Cancer

Cancer
Classification and external resources
A coronal CT scan showing a cancer of right pleural membranes, the outer surface of the lung and inner surface of the chest wall, malignant mesothelioma. Legend: → tumor ←, ★ central pleural effusion, 1 & 3 lungs, 2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver.
ICD-10	D00.
ICD-9	140—239
DiseasesDB	28843
MedlinePlus	001289
MeSH	D009369

Cancer /ˈkænsər/  ( listen) (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, or spreading to other locations in the body via lymph or blood. These three malignant properties of cancers differentiate them from benign tumors, which do not invade or metastasize.
Researchers divide the causes of cancer into two groups: those with an environmental cause and those with a hereditary genetic cause. Cancer is primarily an environmental disease, though genetics influence the risk of some cancers.^[1] Common environmental factors leading to cancer include: tobacco, diet and obesity, infections, radiation, lack of physical activity, and environmental pollutants.^[1] These environmental factors cause or enhance abnormalities in the genetic material of cells.^[2] Cell reproduction is an extremely complex process that is normally tightly regulated by several classes of genes, including oncogenes and tumor suppressor genes. Hereditary or acquired abnormalities in these regulatory genes can lead to the development of cancer. A small percentage of cancers, approximately five to ten percent, are entirely hereditary.
The presence of cancer can be suspected on the basis of symptoms, or findings on radiology. Definitive diagnosis of cancer, however, requires the microscopic examination of a biopsy specimen. Most cancers can be treated. Possible treatments include chemotherapy, radiotherapy and surgery. The prognosis is influenced by the type of cancer and the extent of disease. While cancer can affect people of all ages, and a few types of cancer are more common in children, the overall risk of developing cancer increases with age. In 2007 cancer caused about 13% of all human deaths worldwide (7.9 million). Rates are rising as more people live to an old age and lifestyles change in the developing world.^[3]

Contents 1 Classification 2 Signs and symptoms 3 Causes 3.1 Chemicals 3.2 Diet and exercise 3.3 Infection 3.4 Radiation 3.5 Heredity 3.6 Physical agents 3.7 Physical trauma and inflammation 3.8 Hormones 3.9 Other 4 Pathophysiology 5 Diagnosis 5.1 Pathology 6 Prevention 6.1 Dietary 6.2 Medication 6.3 Vaccination 7 Screening 7.1 Recommendations 7.2 Genetic testing 8 Management 9 Prognosis 10 Epidemiology 11 History 12 Society and culture 13 Research

Classification

Further information: List of cancer types and List of oncology-related terms

Cancers are classified by the type of cell that the tumor resembles and is therefore presumed to be the origin of the tumor. These types include:

• Carcinoma: Cancer derived from epithelial cells. This group includes many of the most common cancers, including those of the breast, prostate, lung and colon.
• Sarcoma: Cancer derived from connective tissue, or mesenchymal cells.
• Lymphoma and leukemia: Cancer derived from hematopoietic (blood-forming) cells
• Germ cell tumor: Cancer derived from pluripotent cells. In adults these are most often found in the testicle and ovary, but are more common in babies and young children.
• Blastoma: Cancer derived from immature "precursor" or embryonic tissue. These are also commonest in children.

Cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root. For example, a cancer of the liver is called hepatocarcinoma; a cancer of fat cells is called a liposarcoma. For some common cancers, the English organ name is used. For example, the most common type of breast cancer is called ductal carcinoma of the breast. Here, the adjective ductal refers to the appearance of the cancer under the microscope, which suggests that it has originated in the milk ducts.
Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the common name of this frequently occurring benign tumor in the uterus is fibroid). Confusingly, some types of cancer also use the -oma suffix, examples including melanoma and seminoma.

Signs and symptoms

Symptoms of cancer metastasis depend on the location of the tumor.

Cancer symptoms can be divided into three groups:

• Local symptoms: are restricted to the site of the primary cancer. They can include lumps or swelling (tumor), hemorrhage (bleeding from the skin, mouth or anus), ulceration and pain. Although local pain commonly occurs in advanced cancer, the initial swelling is often painless.
• Metastatic symptoms: are due to the spread of cancer to other locations in the body. They can include enlarged lymph nodes (which can be felt or sometimes seen under the skin), hepatomegaly (enlarged liver) or splenomegaly (enlarged spleen) which can be felt in the abdomen, pain or fracture of affected bones, and neurological symptoms.
• Systemic symptoms: occur due to distant effects of the cancer that are not related to direct or metastatic spread. Some of these effects can include weight loss (poor appetite and cachexia), fatigue, excessive sweating (especially night sweats), anemia (low blood count) and other specific conditions termed paraneoplastic phenomena. These may be mediated by immunological or hormonal signals from the cancer cells.

