APPENDIX A. What is Cancer?

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1 110 APPENDIX A What is Cancer? Cancer involves the uncontrolled growth of abnormal cells that have mutated from normal tissues. This growth can kill when these cells prevent normal function of vital organs or spread throughout the body, damaging essential systems. There are many different kinds of cancers. Cancer arises out of normal cells in the body, and can develop in almost any organ or tissue, such as the lung, colon, breast, skin, bones, or nerve tissue. In general, cancer appears to be caused by abnormal regulation of cell division. Cancers can occur when cells divide too rapidly or when cells forget how to die. There are multiple causes of cancers such as: Radiation, Sunlight, Tobacco, Certain viruses and Benzene. However, the cause of many cancers remains unknown. The three most common cancers in men are prostate cancer, lung cancer, and colon cancer. In women here, the three most frequently occurring cancers are breast cancer, lung cancer, and colon cancer. The most common cause of cancer-related death is lung cancer. Certain cancers are more common in particular geographic regions. For example, in Japan, there are many cases of gastric cancer, while in the US this type of cancer is relatively rare. Dietary differences may account for the variance. Symptoms of cancer depend on the type and location of the tumor. For example, lung cancer can cause coughing, shortness of breath, or chest pain, while colon cancer often causes diarrhea, constipation, and blood in the stool. Some cancers may not have any symptoms at all. Like symptoms, the signs of cancer vary based on the type and location of the tumor. Most cancers are diagnosed by biopsy. Depending on the location of the tumor, the biopsy may be a simple

2 111 procedure or a serious operation. Most patients with cancer undergo CT scans to determine the exact location of the tumor or tumors. Treatment also varies based on the type of cancer and its stage. The stage of a cancer refers to how much it has grown and whether the tumor has spread from its original location. The outlook varies widely among different types of cancer. Even among people with one particular type of cancer, the outcome varies depending on the stage of the tumor at diagnosis. Some cancers can be cured, some that are not curable can still be treated well, and some patients can live for many years with the cancer. Other tumors are rapidly fatal. One of the best ways to prevent cancer is to not smoke or chew tobacco. Many cancers can be prevented by avoiding risk factors such as excessive exposure to sunlight and heavy drinking. A tumor is a growth of tissue that forms an abnormal mass. Tumors generally provide no useful function and grow at the expense of healthy tissues. In general, tumors appear to be caused by abnormal regulation of cell division. Typically, the division of cells in the body is strictly controlled -- new cells are created to replace older ones or to perform new functions. Cells that are damaged or no longer needed die to make room for healthy replacements. If the balance of cell division and death is disturbed, a tumor may form. Tumors are classified as either benign (slow-growing and often harmless depending on the location) or malignant (faster-growing and likely to spread to other parts of the body and cause problems). Malignant tumors are what we call cancer.

3 112 Breast cancer Breast cancer is a malignant growth that begins in the tissues of the breast. Over the course of a lifetime, one in eight women will be diagnosed with breast cancer. There are several different types of breast cancer. Ductal carcinoma begins in the cells lining the ducts that bring milk to the nipple and accounts for more than 75% of breast cancers. Lobular carcinoma begins in the milk-secreting glands of the breast but is otherwise fairly similar in its behavior to ductal carcinoma. Other varieties of breast cancer can arise from the skin, fat, connective tissues, and other cells present in the breast. Risk factors for breast cancer include: Age and Gender -- As with most cancers, age is a significant factor. In fact, 77% of new cases and 84% of breast cancer deaths occur in women aged 50 and older. More than 80% of breast cancer cases occur in women over 50. Less than 1% of breast cancers occur in men. The risk of breast cancer is clearly related to hormonal influences, but how these affect the disease and particularly types of the disease is not yet clear. Genetic Factors and Family History of Breast Cancer -- Some families appear to have a genetic tendency for breast cancer. Two variant genes have been found that appear to account for this: BRCA1 and BRCA2. The genes p53 and BARD1 also appear to be important. Researchers have identified some other defective genes that may cause breast cancer, including BRCA3 and Noey2 (which is a disease inherited only fromj the father's side of the family). These facts suggest that breast cancer is caused by the growth of genetically damaged cells. Such genetic damage is known to gradually accumulate in the cells of the body over time. Women carrying mutated BRCA1 and/or BRCA2

