Most women share a common fear: developing breast cancer. This is not an unfounded fear when considering that, except for lung cancer, breast cancer is the most common cancer found in women, accounting for one of every three diagnoses.
However, men are also affected by breast cancer. In 2002 the American Cancer Association estimate that 1500 men will be diagnosed with breast cancer, and 400 will die as a result. In 2001 an estimated 192,200 American women were diagnosed with breast cancer and 39,600 women died of the disease (The American Cancer Association). In 2004 an estimated 203,500 new cases of breast cancer will be diagnosed in America.
Fred Hutchinson Cancer Research Center's
Breast Cancer Prevention Video
Breast cancer occurs when cells in the breast tissue divide and grow without control. The cell cycle is the natural mechanism that regulates the growth and death of cells. When the normal cell regulators malfunction and cells do not die at the proper rate, there is a failure of cell death (apoptosis) therefore cell growth goes unchecked. As a result, cancer begins to develop as cells divide without control, accumulating into a mass of extra tissue called a tumor. A tumor can be either non-cancerous (benign) or cancerous (malignant). As a tumor grows, it elicits new blood vessel growth from the surrounding normal healthy tissues and diverts blood supply and nutrients away from this tissue to feed itself. This process is termed “angiogenesis”- the development (genesis) of new blood vessels (angio). Unregulated tumor angiogenesis facilitates the growth of cancer throughout the body.
Cancer cells have the ability to leave the original tumor site, travel to distant locations, and recolonize. This process is called metastasis and it occurs in organs such as the liver, lungs, and bones. Both the bloodstream and lymphatic system (the network connecting lymph nodes throughout the body) serve as ideal vehicles for the traveling cancer. Although, these traveling cancer cells do not always survive beyond the tumor, if they do survive, the cancer cells will again begin to divide abnormally and will create tumors in each new location. A person with untreated or treatment-resistant cancer may eventually die of the disease if vital organs such as the liver or lungs are invaded, overtaken, and destroyed.
Cancerous tumors in the breast usually grow slowly. It is thought that by the time a tumor is large enough to be felt as a lump, it may have been growing for as long as 10 years. This has lead to the belief that undetectable spread of tumor cells (micrometastasis) may have already occurred by the time of the diagnosis. Therefore, preventive measures such as a healthy balanced diet and lifestyle, nutritional supplementation, and exercise are of primary importance against the development of cancer. Early diagnosis is the best way to reduce the risk of dying from breast cancer. This can be accomplished by monthly self-breast exams, annual clinical breast exams and screening mammography. If breast cancer is detected, a multimodality approach incorporating nutritional supplementation, dietary modification, detoxification, and one or more of the following may be considered: surgery, chemotherapy, radiation, hormone therapy, or vaccine therapy.
A wide variety of factors may influence an individual's likelihood of developing breast cancer; these factors are referred to as risk factors. The established risk factors for breast cancer include: female gender, age, previous breast cancer, benign breast disease, hereditary factors (family history of breast cancer), early age at menarche (first menstrual period), late age at menopause, late age at first full-term pregnancy, obesity, low physical activity, use of postmenopausal hormone replacement therapy, use of oral contraceptives, exposure to low-dose ionizing radiation in midlife and exposure to high-dose ionizing radiation early in life.
Correlated risk factors for breast cancer include never having been pregnant, having only one pregnancy rather than many, not breast feeding after pregnancy, diethylstilbestrol (DES), certain dietary practices (high intake of fat and low intakes of fiber, fruits, and vegetables), tobacco, smoking, abortion, breast trauma, breast augmentation, large breast size, synthetic estrogens, electromagnetic fields, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and alcohol consumption. Alcohol is known to increase estrogen levels. Alcohol use appears to be more strongly associated with risk of lobular carcinomas and hormone receptor-positive tumors than it is with other types of breast cancer (Li et al. 2003).
A novel growth inhibitor recently identified as estrogen down-regulated gene 1 (EDG1) was found to be switched off (down-regulated) by estrogens. Inhibiting EDG1 expression in breast cells resulted in increased breast cell growth, whereas over-expression of EDG1 protein in breast cells resulted in decreased cell growth and decreased anchorage-independent growth, supporting the role of EDG1 in breast cancer (Wittmann et al. 2003).
