Breast Cancer

The Breast

The female breasts are modified sweat glands composed of lobes and lobules interspersed with adipose tissue and connective tissue. Ducts drain from each lobule. These converge to form a lactiferous duct that drains from each lobe. The lactiferous ducts merge just beneath the nipple to form a lactiferous sinus.

The functional secretory unit in lactation is the terminal duct lobular unit. Here, each duct has a lining epithelium surrounded by a thin myoepithelial cell layer responsive to oxytocin, the hormone that stimulates lactation.

Neoplasms may arise in either the ductular epithelium, lobules, or the stroma. However, the majority of cancers arise in the ducts.

Incidence of Breast Cancer

Breast cancer is very rare before age 20 and is rarely diagnosed in women younger than age 25. Past that age, the incidence rises steadily to reach a peak around the age of menopause. The rate of increase is lessened after menopause, but older women are still at increasing risk over time.

About 1 in 8 women in the United States and Canada will develop breast cancer. This incidence is similar for many European countries. However, breast cancer is much less common in Asia.

The incidence rate for breast cancer rose 24% in the U.S. between 1973 and 1991, while mortality from breast cancer did not increase. In addition, more localized cancers were diagnosed over time. These statistics indicate that screening for breast cancer, including mammography, probably played a role in detecting more cancers at an earlier stage.

Risk Factors for Breast Cancer

Although a specific cause for breast cancer has not been identified, there are risk factors that increase the likelihood that a woman will develop a breast cancer. These risks include:

Maternal relative with breast cancer. Women whose mother or sister or aunt had breast cancer, particularly at a younger age, have a greater risk.
BRCA1 and BRCA2 genes. The incidence of the BRCA1 gene on chromosome 17 may be 1 in 800 women. The BRCA2 gene on chromosome 13 is less frequent but associated with early onset breast carcinomas. The presence of these genes may explain some of the familial cases, and may be the etiology for about 1% of breast cancers overall.
Longer reproductive span. Women who have an earlier menarche and/or a later menopause, increasing the length of reproductive years, are at greater risk.
Obesity. Women who are overweight are at increased risk. In addition, increased dietary fat intake is a risk.
Nulliparity. Women who have never borne children are at greater risk, while women who have been pregnant are at a lower risk.
Later age at first pregnancy. Women who had their first child over age 30 are at greater risk.
Atypical epithelial hyperplasia. Although fibrocystic changes that produce benign breast "lumps" are not premalignant, the presence of atypical changes in ductular epithelium does increase the risk.
Previous breast cancer. Women who have had breast cancer in the opposite breast are at increased risk for cancer in the remaining breast.
Previous endometrial carcinoma. Women who have had adenocarcinoma of the endometrium are at increased risk for breast cancer.

Aside from the genetic predisposition, the common factor in many of these risks is increased endogenous estrogen exposure over a long time.

Classification of Breast Cancer

Breast cancers can be classifed histologically based upon the types and patterns of cells that compose them. Carcinomas can be invasive (extending into the surrounding stroma) or non-invasive (confined just to the ducts or lobules). The tables below identify the major histologic types of invasive and non-invasive breast cancers, along with their frequency of all breast cancer types, and overall relative 5-year survival (% of patients with that histologic type surviving for 5 years following diagnosis). The "NOS" categories contain carcinomas not easily classified into other histologic types or carcinomas for which minimal tissue was available for diagnosis.

Invasive Carcinomas of the Breast

Histologic Type	Frequency (%)	5-year Survival (%)
Infiltrating Ductal Carcinoma	63.6	79
Infiltrating Lobular Carcinoma	5.9	84
Infiltrating Ductal & Lobular Carcinoma	1.6	85
Medullary Carcinoma	2.8	82
Mucinous (colloid) Carcinoma	2.1	95
Comedocarcinoma	1.4	87
Paget's Disease	1.0	79
Papillary Carcinoma	0.8	96
Tubular Carcinoma	0.6	96
Adenocarcinoma, NOS	7.5	65
Carcinoma, NOS	3.5	62

Non-invasive Carcinomas of the Breast

Histologic Type	Frequency (%)	5-year Survival (%)
Intraductal Carcinoma	3.6	>99
Lobular Carcinoma in situ (LCIS)	1.6	>99
Intraductal & LCIS	0.2	>99
Papillary Carcinoma	0.4	>99
Comedocarcinoma	0.3	>99

Features of these carcinomas is discussed with the images shown below:

Immunohistochemical and Gene Probe Techniques

The hormone receptor status of the breast cancer cells can be useful information for treatment and prognosis. The neoplastic cells can express a variety of receptors. The presence of these receptors can provide a means for controlling cell growth through chemotherapeutic agents.

