NEOPLASIA 2

CANCER EPIDEMIOLOGY

DR IRAM KHURSHID
MBBS, FCPS (Histopath)
Assistant Professor CKMC
•Cancer is a disorder of cell growth and
behavior, its ultimate cause must be
defined at the cellular and molecular
levels. Cancer epidemiology can
contribute substantially to knowledge
about the origin of cancer
•The now well-established concept that
cigarette smoking is causally associated
with lung cancer arose primarily from
epidemiologic studies.

Major insights into the causes of cancer can

be obtained by epidemiologic studies that
relate particular environmental, racial
(possibly hereditary), and cultural influences
to the occurrence of specific neoplasms.
1. INCIDENCE
Over several decades, the death rates for many forms of
cancer have changed. Since 1995, the incidence of
cancer in men and women in the United States has been
roughly stable, but the cancer death rate has decreased
by roughly 20% in men and 10% in women.
Among men, 80% of the decrease is accounted for
cancer of the lung (decrease use of tobacco) prostate,
and colon;
Among women, nearly 60% of the decrease is
due to reductions in death rates from breast and
colorectal cancers (improved detection and
treatment).
The last half-century has also seen a sharp
decline in death rates from cervical cancer and
gastric cancer in the United States.
The decrease in cervical cancer is directly
attributable to widespread use of the
Papanicolaou (PAP) smear test for early
detection of this tumor and its precursor lesions.
The deployment of the human papilloma virus
(HPV) vaccine may nearly eliminate this cancer in
coming years.
2. Geographic and
Environmental variables
▪ Environmental exposures appear to be the dominant
risk factors for many common cancers, suggesting that
a high fraction of cancers are potentially preventable.
▪ This notion is supported by the geographic
differences in death rates from specific forms of
cancer. For instance, death rates from breast cancer
are about four to five times higher in the United
STATES and Europe than in Japan
▪ Conversely, the death rate for stomach
carcinoma in men and women is about seven
times higher in Japan than in the United
States.
▪ All the evidence indicates that these
geographic differences are environmental
rather than genetic in origin
 ENVIRONMENTAL FACTORS:
•The most important environmental
exposures linked to cancer include following:
1. Diet: Obesity, currently epidemic in the United
States, is associated with a modestly
increased risk for developing many different
cancers.
2. Smoking: Smoking, particularly of cigarettes,
has been implicated in cancer of the mouth,
pharynx, larynx, esophagus, pancreas, bladder,
and, most significantly, the lung, as 90% of lung
cancer deaths are related to smoking.
3. Alcohol consumption: Alcohol abuse is an
independent risk factor for cancers of the
oropharynx, larynx, esophagus, and (due to
alcoholic cirrhosis) liver.
4. Reproductive history: There is strong
evidence that life long cumulative exposure to
estrogen stimulation, particularly if unopposed
by progesterone, increases the risk for
developing cancers of the endometrial and
breast, both of which are estrogen-responsive
tissues.
5. Infectious agents: It is estimated that
infectious agents cause approximately 15%
of cancers worldwide.
❖Common tumors due to alcohol
• CA oropharnx CA larynx CA esophagus
• CA liver

❖Common tumors due to cigeratte

smoking
• CA lung 90% CA mouth CA pharynx
• CA larynx CA esophagus CA parncreas
• CA gall bladder
 3. Age
• In general, the frequency of cancer increases
with age. Most cancer deaths occur between 55
and 75 years of age; the rate declines, after 75
years of age.
• The rising incidence of cancer with age may be
explained by the accumulation of somatic
mutations that drive the emergence of malignant
neoplasms. The decline in immune competence
that accompanies aging also may be a factor.
 Although cancer preferentially affects older adults,
it also is responsible for > 10% of all deaths among
children younger than 15 years of age.
• The major lethal cancers in children are
leukemias, tumors of the central nervous
system, lymphomas, and soft-tissue and bone
sarcomas.
4. Acquired Predisposing Conditions
Acquired conditions that predispose to cancer include
disorders associated with chronic inflammation,
immunodeficiency states, and precursor lesions.
1. Many chronic inflammatory conditions create a
fertile “soil” for the development of malignant tumors.
Tumors are mostly carcinomas, but also include
mesothelioma and several kinds of lymphomas.
2. By contrast, immunodeficiency states mainly
predispose to virus-induced cancers, including specific
types of lymphoma (Burkitt’s) and carcinoma(HCC).
3. Precursor lesions are localized disturbances of
epithelial differentiation that are associated with an elevated
risk for developing carcinoma.

