Etiology - Pathophysiology of the Malignant Process

ETIOLOGY

Certain categories of agents or factors implicated in carcino-genesis include viruses and bacteria, physical agents, chemical agents, genetic or familial factors, dietary factors, and hormonal agents.

Viruses and Bacteria

Viruses as a cause of human cancers are hard to determine because viruses are difficult to isolate. Infectious causes are considered or suspected, however, when specific cancers appear in clusters. Viruses are thought to incorporate themselves in the genetic structure of cells, thus altering future generations of that cell population— perhaps leading to a cancer. For example, the Epstein-Barr virus is highly suspect as a cause in Burkitt’s lymphoma, nasopharyn-geal cancers, and some types of non-Hodgkin’s lymphoma and Hodgkin’s disease.

Herpes simplex virus type II, cytomegalovirus, and human papillomavirus types 16, 18, 31, and 33 are associated with dys-plasia and cancer of the cervix. The hepatitis B virus is impli-cated in cancer of the liver; the human T-cell lymphotropic virus may be a cause of some lymphocytic leukemias and lym-phomas; and the human immunodeficiency virus (HIV ) is as-sociated with Kaposi’s sarcoma. The bacterium Helicobacterpylori has been associated with an increased incidence of gastricmalignancy, perhaps secondary to inflammation and injury of gastric cells.

Physical Agents

Physical factors associated with carcinogenesis include exposure to sunlight or radiation, chronic irritation or inflammation, and tobacco use.

Excessive exposure to the ultraviolet rays of the sun, espe-cially in fair-skinned, blue- or green-eyed people, increases therisk for skin cancers. Factors such as clothing styles (sleeveless shirts or shorts), use of sunscreens, occupation, recreational habits, and environmental variables, including humidity, alti-tude, and latitude, all play a role in the amount of exposure to ultraviolet light.

Exposure to ionizing radiation can occur with repeated diag-nostic x-ray procedures or with radiation therapy used to treat disease. Fortunately, improved x-ray equipment appropriately minimizes the risk for extensive radiation exposure. Radiation therapy used in disease treatment or exposure to radioactive ma-terials at nuclear weapon manufacturing sites or nuclear power plants is associated with a higher incidence of leukemias, multi-ple myeloma, and cancers of the lung, bone, breast, thyroid, and other tissues. Background radiation from the natural decay processes that produce radon has also been associated with lung cancer. Homes with high levels of trapped radon should be ven-tilated to allow the gas to disperse into the atmosphere.

Chemical Agents

About 75% of all cancers are thought to be related to the envi-ronment. Tobacco smoke, thought to be the single most lethal chemical carcinogen, accounts for at least 30% of cancer deaths (Heath & Fontham, 2001). Smoking is strongly associated with cancers of the lung, head and neck, esophagus, pancreas, cervix, and bladder. Tobacco may also act synergistically with other sub-stances, such as alcohol, asbestos, uranium, and viruses, to pro-mote cancer development.

Chewing tobacco is associated with cancers of the oral cavity and primarily occurs in men younger than 40 years of age. Many chemical substances found in the workplace have proved to be carcinogens or co-carcinogens. The extensive list of suspected chemical substances continues to grow and includes aromatic amines and aniline dyes; pesticides and formaldehydes; arsenic, soot, and tars; asbestos; benzene; betel nut and lime; cadmium; chromium compounds; nickel and zinc ores; wood dust; beryl-lium compounds; and polyvinyl chloride.

Most hazardous chemicals produce their toxic effects by alter-ing DNA structure in body sites distant from chemical exposure. The liver, lungs, and kidneys are the organ systems most often af-fected, presumably because of their roles in detoxifying chemicals.

Genetic and Familial Factors

Almost every cancer type has been shown to run in families. This may be due to genetics, shared environments, cultural or lifestyle factors, or chance alone. Genetic factors play a role in cancer cell development. Abnormal chromosomal patterns and cancer have been associated with extra chromosomes, too few chromosomes, or translocated chromosomes. Specific cancers with underlying genetic abnormalities include Burkitt’s lymphoma, chronic myelogenous leukemia, meningiomas, acute leukemias, retinoblas-tomas, Wilms’ tumor, and skin cancers, including malignant melanoma.

Approximately 5% to 10% of cancers of adulthood and child-hood display a familial predisposition. Inherited cancer syn-dromes, such as premenopausal breast cancer, tend to occur at an early age and at multiple sites in one organ or pair of organs. In cancers with a familial predisposition, individuals may develop multiple cancers; commonly, two or more first-degree relatives share the same cancer type. Cancers associated with familial in-heritance include retinoblastomas, nephroblastomas, pheochro-mocytomas, malignant neurofibromatosis, and breast, ovarian, endometrial, colorectal, stomach, prostate, and lung cancers. In 1994, the BRCA-1 gene was identified; it is linked to breast and ovarian cancer syndrome. The BRCA-2 gene, which has also been identified, is associated with early-onset breast cancer (Nogueira

•   Appling, 2000). Work continues to identify other specific genes related to cancer incidence (Greco, 2000).

Dietary Factors

Dietary factors are thought to be related to 35% of all environ-mental cancers (Heath & Fontham, 2001). Dietary substances can be proactive (protective), carcinogenic, or co-carcinogenic. The risk for cancer increases with long-term ingestion of car-cinogens or co-carcinogens or chronic absence of proactive sub-stances in the diet.

Dietary substances associated with an increased cancer risk include fats, alcohol, salt-cured or smoked meats, foods contain-ing nitrates and nitrites, and a high caloric dietary intake. Food substances that appear to reduce cancer risk include high-fiber foods, cruciferous vegetables (cabbage, broccoli, cauliflower, Brus-sels sprouts, kohlrabi), carotenoids (carrots, tomatoes, spinach, apricots, peaches, dark-green and deep-yellow vegetables), and pos-sibly vitamins E and C, zinc, and selenium.

Obesity is associated with endometrial cancer and possibly postmenopausal breast cancers. Obesity may also increase the risk for cancers of the colon, kidney, and gallbladder.

Hormonal Agents

Tumor growth may be promoted by disturbances in hormonal balance either by the body’s own (endogenous) hormone pro-duction or by administration of exogenous hormones. Cancers of the breast, prostate, and uterus are thought to depend on en-dogenous hormonal levels for growth. Diethylstilbestrol (DES) has long been recognized as a cause of vaginal carcinomas. Oral contraceptives and prolonged estrogen replacement therapy are associated with increased incidence of hepatocellular, endome-trial, and breast cancers, whereas they appear to decrease the risk for ovarian and endometrial cancers. The combination of estro-gen and progesterone appears safest in decreasing the risk for en-dometrial cancers. Hormonal changes with reproduction are also associated with cancer incidence. Increased numbers of pregnan-cies are associated with a decreased incidence of breast, endometrial, and ovarian cancers.