None of these are diagnostic, as many of these symptoms commonly occur in patients who do not have cancer.

Causes

Cancers are primarily an environmental disease with 90-95% of cases attributed to environmental factors and 5-10% due to genetics.^[1] Environmental, as used by cancer researchers, means any cause that is not genetic. Common environmental factors that contribute to cancer death include: tobacco (25-30%), diet and obesity (30-35%), infections (15-20%), radiation (both ionizing and non ionizing, up to 10%), stress, lack of physical activity, and environmental pollutants.^[1]

Chemicals

Further information: Alcohol and cancer

The incidence of lung cancer is highly correlated with smoking. Source:NIH.

Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with many forms of cancer,^[4] and causes 90% of lung cancer.^[5]
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen.^[6] Such chemicals may promote cancers through stimulating the rate of cell division. Faster rates of replication leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a mutation.
Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas.^[7] Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.^[8] Tobacco is responsible for about one in three of all cancer deaths in the developed world,^[4] and about one in five worldwide.^[8] Lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently^[when?], decreases in smoking followed by decreases in lung cancer death rates in men. However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.^[9]
Cancer related to one's occupation is believed to represent between 2-20% of all cases.^[10] Every year, at least 200,000 people die worldwide from cancer related to their workplace.^[11] Currently, most cancer deaths caused by occupational risk factors occur in the developed world.^[11] It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.^[12] Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces.^[11]

Diet and exercise

Diet, physical inactivity, and obesity are related to approximately 30-35% of cancer cases.^[1][13] In the United States excess body weight is associated with the development of many types of cancer and is a factor in 14-20% of all cancer death.^[13] Physical inactivity is believed to contribute to cancer risk not only through its effect on body weight but also through negative effects on immune system and endocrine system.^[13]
Diets that are low in vegetables, fruits and whole grains, and high in processed or red meats are linked with a number of cancers.^[13] A high salt diet is linked to gastric cancer, aflatoxin B1, a frequent food contaminate, with liver cancer, and Betel nut chewing with oral cancer.^[14] This may partly explain differences in cancer incidence in different countries for example gastric cancer is more common in Japan with its high salt diet^[15] and colon cancer is more common in the United States. Immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.^[16]

Infection

Main article: Infectious causes of cancer

Worldwide approximately 18% of cancers are related to infectious diseases.^[1] This proportion varies in different regions of the world from a high of 25% in Africa to less than 10% in the developed world.^[1] Viruses are usual infectious agents that cause cancer but bacteria and parasites may also have an effect.
A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein-Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.^[17] Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).^[18]

Radiation

Up to 10% of cancers are related to radiation exposure either ionizing or nonionizing.^[1] Sources of ionizing radiation, include medical imaging, and radon gas. Radiation can cause cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid tumors usually take 10–15 years, and up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–10 years to appear.^[19] Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure.^[19] Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.^[19] Ionizing radiation is not a particularly strong mutagen.^[19] Residential exposure to radon gas, for example, has similar cancer risks as passive smoking.^[19] Low-dose exposures, such as living near a nuclear power plant, are generally believed to have no or very little effect on cancer development.^[19] Radiation is a more potent source of cancer when it is combined with other cancer-causing agents, such as radon gas exposure plus smoking tobacco.^[19]
Unlike chemical or physical triggers for cancer, ionizing radiation hits molecules within cells randomly. If it happens to strike a chromosome, it can break the chromosome, result in an abnormal number of chromosomes, inactivate one or more genes in the part of the chromosome that it hit, delete parts of the DNA sequence, cause chromosome translocations, or cause other types of chromosome abnormalities.^[19] Major damage normally results in the cell dying, but smaller damage may leave a stable, partly functional cell that may be capable of proliferating and developing into cancer, especially if tumor suppressor genes were damaged by the radiation.^[19] Three independent stages appear to be involved in the creation of cancer with ionizing radiation: morphological changes to the cell, acquiring cellular immortality (losing normal, life-limiting cell regulatory processes), and adaptations that favor formation of a tumor.^[19] Even if the radiation particle does not strike the DNA directly, it triggers responses from cells that indirectly increase the likelihood of mutations.^[19]
Medical use of ionizing radiation is a growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer.^[19] It is also used in some kinds of medical imaging. One report estimates that approximately 29,000 future cancers could be related to the approximately 70 million CT scans performed in the US in 2007.^[20] It is estimated that 0.4% of current cancers in the United States are due to CTs performed in the past and that this may increase to as high as 1.5-2% with 2007 rates of CT usage.^[21]
Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.^[22] Clear evidence establishes ultraviolet radiation, especially the medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.^[22]
Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources has also been proposed as a cause of cancer, but there is currently little established evidence of such a link.^[23][24]