❑ They may arise secondary to chronic inflammation or

hormonal disturbances (in endocrine-sensitive tissues), or may
occur spontaneously. Molecular analyses shown that precursor
lesions possess some of the genetic lesions found in their
associated cancers.

❑ It is important to recognize precursor lesions because their

removal or reversal lowers cancer risk.
 Many precursor lesions have been described;
most common are the following:
1. Squamous metaplasia and dysplasia of bronchial
mucosa in habitual smokers →Lung carcinoma.
2. Endometrial hyperplasia and dysplasia, seen in women
with unopposed estrogenic stimulation →Endometrial
carcinoma.
3. Leukoplakia of the oral cavity, vulva, and penis, may
progress to squamous cell carcinoma.
4. Villous adenoma of the colon, associated with a high risk
for progression to colorectal carcinoma.
• In this context it also may be asked, “What is
the risk for malignant change in a benign
neoplasm?”—or, stated differently, “Are benign
tumors pre cancers?”
• In general the answer is no, but it is better to say
that each type of benign tumor is associated with
a particular level of risk, ranging from high to
virtually nonexistent.
 CANCER GENES
❑ Cancer genes can be defined as genes that
are recurrently affected by genetic aberrations in
cancers, presumably because they contribute
directly to the malignant behavior of cancer cells.
❑ Causative mutations that give rise to cancer
genes may be acquired by the action of
environmental agents, such as chemicals,
radiation, or viruses, may occur spontaneously, or
may be inherited in the germ line.
Cancer genes number in the hundreds and new ones are
still being discovered.
Cancer genes fall into one of four major functional
classes:
1. Oncogenes are genes that promote increased cell
growth when expressed in cell. The oncogenes are
mutated or over expressed versions of normal cellular
genes, which are called Proto-oncogenes. Most
oncogenes encode transcription factors, factors that
participate in pro- growth signaling pathways, or factors
that enhance cell survival. They are considered dominant
genes because a mutation involving a single allele is
sufficient to produce a pro-oncogenic effect.
2. Tumor suppressor genes are genes that
normally prevent uncontrolled growth and, when mutated
or lost from a cell, allow the transformed phenotype to
develop. Often both normal alleles of tumor suppressor
genes must be damaged for transformation to occur.
Tumor suppressor genes can be placed into two general
groups, “Governors” that act as important brakes on
cellular proliferation, and “Guardians” that are
responsible for sensing genomic damage and leads to the
cessation of proliferation or, if the damage is too great to
be repaired, or induce apoptosis
3. Genes that regulate apoptosis
primarily act by enhancing cell survival,
rather than stimulating proliferation per
se. Understandably, genes of this class
that protect against apoptosis are often
over expressed in cancer cells, whereas
those that promote apoptosis tend to be
under expressed or functionally
inactivated by mutations.
 4. To this list may now be added Genes that
regulate interactions between tumor cells
and host cells, as these genes are also
recurrently mutated or functionally altered in
certain cancers. Particularly important are
genes that enhance or inhibit recognition of
tumors cells by the host immune system.
Etiology of cancer, carcinogenic
agents
• Carcinogenic agents inflict genetic damage, which lies at the
heart of carcinogenesis.
• Three classes of carcinogenic agents can be identified:
(1) Chemicals
(2) Radiant energy
(3) Microbial agents
Chemicals and radiant energy are documented causes of cancer in
humans, and oncogenic viruses are involved in the pathogenesis
of tumors in several animal models and at least in some human
tumors.
