Department of Genetic Engineering And Biotechnology

Shahjalal University of Science and Technology, Sylhet

Assignment
Course code : GEB 315
Course title : Oncology & Virology

Submitted To :
Dr. Md. Abdullah Al Mamun
Professor
Department of Genetic Engineering and Biotechnology
Shahjalal University of Science and Technology, Sylhet

Submitted by :
Nahian Kabir
3rd year 2nd semester
Registraition no : 2019431067
Session : 2019-20
Department of Genetic Engineering and Biotechnology
Shahjalal University of Science and Technology, Sylhet

Date of submission : 05/11/2023

 INDEX

Name of topics Page No.

Table of Contents
CHAPTER 1.........................................................................................................................................................1
INTRODUCTION................................................................................................................................................1
DEFINITIONS & TERMINOLOGIES:........................................................................................................1
Types of tumors :....................................................................................................................................................2
TYPES OF PRE-MALIGNANT TUMORS:................................................................................................3
DIFFERENCE BETWEEN BENIGN AND MALIGNANT TUMORS:.................................................4
TUMOR CELL GROWTH:.............................................................................................................................6
KINETICS OF TUMOR CELL GROWTH:................................................................................................6
THE TNM STAGING SYSTEM:...................................................................................................................6
TNM system:.....................................................................................................................................................................................6
Primary tumor (T):........................................................................................................................................................................7
Regional lymph nodes (N):.........................................................................................................................................................7
Distant metastasis (M):................................................................................................................................................................7
RISK FACTORS OF CANCER:....................................................................................................................8
The risk of developing colorectal cancer increases with age. The incidence is 6 times higher among persons
aged 65 years and older than in comparison to persons aged 40-64 years. The increasing risk of cancer with
age reflects the accumulation of critical genetic mutations...............................................................................10
CHARACTERISTICS OF CANCEROUS CELLS:..................................................................................10
VIRUSES AND CANCER:...........................................................................................................................10
BACTERIAL CAUSE OF CANCER:.........................................................................................................10
INFLAMMATION AND CANCER:...........................................................................................................11
TUMOR MARKERS:.....................................................................................................................................11
CANCER EVOLUTION:...............................................................................................................................11

THE SPREAD OF TUMOR..........................................................................................................................14

TUMOR INVASION:.....................................................................................................................................14
3-STEP MODEL OF TUMOR INVASION:..............................................................................................14
PATTERNS OF SPREAD:............................................................................................................................15
STAGES OF METASTASIS:.......................................................................................................................15
MOLECULAR BASIS OF CANCER:........................................................................................................17
CYTOGENETIC BASIS OF CANCER:.....................................................................................................17
• Mechanism of oncogene activation:........................................................................................................................17
• Oncogenes and their products:.................................................................................................................................19
• Viral oncogenesis:.......................................................................................................................................................20
IMMUNOLOGIC BASIS OF CANCER:...................................................................................................21
• Immune Surveillance:.................................................................................................................................................21
• Immunofacilitaton:......................................................................................................................................................21
• Immunodeficiency Syndromes & Tumor Formation:..........................................................................................22

CARCINOGENESIS.....................................................................................................................................23
 IDENTIFICATION OF SUSCEPTIBLE INDIVIDUAL:.......................................................................23
CLASSIFICATION OF CARCINOGENS:................................................................................................23
Genotoxic carcinogens:.............................................................................................................................................................23
Some common properties of genotoxic compounds :..........................................................................................................23
Classification of genotoxic agents:.........................................................................................................................................24
Carcinogen Metabolism:............................................................................................................................................................24
EPIGENETIC CARCINOGENS:.................................................................................................................25

DIAGNOSIS & MANAGEMENT OF CANCER..........................................................................................26

PRINCIPLES OF CANCER DIAGNOSIS:...............................................................................................26
CANCER STAGING:.....................................................................................................................................27
APPROACH TO EARLY CANCER:..........................................................................................................27
APPROACH TO ADVANCED CANCER:................................................................................................28
CANCER SCREENING:...............................................................................................................................29