Heredity

Less than 0.3% of the population are carriers of a genetic mutation which has a large effect on cancer risk.^[25] They cause less than 3-10% of all cancer.^[25] Some of these syndromes include:

• certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer^[25]
• tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
• Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors) due to mutations of p53
• Turcot syndrome (brain tumors and colonic polyposis)
• Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
• Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
• Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
• Down syndrome patients, who have an extra chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood.

Physical agents

Some substances cause cancer primarily through their physical, rather than chemical, effects on cells.^[23]
A prominent example of this is prolonged exposure to asbestos fibers. Asbestos is a naturally occurring, fibrous rock that causes mesothelioma, a type of lung cancer.^[23] Other substances in this category include both naturally occurring and synthetic asbestos-like fibers, such as wollastonite, attapulgite, glass wool, and rock wool, are believed to have similar effects.^[23]
Nonfibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz, cristobalite, and tridymite).^[23]
Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and require years of exposure to develop cancer.^[23]

Physical trauma and inflammation

Physical trauma resulting in cancer is relatively rare.^[26] Claims that breaking bone resulted in bone cancer, for example, have never been proven.^[26] Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer, or brain cancer.^[26]
One accepted source is frequent, long-term application of hot objects to the body. It is possible that repeated burns on the same part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are also present.^[26] Frequently drinking scalding hot tea may produce esophageal cancer.^[26]
Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during the process of repairing the trauma, rather than the cancer being caused directly by the trauma.^[26] However, repeated injuries to the same tissues might promote excessive cell proliferation, which could then increase the odds of a cancerous mutation. There is no evidence that inflammation itself causes cancer.^[26]

Hormones

Some hormones cause cancer, primarily by encouraging cell proliferation.^[27] Hormones are an important cause of sex-related cancers such as cancer of the breast, endometrium, prostate, ovary, and testis, and also of thyroid cancer and bone cancer.^[27]
An individual's hormone levels are mostly determined genetically, so this may at least partly explains the presence of some cancers that run in families that do not seem to have any cancer-causing genes.^[27] For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone than the daughters of women without breast cancer. These higher hormone levels may explain why these women have higher risk of breast cancer, even in the absence of a breast-cancer gene.^[27] Similarly, men of African ancestry have significantly higher levels of testosterone than men of European ancestry, and have a correspondingly much higher level of prostate cancer.^[27] Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.^[27]
However, non-genetic factors are also relevant: Obese people have higher levels of some hormones associated with cancer, and a higher rate of those cancers.^[27] Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones.^[27] On the other hand, people who exercise far more than average have lower levels of these hormones, and lower risk of cancer.^[27] Osteosarcoma may be caused by growth hormones.^[27] Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels, and thus discouraging hormone-sensitive cancers.^[27]

Other

Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft rejection caused by MHC incompatibility.^[28] In humans and other vertebrates, the immune system uses MHC antigens to differentiate between "self" and "non-self" cells because these antigens are different from person to person. When non-self antigens are encountered, the immune system reacts against the appropriate cell. Such reactions may protect against tumour cell engraftment by eliminating implanted cells. In the United States, approximately 3,500 pregnant women have a malignancy annually, and transplacental transmission of acute leukaemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed.^[28] The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest.^[29] though other cases exist^[30] In fact, cancer from one organism will usually grow in another organism of that species, as long as they share the same histocompatibility genes,^[31] proven using mice; however this would never happen in a real-world setting except as described above.
In non-humans, a few types of transmissible cancer have been described, wherein the cancer spreads between animals by transmission of the tumor cells themselves. This phenomenon is seen in dogs with Sticker's sarcoma, also known as canine transmissible venereal tumor,^[32] as well as devil facial tumour disease in Tasmanian devils.

