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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 a hereditary genetic cause and those an environmental cause. Environmental in this sense means all non-hereditary factors, and encompasses far more than environmental pollution. About 5-10% of cancers are directly due to hereditary genetic factors. The remaining 90-95% of cases are due to environmental factors, such as old age, lifestyle choices, tobacco use, dietary choices, obesity, infections, radiation, lack of physical activity, and environmental pollutants.[1] These environmental factors cause or enhance non-hereditary 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.

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), and the number of cases is rising as more people

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.

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 treatmen

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.^[4]

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.^[5]

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^[6] (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 ognoing process, termed clonal evolution drives progression towards more invasive stages.^[7]

Causes

Cancers are primarily an environmental disease with 90-95% of cases due to environmental factors and 5-10% due to genetics.^[1] "Environmental", as used by cancer researchers, means any cause that is not genetic, and includes everything from natural sunlight to industrial pollution to viruses to behavioral choices to old age. Most environmental causes, such as naturally occurring background radiation, are not modifiable or controllable. Common environmental factors that lead to cancer death include: tobacco (25-30% of deaths), diet and obesity (30-35%), infections (15-20%), radiation (both ionizing and non ionizing), stress, lack of physical activity, and environmental pollutants.^[1]

Chemicals

Further information: Carcinogen

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,^[8] and causes 90% of lung cancer.^[9]

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen.^[10] 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, oesophagus and pancreas.^[11] Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.^[12] Tobacco is responsible for about one in three of all cancer deaths in the developed world,^[8] and about one in five worldwide.^[12] 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.^[13]

Cancer related to one's occupation is believed to represent between 2-20% of all cases.^[14] Every year, at least 200,000 people die worldwide from cancer related to their workplace.^[15] Currently, most cancer deaths caused by occupational risk factors occur in the developed world.^[15] 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.^[16] 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.^[15]

Physical carcinogens

Some substances cause cancer primarily through their physical, rather than chemical, effects on cells.^[17]

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.^[17] 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.^[17]

Nonfibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz, cristobalite, and tridymite).^[17]

Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and require years of exposure to develop cancer.^[17]

Radiation

Sources of ionizing radiation, such as radon gas, can cause cancer. 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.^[18] Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure.^[18] Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.^[18] Ionizing radiation is not a particularly strong mutagen.^[18] Residential exposure to radon gas, for example, has similar cancer risks as passive smoking.^[18] Low-dose exposures, such as living near a nuclear power plant, are generally believed to have no or very little effect on cancer development.^[18] 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.^[18]

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.^[18] 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.^[18] 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.^[18] Even if the radiation particle does not strike the DNA directly, it triggers responses from cells that indirectly increase the likelihood of mutations.^[18]

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.^[18] 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.^[19] 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.^[20]

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.^[21] 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.^[21]

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.^[17]^[22]

Infection

Some cancers can be caused by infection. This is especially true in animals such as birds, but also in humans, with infections responsible for up to 20% of human cancers worldwide.^[23]

Viruses are the most common infectious agents that cause cancer. 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.^[23] 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).^[24]

Viruses

According to some authors, viruses are one of the most important risks factor for cancer development in humans, second only to tobacco use.^[25]

There are two types of cancers caused by viruses: acutely transforming or slowly transforming cancers. In acutely transforming viruses, the virus carries an overactive oncogene, and the infected cell becomes cancerous as soon as the overactive viral gene is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted near a previously existing proto-oncogene in the genome of the infected cell. The virus causes overexpression of that proto-oncogene, which typically induces uncontrolled cell division. Because the virus' genes might not insert near enough to a proto-oncogene to trigger the cancerous changes, and, even if optimally located, it might take some time to become activated, slowly transforming viruses usually cause tumors much longer after infection than the acutely transforming viruses, if at all.

Infection by some hepatitis viruses, especially hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in about 1 in 200 of people infected with hepatitis B each year (more in Asia, fewer in North America), and in about 1 in 45 of people infected with hepatitis C each year.^[26] People with chronic hepatitis B infection are more than 200 times more likely to develop liver cancer than uninfected people.^[26] Liver cirrhosis, whether from chronic viral hepatitis infection or alcohol abuse or some other cause, is independently associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Because chronic viral hepatitis is so common, and liver cancer so deadly, liver cancer is one of the most common causes of cancer-related deaths in the world, and is especially common in East Asia and parts of sub-Sarahan Africa.

