Download Principles of Carcinogenesis

Principles of Carcinogenesis
1
INTRODUCTION
Cancer is a group of more than 100 different
diseases that are characterized by uncontrolled
cellular growth, local tissue invasion, and
distant metastases. It is now the leading cause
of mortality in Americans younger than age 85
years. About 1.5 million cases of cancer were
diagnosed in 2009, and cancer claimed an
estimated 562,340 lives in the United States.
2
3
4
5
6
Each year, the American Cancer Society (ACS) publishes the estimated number of new cases
and number of cancer-related deaths. The National Cancer Institute (NCI) publishes cancer
7
statistics that also include cancer risk, prevalence, and survival information.
NOMENCLATURE
Neoplasia means “new growth,” and a new
growth is called a neoplasm. Tumor originally
applied to the swelling caused by inflammation,
but the non-neoplastic usage of tumor has
almost vanished; thus, the term is now equated
with neoplasm.
8
• “A neoplasm is an abnormal mass of tissue, the growth of
which exceeds and is uncoordinated with that of the
normal tissues and persists in the same excessive manner
after cessation of the stimuli which evoked the change.”
• A tumor is said to be benign when its microscopic and
gross characteristics are considered relatively innocent,
implying that it will remain localized, it cannot spread to
other sites, and it is generally amenable to local surgical
removal; the patient generally survives.
• Malignant tumors are collectively referred to as cancers.
• Malignant, as applied to a neoplasm, implies that the
lesion can invade and destroy adjacent structures and
spread to distant sites (metastasize) to cause death. Not
all cancers pursue so deadly a course.
9
• In general, benign tumors are designated by attaching the suffix -oma
to the cell of origin. Tumors of mesenchymal cells generally follow this
rule. For example, a benign tumor arising in fibrous tisssue is called a
fibroma, whereas a benign cartilaginous tumor is a chondroma. In
contrast, the nomenclature of benign epithelial tumors is more
complex. These are variously classified, some based on their cells of
origin, others on microscopic pattern, and still others on their
macroscopic architecture.
• Adenoma is applied to a benign epithelial neoplasm derived from
glands, although they may or may not form glandular structures.
• Benign epithelial neoplasms producing microscopically or
macroscopically visible finger-like or warty projections from epithelial
surfaces are referred to as papillomas. Those that form large cystic
masses, as in the ovary, are referred to as cystadenomas. Some
tumors produce papillary patterns that protrude into cystic spaces and
are called papillary cystadenomas. When a neoplasm, benign or
malignant, produces a macroscopically visible projection above a
mucosal surface and projects, for example, into the gastric or colonic
lumen, it is termed a polyp.
10
• All tumors, benign and malignant, have two basic
components: (1) clonal neoplastic cells that constitute
their parenchyma and (2) reactive stroma made up of
connective tissue, blood vessels, and variable numbers
of macrophages and lymphocytes. Although the
neoplastic cells largely determine a tumor's behavior
and pathologic consequences, their growth and
evolution is critically dependent on their stroma.
• Malignant tumors arising in mesenchymal tissue are
usually called sarcomas (Greek sar = fleshy), because
they have little connective tissue stroma and so are
fleshy (e.g., fibrosarcoma, chondrosarcoma,
leiomyosarcoma, and rhabdomyosarcoma). Malignant
neoplasms of epithelial cell origin, derived from any of
the three germ layers, are called carcinomas.
11
12
13
CARCINOGENESIS
The mechanisms by which cancers occur are
incompletely understood. A cancer, or neoplasm, is
thought to develop from a cell in which the normal
mechanisms for control of growth and proliferation
are altered. Current evidence supports the concept of
carcinogenesis as a multistage process that is
genetically regulated. The first step in this process is
initiation, which requires exposure of normal cells to
carcinogenic substances. These carcinogens produce
genetic damage that, if not repaired, results in
irreversible cellular mutations. This mutated cell has
an altered response to its environment and a selective
growth advantage, giving it the potential to develop
14
into a clonal population of neoplastic cells.