TREATMENT OF CANCER..........................................................................................................................31
SIGNS & SYMPTOMS OF CANCER:.......................................................................................................31
TREATMENT OF CANCER:.......................................................................................................................31
 CHAPTER 1
INTRODUCTION

DEFINITIONS & TERMINOLOGIES :

• ONCOLOGY:
Oncology is a branch of medicine that deals with the prevention, diagnosis, and treatment of cancer.
• ONCOLOGIST:
A medical professional who practices oncology is an oncologist.
• TUMOR:
A tumor is a mass or lump of tissue that may be similar to swelling. Not all tumors are cancerous, but
it is a good idea to see a doctor if one appears.
• CANCER:
Cancer is a group of diseases that induce abnormal cell growth with the potential to invade or spread
to other parts of the body. Cancers form a subset of neoplasm.
• NEUPLASM:
A neoplasm or tumor is a group of cells that have undergone unregulated growth and will form a
mass or lump but may be distributed diffusely.
• BENIGN TUMOR:
A benign tumor is a mass of cells that cannot either invade neighboring tissues or spread through the
body and when removed, benign tumors do not usually grow back.
• PRE-MALIGNANT TUMOR:
Tumor cells that are not yet cancerous but have the potential to become malignant are called pre-
malignant tumors.
• MALIGNANT TUMOR:
A tumor that invades surrounding tissues is usually capable of producing metastases, may persist after
attempted removal, and is likely to cause death unless adequately treated is referred to as a malignant
tumor.
• METASTASIS:
The process in which malignant tumors grow and spread to other parts of the body is called
metastasis.
• MALIGNANT PROGRESSION:
The progression from normal cells to cells that can form a detectable mass to outright cancer involves
multiple steps known as malignant progression.

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• ONCOGENES:
Genes involved in oncogenesis are called are called oncogenes. They usually remain latent within our
body but can turn out to be harmful in the presence of environmental stimuli.
• PROTO-ONCOGENES:
Oncogenes that remain latent within our body and can’t express without any enhancers or stimuli
are called proto-oncogenes.
• CARCINOGENESIS:
Carcinogenesis refers to the study of the origin of cancer progression.

Types of tumors :

TYPES OF BENIGN TUMOR:

1. Adenomas:
Adenomas develop in glandular epithelial tissue, which is the thin membrane that covers glands,
organs, and other structures in the body. 1) polyps in the colon, b) fibro adenomas, a common
form of benign breast tumor, and c) hepatic adenomas, which occur on the liver. Adenomas do
not start as cancer. However, some can change and become adenocarcinomas, which are
cancerous.

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2. Fibroids:
Fibroids or fibromas, are benign tumors that can grow on the fibrous or connective tissue of any
organ.
• Uterine fibroids are common and can cause; Vaginal bleeding, pelvic pain, or discomfort.
• Urinary incontinence, which can be “soft” or “hard,” depending on the proportion of fibers to
cells.
• There are many types of fibroma, including angiofibroma, which can appear as small red
bumps on the face.
• Dermatofibromas appear on the skin, often on the lower legs. Some fibromas can cause
symptoms and may need surgery. In rare cases, fibroids can change and become fibro-
sarcomas. These are cancerous.

3. Hemangiomas:
Hemangiomas are benign tumors that form when blood vessels grow excessively. They can
appear as red “strawberry marks” on the skin or they can develop inside the body. They are often
present at birth and disappear during childhood.
Hemangiomas do not usually need treatment, but laser surgery and other options are available if
they do not go away.

4. Lipomas:
Lipomas are a form of soft tissue tumor and consist of fat cells. They can appear at any age but
often affect people from 40-50 years old. Most lipomas are small, painless, rubbery, soft to the
touch, and movable. They often appear on the back, shoulders, arms, buttocks, and the tops of
the legs. They are unlikely to become cancerous. Types of lipoma include fibro-lipomas, which
contain fat cells and fibrous connective tissue, and angiolipomas, which appear under the skin.