Pathophysiology

Main article: Carcinogenesis

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Cancer is fundamentally a disease of failure of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered.^[33]
The affected genes are divided into two broad categories. Oncogenes are genes which promote cell growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.^[34]
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and resulting in the expression of viral oncogenes in the affected cell and its descendants.
Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.
Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia^[35] (see causes, below).
The errors which cause cancer are self-amplifying and compounding, for example:

• A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly
• A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
• A further mutation may cause loss of a tumour suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal.
• A further mutation in signaling machinery of the cell might send error-causing signals to nearby cells

The transformation of normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape the controls that limit normal tissue growth. This rebellion-like scenario becomes an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution drives progression towards more invasive stages.^[36]

Diagnosis

Chest x-ray showing lung cancer in the left lung.

Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist, a type of physician (medical doctor) who specializes in the diagnosis of cancer and other diseases. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.

Pathology

A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.
The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade, genetic abnormalities, and other features of the tumor. Together, this information is useful to evaluate the prognosis of the patient and to choose the best treatment. Cytogenetics and immunohistochemistry are other types of testing that the pathologist may perform on the tissue specimen. These tests may provide information about the molecular changes (such as mutations, fusion genes, and numerical chromosome changes) that has happened in the cancer cells, and may thus also indicate the future behavior of the cancer (prognosis) and best treatment.

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  An invasive ductal carcinoma of the breast (pale area at the center) surrounded by spikes of whitish scar tissue in the surrounding yellow fatty tissue.
  
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  An invasive colorectal carcinoma (top center) in a colectomy specimen.
  
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  A squamous cell carcinoma (the whitish tumor) near the bronchi in a lung specimen.
  
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  A large invasive ductal carcinoma in a mastectomy specimen.
  

Prevention

Cancer prevention is defined as active measures to decrease the incidence of cancer.^[37] The vast majority of cancer risk factors are environmental or lifestyle-related, thus cancer is largely a preventable disease.^[38] Greater than 30% of cancer is preventable via avoiding risk factors including: tobacco, overweight or obesity, low fruit and vegetable intake, physical inactivity, alcohol, sexually transmitted infections, and air pollution.^[39]

Dietary

Main article: Diet and cancer

Dietary recommendations to reduce the risk of developing cancer, including: (1) reducing intake of foods and drinks that promote weight gain, namely energy-dense foods and sugary drinks, (2) eating mostly foods of plant origin, (3) limiting intake of red meat and avoiding processed meat, (4) limiting consumption of alcoholic beverages, and (5) reducing intake of salt and avoiding mouldy cereals (grains) or pulses (legumes).^[40][41]
Proposed dietary interventions for cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer,^[42] and reports that consumption of coffee is associated with a reduced risk of liver cancer.^[43] Studies have linked consumption of grilled meat to an increased risk of stomach cancer,^[44] colon cancer,^[45] breast cancer,^[46] and pancreatic cancer,^[47] a phenomenon which could be due to the presence of carcinogens in foods cooked at high temperatures.^[48] Whether reducing obesity in a population also reduces cancer incidence is unknown. Some studies have found that consuming lots of fruits and vegetables has little if any effect on preventing cancer.^[49] A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time.^[50] These results were amplified by a 2006 study. Over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006.^[51]

Medication

The concept that medications could be used to prevent cancer is an attractive one, and many high-quality clinical trials support the use of such chemoprevention in defined circumstances. Aspirin has been found to reduce the risk of death from cancer.^[52] Daily use of tamoxifen or raloxifene has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%.^[53] Finasteride has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors.^[54] The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients^[55] and in the general population.^[56][57] In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.
Vitamins have not been found to be effective at preventing cancer,^[58] although low levels of vitamin D are correlated with increased cancer risk.^[59][60] Whether this relationship is causal and vitamin D supplementation is protective is yet to be determined.^[61] Beta-carotene supplementation has been found to increase slightly, but not significantly, risks of lung cancer.^[62] Folic acid supplementation has not been found effective in preventing colon cancer and may increase colon polyps.^[63]

Vaccination

Vaccines have been developed that prevent some infection by some viruses that are associated with cancer, and therapeutic vaccines are in development to stimulate an immune response against cancer-specific epitopes.^[64] Human papillomavirus vaccine (Gardasil and Cervarix) decreases the risk of developing cervical cancer.^[64] The hepatitis B vaccine prevents infection with hepatitis B virus and thus decreases the risk of liver cancer.^[64]
Advances in cancer research have made a vaccine designed to prevent cancers available. In 2006, the U.S. Food and Drug Administration approved a human papilloma virus vaccine, called Gardasil. The vaccine protects against 6,11,16,18 strains of HPV, which together cause 70% of cervical cancers and 90% of genital warts. It also lists vaginal and vulvar cancers as being protected. In March 2007, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11–12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization. There is a second vaccine from Cervarix which protects against the more dangerous HPV 16,18 strains only. In 2009, Gardasil was approved for protection against genital warts. In 2010, the Gardasil vaccine was approved for protection against anal cancer for males and reviewers stated there was no anatomical, histological or physiological anal differences between the genders so females would also be protected.