4 113 genes have a "head start" in this process. Hormonal influences are important because they encourage cell growth. High levels of hormones during a woman's reproductive years, especially when they are not interrupted by the hormonal changes of pregnancy, appear to increase the chances that genetically damaged cells will grow and cause cancer. Early Menstruation and Late Menopause -- Women who started menstrual periods early (before age 12) or went through menopause late (after age 55) are at higher risk. Also, women who have never had children or who had them only after the age of 30 have an increased risk. Oral Contraceptives (birth control pills) -- Birth control pills may slightly increase the risk for breast cancer, depending on age, length of use, and other factors. No one knows how long the effects of the pill last after stopping it. Hormone Replacement Therapy -- Use of HRT has been shown to increase the risk of breast cancer. Physical Characteristics -- Obesity is controversial as a risk factor. Some studies report obesity as a risk of breast cancer, possibly associated with higher levels of estrogen production in obese women. Alcohol Consumption -- Excessive alcohol use (more than 1-2 drinks a day) has been associated with an increased risk of breast cancer. Chemicals -- Some studies have pointed to exposure to estrogen-like chemicals that are found in pesticides and other industrial products as a possible increased risk of breast cancer. DES -- Women who took diethylstilbestrol (DES) to prevent miscarriage may have an increased risk of breast cancer.

5 114 Radiation -- People exposed to radiation, particularly during childhood, may face an increased risk for breast cancer in adulthood. Especially at risk are those that received chest irradiation for prior cancers. Additional Risk Factors -- Some studies show previous breast, uterine, ovarian, or colon cancer, and a strong history of cancer in the family may increase the risk for breast cancer. The Gail Model is a simple breast cancer risk assessment tool that is available online and takes into account the most important risk factors. Symptoms Breast lump or breast mass noted upon breast exam -- usually painless, firm to hard and usually with irregular borders Lump or mass in the armpit A change in the size or shape of the breast Abnormal nipple discharge Usually bloody or clear-to-yellow or green fluid May look like pus (purulent) Change in the color or feel of the skin of the breast, nipple, or areola Dimpled, puckered, or scaly Retraction, "orange peel" appearance Redness Accentuated veins on breast surface Change in appearance or sensation of the nipple Pulled in (retraction), enlargement, or itching

6 115 Breast pain, enlargement, or discomfort on one side only Any breast lump, pain, tenderness, or other change in a man Symptoms of advanced disease are bone pain, weight loss, swelling of one arm, and skin ulceration Signs and tests Any worrisome breast changes should be confirmed and investigated by a medical professional. After getting as much information as possible about the symptom and any risk factors, the physician performs a physical examination including both breasts, armpits, and the area of the neck and chest. Additional tests and treatment may then be recommended: X-ray mammography may help identify the breast mass. Ultrasound (sonogram) can show whether the lump is solid or fluidfilled. Needle aspiration or needle biopsy of breast lumps can demonstrate if they are fluid-filled and provide material to send to the laboratory for analysis. In the case of very small abnormalities visible only on mammography, special techniques are necessary. A surgical biopsy or breast lump removal provides a portion or all of a breast lump for laboratory study. If breast cancer is diagnosed, additional testing is performed, including chest X-ray and blood tests. Surgery, radiation, chemotherapy, or a combination of these may then be recommended, not only for treatment, but also to help determine the stage of disease. Staging is important to help guide future treatment and follow-up, and to give some idea of what to expect in the future.