TYPES OF PRE-MALIGNANT TUMORS:

1. Actinic keratosis:
Also known as solar keratosis, this growth involves patches of crusty, scaly, and thick skin. It is
more likely to affect fair-skinned people, and sun exposure increases the risk. Sometimes, actinic
keratosis will transform into squamous cell carcinoma.

2. Cervical dysplasia:
In cervical dysplasia, a change occurs in the cells that line the cervix. It may find these cells
during a Pap smear. Cervical dysplasia often stems from the human papillomavirus (HPV), an
infection that is common in young people. The cells are not cancerous, but they may become
malignant 10- 30 years later, resulting in cervical cancer.

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3. Metaplasia:
These growths occur in the bronchi, the tubes that carry air into the lungs. The lining of the
bronchi contains glandular cells. In some people, including smokers, these can change and
become squamous cells, or cancer.

4. Leukoplakia:
Leukoplakia causes thick white patches to form in the mouth. These patches: are painless, have
an irregular shape, are slightly raised, and are not possible to scrape off.

DIFFERENCE BETWEEN BENIGN AND MALIGNANT TUMORS:

BENIGN TUMOR MALIGNANT TUMOR

1. Grow Slowly
2. Well-defined capsule
3. Not invasive
4. Usually do not grow back
5. Well differentiated
6. Low mitotic index
7. Do not metastasize
1. Grow Rapidly
2. Not encapsulated
3. Invasive
4. Sometimes do grow back
5. Poorly differentiated
6. High mitotic index
7. Can spread distantly (metastasis)

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TYPES OF MALIGNANT TUMORS :
1. Carcinoma:
These tumors form from epithelial cells, which are present in the skin and the tissue. Carcinomas
can occur in the stomach, prostate, pancreas, lung, liver, colon, or breast. They are a common
type of malignant tumor.

2. Sarcoma:
These tumors start in connective tissue, such as cartilage, bones, fat, and nerves. They originate
in the cells outside the bone. Most sarcomas are malignant.

3. Germ cell tumor:

These tumors develop in the cells that produce sperm and eggs. They usually occur in the ovaries
or testicles, but they may also appear in the brain, abdomen, or chest. Testicular cancer starts in
the germ cells.
4. Blastoma:
These tumors form from embryonic tissue or developing cells. Blastomas are much more common
in children than in adults. They can lead to tumors in the brain, eye, or nervous system.

5. Leukemia: Cancers of blood-forming cells are called leukemia.

6. Lymphoma: Cancers of lymphatic tissue are lymphomas.

7. Carcinoma in situ (CIS):

Epithelial malignant tumors that have not broken through BM or invaded the surrounding stroma.

TUMOR CELL GROWTH :

Tumors arise at great frequency, especially in older animals and humans, but most pose a risk to
their host because they are localized and of small size. We call such tumors benign; an example
is warts. It is usually apparent when a tumor is benign because it contains cells that closely
resemble, and may function like normal cells, localized to apparent tissues.
In contrast, the cells composing a malignant tumor or cancer, express some protein
characteristics of the cell type from which it arose, and a high fraction of the cells grow and
divide more rapidly than normal. Some malignant tumors remain localized and encapsulated, at
least for a time; an example is carcinoma in situ in the ovary or breast. Most, however, do not
remain in their original site. Instead, they invade surrounding tissues, get into the body’s
circulatory system, and set up areas of proliferation away from the site of their original
appearance. The spread of tumor cells and their establishment in secondary areas for growth is
called metastasis. Most malignant tumors eventually acquire the ability to metastasize. Thus, the
major characteristics that differentiate metastatic (or malignant) tumors from benign ones are
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their invasiveness and spread.

KINETICS OF TUMOR CELL GROWTH :

Kinetics is the study of movement and changes in magnitude over time. Kinetics is a central
concept in oncology; cancer progression reflects changes in cancer cell numbers, metastatic sites,
and tumor mass as a function of time.

THE TNM STAGING SYSTEM :

The TNM system is the most widely used cancer staging system. Examples of cancers with
different staging systems include brain and spinal cord tumors and blood cancers.