 1. Chemical carcinogens
•Direct acting agents: require no metabolic
conversion to become carcinogenic.
• They are in general weak carcinogens but are important
because some of them are cancer chemotherapeutic drugs
,that have successfully cured, controlled, or delayed
recurrence of certain types of cancer (e.g. Alkylating
agents used for Hodgkin’s lymphoma),only to evoke later a
second form of cancer, usually leukemia. The risk of
induced cancer is low, but its existence dictates
judicious use of such agents
• Indirect acting agents; chemicals that require metabolic
conversion most commonly through cytochrome P-450 mixed
function oxidases to an ultimate carcinogen before they
become active (e.g., polycyclic hydrocarbons and
benzo[a]pyrene).
• Polycyclic hydrocarbons may be produced with burning of
fossil fuels, plants and also from animal fats during the
process of broiling meats and are present in smoked meats
and fish. In the body, benzopyrene is metabolized to
Epoxides, which form covalent adducts (addition products)
with molecules in the cell, principally DNA, but also with
RNA and proteins
Benzo[a]pyrene and other carcinogens formed
during the combustion of tobacco are implicated in
the causation of lung cancer, and in olden days,
benzo[a]pyrene created during the burning of coal
was likely responsible for the high incidence of
scrotal cancer in chimney sweeps.
 Mechanism of action
• Carcinogens are mutagenic
• All direct and ultimate carcinogens contain highly reactive
electrophile groups that form chemical adducts with DNA, as
well as with proteins and RNA
• Although any gene may be the target of chemical carcinogens,
the commonly mutated oncogenes and tumor suppressors,
such as RAS and p53, are important targets of chemical
carcinogens
• Indeed, specific chemical carcinogens, such as aflatoxin B1,
produce characteristic mutations in the p53 gene, such that
detection of the "signature mutation" within the p53 gene
establishes aflatoxin as the causative agent
 2. Radiation carcinogenesis
• The oncogenic properties of ionizing radiation are related to its
mutagenic effects; The ability of ionizing radiation to cause cancer
liesin its ability to induce DNA mutations; these can occur directly or
indirectly by the generation of free radicals from water or oxygen.
• In humans, radiation- induced neoplasms:
• Most common are myeloid leukemias, followed by thyroid cancer
in children.
• Cancers of the breast and lung are less commonly radiation induced.
• Skin, bone, and gut are the least susceptible to radiation
carcinogenesis
 3. Viral & microbial oncogenesis
• Although a variety of DNA and RNA viruses cause cancer in
animals, relatively few are yet implicated in human cancer:
• RNA oncogenic viruses:
HTLV-1 → T- cell leukemias
• DNA oncogenic viruses:
Human papilloma virus → CA Cervix
Epstein Bar virus → Burkitt and hodgkin’s Lymphomas
• Hepatitis B & C virus → Hepatocellular CA
• H-pylori infection → Gastric CA and MALT Lymphoma.
• Human herpesvirus type 8 (HHV-8) → Kaposi sarcoma
 Human papilloma virus
• Genital warts with low malignant potential are caused by
distinct HPV types (low-risk types, e.g., HPV-6 and HPV-11)
• Cervical squamous cell cancers contain HPV types 16 or
18 in more than 90% of cases.
• In HPV-associated cervical carcinomas there is random
integration of the viral genomes into the host cell DNA. The
key feature is that integration interrupts the viral DNA leading
to loss of the E2 viral repressor and subsequent over
expression of the E6 and E7 viral proteins.
These proteins transform cells by binding to and
inhibiting the functions of Rb and p53 tumor
suppressor proteins.

HPV infection alone is typically not sufficient for

carcinogenesis; interaction with cigarette smoking,
other infections, dietary deficiencies, and hormones
are also required.