During the second phase, known as promotion,
carcinogens or other factors alter the environment to
favor growth of the mutated cell population over normal
cells. The primary difference between initiation and
promotion is that promotion is a reversible process.
At some point, however, the mutated cell becomes
cancerous (conversion or transformation). Depending on
the type of cancer, 5 to 20 years may elapse between the
carcinogenic phases and the development of a clinically
detectable cancer. The final stage of neoplastic growth,
called progression, involves further genetic changes
leading to increased cell proliferation. The critical
elements of this phase include tumor invasion into local
15
tissues and the development of metastases.
16
Substances that may act as carcinogens or initiators
include chemical, physical, and biologic agents.
Exposure to chemicals may occur by virtue of
occupational and environmental means, as well as
lifestyle habits. The association of aniline dye
exposure and bladder cancer is one such example.
Benzene is known to cause leukemia. Some drugs and
hormones used for therapeutic purposes are also
classified as carcinogenic chemicals. Physical agents
that act as carcinogens include ionizing radiation and
ultraviolet light. These types of radiation induce
mutations by forming free radicals that damage DNA
and other cellular components.
17
18
Viruses are biologic agents that are associated
with certain cancers. The Epstein-Barr virus is
believed to be an important factor in the
initiation of Burkitt lymphoma. Likewise,
infection with human papilloma virus is known
to be a major cause of cervical cancer.
All the previously mentioned carcinogens, as
well as age, gender, diet, growth factors, and
chronic irritation, are among the factors
considered to be promoters of carcinogenesis.
19
20
GENETIC & MOLECULAR BASIS
Two major classes of genes are involved in carcinogenesis:
oncogenes and tumor suppressor genes. Oncogenes develop
from normal genes, called proto-oncogenes, and may have
important roles in all phases of carcinogenesis. Protooncogenes are present in all cells and are essential regulators
of normal cellular functions, including the cell cycle. Genetic
alteration of the proto-oncogene through point mutation,
chromosomal rearrangement, or gene amplification activates
the oncogene. These genetic alterations may be caused by
carcinogenic agents such as radiation, chemicals, or viruses
(somatic mutations), or they may be inherited (germ-line
mutations). Once activated, the oncogene produces either
excessive amounts of the normal gene product or an abnormal
gene product.
21
22
Tumor suppressor genes regulate and inhibit
inappropriate cellular growth and proliferation. Gene
loss or mutation results in loss of control over normal
cell growth. Two common examples of tumor
suppressor genes are the retinoblastoma and p53
genes. Mutation of p53 is one of the most common
genetic changes associated with cancer, and is
estimated to occur in half of all malignancies. The
normal gene product of p53 is responsible for
negative regulation of the cell cycle, allowing the cell
cycle to halt for repairs, corrections, and responses to
other external signals. Inactivation of p53 removes
this checkpoint, allowing mutations to occur.
23
24
25
26
PATHOLOGY OF CANCER: TUMOR ORIGIN
Tumors may arise from any of four basic tissue
types: epithelial tissue, connective tissue (i.e.,
muscle, bone, and cartilage), lymphoid tissue, and
nerve tissue. Although some malignant cells are
atypical of their cells of origin, the involved cells
usually retain enough of their parent's traits to
identify their origin. Benign tumors are named by
adding the suffix -oma to the name of the cell type.
Hence, adenomas are benign growths of glandular
origin, or growths that exhibit a glandular pattern.
27
28
TUMOR CHARACTERISTICS
Tumors may be either benign or malignant. Benign
tumors are noncancerous growths that are often
encapsulated, localized, and indolent. Cells of benign
tumors resemble the cells from which they developed.
These masses seldom metastasize, and once removed
they rarely recur. In contrast, malignant tumors invade
and destroy the surrounding tissue. The cells of malignant
tumors are genetically unstable, and loss of normal cell
architecture results in cells that are atypical of their tissue
or cell of origin. These cells lose the ability to perform
their usual functions. This loss of structure and function is
defined as anaplasia. In contrast to benign tumors,
malignant tumors tend to metastasize, and consequently,
recurrences are common after removal or destruction of
the primary tumor.
