three scores are then added together for a final sum that ranges from 3 to 9.  Generally, a lower total number is associated with a more favorable prognosis. One of the most popular grading systems in the United States is the modified Scarff-Bloom-Richardson grading scale.

Hormone receptor status refers to the estrogen and progesterone receptors on the surface of cells that bind to circulating hormones. Tumors that contain estrogen and progesterone receptors are referred to as ER-positive and PR-positive, or hormone receptive positive. About two-thirds of breast cancers are ER-positive, with the likelihood of ER-positivity increasing with age. Hormone receptive positive breast cancers predict response to hormone therapy (e.g., tamoxifen, aromatase inhibitors) and their prognosis is generally more favorable than cancers without this feature. However, recent research has shown that advances in chemotherapy have resulted in improved outcomes for patients with ER-negative tumors, with prognoses approaching that of patients with optimally treated ER-positive disease.⁶  

HER-2/neu expression refers to a type of cell surface receptor that functions to regulate cell growth. Testing for HER-2/neu is of clinical value in assessing prognosis and choice of treatment. While HER-2/neu overexpression is generally associated with an adverse prognosis, it also predicts response to the monoclonal antibody, trastuzumab (Herceptin). HER-2/neu overexpression affects approximately 20% to 30% of breast cancer patients.

DNA content (ploidy) and cell proliferation rate (S-phase fraction) are measured by flow cytometry, which is a technique that separates, classifies and quantifies cell types. The ploidy of cancer cells refers to the amount of DNA they contain which has prognostic implications. Tumors with a normal amount of DNA are described as diploid; those with an abnormal amount are described as aneuploid. The prognosis is usually worse for breast cancers with a greater degree of cellular aneuploidy. Cell proliferation rate, or S-phase fraction, refers to the rate at which cells divide and grow. High values indicate faster rates of growth and less favorable disease outcomes than low values.

Notes

¹Edge SB, Hurd TC. Best Practice of Medicine: Breast Cancer (Mar., 2003.) Merck Medicus. Retrieved Jun. 8, 2006 at: http://merck.micromedex.com/index.asp?page=bpm_brief&article _id=BPM01ON03

²See note 1.

³National Cancer Institute. Improving Methods for Breast Cancer Detection and Diagnosis (updated, Apr. 26, 2002). Retrieved Jun. 8, 2006 at: http://www.cancer.gov/cancertopics/factsheet /Detection/breast-cancer

⁴Table content was compiled from information published on the American Cancer Society (ACS) web page: How is Breast Cancer Staged? (revised, Sep. 2, 2005). Retrieved May 28, 2006 at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_breast_cancer_staged _5.asp? sitearea=CRI

⁵See note 4.

⁶OncoLink Cancer News. Prognosis similar in estrogen positive and negative breast cancer  (Apr. 12, 2006). Retrieved Jun. 7, 2006 at: http://www.oncolink.com/resources/article.cfm?c=3&s= 8&ss=23&id=13051&month=04&year=2006

Updated: June 4, 2008.

Source URL: http://qap.sdsu.edu/education/bcrl/Bcrl_diagstag/bcrl_diagstag_index.html

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