7 116 Treatment The choice of initial treatment is based on many factors. For stage I, II, or III cancers, the main considerations are to adequately treat the cancer and prevent a recurrence either at the place of the original tumor (local) or elsewhere in the body (metastatic). For stage IV cancer, the goal is to improve symptoms and prolong survival. However, in most cases, stage IV breast cancer cannot be cured. Surgery may consist only of breast lump removal (lumpectomy), or partial, total, or radical mastectomy, usually with the removal of one or more lymph nodes from the axilla (armpit). Special procedures to find the most likely lymph nodes to which cancer may have spread (sentinel nodes) are often used. Radiation therapy can be directed at the tumor, the breast, the chest wall, or other tissues known or suspected to have remaining cancer cells. Chemotherapy is used to help eliminate cancer cells that may still remain in the breast or that may have already spread to other parts of the body. Hormonal therapy with tamoxifen is used to block the effects of estrogen that may otherwise help breast cancer cells to survive and grow. Most women with breast cancers which express estrogen or progesterone on their surface benefit from treatment with tamoxifen. A new class of medicines called aromatase inhibitors, such as Aromasin, have been shown to be as good or possibly even better than tamoxifen in women with stage IV breast cancer. Most women receive a combination of these treatments. For stage 0 breast cancer, mastectomy or lumpectomy plus radiation is the standard treatment. However, there is some controversy on how best to

8 117 treat DCIS. For stage 1 and 2 disease, lumpectomy (plus radiation) or mastectomy with at least "sentinel node" lymph node removal is standard treatment. Chemotherapy, hormone therapy, or both may be recommended following surgery. The presence of breast cancer in the axillary lymph nodes is very useful for staging and the appropriate follow-up treatment. Stage III patients are ususally treated with surgery followed by chemotherapy with or without hormonal therapy. Radiation therapy may also be considered under special circumstances. Stage IV breast cancer may be treated with surgery, radiation, chemotherapy, hormonal therapy, or a combination of these (depending on the situation).. Expectations (prognosis) The clinical stage of breast cancer is the best indicator for prognosis (probable outcome), in addition to some other factors. Five-year survival rates for individuals with breast cancer who receive appropriate treatment are approximately: 95% for stage 0 88% for stage I 66% for stage II 36% for stage III 7% for stage IV The axillary (armpit) lymph nodes are the main passageway that breast cancer cells must use to reach the rest of the body. Their involvement at any time strongly affects the prognosis.

9 118 Chemotherapy and hormone therapy can improve prognosis in all patients and increase the likelihood of cure in patients with stage I, II, and III disease. Complications Even with aggressive and appropriate treatments, breast cancer often spreads (metastasizes) to other parts of the body such as the lungs, liver and bones. The recurrence rate is about 5% after total mastectomy and removing armpit lymph nodes when the nodes are found not to have cancer. The recurrence rate is 25% in those with similar treatment when the nodes have cancer. Other complications can be the result of surgery, altered drainage of the lymph from the arm, radiation changes and treatment with chemotherapy and tamoxifen. But the results of delaying or avoiding early detection and treatment of breast cancer are far more distressing and often deadly. Calling your health care provider See your health care provider if you are a man or a woman who notices any of the symptoms which could indicate breast cancer or: If you are a woman, 40 years or older, and have not had a mammogram in the last year. If you are a woman, 35 years or older, and have a mother or sister with breast cancer, or have already had cancer of the breast, uterus, ovary, or colon. If you are a woman, 20 years or older, and do not know how or need help to learn how to perform a breast self-examination. Prevention Many risk factors cannot be controlled. Some experts in the field of diet and cancer agree that changes in diet and lifestyle may reduce the incidence of cancer generally.