Screening

Main article: Cancer screening

Unlike diagnosis efforts prompted by symptoms and medical signs, cancer screening involves efforts to detect cancer after it has formed, but before any noticeable symptoms appear.^[65] This may involve physical examination, blood or urine tests, or medical imaging.^[65]
Cancer screening is not currently possible for some types of cancers, and even when tests are available, they are not recommended to everyone. Universal screening or mass screening involves screening everyone.^[66] Selective screening identifies people who are known to be at higher risk of developing cancer, such as people with a family history of cancer.^[66]
Several factors are considered to determine whether the benefits of screening outweigh the risks and the costs of screening.^[65] These factors include:

• Possible harms from the screening test: Some types of screening tests, such as X-ray images, expose the body to potentially harmful ionizing radiation. There is a small chance that the radiation in the test could cause a new cancer in a healthy person. Screening mammography, used to detect breast cancer, is not recommended to men or to young women because they are more likely to be harmed by the test than to benefit from it. Other tests, such as a skin check for skin cancer, have no significant risk of harm to the patient. A test that has high potential harms is only recommended when the benefits are also high.
• The likelihood of the test correctly identifying cancer: If the test is not sensitive, then it may miss cancers. If the test is not specific, then it may wrongly indicate cancer in a healthy person. All cancer screening tests produce both false positives and false negatives, and most produce more false positives. Experts consider the rate of errors when making recommendations about which test, if any, to use. A test may work better in some populations than others. The positive predictive value is a calculation of the likelihood that a positive test result actually represents cancer in a given individual, based on the results of people with similar risk factors.
• The likelihood of cancer being present: Screening is not normally useful for rare cancers. It is rarely done for young people, since cancer is largely a disease found in people over the age of 50. Countries often focus their screening recommendations on the major forms of treatable cancer found in their population. For example, the United States recommends universal screening for colon cancer, which is common in the US, but not for stomach cancer, which is less common; by contrast, Japan recommends screening for stomach cancer, but not colon cancer, which is rarer in Japan. Screening recommendations depend on the individual's risk, with high-risk people receiving earlier and more frequent screening than low-risk people.
• Possible harms from follow-up procedures: If the screening test is positive, further diagnostic testing is normally done, such as a biopsy of the tissue. If the test produces many false positives, then many people will undergo needless medical procedures, some of which may be dangerous.
• Whether suitable treatment is available and appropriate: Screening is discouraged if no effective treatment is available.^[66] When effective and suitable treatment is not available, then diagnosis of a fatal disease produces significant mental and emotional harms. For example, routine screening for cancer is typically not appropriate in a very frail elderly person, because the treatment for any cancer that is detected might kill the patient.
• Whether early detection improves treatment outcomes: Even when treatment is available, sometimes early detection does not improve the outcome. If the treatment result is the same as if the screening had not been done, then the only screening program does is increase the length of time the person lived with the knowledge that he had cancer. This phenomenon is called lead-time bias. A useful screening program reduces the number of years of potential life lost (longer lives) and disability-adjusted life years lost (longer healthy lives).
• Whether the cancer will ever need treatment: Diagnosis of a cancer in a person who will never be harmed by the cancer is called overdiagnosis. Overdiagnosis is most common among older people with slow-growing cancers. Concerns about overdiagnosis are common for breast and prostate cancer.
• Whether the test is acceptable to the patients:If a screening test is too burdensome, such as requiring too much time, too much pain, or culturally unacceptable behaviors, then people will refuse to participate.^[66]
• Cost of the test: Some expert bodies, such as the U.S. Preventive Services Task Force, completely ignore the question of money. Most, however, include a cost-effectiveness analysis that, all else being equal, favors less expensive tests over more expensive tests, and attempt to balance the cost of the screening program against the benefits of using those funds for other health programs. These analyses usually include the total cost of the screening program to the healthcare system, such as ordering the test, performing the test, reporting the results, and biopsies for suspicious results, but not usually the costs to the individual, such as for time taken away from employment.