In general, cancers in which the cells express estrogen receptor (ER) in their nuclei will have a better prognosis. This is because such positive neoplastic cells are better differentiated, and they can respond to hormonal manipulation. The drug tamoxifen is often utilized for this purpose. Almost three-fourths of breast cancers expressing ER will respond to this therapy, whereas less than 5% not expressing ER will respond.

The significance of progesterone receptor (PR) positivity in a breast carcinoma is less well understood. In general, cancers that are ER positive will also be PR positive. However, carcinomas that are PR positive, but not ER positive, may have a worse prognosis.

There are other markers that can be identified in breast carcinomas. Cathepsin D is an acidic lysosomal protease that can be found in the cytoplasm of breast carcinoma cells, and it is also found in the stroma between the cells. There is a correlation between cathepsin D positivity and presence of metastases (particularly lymph nodes). Non-ductal carcinomas (a minority of breast cancers) are more likely to stain with Cathepsin D. C-erb B-2 (HER-2/neu) is another marker in breast carcinomas, and it is identified around the cytoplasmic membrane of the cells with immunohistochemical methods. HER-2 oncogene overexpression is typically the result of gene amplification (more gene copies) and is detected by the fluorescence in situ hybridization (FISH) assay, but in a few cases may be due to transcription activation. This gene encodes for an epithelial growth factor receptor on the cell membrane that stimulates cellular proliferation. There is a correlation between HER-2 positivity and high nuclear grade and aneuploidy.

Flow Cytometry

The amount of DNA contained in the nuclei of breast carcinoma cells will provide an indication of their malignant potential. Flow cytometry is a means for measuring the amount of DNA. Normal cells, or those of a benign neoplasm, tend to have a single homogenous population of cells with a "euploid" DNA content. However, malignant cells are less differentiated and have abnormal expression of DNA content. This is measurable as the degree of "aneuploidy" by flow cytometry. The prognosis is worse for carcinomas with a greater degree of cellular aneuploidy.

Breast cancer analyzed by flow cytometry

Integrated Report

The data generated from testing can be integrated into an interpretive report.

Breast cancer integrated report

Diagnostic Procedures

One of the best methods for detection of breast abnormalities is self-examination. In women of reproductive age, this is best carried out just after menstruation as a new menstrual cycle is beginning. Thorough self-examination on a regular basis will bring attention to any changes that may occur, as a woman can become familiar with the normal appearance of her breasts on palpation. Breast examination is part of a routine physical examination performed by a physician or other health care worker. However, a breast cancer may have been present for 5 to 10 years before reaching a size (about 1 cm) that is detectable by palpation.

The location of breast cancers is as follows:

Upper outer quadrant: 50%
Central area: 20%
Lower outer quadrant: 10%
Upper inner quadrant: 10%
Lower inner quadrant: 10%

The most sensitive and specific method to detect breast cancer is mammography. This procedure is performed by compressing each breast between metal plates and producing an image of the breast on a radiographic film. The film is then examined by a radiologist for any abnormalities. Current mammographic methods employ very small amounts of radiation, which cumulatively are not enough to be a hazard even with yearly mammographic examinations. If a palpable "lump" is present, then diagnostic mammography can aid in defining and localizing it. However, mammography can detect masses that are not palpable, because carcinomas generally have a density greater than the surrounding breast tissue. The presence of breast implants makes it difficult to see lesions in the breast mammographically.

Mammography is optimally performed when the woman has no cyclic breast tenderness or other conditions that would increase breast density. There is no consensus as to recommendations for use of routine mammographic screening; the patient and her physician can decide what is needed based upon individual circumstances. A screening mammogram for asymptomatic women includes standard views of both breasts. The major purpose of a screening mammogram is to separate normal from abnormal findings and to identify patients who need further evaluation. The films can be compared to previous films, if available. If the patient has an abnormal screening mammogram or signs and symptoms of a breast abnormality, then a diagnostic mammogram is performed.

Following detection of an abnormality by palpation and/or by mammography, a tissue sample can be obtained. For small lumps that are not clearly cancers, a procedure called "fine needle aspiration" or FNA is performed. The physician performing an FNA will guide a thin needle, under local anesthetic, into the breast to the location of the abnormality. Then, cells are aspirated into the needle with several passes through the abnormal area. The cells are placed on glass slides, stained to highlight the cells, and then examined by a cytopathologist. The cytopathologist tries to determine if malignant cells are present. In general, false positive diagnoses (a lesion is called cancer, but in reality is not) are rare. However, with this technique, false negative diagnoses (in which a cancer may be missed) are possible some of the time, because of sampling error or the small number of cells examined or the nature of the lesion.

