| Molecular Subtypes
Histologic Subtypes of Breast Cancer
Breast cancers can be categorized by the microscopic appearance of the cancer cells and the patterns they make in tissue, that is, by histology. This is done because the behavior and prognosis of different histologic types of breast cancer varies.
Ductal Carcinoma in Situ (DCIS)
Breast cancer most commonly originates in the cells lining the ducts. When the cancer cells are confined to the ducts, inside the duct lining, the basement membrane, the cancer is called ductal carcinoma in-situ. This is the earliest, most favorable type of breast cancer. DCIS, also called intraductal carcinoma, comprised only 3-5% of breast cancers before screening mammography became widespread, but it now accounts for 25% of breast cancers. Currently, DCIS is most often detected by finding a group of tiny calcium deposits, clustered microcalcifications, on a screening mammogram. Certain mammographic patterns of clustered microcalcifications are more suspicious, for example, linear or branched patterns, which suggest the calcifications are following a ductal pattern. There are different subtypes of DCIS. The specific subtype can affect how likely it is for DCIS to recur, or come back in the breast, especially after breast- conserving treatment. The Van Nuys Prognostic Index, is based on the size (microscopic extent), class (appearance of the cancer cell nuclei and presence or absence of necrosis -dead cells within the ducts), margin status (width of normal tissue removed around the cancer) and age at diagnosis. A score of 1-3 is given for each factor and the overall grade is based on the additive score: low (4, 5, 6), intermediate (7, 8, 9) or high (10, 11, 12) grade. The second system is based on the appearance and patterns of cells: comedo, cribriform, clinging, solid, papillary or micropapillary. Comedo and high grade DCIS are more likely to recur in the breast with breast-conserving treatment, although the most significant predictor of in-breast recurrence is whether margins are negative, close or positive.
20-30% of low grade DCIS will progress to invasive ductal carcinoma if it is not properly treated, and this is likely much higher with high grade or comedo-type DCIS. Theoretically ductal carcinoma in situ should not have the capacity to metastasis (spread to other parts of the body) because the cancer cells are contained within the ducts and do not have access to blood vessels or lymphatics. From a practical point of view, we know that in-situ or non invasive ductal carcinomas metastasize in < 2% of cases.
Lobular Carcinoma in Situ (LCIS)
Lobular Carcinoma in Situ (LCIS) is actually not a form of breast cancer, but this term is very ingrained in the medical literature, despite attempts to rename it. This benign finding is associated with an increased risk for developing breast cancer in the future. LCIS does not usually cause any breast symptoms or findings on breast exam or abnormalities on mammograms; it is typically found in breast tissue when a biopsy is done for another reason. LCIS is more akin to having a family history of breast cancer, in that both of these factors tell us that this woman’s breast tissue has a higher than average propensity for developing breast cancer. Because both breasts are at risk, cancer could develop in the breast opposite from the one in which a biopsy showed LCIS or in the same breast. LCIS is associated with a 20-25% risk for developing breast cancer over 20-25 years after the biopsy. In women with LCIS and a family history of breast cancer in a mother, sister or daughter (first degree relative) the risk for developing breast cancer is 40%. There is one form of LCIS, called pleomorphic LCIS, which may be a precursor which can progress to invasive lobular carcinoma, the way DCIS can progress to invasive ductal carcinoma. There is controversy about whether pleomorphic LCIS should be treated the same way DCIS is treated.
Infiltrating Ductal Carcinoma
Infiltrating ductal carcinoma, also called invasive ductalcarcinoma, is the most common type of breast cancer, comprising about 75% of breast cancers. With this type, breast cancer arises from cells lining the breast ducts, but grows through (invades) the ductal basement into the supporting tissue around the ducts, the periductal stroma, which is connective and fatty tissue containing blood vessels and lymphatics. Once the cancer cells invade the stroma, there is the possibility for cancer cells to spread (metastasize) to the lymph nodes in the under- arm (via the lymphatic channels) or to other organs (via the blood vessels). Infiltrating ductal carcinoma includes a number of subtypes. The most common subtype which does not have any of the specific features described below is called infiltrating ductal carcinoma- NOS (Not Otherwise Specified). The special histologic subtypes of infiltrating ductal carcinoma include tubular, invasive papillary, colloid or mucinous, and medullary. It is important to identify these subtypes because when found in their pure form, they are more favorable than typical infiltrating ductal carcinoma- NOS. A combination of one of these subtypes and typical infiltrating ductal carcinoma- NOS has the same prognosis as pure infiltrating ductal carcinom-NOS.
Tubular carcinomas are uncommon, comprising 1-2% of breast cancers. They have an appearance which mimics normal ducts in that they are comprised of tubular structures with a somewhat triangular shape, a “ship’s prow” appearance. They are well- differentiated (low- grade), usually small and hormone receptor positive, often with a limited component of DCIS. The likelihood of axillary lymph node involvement is low.
Invasive papillary carcinoma is another uncommon form of infiltrating ductal carcinoma occurring in <1-2% of breast cancers, typically in post-menopausal women. In this form of cancer, tufts or finger-like projections of cancer cells form. It can be difficult or impossible to distinguish benign papillomas, papillary ductal carcinoma in situ or invasive papillary carcinoma on core needle biopsies, so if papillary findings are seen on a core needle biopsy, a surgical, excisional biopsy is usually necessary to make this distinction.
