C h a p t e r 7
Neoplasia
143
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
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