TNM system:
• The T refers to the size and extent of the main tumor. The main tumor is usually called
the primary tumor.
• The N refers to the number of nearby lymph nodes that have cancer.
• The M refers to whether the cancer has metastasized. This means that the cancer has
spread from the primary tumor to other parts of the body.
When cancer is described by the TNM system, there will be numbers after each letter that give
more details about the cancer-for example, T1N0MX or T3N1M0. The following explains what
the letters and numbers mean-

Primary tumor (T) :

TX: The main tumor cannot be measured.
T0: The main tumor cannot be found.
T1, T2, T3, T4: Refers to the size and/or extent of the main tumor. The higher the number after
the T, the larger the tumor or the more it has grown into nearby tissues. T's may be further
divided to provide more detail, such as T3a and T3b.

Regional lymph nodes (N) :

NX: Cancer in nearby lymph nodes cannot be measured.
N0: There is no cancer in nearby lymph nodes.

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N1, N2, N3: Refers to the number and location of lymph nodes that contain cancer. The higher
the number after the N, the more lymph nodes that contain cancer.

Distant metastasis (M):

MX: Metastasis cannot be measured.
M0: Cancer has not spread to other parts of the body.
M1: Cancer has spread to other parts of the body.

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RISK FACTORS OF CANCER :
Anything that has the potential to make a normal body cell develop abnormally can cause cancer.
Some cancer causes remain unknown while other cancers have environmental or lifestyle
triggers or may develop from more than one cause. Some may be developmentally influenced by
a person’s genetic makeup. Many patients develop cancer due to a combination of these risk
factors-

TOBACCO
• Multipotent carcinogenic mixture.
• Linked to cancers of the lung, lower urinary tract, aerodigestive tract, liver, kidney, pancreas, cervix.
• Linked to myeloid leukemia

HEREDITY:
Several specific genes have been linked to human genes and are as follows: breast, ovarian,
colorectal, prostate, skin, and melanoma. The higher the amount or level of cancer-causing
materials a person is being exposed to, the higher the chance that the person will develop cancer.
In addition, people with genetic links to cancer may not develop it due to a lack of enough
stimulus to make the cancer-causing genes functional. Some people may have a heightened
immune response that controls or eliminates cells that are or potentially may become cancer
cells.

OBESITY
• Correlates with the body mass index (BMI).
• Adipose tissue is active endocrine and metabolic tissue.
• In response to endocrine and metabolic signaling, adipose tissue releases free fatty acids.
• Increased free fatty acids gives rise to insulin resistance and causes chronic hyperinsulinemia.
• Correlates with colon, breast, pancreatic, and endometrial cancers

IONIZING RADIATION :
Uranium, Radon, UV rays from sunlight, radiation from α, β, γ, and X-ray emitting sources can
predispose to cancer by rupturing DNA strands, thus causing mutations.

CHEMICAL SUBSTANCES :
Chemical substances that can cause cancer are called carcinogens which include- Benzene,
Asbestos, Nickel, Cadmium, Vinyl chloride, Benzidine, N-nitrosamines, tobacco or cigarette
smoke, etc.
Sexual reproductive behavior
Carcinogenic types of human papillomavirus.
High-risk HPV.

Physical activity
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  Decreases insulin and insulin-like growth factors.
 Decreases obesity.
 Decreases inflammatory mediators and free radicals.
 Increased gut motility

Occupational hazards
 Substantial number of occupational carcinogenic agents.
 Asbestos
 Dyes, rubber, paint, explosives, rubber cement, heavy metals, air pollution, etc.
 Radon.

