Breast cancer classification
Breast cancer classification divides all forms of breast cancer according to four different schemes, each based on different criteria and serving a different purpose. The four approaches consider pathology, the grade of the tumor, expression of proteins and genes, and the stage of the tumor.
Classifications of breast cancer are usually, but not always, classified by the histological appearance of tissue in the tumor. Rare variants are defined on the basis of physical exam findings. For example, Inflammatory breast cancer (IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinomas by the inflamed appearance of the affected breast. In the future, some pathologic classifications may be changed. For example, a subset of ductal carcinomas may be re-named basal-like carcinoma (part of the "triple-negative" tumors).
Schemes or aspects
Breast cancers can be classified by different schemata. Every aspect influences treatment response and prognosis. Description of a breast cancer would optimally include multiple classification aspects, as well as other findings, such as signs found on physical exam. Classification aspects include stage (TNM), pathology, grade, receptor status, and the presence or absence of genes as determined by DNA testing:
Stage. The TNM classification for breast cancer is based on the size of the tumor (T), whether or not the tumor has spread to the lymph nodes (N) in the armpits, and whether the tumor has metastasized (M) (i.e. spread to a more distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis.
The main stages are:
Stage 0 is a pre-malignant disease or marker (sometimes called DCIS: Ductal Carcinoma in Situ) .
Stages 1–3 are defined as 'early' cancer and potentially curable.
Stage 4 is defined as 'advanced' and/or 'metastatic' cancer and incurable.
Histopathology. Breast cancer is usually, but not always, primarily classified by its histological appearance. Most breast cancers are' derived from the epithelium lining the ducts or lobules, and are classified as mammary ductal carcinoma. Carcinoma in situ is proliferation of cancer cells within the epithelial tissue without invasion of the surrounding tissue. In contrast, invasive carcinoma invades the surrounding tissue. Cells that are dividing more quickly have a worse prognosis. One way to measure tumor cell growth is with the presence of protein Ki67, which indicates that the cell is in S phase, and also indicates susceptibility to certain treatments.
Grade (Bloom-Richardson grade). When cells become differentiated, they take different shapes and forms to function as part of an organ. Cancerous cells lose that differentiation. Cells that normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade). Poorly differentiated cancers have a worse prognosis.
Receptor status. Cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers such as hormones bind to receptors, and this causes changes in the cell. Breast cancer cells may or may not have three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. Cells with these receptors are called ER positive (ER+), ER negative (ER-), PR positive (PR+), PR negative (PR-), HER2 positive (HER2+), and HER2 negative (HER2-). Cells with none of these receptors are called basal-like or triple negative. ER+ cancer cells depend on estrogen for their growth, so they can be treated with drugs to reduce estrogen (e.g.tamoxifen), and generally have a better prognosis.
Generally, HER2+ had a worse prognosis, however HER2+ cancer cells respond to drugs such as the monoclonal antibody, trastuzumab, (in combination with conventional chemotherapy) and this has improved the prognosis significantly.
All of these receptors are identified by immunohistochemistry.
Receptor status is used to divide breast cancer into four molecular classes: (1) Basal-like, which are ER-, PR- and HER2- (triple negative, TN). Most BRCA1 breast cancers are basal-like TN. (2) Luminal A, which are ER+ and low grade (3) Luminal B, which are ER+ but often high grade (4) HER2+, which have amplified ERBB2.
Finally, receptor status has become a critical assessment for all breast cancers, as it determines the suitability of using targeted treatments e.g. tamoxifen and or trastuzumab. These treatments are now some of the most effective adjuvant treatments of breast cancer. Conversely, triple negative cancer (i.e. no positive receptors) is now thought to indicate a poor prognosis. More genes and/or proteins may be tested in the future (eg PAX2).