10 119 Efforts have focused on early detection since breast cancer is more easily treated and often curable if it is found early. Breast selfexamination (BSE), clinical breast examination (CBE) by a medical professional, and screening mammography are the three tools of early detection. Most recommend breast self-examinations (BSE) once a month -- the week following your menstrual period if you are age 20 or older. Regular clinical breast examinations (CBE) by a health professional are recommended for women between ages 20 and 39, at least every 3 years. After age 40, women should have a CBE by a health professional every year. Mammography is the most effective way of detecting breast cancer early. The American Cancer Society recommends mammogram screening every year for all women age 40 and older. The National Cancer Institute (NCI) recommends mammogram screening every 1-2 years for women age 40 and older. For those with risk factors, including a close family member with the disease, annual mammograms should begin 10 years earlier than the age at which the relative was diagnosed. Questions have been raised about the benefit of screening mammography. Some respected medical organizations such as PDQ, part of the NCI, no longer recommend screening mammography. This is a topic fraught with controversy, and a woman needs to have an informed and balanced discussion with her doctor, along with doing additional reading and researching on her own, to determine if mammography is right for her.

11 120 Two drugs are being studied currently that have been shown to reduce the risk of breast cancer: tamoxifen (Nolvadex ) and raloxifene (Evista ). Both are anti-estrogens in breast tissue. Tamoxifen is already widely used to prevent recurrence in women who have been treated for breast cancer. Many other newer hormonal agents, such as aromatase inhibitors and others, are being used after Tamoxifen is stopped, or even in place of Tamoxifen. For some women at very high risk of breast cancer, preventive use of these drugs may be appropriate. This should be discussed with a qualified physician. Preventive Mastectomy, which is the surgical removal of one or both breasts, is an option to prevent breast cancer for women who are at very high risk for breast cancer. Possible candidates for this procedure are women who have already had one breast removed due to cancer, women with a strong family history of breast cancer and those who have a mutation in genes p53, BRCA1, or have gene BRCA2. For additional information on breast cancer, see the website of the American Cancer Society. Mammography Alternative names Mammogram Definition A mammogram is an X-ray picture of the breasts. It is used to detect tumors and cysts and to help differentiate benign (noncancerous) and malignant (cancerous) disease.

12 121 How the test is performed You will be asked to undress from the waist up and will be given a gown to wear. Depending on the type of equipment used, you will sit or stand. One breast at a time is rested on a flat surface that contains the X- ray plate, and a device called a compressor will be pressed firmly against the breast to help flatten out the breast tissue. The X-ray pictures are taken from several angles. You may be asked to hold your breath as each picture is taken. How to prepare for the test Do not wear deodorant, perfume, powders, or ointments under the arms or on the breasts on the day of the mammogram. These substances may obscure the images. Remove all jewelry from your neck. Notify your health care provider (and/or the radiologist) if you are pregnant or breast-feeding. be some discomfort. How the test will feel When the breast is compressed, there may Why the test is performed Mammography is performed to screen healthy women for signs of breast cancer. It is also used to evaluate a woman who has symptoms of a breast disease, such as a lump, nipple discharge, breast pain, dimpling of the skin on the breast, or retraction of the nipple. Screening mammograms are important for early breast cancer detection. The American Cancer Society recommends mammogram screening every year for all women age 40 and older. The National Cancer Institute

13 122 recommends mammogram screening every 1 to 2 years for women age 40 and older. In addition to mammography, clinical breast exams (where the clinician palpates with the fingers) and breast self-examinations are important for breast cancer screening. Women age 20 and older should receive clinical beast exams every 3 years; women age 40 and older should receive clinical breast exams every year. The American Cancer Society recommends that all women age 20 and older perform monthly breast self-examination. These are general recommendations for mammography, clinical breast exams, and breast self-exam. Women should discuss with their personal physician how often to receive breast cancer screening, including mammography and clinical breast exam. Recommendations vary depending on personal risk factors such a strong family history of breast cancer. Normal Values Breast tissue that shows no evidence of mass (aggregations of cells) or calcification is considered normal. What abnormal results mean A well-outlined, regular, clear spot is more likely to be a benign lesion, such as a cyst (non-cancerous). A poorly outlined, opaque area is more likely to suggest breast cancer. However, not all benign lesions are perfectly round, and some cancers may appear well-defined. Sometimes, the doctor will use ultrasound to further examine the abnormality and evaluate the next best step. When findings from a mammogram or ultrasound look suspicious, a biopsy is performed to determine if a lesion is benign or cancerous. following: Conditions under which the test may be performed include the