Colloid or mucinous carcinomas, the terms are synonymous, are associated with an amorphous, acellular material, mucous.
Medullary carcinomas are often big, bulky tumors whose aggressive histologic appearance under the microscope contrasts with in more favorable behavior. They comprise 3-5% of breast cancers. They are found with greater frequency in women with BRCA 1 mutations.
Infiltrating Lobular Carcinoma
This comprises about 10% of breast cancers. In this type, cancer arises from the cells lining the lobules, and these lobular cancer cells grow through the lobular basement membrane into the stoma. Infiltrating lobular cancers usually form single file lines of cancer cells which interdigitate within the normal breast tissue. They don’t cause the same tissue reaction as infiltrating ductal cancers, so they don’t cause as much change in the breast tissue, or signs on breast exam or mammogram. Because of this, they can be difficult to detect until they are quite large. It is not uncommon for infiltrating lobular carcinoma to be detected only once it has spread to lymph nodes or metastasized to distant sites, such as bones. It has a slightly different pattern of spread from infiltrating ductal cancers and sometimes spreads to the intra- abdominal (peritoneal) cavity. However, these are well-differentiated and usual hormone receptor positive tumors. An infiltrating lobular carcinoma will have a somewhat better prognosis than an infiltrating ductal carcinoma of the same stage.
Paget’s Disease of the Breast
Pagets disease of the breast or nipple is an uncommon form of breast cancer which typically causes a scaly, ulcerated lesion of the nipple. This can extend onto the areola, the dark skin surrounding the nipple, but it will always involve the nipple itself and not only the areola. It is associated with an underlyingductal carcinoma which can be intraductal or infiltrating ductal. Rarely, the underlying ductal cancer cannot be identified. Paget’s disease is thought to ocur when ductal cancer cells grow along the breast ducts onto onto the surface of the nipple. Another less widely accepted theory is that it arises from the cells of the nipple itself. It is diagnosed by seeing characteristic Paget’s cells microscopically. The prognosis depends on the characteristics of the underlying ductal carcinoma.
Inflammatory Breast Cancer (IBC)
This is an aggressive form of breast cancer associated with breast skin changes which mimic infection or inflammation: redness, skin thickening, and prominence of the skin pores (erythema, edema and peau dorange respectively). Unlike a breast infection which is almost always painful, inflammatory breast cancer may not be painful. It typically occurs in women in their forties, but can develop at any age. It is associated with an underlying invasive breast cancer. It is caused by blockage of lymphatics in the breast skin by cancer cells (dermal lymphatic invasion). Rarely, inflammatory breast cancer doesnt cause these characteristic skin changes but is diagnosed when the pathologist sees dermal lymphatic invasion microscopically on biopsy. There is a greater chance that this cancer will have spread to lymph nodes when it is diagnosed and it has a higher chance of metastasizing. Treatment begins with neoadjuvant chemotherapy followed by mastectomy and axillary node dissection, then radiation therapy. Other forms of treatment may be used based on the tumor characteristics.
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Molecular Subtypes of Breast Cancer
Classifying breast cancers based on genetic and molecular characteristics may be helpful in assessing prognosis and designing targeted treatments tailored to the specific tumor characteristics at the genetic and molecular level. Breast cancer can be divided into four molecular subtypes. The profile of each subtype is based on gene expression patterns of the cancer cells, with analysis of hundreds of genes. Hormone receptor status, HER2/neu status and Ki67 proliferation rate can be used to approximate the four major subtypes:
Luminal A (40-50%): ER+ and/or PR+, HER2-, low Ki67
Luminal A tumors tend to be low to moderate grade with the most favorable prognosis, with high survival and low recurrence rates. Treatment usually includes endocrine therapy with tamoxifen or aromatase inhibitors.
Luminal B (5-20%): ER+ and/or PR+, HER2+ (or HER2- with high Ki67)
Luminal B tumors are often diagnosed at a younger age, are more likely to be larger, higher grade, lymph node positive and not have quite as good a prognosis as Luminal A tumors. Both endocrine therapy and antibody-based therapy such as trastuzumab (Herceptin) may be considered.
Triple negative/basal-like (15-20%): ER-, PR-, HER2-, cytokeratin 5/6 + and/or HER1+
Triple Negative breast cancers test negative for estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2, Her-2/neu. It is more common in women between 40 and 50-years-old, and African-American and Hispanic women, although it can occur in other women as well. Most BRCA1 breast cancers are triple negative and basal-like. Women under 60 years with triple negative breast cancer have a higher risk for BRCA mutations, and should be offered genetic counseling and/or testing. Triple negative/basal-like tumors have a poorer prognosis than luminal A and luminal B tumors. Treatment almost always includes chemotherapy, to which these tumors seem to be more sensitive than Luminal A or B tumors. These tumors do not respond to hormonal therapy like tamoxifen or aromatase inhibitors or to antibody-based therapy like trastuzumab (Herceptin).
HER2 type (10-15%): ER-, PR-, HER2+
HER2 type tumors tend to occur in younger women and have a poorer prognosis than luminal A or B tumors. HER2/neu-positive tumors can be treated with trastuzumab (Herceptin) and appear to be more sensitive to chemotherapy.
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