ANATOMY OF THE BREAST
The breast is composed mainly of fat (adipose tissue) and breast tissue, along with connective tissue, nerves, veins, and arteries. Breast tissue is a complex network known as the mammary gland. Within the mammary gland, there are 15-20 lobes or compartments separated by adipose tissue. Within each lobe are several smaller compartments called lobules.
Lobules are composed of grapelike clusters of milk-secreting glands termed alveoli, which are found embedded in connective tissue. Spindle-shaped cells called myoepithelial cells, whose contractions help propel milk toward the nipple, surround the alveoli. There are about one million lobules contained within each breast (Spratt et al. 1995). The lobules are connected by tiny ducts that are joined together (much like a grape stem) into increasingly larger ducts. Within each breast there are between five and ten ductal systems, each with its own opening at the nipple.
Surrounding the nipple is a darkly shaded circle of skin called the areola. The areola appears rough because it contains modified sebaceous (oil) glands. These glands secrete small amounts of fluid to lubricate the nipple during breast-feeding.
Of all breast cancers, about 80% originate in the mammary (lactiferous) ducts, while about 20% arise in the lobules (IOM 1997). One of the most important distinctions to understand is the difference between invasive breast cancer and carcinoma in situ.
TYPES OF BREAST CANCER
Carcinoma In Situ
Ductal Carcinoma In Situ
Lobular Carcinoma In Situ
When abnormal cells from within the lobules or mammary ducts break out into the surrounding tissue the condition is referred to as invasive breast cancer. However, this term does not necessarily mean that metastases have been found anywhere beyond the breast.
Carcinoma In Situ
Carcinoma in situ is referred to as precancerous condition because it can increase the risk of developing cancer. When abnormal cells grow within the lobules or mammary ducts and there is no sign that the cells have spread into the surrounding tissue or beyond, the condition is called carcinoma in situ. The term in situ means “in place”. There are two main categories of carcinoma in situ: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS).
Non-invasive cancer is grouped into four subcategories, based on how the cancer cells grow relative to each other within the center of the milk duct:
Solid: There is wall-to-wall cell growth
Cribiform: There are holes between groups of cancer cells, making it look like Swiss cheese.
Papillary: The cells grow in fingerlike projections, toward the inside of the duct.
Comedo: There are areas of "necrosis," which is debris from dead cancer cells; this indicates that a tumor is growing so fast that some tumor cells die because there is insufficient blood supply.
Carcinoma in situ is generally considered a slow-growing cancer. The solid, cribiform, and papillary growth patterns are also referred to as "low-grade" cancers. However, Comedo is considered a faster growing cancer and is referred to as a "high-grade" non-invasive cancer, but is more likely than other categories to become invasive.
Ductal Carcinoma In Situ
Mammary ducts are hollow to allow fluid to pass through. However, with ductal carcinoma in situ (DCIS) excess cells grow inside the mammary ducts. DCIS is not invasive cancer. It is a precancerous condition that has the potential to develop into breast cancer. DCIS is, however, a risk factor for breast cancer.
Lobular Carcinoma In Situ
The lobules of the breast tissue have open space inside them much like the mammary ducts. Lobular carcinoma in situ (LCIS) is the growth and accumulation of large numbers of abnormal cells within the lobules. LCIS is often referred to as lobular neoplasia in situ. LCIS is not a direct cancer precursor. The abnormal cells found inside the lobules are not likely to mutate into cancer. LCIS is, however, a risk factor for breast cancer.
SPECIAL MANIFESTATIONS OF CANCER
Paget's Disease of the Nipple
Inflammatory Breast Cancer
Paget's Disease of the Nipple
Paget's disease is a rare, slowly growing cancer of the nipple. Paget's disease is usually associated with in situ or invasive cancer. One of the biggest problems with Paget's disease of the nipple is that its symptoms appear to be harmless. It is frequently thought to be a skin inflammation or infection, leading to unfortunate delays in disease detection, diagnosis and treatment. Symptoms of Paget's disease include persistent redness, itching, oozing, crusting, and fluid discharge from the nipple or a sore on the nipple that does not heal. Typically, only one nipple is affected. Treatment and prognosis for the disease are directly related to the type and extent of the underlying cancer.