DNA microarrays have compared normal cells to breast cancer cells and found differences in hundreds of genes, but the significance of most of those differences is unknown. Several screening tests are commercially marketed, but the evidence for their value is limited. The only test supported by Level II evidence is Oncotype DX, which is not approved by the U.S. Food and Drug Administration (FDA) but is endorsed by the American Society of Clinical Oncology. MammaPrint is approved by the FDA but is only supported by Level III evidence. Two other tests have Level III evidence: Theros and MapQuant Dx. No tests have been verified by Level I evidence (in a prospective, randomized controlled trial, patients who used the test had a better outcome than those who did not). In a review, Sotirou concluded, "The genetic tests add modest prognostic information for patients with HER2-positive and triple-negative tumors, but when measures of clinical risk are equivocal (e.g., intermediate expression of ER and intermediate histologic grade), these assays could guide clinical decisions."
TNM (tumor, node, metastasis) system
TNM staging system
Tumor - There are five tumor classification values (Tis, T1, T2, T3 or T4) which depend on the presence or absence of invasive cancer, the dimensions of the invasive cancer, and the presence or absence of invasion outside of the breast (e.g. to the skin of the breast, to the muscle or to the rib cage underneath):
Tx - Primary tumor cannot be assessed.
T0 - No evidence of primary tumor.
Tis - Carcinoma in situ.
Tis(DCIS) - Intraductal Carcinoma in situ.
Tis(LCIS) - Lobular Carcinoma in situ.
Tis(Paget's) - Paget's disease of the nipple with no tumor.
T1 - Tumor 2 cm or less in its greatest dimension.
T1mic - Microinvasion 0.1 cm or less in greatest dimension.
T1a - Tumor more than 0.1 cm but not more than 0.5 cm in its greatest dimension.
T1b - Tumor more than 0.5 cm but not more than 1.0 cm in its greatest dimension.
T1c - Tumor more than 1.0 cm but not more than 2.0 cm in its greatest dimension.
T2 - Tumor more than 2.0 cm but not more than 5.0 cm in its greatest dimension.
T3 - Tumor more than 5 cm in its greatest dimension.
T4 - Tumor of any size with direct extension to (a) chest wall or (b) skin as described below:
T4a - Extension to chest wall.
T4b - Edema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules confined to the same breast.
T4c - Both T4a and T4b.
T4d - Inflammatory breast cancer.
Lymph Node - There are four lymph node classification values (N0, N1, N2 or N3) which depend on the number, size and location of breast cancer cell deposits in lymph nodes.
Nx - regional lymph nodes cannot be assessed. Perhaps due to previous removal.
N0 - no regional lymph node metastasis.
N1 - metastasis to movable regional axillary lymph nodes on the same side as the affected breast.
N2 - metastasis to fixed regional axillary lymph nodes, or metastasis to the internal mammary lymph nodes, on the same side as the affected breast.
N3 - metastasis to supraclavicular lymph nodes or infraclavicular lymph nodes or metastasis to the internal mammary lymph nodes with metastasis to the axillary lymph nodes.
Metastases - There are three metastatic classification values (Mx, M0 or M1) which depend on the detectability, absence or presence, respectively, of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung). The Mx classification may be applied by pathologists where clinical information about spread of cancer to other body sites is not available at the time the cancer pathology report is written.
Overall stage grouping
Overall stage grouping of breast cancer are classified as Stage 0 to IV:
Stages Features Overall 5-year survival
Stage 0 Ductal (DCIS) or lobular carcinoma in situ (LCIS) without microinvasion 92%
Stage I Invasive carcinoma of 2cm or less in diameter (including invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), as well as DCIS and LCIS with microinvasion) without lymph node involvement or metastases of less than 0.02 cm in diameter 87%
Stage II Invasive carcinoma (mainly IDC and ILC)
of 5 cm or less in diameter with up to three involved axillary nodes, or
greater than 5 cm but without lymph node involvement.