DIETARY FACTORS:

a. Meat: Meat intake has been associated with the risk of digestive tract cancers.
Consumption of red and white meat is known to increase the risk of colon cancer. A high
intake of fish sauce may be a risk factor for gastric cancer.

b.Energy balance: The relationship between body weight, body mass index, or relative body
weight and site-specific cancer is positively associated with the cancers of the breast,
endometrium, gall bladder, and kidney. Physical inactivity, high energy intake, and large
body mass are associated with an increased risk of developing colon cancer in both men
and women.

c. Fat: A high intake of saturated fat increases the risk of prostate cancer.
d.Protein: Increased meat intake is associated with an increased risk of colon cancer and
advanced prostate cancer.
e. Alcohol: Alcohol has a causal role in carcinogenesis, especially for cancers of the mouth,
pharynx, and esophagus. Alcohol has an increased effect on those tissues that directly get
exposed to it during its consumption and tends to act synergistically with tobacco. Beer
consumption has been associated with an increased risk for colorectal cancer.
f. Nitrates: Nitrates are present in a variety of foods, and the main dietary sources are
vegetables and drinking water. Sodium and potassium nitrates are used in the processes of
salting, pickling, and curing foods. Nitrosamines are present in tobacco and tobacco
smoke. Nitrosamines related to nitrates and nitrates are potent carcinogens.

ESTROGEN :
Estrogens have been given for the relief of post-menopausal symptoms and the prevention of
osteoporosis. Estrogens may play a role in the production of breast and endometrial cancer.

VIRUSES :
Viruses may act as cofactors in the development of some malignant diseases. There may be a
possible role of hepatitis B virus in human primary liver cancer. Human papillomavirus and the
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Epstein-Barr virus are considered oncogenic.

STRESS :
Stress may cause damage to the thymus gland, and the immune system, and hormonal effects
mediated through the hypothalamus, pituitary, and adrenal cortex. This may provide the
neurologic currency that converts anxiety to malignancy.

AGE:
The risk of developing colorectal cancer increases with age. The incidence is 6 times higher among
persons aged 65 years and older than in comparison to persons aged 40-64 years. The increasing risk
of cancer with age reflects the accumulation of critical genetic mutations.

CHARACTERISTICS OF CANCEROUS CELLS:

1. Cell growth and division absent the proper signals.
2. Continuous growth and division even given differing signals.
3. Avoidance of programmed cell death.
4. Limitless number of cell divisions.
5. Promoting blood vessel formation.
6. Invasion of tissue and formation of metastases.

VIRUSES AND CANCER :

Implicated-
1. Hepatitis B and C viruses
2. Epstein-Barr virus (EBV)
3. Kaposi’s sarcoma herpesvirus (KSHV)
4. Human papillomavirus (HPV)
5. Human T cell leukemia-lymphoma virus (HTLV)

BACTERIAL CAUSE OF CANCER :

Helicobacter pylori:
Chronic infections are associated with:
• Peptic ulcer disease
• Stomach carcinoma
• Mucosa-associated lymphoid tissue lymphomas

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INFLAMMATION AND CANCER :
Chronic inflammation is an important factor in the development of cancer
• Cytokine release from inflammatory cells
• Free radicals
• Mutation promotion
• Decreased response to DNA damage.

TUMOR MARKERS :
Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found
on plasma cell membranes, in the blood. Such as-
• Cerebrospinal Fluid (CSF), or urine.
• Hormones (Epinephrine–in blood, adrenal medullary tumor).
• Enzymes.
• Genes.
• Antigens (prostate-specific antigen–in blood, prostate cancer).
• Antibodies.

CANCER EVOLUTION :
There are seven principles of cancer evolution. Which are-
1. Cancer is mediated by somatic evolution.
2. Cancer is many tissue-specific and age-associated diseases, commonality in uncontrolled
cell replication.
3. The somatic evolution of cancer is mediated by the population-genetic forces of
mutation, selection, and genetic drift, in a phylogenetic, phylogeographic context.
4. Cancer is a polygenic, heritable, and environmental disease, mediated in part by
mismatches between current and ancestral conditions.
5. The ultimate causes of cancer involve evolutionary trade-offs and co-option of normal
evolved functions involving growth, maintenance, and reproduction.
6. Anticancer adaptations have evolved.
7. Cancer cell populations evolve in response to therapies.