29
Hyperplasia is an increase in the number of cells in
a particular tissue or organ, which results in an
increased size of the organ. It should not be
confused with hypertrophy, which is an increase in
the size of the individual cells. Hyperplasia occurs in
response to a stimulus and reverses when the
stimulus is removed.
Dysplasia is defined as an abnormal change in the
size, shape, or organization of cells or tissues.
Hyperplasia and dysplasia may precede the
appearance of a cancer by several months or years.
30
31
32
Screening of Cancer
Because cancers are most curable with surgery or radiation
before they have metastasized, early detection and treatment
have obvious potential benefits. In addition, small tumors are
more responsive to chemotherapy. Early diagnosis is difficult
for many cancers because they do not produce clinical signs or
symptoms until they have become large or have metastasized.
Cancer screening programs are designed to detect signs of
cancer in people who have not yet developed symptoms from
cancer. Lack of effective screening methods for some cancers
and inaccessibility of some anatomic sites further complicate
the process. Other limitations of screening methods include
false-negatives (related to the sensitivity of the test), falsepositives (related to the specificity), and overdiagnosis (true
positives that will not become clinically significant).
33
34
35
Diagnosis
 The presenting signs and symptoms of cancer vary widely and
depend on the type of cancer. The presentation in adults may
include any of cancer's seven warning signs, as well as pain or
loss of appetite.
 The warning signs of cancer in children are different, and reflect
the types of tumors more common in this patient population.
 The definitive diagnosis of cancer relies on the procurement of a
sample of the tissue or cells suspected of malignancy and
pathologic assessment of this sample. This sample can be
obtained by numerous methods, including biopsy, exfoliative
cytology, or fine-needle aspiration. A tissue diagnosis is
essential, because many benign conditions can masquerade as
cancer. Definitive treatment should not begin without a
pathologic diagnosis.
36
Diagnosis
37
38
39
40
STAGING
Tumors should be staged to determine the extent of disease
before any definitive treatment is initiated. The process is dictated
by knowledge of the biology of the tumor and by the signs and
symptoms elicited in the history and physical examination.
Staging provides information on prognosis and guides treatment
selection. After treatment is implemented, the staging workup is
usually repeated to evaluate the effectiveness of the treatment.
Uniform staging criteria are important in clinical trials that
evaluate cancer treatment regimens.
A staging workup may involve radiographs, computed tomography
scans, magnetic resonance imaging, positron emission
tomography scans, ultrasonograms, bone-marrow biopsies, bone
scans, lumbar puncture, and a variety of laboratory tests,
including appropriate tumor markers.
41
The most commonly applied staging system for solid tumors is
the TNM classification, where T = tumor, N = node, and M =
metastases. A numerical value is assigned to each letter to
indicate the size or extent of disease.
The designated rating for tumor describes the size of the
primary mass and ranges from T1 to T4. Carcinoma in situ is
designated Tis.
Nodes are described in terms of the extent of the spread of
regional lymph nodal involvement (N0 to N3).
Metastases are generally scored depending on their presence
or absence (M0 or M1).
42
To simplify the staging process, most cancers are classified
according to the extent of disease by a numerical system involving
stages I through IV.
Stage I usually indicates localized tumor, stages II and III represent
local and regional spread of disease, and stage IV denotes the
presence of distant metastases. The assigned TNM rating translates
into a particular stage classification. For example, T3 N1 M0
describes a moderate-to-large-sized primary mass, with regional
lymph node involvement and no distant metastases, and for most
cancers is stage III. The criteria for classifying disease extent are
quite specific for each different type of cancer.
For some tumors, such as prostate cancer, alternative alphabetical
systems (stage A, B, C, or D) are used in clinical practice.