Recommendations

The U.S. Preventive Services Task Force (USPSTF) strongly recommends cervical cancer screening in those who are sexually active and have a cervix at least until the age of 65.^[67] They recommend mammography for breast cancer screening every two years for those 50–74 years old, however do not recommend either breast self-examination or clinical breast examination.^[68] Colorectal cancer screening is recommended via fecal occult blood testing, sigmoidoscopy, or colonoscopy starting at age 50 until age 75.^[69] There is insufficient evidence to recommend for or against screening for skin cancer,^[70] oral cancer,^[71] lung cancer,^[72] or prostate cancer in men under 75.^[73] Routine screening is not recommended for bladder cancer,^[74] testicular cancer,^[75] ovarian cancer,^[76] pancreatic cancer,^[77] or prostate cancer in men over 75.^[73] A 2009 Cochrane review came to slightly different conclusions with respect to breast cancer screening stating that routine mammography may do more harm than good.^[78] Japan screens for gastric cancer using photofluorography due to the high incidence there.^[3]

Genetic testing

See also: Cancer syndrome

Gene	Cancer types
BRCA1, BRCA2	Breast, ovarian, pancreatic
HNPCC, MLH1, MSH2, MSH6, PMS1, PMS2	Colon, uterine, small bowel, stomach, urinary tract

Genetic testing for individuals at high-risk of certain cancers is recommended. ^[79] Carriers of these mutations may than undergo enhanced surveillance, chemoprevention, or preventative surgery to reduce their subsequent risk.^[79]

Management

Main article: Management of cancer

Many management options for cancer exist including: chemotherapy, radiation therapy, surgery, immunotherapy, monoclonal antibody therapy and other methods. Which treatments are used depends upon the type of cancer, the location and grade of the tumor, and the stage of the disease, as well as the general state of a person's health.
Complete removal of the cancer without damage to the rest of the body is the goal of treatment for most cancers. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. Surgery often required the removal of a wide surgical margin or a free margin. The width of the free margin depends on the type of the cancer, the method of removal (CCPDMA, Mohs surgery, POMA, etc.). The margin can be as little as 1 mm for basal cell cancer using CCPDMA or Mohs surgery, to several centimeters for aggressive cancers. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.
Because cancer is a class of diseases,^[80][81] it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.^[82] Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but this has not been the case in practice.^[83]
Experimental cancer treatments are treatments that are being studied to see whether they work. Typically, these are studied in clinical trials to compare the proposed treatment to the best existing treatment. They may be entirely new treatments, or they may be treatments that have been used successfully in one type of cancer, and are now being tested to see whether they are effective in another type.
Alternative cancer treatments are treatments used by alternative medicine practitioners. These include mind–body interventions, herbal preparations, massage, electrical devices, and strict dietary regimens. Alternative cancer treatments are ineffective at killing cancer cells. Some are dangerous, but more are harmless or provide the patient with a degree of physical or emotional comfort. Alternative cancer treatment has also been a fertile field for hoaxes aimed at stripping desperate patients of their money.^[84]

Prognosis

See also: Cancer survivor

Cancer has a reputation as a deadly disease. Taken as a whole, about half of patients receiving treatment for invasive cancer (excluding carcinoma in situ and non-melanoma skin cancers) die from cancer or its treatment. However, the survival rates vary dramatically by type of cancer, with the range running from basically all patients surviving to almost no patients surviving.
Patients who receive a long-term remission or permanent cure may have physical and emotional complications from the disease and its treatment. Surgery may have amputated body parts or removed internal organs, or the cancer may have damaged delicate structures, like the part of the ear that is responsible for the sense of balance; in some cases, this requires extensive physical rehabilitation or occupational therapy so that the patient can walk or engage in other activities of daily living. Chemo brain is a usually short-term cognitive impairment associated with some treatments. Cancer-related fatigue usually resolves shortly after the end of treatment, but may be lifelong. Cancer-related pain may require ongoing treatment. Younger patients may be unable to have children. Some patients may be anxious or psychologically traumatized as a result of their experience of the diagnosis or treatment.
Survivors generally need to have regular medical screenings to ensure that the cancer has not returned, to manage any ongoing cancer-related conditions, and to screen for new cancers. Cancer survivors, even when permanently cured of the first cancer, have approximately double the normal risk of developing another primary cancer. Some advocates have promoted "survivor care plans"—written documents detailing the diagnosis, all previous treatment, and all recommended cancer screening and other care requirements for the future—as a way of organizing the extensive medical information that survivors and their future healthcare providers need.
Progressive and disseminated malignant disease harms the cancer patient's quality of life, and some cancer treatments, including common forms of chemotherapy, have severe side effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care aims to improve the patient's immediate quality of life, regardless of whether further treatment is undertaken. Hospice programs assist patients similarly, especially when a terminally ill patient has rejected further treatment aimed at curing the cancer. Both styles of service offer home health nursing and respite care.
Predicting either short-term or long-term survival is difficult and depends on many factors. The most important factors are the particular kind of cancer and the patient's age and overall health. Medically frail patients with many comorbidities have lower survival rates than otherwise healthy patients. A centenarian is unlikely to survive for five years even if the treatment is successful. Patients who report a higher quality of life tend to survive longer.^[85] People with lower quality of life may be affected by major depressive disorder and other complications from cancer treatment and/or disease progression that both impairs their quality of life and reduces their quantity of life. Additionally, patients with worse prognoses may be depressed or report a lower quality of life directly because they correctly perceive that their condition is likely to be fatal.
Despite strong social pressure to maintain an upbeat, optimistic attitude or act like a determined "fighter" to "win the battle", personality traits have no connection to survival.^[86]