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The evolution of normal cells to cells that can form a detectable mass to outright cancer involves
multiple steps-

Clinical Manifestations of Cancer :

1. Pain:
• Little or no pain is associated with early stages of malignancy.
• Influenced by fear, anxiety, sleep loss, fatigue, and overall physical deterioration.
• Mechanisms: Pressure, obstruction, invasion of sensitive structures, stretching of visceral
surfaces, tissue destruction, and inflammation.

2. Fatigue:
• Subjective clinical manifestation: Tiredness, weakness, lack of energy, exhaustion,
lethargy, inability to concentrate, depression, sleepiness, boredom, and lack of
motivation.
• Suggested causes: Sleep disturbance, biochemical changes (cytokines), secondary to
disease and treatment, psychosocial factors, level of activity, nutritional status, and
environmental factors.

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3. Cachexia syndrome:
• Most severe form of malnutrition.
• Present in 80% of cancer patients at death.
• Includes: Anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, and
altered protein, lipid, and CHO metabolism.

4. Anemia:
• A decrease of hemoglobin in the blood.
• Mechanisms: Chronic bleeding resulting in iron deficiency, severe malnutrition, medical
therapies, or malignancy in blood-forming organs.

5. Leukopenia and thrombocytopenia:

• Direct tumor invasion of the bone marrow causes leukopenia and thrombocytopenia.
• Chemotherapy drugs are toxic to the bone marrow.

6. Infection:
• Risk increases when the absolute neutrophil and lymphocyte counts fall.

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 CHAPTER 02
THE SPREAD OF TUMOR
TUMOR INVASION :
Tumor Invasion refers to the direct extension and penetration of tumor or cancer cells into
neighboring tissues. The proliferation of transformed cells and the progressive increase in tumor
size eventually lead to a breach in the barriers between tissues, leading to tumor extension into
adjacent tissue. Local invasion is also the first stage in the process that leads to the development
of secondary tumors or metastases. Benign tumors (with very few exceptions) are encapsulated
and grow simply by expanding and pushing the surrounding tissue aside. Malignant tumors (with
very few exceptions), are unencapsulated and grow by reaching into the surrounding tissue.

3-STEP MODEL OF TUMOR INVASION:

Tumor invasion has three following steps -
1. The first step is the adhesion of the invading cell to the basement membrane or other ECM
(e.g. perivascular or sub-epithelial stroma). Adhesion is mediated by one or more integrin
family adhesion molecules.

2. The second step is proteolytic degradation of the matrix by cell surface or locally active
proteases that are localized at the tips of protruding actin-rich pseudopods. The pseudopods
direct the proteolysis at the leading edge of the invading cell. This step is very important.

3. The third step is de-adhesion and reversal of proteolysis by tissue inhibitor of

metalloproteinases (TIMPs), and other mechanisms so that the cell body is released to
migrate forward into and through the pathway created by the pseudopod. This step is very
important for the progression of tumor invasion. Without the last step tumor invasion will not
be complete.
Invasion is a complicated tightly regulated cyclical process of adhesion and de-adhesion,
proteolysis and anti-proteolysis, and migration triggered by chemotaxis and haptotaxis. The
source of the chemotactic molecules can be generated as a soluble gradient or can be bound to
ECM molecules in the solid phase. The successful invading cells must be able to coordinate all
of these functions.

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PATTERNS OF SPREAD :
1. Direct extension :
Carcinomas begin as localized growths (direct seeding of body cavities or surfaces) when they
arise. In the early stage, cancers do not penetrate the basement membrane (carcinoma in situ).
When the in situ tumor acquires invasive potential it extends directly to compromise neighboring
cells and to metastasize. E.g. Peritoneal carcinomatosis (metastatic ovarian carcinoma).