Inflammatory Breast Cancer (IBC)
Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer that is usually not detected by mammograms or ultrasounds. IBC usually grows in nests or sheets rather than as a confined solid tumor and can be diffuse throughout the breast with no palpable mass. The cancer cells clog the lymphatic system just below the skin, resulting in lymph node involvement. Increased breast density compared to prior mammograms should be considered suspicious.
However, the main symptoms of IBC are breast swelling, inflammation, pink, red, or a dark colored area (erythema), sometimes with texture similar to the skin of an orange (peau d'orange), ridges and thickened areas of the breast skin, an area of the breast that is warm to the touch, what appears to be a persistent bruise, itching (pruritus) that is unrelenting and unaffected by medicated creams and ointments, increase in breast size over a short period of time, nipple flattening, retraction, or discharge, breast pain that is not cyclic in nature and may be constant or stabbing, or swollen lymph nodes in the armpit or above the collar bone. Since many of these symptoms mimic a breast infection, doctors frequently treat inflammatory breast cancer merely as an infection. When symptoms do not improve after antibiotic treatment for the suspected “infection” only then is the inflammatory breast cancer diagnosed.
IBC has an extremely high risk of recurrence and a very poor prognosis. It is the most lethal form of breast cancer. To improve the chances of survival it is important that symptoms are recognized early, resulting in an immediate diagnosis and treatment. Chemotherapy is usually begun within days of diagnosis. Without treatment, chances of 5-year survival for individuals with inflammatory breast cancer are very poor. With treatment, about 50% of patients will be living 5 years after diagnosis.
There are a variety of breast diseases, ranging from infections to excessive cell growth (neoplasms). Unfortunately, many breast diseases mimic the symptoms of cancer and therefore require tests and possibly surgical biopsy to obtain an accurate diagnosis. The majority of biopsies are found to be benign (non-cancerous) forms of breast disease. While most breast diseases are not dangerous in themselves, they may increase the risk of developing breast cancer. Hyperplasia, cysts, fibroadenomas, and calcifications are the common benign breast diseases.
Calcifications are randomly scattered residues of calcium that in older women may have left the bones to appear in other parts of the body, such as the joints or breasts. Microcalcifications are small, tight clusters of tiny calcifications in the ducts that can be seen on a mammogram and may indicate a precancerous or cancerous condition.
Cysts are sacs filled with fluid; they are almost always benign. Although most are too small to feel, approximately a third of women between the ages of 35-50 have cysts in their breasts. If large enough, cysts may feel like lumps in the breast. Normally, cysts are left untreated. However, if a cyst becomes painful, it can be aspirated or drained of its fluid. Some women may prefer to have a cyst removed if, after being aspirated repeatedly, it continues to recur.
Cysts are not associated with an increased risk of cancer; yet, they are more common in women as they approach menopause and occur much less frequently after menopause (Donegan 1995). What causes cysts to develop is unknown; however, certain dietary factors, such as the intake of caffeine have been proposed as possible risk factors for the development of breast cysts.
Fibroadenomas are a type of benign lump most commonly found in younger women. They are usually not removed since they pose no risk. If a fibroadenoma is large, uncomfortable, and produces a lump, it may be removed. In older women, fibroadenomas are generally removed to ensure that they are not malignant tumors. Fibroadenomas do not pose an increased risk of cancer.
Hyperplasia is not a precancerous condition. It is the excessive accumulation or proliferation of normal cells typically found on the inside of the lobules or the ducts in the breast tissue. Hyperplasia is associated with approximately a two-fold risk of breast cancer.
Atypical hyperplasia occurs when excess cells in the lobules or ducts are abnormal. This condition falls between hyperplasia (too many normal cells) and carcinoma in situ (too many abnormal cells). However, atypical hyperplasia is associated with an approximately 3.5-5 times increased risk of developing breast cancer (Page et al. 1985; Colditz 1993; Marshall et al. 1997).