Epidemiology

Main article: Epidemiology of cancer

Death rate from malignant cancer per 100,000 inhabitants in 2004.^[87]

  no data

  ≤ 55

  55-80

  80-105

  105-130

  130-155

  155-180

  180-205

  205-230

  230-255

  255-280

  280-305

  ≥ 305

In 2008 approximately 12.7 million cancers occurred and 7.6 million people died of cancer worldwide.^[3] Cancers as a group account for approximately 13% of all deaths each year with the most common being: lung cancer (1.3 million deaths), stomach cancer (803,000 deaths), colorectal cancer (639,000 deaths), liver cancer (610,000 deaths), and breast cancer (519,000 deaths).^[88] This makes it the leading cause of death in the developed world and the second leading cause of death in the developing world.^[3] Over half of cases occur in the developing world.^[3]
Global cancer rates have been increasing primarily due to an aging population and lifestyle changes in the developing world.^[3] The most significant risk factor for developing cancer is old age.^[89] Although it is possible for cancer to strike at any age, most people who are diagnosed with invasive cancer are over the age of 65.^[89] According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer."^[90] Some of the association between aging and cancer is attributed to immunosenescence,^[91] errors accumulated in DNA over a lifetime, and age-related changes in the endocrine system.^[92]
The three most common childhood cancers are leukemia (34%), brain tumors (23%), and lymphomas (12%).^[93] Rates of childhood cancer have increased between 0.6% per year between 1975 to 2002 in the United States^[94] and by 1.1% per year between 1978 and 1997 in Europe.^[93]
In the developed world, one in three people will develop cancer during their lifetimes. If all people with cancer survived and cancer occurred randomly, the lifetime odds of developing a second primary cancer would be one in nine.^[95] However, cancer survivors have an increased risk of developing a second primary cancer, and the odds are about two in nine.^[95] About half of these second primaries can be attributed to the normal one-in-nine risk associated with random chance.^[95] The increased risk is believed to be primarily due to the same risk factors that produced the first cancer (such as the person's genetic profile, alcohol and tobacco use, obesity, and environmental exposures), and partly due to the treatment for the first cancer, which typically includes mutagenic chemotherapeutic drugs or radiation.^[95] Cancer survivors may also be more likely to comply with recommended screening, and thus may be more likely than average to detect cancers.^[95]

History

Hippocrates (ca. 460 BC – ca. 370 BC) described several kinds of cancers, referring to them with the Greek word carcinos (crab or crayfish), among others.^[96] This name comes from the appearance of the cut surface of a solid malignant tumour, with "the veins stretched on all sides as the animal the crab has its feet, whence it derives its name".^[97] Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.

Engraving with two views of a Dutch woman who had a tumor removed from her neck in 1689.