2. Metastatic spread :
Transfer of malignant cells from one site to another (not directly connected with it). Invasive
properties of malignant tumors bring them into contact with blood and lymphatic vessels.
• Hematogenous metastases
• Lymphatic metastases

METASTASIS :
Metastasis is the process by which a tumor cell leaves the primary tumor, travels to a distant site
via the circulatory system, and establishes a secondary tumor. This enables cancer cells to
survive in a new environment where there are no initial space and nutrient limitations. It
represents the end products of a multi-step biological process termed the invasion-metastasis
cascade, which involves the dissemination of cancer cells to anatomically distant organ sites and
their subsequent adaption to foreign tissue microenvironments. The events that lead to cancer-
metastasis include changes in cell-cell and cell-matrix adhesion, alteration in cell shape,
deformability & motility, invasion of surrounding normal tissues, gaining access to lymphatic or
vascular channels, dissemination via blood or lymph, survival of host defense mechanism, and
finally extravasation and colonization of secondary sites.

STAGES OF METASTASIS :
Metastasis does not occur randomly but is the result of a complicated series of tumor-host
interactions. Metastatic cascade of all these steps includes-

1. Invasion:
During tumor invasion, malignant cells penetrate a variety of extracellular matrices, including
basement membranes, interstitial stroma, cartilage, and bone. Penetration of the extracellular
matrix takes place by cyclic repetition of 3 biochemical steps.

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2. Angiogenesis:
Tumor invasion is accompanied by angiogenesis, the growth of new host blood cells into the
tumor. The process is induced at a post-capillary venule level by the release of tumoral and
stromal angiogenesis factors. The rate of proliferation of vascular endothelial cells is 20-2000
times.

3. Intravasation:
Intravasation is the entry of tumor cells into the bloodstream. Newly formed tumor vessels are
often defective, a property that may facilitate the entry of tumor cells into the circulation. At the
invasion front, tumor cells also may invade pre-established host vessels.

4. Circulation:
Tumor cells are discharged into the vascular system in the form of single cells or clumps. From
rapidly growing tumors of 1cm in size, millions of tumor cells can be shed into the circulation
every day. The blood compartment is a hostile environment for circulating tumor cells. Only a
small percentage (<0.01%) of circulating tumor cells initiates metastatic colonies.

5. Arrest:
Circulating tumor cells use a variety of means to arrest the vessels of the target organ, including
mechanical wedging, entrapment with platelets and fibrin, and attachment to target organ
endothelium via specific tumor cell surface receptors. Different tumors exhibit different
attachment actors and adhesion patterns, reflecting preferred sites of metastases. This is one of
the mechanisms responsible for organ tropism, which is the development of metastases in sites
that can’t be predicted from anatomic considerations alone.

6. Extravasation:
The time course of arrested tumor cells differs depending on where they are lodged. Among
circulating cells, 90% leave the circulation at the capillary or venule level. After adherence of the
tumor cells, the endothelial cells react, exposing the basement membrane and extravasation is
accomplished within 8-24 hrs. Altered host tissues can modify the arrest and extravasation of
blood-borne malignant cells. Metastases often form at sites of inquiry or inflammation, such as
sites of trauma, surgical scars, percutaneous needle biopsies, subcutaneous injections of
medications, and dental extractions.

7. Growth:
Extravasated tumor cells proliferate as colonies but require a new vascular supply to grow larger
than 0.5mm in diameter. Angiogenesis is therefore necessary at the beginning and end of the
metastatic cascade. Multiple host and tumor actors can alter the microenvironment required for
tumor survival and growth. Tumor cells can synthesize and secrete their own functionally active
growth factors (autocrine growth factors). Organ-derived growth factors and inhibitory factors
(paracrine factors) not only play a significant role in the growth and survival of metastatic
colonies but also provide another mechanism for organ tropism.

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 CHAPTER 03
THE MOLECULAR, CYTOGENETIC &, IMMUNOLOGIC BASIS OF CANCER

MOLECULAR BASIS OF CANCER:

At molecular levels, cancer can be caused by mutations, any change in the amount or presence or
absence of growth factors, binding factors, hormonal factors, growth receiver factors, etc.