TYPES OF STANDARD SCREENING TECHNIQUES
Clinical Breast Exam
In order to detect breast cancer at its earliest, most treatable stage, the importance of regular monthly breast self-exams, and yearly clinical breast exams, cannot be overemphasized. Mammography, sonography, contrasting magnetic resonance imaging (MRI) and digital infrared thermal imaging are all viable diagnostic tools, which will be discussed later in this article. Having regular breast-cancer screening exams is considered the single most effective way to lower the risk of dying from breast cancer.
"Early-stage" invasive cancer is considered very treatable because the tumor is relatively small and the cancer cells have not spread to the lymph nodes. However, when a tumor has become very large or has spread to other organs (such as the liver, lungs, or bones), it is considered "advanced-stage" invasive cancer and is far less treatable.
Breast cancer was thought to grow in an orderly progression from a small tumor in the breast tissue to a larger tumor. The cancer was believed to then travel from the breast into the adjacent lymph nodes, spreading throughout the distant nodes and finally metastasizing in other areas of the body. However, a growing body of research now contends that cancer cells are capable of traveling from the breast throughout the blood and lymphatic systems very early in the course of the disease. This strengthens the rationale for early detection and treatment.
How to Do Breast Self-Exam (7A1)
A breast self-exam provides an opportunity to detect tumors that may develop in the time between yearly clinical breast exams. To increase a woman's chances of detecting a small tumor at a time when it may be more responsive to treatment, a breast self-exam should be performed monthly, usually 2-3 days after menstruation. For women with irregular periods, it is important to remember to perform a monthly exam on the same day each month. Keep in mind that prior to menstruation or during pregnancy, breasts may be somewhat lumpy or more tender than usual.
By performing self-exams once a month, women can become familiar with the normal appearance and "feel" of their breasts, increasing the likelihood of recognizing changes such as thickening, lumps, or spontaneous nipple discharge. Because breast tissue normally has a bumpy texture, it may feel lumpy. However, there can be a great deal of individual variation. If a breast has lumpiness throughout, then it is probably just the normal contours of the breast tissue and in most cases is no cause to worry. Dominant lumps are firmer than the rest of the breast and are of more concern. When a dominant lump is found, there is an increased risk that it may be cancer, even though cysts and fibroadenomas can cause similar lumps. Any time a woman discovers a lump that feels dominant, it should be checked by a medical professional.
How to Do Breast Self-Exam
Lie down. Flatten your right breast by placing a pillow or towel under your right shoulder. Place your right arm behind your head. Examine your right breast with your left hand.
Use the pads, not the tips, of the middle three fingers on your left hand. With fingers flat, press gently using a circular, rubbing motion and feel for lumps. In small, dime-sized circles without lifting the fingers, start at the outermost top edge of your breast and spiral in toward the nipple.
Press firmly enough to feel the different breast tissues, using three different pressures. First, light pressure to just move the skin without jostling the tissue beneath, then medium pressure pressing midway into the tissue, and finally deep pressure to probe more deeply down to the ribs or to the point just short of discomfort.
Completely feel all of the breast and chest area up under your armpit, up to the collarbone, and all the way over to your shoulder to cover breast tissue that extends toward the shoulder.
Gently squeeze both nipples and look for discharge.
After you have completely examined your right breast, examine your left breast using the same method with your right hand. You may want to examine your breasts or do an extra exam while showering. It's easy to slide soapy hands over your skin and to feel anything unusual. You should also check your breasts in a mirror, looking for any change in size or contour, dimpling of the skin, or spontaneous nipple discharge.
Clinical Breast Exam
Clinical breast exams are physical examinations to check the appearance and "feel" of the breasts for signs of lumps. A physician, nurse practitioner, or other trained medical staff person will examine the breasts, both when the woman is sitting upright and when she is lying down.
Clinical breast exams are an important part of breast cancer screening. For younger women, clinical breast exam may have an advantage over mammography; mammography images can be more difficult to read in some younger women because of their dense breast tissue. For this reason, clinical breast exams are generally started much earlier than mammograms.
Mammography is an x-ray technique used to locate small or indistinctly shaped breast lumps that may not be felt during an exam. A mammogram takes about 15 minutes and consists of compressing each breast individually between two plates to makean x-ray image. Afterwards, a radiologist will read the film and look for any signs of abnormal tissue.