43
44
THERAPY
Four primary modalities are employed in the approach to cancer
treatment: surgery, radiation, chemotherapy, and biologic therapy. The
oldest of these is surgery, which plays a major role in the diagnosis and
treatment of cancer. Surgery remains the treatment of choice for most
solid tumors diagnosed in the early stages. Radiation therapy was first
used for cancer treatment in the late 1800s and remains a mainstay in
the management of cancer. Although very effective for treating many
types of cancer, surgery and radiation are local treatments. These
modalities are likely to produce a cure in patients with truly localized
disease. But because most patients with cancer have metastatic
disease at diagnosis, localized therapies often fail to completely
eliminate the cancer. In addition, systemic diseases such as leukemia
cannot be treated with a localized modality. Chemotherapy (including
hormonal therapy) accesses the systemic circulation and can
theoretically treat the primary tumor and any metastatic disease.
Biologic therapies are currently considered in the broader sense of
immunotherapy or "targeted therapies." Immunotherapy, the earliest
important form of biologic therapy, usually involves stimulating the
host's immune system to fight the cancer.
45
Many cancers appear to be eliminated by surgery or
radiation. However, the high incidence of later
recurrence implies that the primary tumor began to
metastasize before it was removed. These early
metastases are too small to detect with currently
available diagnostic tests and are known as
micrometastases. Adjuvant therapy is defined as
the use of systemic agents to eradicate
micrometastatic disease following localized
modalities such as surgery or radiation or both. The
goal of systemic therapy given in this setting is to
reduce subsequent recurrence rates and prolong
long-term survival. Thus, adjuvant therapy is given
to patients with potentially curable malignancies
who have no clinically detectable disease after
surgery or radiation.
46
47
TUMOR GROWTH
The study of tumor growth forms the foundation for many of the basic
principles of modern cancer chemotherapy. The growth of most
tumors is illustrated by the gompertzian tumor growth curve. In the
early stages, tumor growth is exponential, which means that the
tumor takes a constant amount of time to double its size. During this
early phase, a large portion of the tumor cells is actively dividing. This
population of cells is called the growth fraction. The doubling time, or
time required for the tumor to double in size, is very short.
Because most anticancer drugs have greater effect on rapidly dividing
cells, tumors are most sensitive to the effects of chemotherapy when
the tumor is small and the growth fraction is high. However, as the
tumor grows, the doubling time is slowed. The growth fraction is
decreased, probably owing to the tumor outgrowing its blood and
nutrient supply or the inability of blood and nutrients to diffuse
throughout the tumor mass. Wide variability exists in measured
doubling times for different cancers. The doubling time of most solid
tumors is about 2 to 3 months. However, some tumors have doubling
times of only days (e.g., aggressive lymphomas) and others have even
longer doubling times (e.g., some salivary gland tumors)
48
Gompertzian kinetics tumor-growth curve: relationship to symptoms, diagnosis, and various treatment 49
regimens.
It takes about 109 cancer cells (1-g mass, 1 cm in diameter) for a tumor to
be clinically detectable by palpation or radiography. Such a tumor has
undergone about 30 doublings in cell number. It only takes 10 additional
doublings for this 1 g mass to reach 1 kg in size. A tumor possessing 1012
cancer cells (1-kg mass) is considered lethal. Thus, a tumor is clinically
undetectable for most of its life span. Tumor burden also impacts
response to chemotherapy. The cell kill hypothesis states that a certain
percentage of cancer cells (not a certain number of cells) will be killed
with each course of chemotherapy. For example, if a tumor consists of
1,000 cancer cells and the chemotherapy regimen kills 90% of the cells,
then 10% or 100 cancer cells remain. The second chemotherapy course
kills another 90% of cells, and again only 10% or 10 cells remain.
According to this hypothesis, the tumor burden will never reach zero.
Tumors consisting of less than 104 cells are believed to be small enough
for elimination by host factors, including immunologic mechanisms, and
these factors must be in place for a cure to be possible. The limitations of
this theory are that it assumes all cancers are equally responsive and that
resistance to anticancer agents and metastases do not occur.
50
51