Human papillomaviruses (HPV) are another particularly common cancer-causing virus. HPV is well-known for causing genital warts and essentially all cases of cervical cancer, but it can also infect and cause cancer in several other parts of the body, including the larynx, lining of the mouth, nose, and throat, anus, and esophagus. The Papanicolaou smear ("Pap" smear) is a widely used cancer screening test for cervical cancer. DNA-based tests to identify the virus are also available.^[27]

Herpesviruses are a third group of common cancer-causing viruses. Two types of herpesviruses have been associated with cancer: the Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8).^[28] EBV appears to cause all nonkeratinizing nasopharyngeal carcinomas and some cases of lymphoma, including Burkitt’s lymphoma—the association is especially strong in Africa—and Hodgkin’s disease.^[28] EBV has also been found in a variety of other types of cancer cells, although its role in causing these other cancers is not well established. HHV-8 causes all cases of Kaposi’s sarcoma, and has been found in some cases of a cancer-related condition called Castleman's disease.^[28] Studies involving other kinds of cancer, particularly prostate cancer, have been inconsistent.^[28] Both of these herpesviruses are commonly found in cancerous cells of primary effusion lymphoma.^[28] Herpesviruses also cause cancer in animals, especially leukemias and lymphomas.^[28]

HIV does not directly cause cancer, but it is associated with a number of malignancies, especially Kaposi's sarcoma, non-Hodgkin's lymphoma, anal cancer and cervical cancer. Kaposi's sarcoma is caused by human herpesvirus 8. AIDS-related cases of anal cancer and cervical cancer are commonly caused by human papillomavirus. After HIV destroys the immune system, the body is no longer able to control these viruses, and the infections manifest as cancer.^[29] Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.^[30]

Bacterial infections

In addition to viruses, certain kinds of bacteria can cause some cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer.^[31]^[32] Although only a minority of those infected with Helicobacter go on to develop cancer, since this bacterial infection is quite common, it may be responsible for most of these cancers.^[33]

Parasites

The parasites that cause schistosomiasis (bilharzia), especially S. haematobium, can cause bladder cancer and cancer at other sites.^[34] Inflammation triggered by the worm's eggs appears to be the mechanism by which squamous cell carcinoma of the bladder is caused. In Asia, infection by S. japonicum is associated with colorectal cancer.^[34]

Distomiasis, caused by parasitic liver flukes, is associated with cholangiocarcinoma (cancer of the bile duct) in East Asia.^[34]

Malaria is associated with Burkitt's lymphoma in Africa, especially when present in combination with Epstein-Barr virus, although it is unclear whether it is causative.^[34]

Parasites are also a significant cause of cancer in animals. Cysticercus fasciolaris, the larval form of the common tapeworm of the cat, Taenia taeniaformis, causes cancer in rats.^[34] Spirocerca lupi is associated with esophageal cancer in dogs, at least within the southern United States.^[34]

Heredity

Less than 0.3% of the population are carriers of a genetic mutation which has a large effect on cancer risk.^[35] They cause less than 3-10% of all cancer.^[35] 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^[35]
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.

Hormones

Some hormones cause cancer, primarily by encouraging cell proliferation.^[36] 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.^[36]

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.^[36] For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone that 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.^[36] 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.^[36] Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.^[36]

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.^[36] Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones.^[36] On the other hand, people who exercise far more than average have lower levels of these hormones, and lower risk of cancer.^[36]

Osteosarcoma (bone cancer) may be caused by growth hormones.^[36]

Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels, and thus discouraging hormone-sensitive cancers.^[36]

Physical trauma and inflammation

Physical trauma resulting in cancer is relatively rare.^[37] Claims that breaking bone resulted in bone cancer, for example, have never been proven.^[37] Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer, or brain cancer.^[37]

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.^[37] Frequently drinking scalding hot tea may produce esophageal cancer.^[37]

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.^[37] 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.^[37]

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.^[38] 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.^[38] 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.^[39] though other cases exist^[40] In fact, cancer from one organism will usually grow in another organism of that species, as long as they share the same histocompatibility genes,^[41] 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,^[42] as well as devil facial tumour disease in Tasmanian devils.

Prevention

Cancer prevention is defined as active measures to decrease the incidence of cancer.^[43] The vast majority of cancer risk factors are environmental or lifestyle-related, thus cancer is largely a preventable disease.^[44] 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 infection, air pollution.^[45]

Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (80% of women with lung cancer have smoked in the past, and 90% of men^[46]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight / obese (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases (such as those conveyed by the human papillomavirus), the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation from the sun or from tanning beds, and certain occupational and chemical exposures.