X-ray images appear in gradations of black, gray, and white depending on the density or hardness of the tissue. For example, since bone is especially dense, it appears white on an x-ray, while fat appears dark gray. Cancerous tumors and some other noncancerous abnormalities appear as a lighter shade of gray. Unfortunately, this may pose a problem because normal, dense breast tissue may appear light gray on a mammogram. Breast density changes with age. Younger women have proportionately more breast tissue than fat and therefore denser breasts, making mammograms difficult to interpret. In older women's breasts, density dissipates with age, leaving breasts that are composed mostly of fat. A mammogram that shows the light gray patch of a tumor or lesion surrounded by the dark gray image of fat tissue is most easily recognized.
Cysts and fibroadenomas appear as circular or oval patches with stark outer edges on x-rays, allowing a radiologist to identify where the border of the benign abnormal tissue ends and the surrounding normal tissue begins. On an x-ray, the core cancerous cells appear as a light patch, while the cancer cells that invade the surrounding tissue create a fuzzy or spiky appearance along the outer edge (called "spiculated"), producing an image with no clear borders.
There is growing controversy regarding the safety and efficacy of mammography. The National Cancer Institute clearly states on their website “Being exposed to radiation is a risk factor for breast cancer” (National Cancer Institute 2003). Further, both low-filtered (30 kVp) x-rays and mammography x-rays have mutagenic effect on mammalian cells. A re-evaluation of the risk assessment of mammography, especially for familial predisposed women is recommended. People with known increased risk of breast cancer, particularly those with a familial predisposition, are advised to be cautious and avoid early and frequent mammography exposure. Alternative examination methods should be considered for women with an inherited increased risk of breast cancer (Frankenberg-Schwager et al. 2002).
There is evidence that high-quality mammography may reduce breast cancer mortality in women aged 50 to 69. In fact, the risk of radiation-induced breast cancer decreases with increasing age at radiation exposure (Jung 2001). There has been difficulty in establishing the benefit of screening mammography in younger women. This difficulty has been attributed to both the technical limitations introduced by younger women’s dense breast tissue and to differences in breast cancer biology in younger women. Equally, women with inherited increased risk for breast cancer may gain no benefits from early screening.
The false positive rate ranges from 2.6% to 15.9% (Elmore et al. 2002). False positives usually result in additional diagnostic tests, which can include an additional x-ray examination, or a biopsy, which is the removal of a small portion of breast tissue for microscopic examination. A portion of the population’s mammograms are misread as false negatives. A false negative mammogram occurs when the mammogram is read as “normal” or “negative” although a malignancy is present. Screening mammograms from a population-based screening registry estimated a missed detectable cancer rate of 29% (Yankaskas et al. 2001). Other studies report a missed detectable cancer rate by mammograms of approximately 12% to 37% (Woolf 2001).
Regardless of the high rates of false-positives and false-negatives, x-ray mammography is still considered the gold standard of breast cancer screening since it can detect tumors at an early stage when they are small and responsive to treatment. Most physicians recommend annual mammograms for women over 40, and for those at high risk with a family history of breast cancer.
Ultrasound, also known as sonography, is an imaging method that utilizes very-high frequency sound waves to produce a picture that outlines the breast without exposure to ionizing radiation. During a sonogram, (also known as echogram) sound waves are transmitted through the breast. Depending on the nature of the breast tissue, the sound waves are reflected back or are transmitted through the tissue being examined. The pictures generated are the results of such echoes; they are picked up and translated by a computer resulting in the ultrasound image. Breast ultrasonography can be used to evaluate breast problems found during a mammogram or a physical exam.
Ultrasound is useful for some breast masses. It can be used to determine if a breast mass is solid (and more likely to be malignant) or if it is cystic and filled with fluid (and more likely to be benign). The ultrasound facilitates analysis by enabling the radiologist to guide a needle to biopsy a solid mass or to remove fluid if it is a cystic fluid-filled mass. The limitation of both mammography and ultrasound is that both have diagnostic features, which depend primarily on structural distinction and anatomical variation of a tumor from the surrounding breast tissue. These limitations make distinguishing benign microcalcifications from malignancies nearly impossible.