Stage III Invasive carcinoma (mainly IDC and ILC)
of 5 cm or less in diameter with four or more involved axillary lymph nodes, or
greater than 5 cm with any lymph node involvement, or
involving the ipsilateral internal mammary lymph nodes, or
involving the skin, with e.g. edema, ulceration or satellite skin nodules, chest wall fixation
showing chest wall fixation
Clinical inflammatory carcinoma
Stage IV Any breast cancer showing distant metastasis 13%
Histopathologic classification is based upon characteristics seen upon light microscopy of biopsy specimens. The most common pathologic types of breast cancer are:
Invasive ductal carcinoma - 55% of breast cancer incidence upon diagnosis, according to statistics from the United States in 2004
Ductal carcinoma in situ - 13%
Invasive lobular carcinoma - 5%
These three pathologic types represent approximately ¾ of breast cancer incidence.
For an extensive list, the latest (2003) World Health Organization (WHO) classification of tumors of the breast recommends the following pathological types, which includes benign (harmless) tumors along with malignant (cancerous) tumors:
Invasive breast carcinomas,Invasive ductal carcinoma,Most are "not otherwise specified",The remainder are given subtypes:,Mixed type carcinoma,Pleomorphic carcinoma,Carcinoma with osteoclastic giant cells,
Carcinoma with choriocarcinomatous features,Carcinoma with melanotic features,Invasive lobular carcinoma,Tubular carcinoma,Invasive cribriform carcinoma,Medullary carcinoma,Mucinous carcinoma and other tumours with abundantmucin,Mucinous carcinoma,Cystadenocarcinoma and columnar cellmucinous carcinoma,Signet ring cell carcinoma,Neuroendocrine tumours,Solid neuroendocrine carcinoma (carcinoid of the breast),Atypical carcinoid tumour,Small cell / oat cell carcinoma,
Large cell neuroendocrine carcioma,Invasive papillary carcinoma,Invasive micropapillary carcinoma,
Apocrine carcinoma,Metaplastic carcinomas,Pure epithelial metaplastic carciomas,Squamous cell carcinoma,Adenocarcinoma with spindle cell metaplasia,Adenosquamous carcinoma,Mucoepidermoid carcinoma,Mixed epithelial/mesenchymal metaplastic carcinomas,Lipid-rich carcinoma,Secretory carcinoma,Oncocytic carcinoma,Adenoid cystic carcinoma,Acinic cell carcinoma,Glycogen-rich clear cell carcinoma,Sebaceous carcinoma,Inflammatory carcinoma,Bilateral breast carcinoma,
Mesenchymal tumors (including sarcoma),Haemangioma,Angiomatosis,Haemangiopericytoma,
Pseudoangiomatous stromal hyperplasia,Myofibroblastoma,Fibromatosis (aggressive),Inflammatory myofibroblastic tumour,Lipoma,Angiolipoma,Granular cell tumour,Neurofibroma,Schwannoma,
Precursor lesions,Lobular neoplasia,lobular carcinoma in situ,Intraductal proliferative lesions,
Usual ductal hyperplasia,Flat epithelial hyperplasia,Atypical ductal hyperplasia,Ductal carcinoma in situ,Microinvasive carcinoma,Intraductal papillary neoplasms,Central papilloma,Peripheral papilloma,
Atypical papilloma,Intraductal papillary carcinoma,Intracystic papillary carcinoma,Benign epithelial lesions,Adenosis, including variants,Sclerosing adenosis,Apocrine adenosis,Blunt duct adenosis,
Microglandular adenosis,Adenomyoepithelial adenosis,Radial scar / complex sclerosing lesion,Adenomas,
Tubular adenoma,Lactating adenoma,Apocrine adenoma,Pleomorphic adenoma,
Ductal adenoma,Myoepithelial lesions,Myoepitheliosis,Adenomyoepithelial adenosis,
Adenomyoepithelioma,Malignant myoepithelioma,Fibroepithelial tumours,Fibroadenoma,Phyllodes tumour,
Benign,Borderline,Malignant,Periductal stromal sarcoma, low grade,Mammary hamartoma,Tumours of the nipple,Nipple adenoma,Syringomatous adenoma,Paget's disease of the nipple,Malignantlymphoma,Metastatic tumours,Tumours of the male breast,Gynecomastia,Carcinoma,