Celsus (ca. 25 BC - 50 AD) translated carcinos into the Latin cancer, also meaning crab. Galen (2nd century AD) called benign tumours oncos, Greek for swelling, reserving Hippocrates' carcinos for malignant tumours. He later added the suffix -oma, Greek for swelling, giving the name carcinoma.
The oldest known description and surgical treatment of cancer was discovered in Egypt and dates back to approximately 1600 BC. The Papyrus describes 8 cases of ulcers of the breast that were treated by cauterization, with a tool called "the fire drill." The writing says about the disease, "There is no treatment."^[98]
Another very early surgical treatment for cancer was described in the 1020s by Avicenna (Ibn Sina) in The Canon of Medicine. He stated that the excision should be radical and that all diseased tissue should be removed, which included the use of amputation or the removal of veins running in the direction of the tumor. He also recommended the use of cauterization for the area treated if necessary.^[99]
In the 16th and 17th centuries, it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.^[100]
The first cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.
With the widespread use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874.^[101] The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 19th century felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.
The genetic basis of cancer was recognised in 1902 by the German zoologist Theodor Boveri, professor of zoology at Munich and later in Würzburg.^[102] He discovered a method to generate cells with multiple copies of the centrosome, a structure he discovered and named. He postulated that chromosomes were distinct and transmitted different inheritance factors. He suggested that mutations of the chromosomes could generate a cell with unlimited growth potential which could be passed onto its descendants. He proposed the existence of cell cycle check points, tumour suppressor genes and oncogenes. He speculated that cancers might be caused or promoted by radiation, physical or chemical insults or by pathogenic microorganisms.

1938 poster identifying surgery, x-rays and radium as the proper treatments for cancer.

When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation also came the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient's treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.
A founding paper of cancer epidemiology was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published "Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors" followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries to study the interdependence of environmental and cultural factors on cancer incidence.
Cancer patient treatment and studies were restricted to individual physicians' practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of victims of the atomic bombings of Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since World War II, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them to find cures through epidemiology and international partnerships.

Society and culture

While many diseases (such as heart failure) may have a worse prognosis than most cases of cancer, it is the subject of widespread fear and taboos. Euphemisms, once "a long illness", and now informally as "the big C", provide distance and soothe superstitions.^[103] This deep belief that cancer is necessarily a difficult and usually deadly disease is reflected in the systems chosen by society to compile cancer statistics: the most common form of cancer—non-melanoma skin cancers, accounting for about one-third of all cancer cases worldwide, but very few deaths^[104][105]—are excluded from cancer statistics specifically because they are easily treated and almost always cured, often in a single, short, outpatient procedure.^[106]
Cancer is regarded as a disease that must be "fought" to end the "civil insurrection"; a War on Cancer has been declared. Military metaphors are particularly common in descriptions of cancer's human effects, and they emphasize both the parlous state of the affected individual's health and the need for the individual to take immediate, decisive actions himself, rather than to delay, to ignore, or to rely entirely on others caring for him. The military metaphors also help rationalize radical, destructive treatments.^[107][108]
In the 1970s, a relatively popular alternative cancer treatment was a specialized form of talk therapy, based on the idea that cancer was caused by a bad attitude.^[84] People with a "cancer personality"—depressed, repressed, self-loathing, and afraid to express their emotions—were believed to have manifested cancer through subconscious desire. Some psychotherapists said that treatment to change the patient's outlook on life would cure the cancer.^[84] Among other effects, this belief allows society to blame the victim for having caused the cancer (by "wanting" it) or having metaphysically prevented its cure (by not becoming a sufficiently happy, fearless, and loving person).^[109] It also increases patients' anxiety, as they incorrectly believe that natural emotions of sadness, anger or fear shorten their lives.^[109] The idea was excoriated by the notoriously outspoken Susan Sontag, who published Illness as Metaphor while recovering from treatment for breast cancer in 1978.^[84]
Although the original idea is now generally regarded as nonsense, the idea partly persists in a reduced form with a widespread, but incorrect, belief that deliberately cultivating a habit of positive thinking will increase survival.^[109] This notion is particularly strong in breast cancer culture.^[109]

Research

Main article: Cancer research

Cancer research is the intense scientific effort to understand disease processes and discover possible therapies.
Research about cancer causes focusses on the following issues:

• Agents (e.g. viruses) and events (e.g. mutations) which cause or facilitate genetic changes in cells destined to become cancer.
• The precise nature of the genetic damage, and the genes which are affected by it.
• The consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events which lead to further progression of the cancer.

The improved understanding of molecular biology and cellular biology due to cancer research has led to a number of new, effective treatments for cancer since President Nixon declared "War on Cancer" in 1971. Since 1971 the United States has invested over $200 billion on cancer research; that total includes money invested by public and private sectors and foundations.^[110] Despite this substantial investment, the country has seen a five percent decrease in the cancer death rate (adjusting for size and age of the population) between 1950 and 2005.^[111]
Leading cancer research organizations and projects include the American Association for Cancer Research, the American Cancer Society (ACS), the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, the National Cancer Institute, the National Comprehensive Cancer Network, and The Cancer Genome Atlas project at the NCI.