Diet and obesity

Main article: Diet and cancer

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.^[72]

Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. Raloxifene also a SERM; has been shown to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. It had fewer side effects than tamoxifen, though it did permit more DCIS to form.^[73]

Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors.^[74] 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^[75] and in the general population.^[76]^[77] 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,^[78] although low levels of vitamin D are correlated with increased cancer risk.^[79]^[80] Whether this relationship is causal and vitamin D supplementation is protective is yet to be determined.^[81] Beta-carotene supplementation has been found to increase slightly, but not significantly, risks of lung cancer.^[82] Folic acid supplementation has not been found effective in preventing colon cancer and may increase colon polyps.^[83]

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.^[84] Human papillomavirus vaccine (Gardasil and Cervarix) decreases the risk of developing cervical cancer.^[84] The hepatitis B vaccine prevents infection with hepatitis B virus and thus decreases the risk of liver cancer.^[84]

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.^[85] This may involve physical examination, blood or urine tests, or medical imaging.^[85]

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.^[86] Selective screening identifies people who are known to be at higher risk of developing cancer, such as people with a family history of cancer.^[86]

Several factors are considered to determine whether the benefits of screening outweigh the risks and the costs of screening.^[85] 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.^[86] 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.^[86]
How much the test costs: 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.^[87] 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.^[88] Colorectal cancer screening is recommended via fecal occult blood testing, sigmoidoscopy, or colonoscopy starting at age 50 until age 75.^[89] There is insufficient evidence to recommend for or against screening for skin cancer,^[90] oral cancer,^[91] lung cancer,^[92] or prostate cancer in men under 75.^[93] Routine screening is not recommended for bladder cancer,^[94] testicular cancer,^[95] ovarian cancer,^[96] pancreatic cancer,^[97] or prostate cancer in men over 75.^[93] 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.^[98]

Genetic testing

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

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,^[100]^[101] 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.^[102] 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.^[103]

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.^[104]

Prognosis

Epidemiology

Main article: Epidemiology of cancer

Death rate from malignant cancer per 100,000 inhabitants in 2004.^[107]

no data

≤ 55

55-80

80-105

105-130

130-155

155-180

180-205

205-230

230-255

255-280

280-305

≥ 305

As of 2004^[update], worldwide cancer caused 13% of all deaths (7.4 million). The leading causes were: lung cancer (1.3 million deaths/year), stomach cancer (803,000 deaths), colorectal cancer (639,000 deaths), liver cancer (610,000 deaths), and breast cancer (519,000 deaths).^[108] The most significant risk factor is age. According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer."^[109] Essentially all of the increase in cancer rates between ancient times and the beginning of the 20th century in England is due to increased lifespans.^[109] Since then, some other factors, especially the increased use of tobacco, have further raised the rates.^[109]

In the United States, cancer is responsible for 25% of all deaths with 30% of these from lung cancer. The most commonly occurring cancer in men is prostate cancer (about 25% of new cases) and in women is breast cancer (also about 25%). Cancer can occur in children and adolescents, but it is uncommon (about 150 cases per million in the U.S.), with leukemia the most common.^[110] In the first year of life the incidence is about 230 cases per million in the U.S., with the most common being neuroblastoma.^[111]

In the developed world, one in three people will develop cancer during their lifetimes. If all cancer patients survived and cancer occurred randomly, the lifetime odds of developing a second primary cancer would be one in nine.^[112] However, cancer survivors have an increased risk of developing a second primary cancer, and the odds are about two in nine.^[112] About half of these second primaries can be attributed to the normal one-in-nine risk associated with random chance.^[112] 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.^[112] Cancer survivors may also be more likely to comply with recommended screening, and thus may be more likely than average to detect cancers.^[112]

Most common cancers in US males, by occurrence^[110]

in US females, by occurrence^[110]

in US males, by mortality^[110]

in US females, by mortality^[110]

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.^[113] 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".^[114] 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."^[115]

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.^[116]

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.^[117]

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.^[118] 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.^[119] 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.^[120] 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^[121]^[122]—are excluded from cancer statistics specifically because they are easily treated and almost always cured, often in a single, short, outpatient procedure.^[123]

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.^[124]^[125]

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.^[104] 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.^[104] 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).^[126] It also increases patients' anxiety, as they incorrectly believe that natural emotions of sadness, anger or fear shorten their lives.^[126] The idea was excoriated by the notoriously outspoken Susan Sontag, who published Illness as Metaphor while recovering from treatment for breast cancer in 1978.^[104]

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.^[126] This notion is particularly strong in breast cancer culture.

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