14 123 Breast cancer Breast infection Fibrocystic breast disease Lumps in the breasts Breast pain Nipple discharge What the risks are the levels of radiation is low and any risk from mammography is exceedingly low. If you are pregnant and need to have an abnormality checked, the abdominal area will be shielded by a lead apron. Special considerations Mammography is important because it can, in some cases, detect breast cancers before you can feel them with your fingers. Figure A.A.1 Screenshot from the implementation of Bilateral Subtraction using ACO. And developed by MATLAB v6.5

15 124 APPENDIX B MIAS Mammographic Image Analysis Society When benchmarking an algorithm it is recommendable to use a standard test database (data set) for researchers to be able to directly compare the results. Most of the mammographic databases are not publicly available. The most easily accessed databases and therefore the most commonly used databases are the Mammographic Image Analysis Society (MIAS) database and the Digital Database for Screening Mammography (DDSM). Besides, there are currently few projects developing new mammographic image databases as well as several old projects. MIAS MiniMammographic Database The Mammographic Image Analysis Society (MIAS) is an organization of UK research groups interested in the understanding of mammograms and has generated a database of digital mammograms. Films taken from the UK National Breast Screening Programme have been digitized to 50 micron pixel edge with a Joyce-Loebl scanning microdensitometer, a device linear in the optical density range and representing each pixel with an 8-bit word. The database contains 322 digitised films and is available on 2.3GB 8mm (ExaByte) tape. It also includes radiologist's "truth"-markings on the locations of any abnormalities that may be present. The database has been reduced to a 200 micron pixel edge and padded/clipped so that all the images are 1024x1024. Mammographic images are available via the Pilot European Image Processing Archive (PEIPA) at the University of Essex.

16 125 Digital Database for Screening Mammography (DDSM) The Digital Database for Screening Mammography (DDSM) is another resource for possible use by the mammographic image analysis research community. It is a collaborative effort between Massachusetts General Hospital, Sandia National Laboratories and the University of South Florida Computer Science and Engineering Department. The database contains approximately 2,500 studies. Each study includes two images of each breast, along with some associated patient information (age at time of study, ACR (American College of Radiology) breast density rating, subtlety rating for abnormalities, and ACR keyword description of abnormalities) and image information (scanner, spatial resolution...). Images containing suspicious areas have associated pixel-level "ground truth" information about the locations and types of suspicious regions. Also provided is software both for accessing the mammogram and truth images and for calculating performance figures for automated image analysis algorithms. The images used in this work were taken from the Mammography Image Analysis Society (MIAS). The database consisting of 320 images, which belong to three normal categories: normal, benign and malign. There are 206 normal images, 63 benign and 51 malign. In this paper, median filtering is applied to remove the noise from the mammogram image. Data Acquisition and Preprocessing 161 pairs of mammograms are obtained from the MIAS database to analyze the proposed methods. In this chapter, median filtering is applied to enhance the mammogram images. The mammogram images are normalized and the pectoral muscle region is removed from the breast region.

17 126 Figure A.B.1 an example of breast region segmentation performed on an MIAS mammogram: (a) Original Mammogram; (b) Enhanced Image; (c) Extracted Breast Region; (d) Contour overlain on a LOG-attenuated version of (a). (a) (b)

18 127 (c) (d) Figure A.B.1 An example of breast region segmentation performed on an MIAS mammogram: (a) Original Mammogram; (b) Enhanced Image; (c) Extracted Breast Region; (d) Contour overlain on a LOG-attenuated version of (a).

19 128 And one of the demerits is, the proposed algorithm will work only for the mammogram images with the dimension of In the MIAS database, all the digital mammogram images are available with this size. As an extension of this work, we are generalizing our algorithm to suit for the mammogram images from any database. The Signal-to-noise ration can be used as an optimal parameter to analyze the performance of the enhancement techniques. The statistical result shows that our proposed method can perform better than other existing works.