Porth's Essentials of Pathophysiology, 4e

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radiation usually are additive, and there usually is a long delay between the time of exposure and the time that cancer can be detected. Viral and Microbial Agents An oncogenic virus is one that can induce cancer. Many DNA and RNA viruses have proved to be oncogenic in animals. However, only four DNA viruses have been implicated in human cancers: the human papilloma virus (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human herpesvirus 8 (HHV-8). 2,4,31 HHV-8, which causes Kaposi sarcoma in persons with AIDS, is discussed in Chapter 16. There is also an association between infection with the bacterium Helicobacter pylori and gastric adenocarcinoma and gastric lympho- mas 2,3 (discussed in Chapter 29). There are over 70 genetically different types of HPV. 2 Some types (i.e., types 1, 2, 4, 7) have been shown to cause benign squamous papillomas (i.e., warts). By con- trast, high-risk HPVs (e.g., types 16 and 18) are impli- cated in the pathogenesis of squamous cell carcinoma of the cervix and anogenital region. 2,3 Thus, cervical cancer can be viewed as a sexually transmitted disease, caused by transmission of HPV. In addition, at least 20% of oropharyngeal cancers are associated with high-risk HPVs. 2 A vaccine to protect against HPV types 6, 11, 16, and 18 is now available 32 (see Chapter 40). Epstein-Barr virus is amember of the herpesvirus fam- ily. It has been implicated in the pathogenesis of several human cancers, including Burkitt lymphoma, a tumor of B lymphocytes. In persons with normal immune func- tion, the EBV-driven B-cell proliferation is readily controlled and the person becomes asymptomatic or experiences a self-limited episode of infectious mono- nucleosis (see Chapter 11). However, in regions of the world where Burkitt lymphoma is endemic, such as parts of East Africa, concurrent malaria or other infec- tions cause impaired immune function, allowing sus- tained B-lymphocyte proliferation. Epstein-Barr virus is also associated with B-cell lymphomas in immuno- suppressed individuals, such as those with AIDS or with drug-suppressed immune systems (e.g., individu- als with transplanted organs). There is strong epidemiologic evidence linking chronic HBV and hepatitis C virus (HCV) infection with hepa- tocellular carcinoma (discussed in Chapter 30). It has been estimated that 70% to 85% of hepatocellular can- cers worldwide are due to infection with HBV or HCV. 2 The precise mechanism by which these viruses induce hepatocellular cancer has not been fully determined. It seems probable that the oncogenic effects are multifac- torial, with immunologically mediated chronic inflam- mation leading to persistent liver damage, regeneration, and genomic damage. The regeneration process is medi- ated by a vast array of growth factors, cytokines, che- mokines, and bioactive substances produced by immune cells that promote cell survival, tissue remodeling, and angiogenesis. Although a number of retroviruses (RNA viruses) cause cancer in animals, human T-cell leukemia virus-1

by concomitant consumption of alcohol; persons who smoke and drink considerable amounts of alcohol are at increased risk for development of cancer of the oral cavity, larynx and esophagus. The effects of carcinogenic agents usually are dose dependent—the larger the dose or the longer the dura- tion of exposure, the greater the risk that cancer will develop. Some chemical carcinogens may act in concert with other carcinogenic influences, such as viruses or radiation, to induce neoplasia. There usually is a time delay ranging from 5 to 30 years from the time of chem- ical carcinogen exposure to the development of overt cancer. This is unfortunate because many people may have been exposed to the agent and its carcinogenic effects before the association was recognized. Radiation The effects of ionizing radiation in carcinogenesis have been well documented in atomic bomb survivors, in patients diagnostically exposed, and in industrial work- ers, scientists, and physicians who were exposed dur- ing employment. Malignant epitheliomas of the skin and leukemia were significantly elevated in these popu- lations. Between 1950 and 1970, the death rate from leukemia alone in the most heavily exposed population groups of the atomic bomb survivors in Hiroshima and Nagasaki was 147 per 100,000 persons, 30 times the expected rate. 30 The type of cancer that developed depended on the dose of radiation, the sex of the person, and the age at which exposure occurred. The length of time between exposure and the onset of cancer is related to the age of the individual. For example, children exposed to ionizing radiation in utero have an increased risk for developing leukemias and childhood tumors, particu- larly 2 to 3 years after birth. Therapeutic irradiation to the head and neck can give rise to thyroid cancer years later. The carcinogenic effect of ionizing radiation is related to its mutagenic effects in terms of causing chro- mosomal breakage, translocations, and, less frequently, point mutations. 2 The association between sunlight and the develop- ment of skin cancer (see Chapter 46) has been reported for more than 100 years. Ultraviolet radiation emits relatively low-energy rays that do not deeply penetrate the skin. The evidence supporting the role of ultra- violet radiation in the cause of skin cancer includes skin cancer that develops primarily on the areas of skin more frequently exposed to sunlight (e.g., the head and neck, arms, hands, and legs), a higher inci- dence in light-complexioned individuals who lack the ultraviolet-filtering skin pigment melanin, and the fact that the intensity of ultraviolet exposure is directly related to the incidence of skin cancer, as evidenced by higher rates occurring in Australia and the American Southwest. There also are studies that suggest that intense, episodic exposure to sunlight, particularly dur- ing childhood, is more important in the development of melanoma than prolonged low-intensity exposure. As with other carcinogens, the effects of ultraviolet