Breast biopsy is performed to remove a lesion and make a definitive diagnosis, if a malignancy has not been demonstrated by FNA but is still suspected, or if a lump is likely to be malignant. Such a biopsy can be done under local or general anesthesia. The biopsy can also be directed radiographically by placing a needle and/or colored dye into the area that is abnormal. The biopsy can be examined by frozen section by the pathologist for a quick, preliminary diagnosis. More commonly, the biopsy is processed routinely, and a diagnosis is made. If a malignancy is found, the biopsy can be further studied via immunoperoxidase staining to determine receptor status.

Grading and Staging

A completely uniform system of grading for breast cancers is not possible because of the wide variety of histologic cell types. The cell types themselves, along with the invasiveness of the cancer, help to predict the biologic behavior of the cancer. A grading system (a modified Scarff-Bloom-Richardson system) outlined below utilizes histologic characteristics of the breast carcinoma.

Tubule Formation (% of carcinoma composed of tubular structures)	Score
>75%	1
10-75%	2
less than 10%	3
Nuclear Pleomorphism	Score
Small, uniform cells	1
Moderate increase in size and variation	2
Marked variation	3
Mitotic Count (per 10 high power fields)	Score
Up to 7	1
8 to 14	2
15 or more	3

The grade is calculated by adding the above scores. The grade correlates with survival as follows:

Grade	Score	5-year Survival (%)	7-year Survival (%)
1	3 to 5	95	90
2	6 or 7	75	65
3	8 or 9	50	45

Carcinomas have a propensity to spread via lymphatics. Breast cancers, when they metastasize, often go first to the axillary lymph nodes where most lymphatics from the breast drain. Spread of carcinoma to the dermal lymphatics produces a so-called "inflammatory carcinoma" which is a descriptive term, not a histologic type. This term arose from the grossly red to orange and firm, indurated appearance of such a lesion. More distant metastases are also possible. Supraclavicular lymph nodes can be involved. Other organs can be sites of metastases, and such sites as lung, bone, and liver are more common.

The least aggressive cancers--ones that rarely metastasize outside of the breast--histologically are: non-invasive intraductal and lobular carcinoma in situ. Carcinomas which can potentially metastasize but less commonly do so are: colloid carcinoma, medullary carcinoma (when a lymphoid stroma is present), and papillary carcinoma. All other cancers have a greater potential to metastasize than those listed above.

The stage of a breast cancer is based upon its size and degree of spread. The staging system goes from stage I to stage IV as follows:

Stage	Definition	5-year Survival (%)	7-year Survival (%)
I	Tumor 2 cm or less in greatest diameter and without evidence of regional (nodal) or distant spread	96	92
II	Tumor more than 2 cm but not more than 5 cm in greatest dimension, with regional lymph node involvement but without distant metastases, OR > a tumor of more than 5 cm in diameter without regional (nodal) and distant spread	81	71
III	Tumors of any size with possible skin involvement, pectoral and chest wall fixation, and axillary or internal mammary nodal involvement, fixed, but without distant metastases	52	39
IV	Tumor of any size with or without regional spread but with evidence of distant metastases	18	11

Treatment and Prognosis

Treatment of breast cancer can take a variety of forms, depending upon the grade and stage of the cancer as well as the overall health of the patient and the wishes of the patient. Therapy needs to be appropriate for each individual woman.

At a minimum, a localized carcinoma can be removed completely with local excision (lumpectomy) with margins free of tumor. This is termed "breast conserving surgery" (BCS). At the same time sampling of axillary lymph nodes can be done to determine if lymph node metastases are present. A total mastectomy with removal of the breast can be performed. The survival following BCS is generally as good as for total mastectomy, other factors being equal.

Surgical procedures may be combined with radiation therapy and or chemotherapy, depending upon the type of cancer present and hormone receptor status. Radiation, coupled with BCS, may help to reduce the incidence of a second cancer in the breast when intraductal carcinoma is diagnosed. More extensive cancers may be treated with a modified radical mastectomy with removal of the entire breast and axillary lymph nodes. Some breast carcinomas that have a higher stage may be amenable to more aggressive chemotherapy which can be coupled with total body radiation and bone marrow transplantation.

Prognosis cannot be completely predicted. There are some general guidelines as to the potential biologic behavior of a breast carcinoma. In general, a better prognosis will accompany cancers:

Less than 2 cm in size
Without axillary lymph node involvement
That are non-invasive ductal carcinoma and LCIS
With ER and PR positivity
Which lack of aneuploidy

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