Magnetic Resonance Imaging (MRI) of the breast, also known as a breast MRI, is an imaging method consisting of a high field (1.5 Tesla) magnet with dedicated breast coils linked to a computer. The most useful MRI breast examination combines a contrast material, known as Gadolinium DTPA, magnetization, and radio waves to provide detailed pictures of an area inside the breast by a computer without the use of radiation. Every MRI produces hundreds of images of the breast from side-to-side, top-to-bottom, and front-to-back.
MRI is the most sensitive imaging modality for detection of breast cancer (Kuhl et al. 2000; Warner et al. 2001). Unfortunately, an MRI cannot always accurately distinguish between cancer and benign (noncancerous) breast conditions. Like ultrasound, MRI cannot detect microcalcifications. MRI is, however, effective in evaluating dense breast tissue and may be useful in screening younger women at high risk for breast cancer due to a predisposing family history of breast cancer.
MRI can be used to evaluate women who have had augmentation or breast enlargement surgery using implants. In such context, MRI is an excellent tool for imaging the augmented breast, including the breast implants itself, and the surrounding tissue, since abnormalities or signs of breast cancer are sometimes obscured by the implant. In contrast, the x-rays used in mammography are not able to penetrate silicone or saline implants sufficiently to image the overlying or underlying breast tissue. Compared to mammography or ultrasound, MRI is more accurate in women with augmented breasts.
Digital Infrared Thermal Imaging, also known as thermography, is a painless, non-invasive diagnostic technique, which does not involve any radiation exposure. This technology at one time appeared promising but lost favor about 20 years ago. However, with new ultra-sensitive high-resolution digital infrared devices, its efficacy has been improved. Infrared imaging software utilizes high precision pixel temperature measurements which can detect minute temperature variations related to blood flow and can demonstrate abnormal blood flow patterns associated with the initiation and progression of a chaotic tumor vasculature (blood flow system). Angiogenesis is a key factor that facilitates the growth of cancer and it is this biological feature of cancer on which thermography is based. Due to thermography’s sensitivity to blood flow and metabolic changes, it can detect tumors at a smaller size than mammography.
Unfortunately, there are no studies involving the detection of breast cancer that compare the accuracy of Digital Infrared Thermal Imaging to that of mammography, ultrasound, and MRI. However, studies have been conducted to evaluate the accuracy of mammography versus ultrasound versus MRI. In a study that screened 192 women at high risk for breast cancer, cancer was detected in nine patients. Mammography and ultrasound detected 6 of the nine cases of cancer whereas MRI detected all nine cases of breast cancer (Kuhl et al. 2000).
Another study comparing the accuracy of these three modalities screened 196 women at high risk for hereditary breast cancer and detected a total of six cases of invasive breast cancer. Mammography detected 2 of the 6 cases, ultrasound detected 3 of the 6, and MRI detected all 6 cases(Warner et al. 2001).
Regular screening is especially important for women who are at high risk of breast cancer. A woman can be placed in a high-risk category if she possesses either a single factor that greatly increases her risk or a combination of lesser factors that together increase her risk.
Single factors that can place a woman in a high-risk category include a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and exposure to high doses of ionizing radiation in childhood or young adulthood (for instance, for treatment of Hodgkin's disease) (Hancock et al. 1993; USPSTF 1996; Harris et al. 1997). A family history of breast cancer, especially in a mother, sister, or daughter, or a particular genetic mutation can also place a woman at high risk of breast cancer. In addition, research on genetic markers for breast-cancer risk has pinpointed a number of genes, two of which, BRCA1 and BRCA2, are associated with a markedly elevated risk of breast and ovarian cancer. As many as 60-80% of women with mutations in either of these two genes may develop breast cancer in their lifetimes (Alberg et al. 1997; Struewing et al. 1997; Whittemore 1997).
There are also several moderate risk factors for breast cancer, which occurring together can place a woman at high risk. They include having a first period (menarche) before age 12, not bearing a child, and having a first child after age 30. It is recommended that women at high risk for breast cancer have annual clinical breast examinations more frequently than women at average risk.
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