CYTOGENETIC BASIS OF CANCER:

Clinical observations show that certain tumors exhibit defined familial inheritance patterns and
by observations that specific chromosomal abnormalities are associated with particular tumors.
Specific genetic elements or alterations involved in tumor formation were derived from studies
of animal retroviruses that cause specific cancers. Characterization of tumorigenic DNA has led
to the identification of altered cellular genes, which are known as the oncogenes. Activation of
these genes upon environmental stimuli can cause cancer.

• Mechanism of oncogene activation:

The mechanisms by which normal cellular genes acquire oncogenic activities are mutation,
chromosomal translocation, amplification, insertion, and deletion.

1. Spontaneous mutation :
A cellular proto-oncogene can be converted to an oncogene via a single-point mutation, causing
a change of a single amino acid in the gene product. Genetic lesions of this type have been
demonstrated to activate a number of the ras oncogenes; these single base changes result in the
production of an altered p2l ras gene product. The normal ras gene product is a protein with a
molecular weight of 21,000 referred to as p21. In bladder carcinoma T24/EJ, a change from G to
T in the p21 DNA coding sequence results in the incorporation of valine into the peptide chain
instead of glycine at position 12. This small change is capable of changing the cell's phenotype.
Chemical or environmental agents could induce transformation by generating mutations within
these proto-oncogenes.

2. Chromosomal translocation :
Chromosomal rearrangements, particularly the transfer of a gene from its normal position on one
chromosome to another chromosome, have been demonstrated in several tumors. Some
translocations occur consistently in certain tumors. The consistent and specific appearance of
particular rearrangements supports the notion that they play a significant etiologic role in

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tumorigenesis. These rearrangements may lead to the activation of proto-oncogenes, as in
Burkitt's lymphoma, or to the production of chimeric (fusion) proteins resulting from gene
fusion, as in chronic myelogenous leukemia.

3. Amplification :
Amplification is the increase in the number of copies of a particular gene or DNA Sequence. The
amplification of a gene may result in overexpression of the product encoded by this Gene. Many
oncogenes are amplified and their gene products are overexpressed as a result of this change in
copy number. For example, N-myc amplificati6n has been demonstrated in both neuroblastoma
and retinoblastoma, whereas a 16-fold amplification of c-myc has been shown in colon
carcinoma and a 20 to 30-fold amplification in the human leukemia line HL60. The prognosis for
individuals with certain tumors correlates with amplification or overexpression of particular
oncogenes and their products, e.g., the HER-2/neu oncogene in breast and ovarian cancers.

4. Insertion :
Insertion of endogenous cellular DNA regulatory sequences, either by direct transposition or
retrovirus-like integration, can result in the activation of proto-oncogenes. The integration of
regulatory sequences within viral long terminal repeats (LTRs) at a position near cellular proto-
oncogenes can result in their activation. The insertion of an intracisternal, particle genome near
the proto-oncogene c-myc has been shown in mouse plasmacytoma. The activation of the c-myc
is the result of the reinsertion of an endogenous intracisternal. The exact mechanism of this
insertion has not been determined.

5. Deletion :
Deletion may involve the loss of a whole chromosome, a chromosomal segment, or a gene. Some
deletions are tumor-specific while others are common to tumors of diverse cellular origins. The
loss of the retinoblastoma gene on chromosome 13 and the loss of a specific region (q13) on
chromosome 11 are unique to retinoblastoma and Wilms' tumor respectively. On the other hand,
loss of a specific region on chromosome 3 is observed in small cell carcinoma of the lung, renal
cell carcinoma, and ovarian carcinoma.
Deletion often results in the loss of tumor suppressor genes (also referred to as anti-oncogenes or
recessive oncogenes) which function as negative growth regulators i.e. they regulate
uncontrolled cellular proliferation by inhibiting cell division or by enhancing differentiation.
Therefore, the loss of these suppressor genes or a mutation that leads to the loss of their function
results in tumorigenesis. Because of their recessive behavior, the involved mutation or loss
should affect both gene copies on homologous chromosomes.

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• Oncogenes and their products :
Oncogenes can be classified by the relatedness of nucleic acid sequences, by the amino acid
sequences of gene products, or by the enzymatic activity of these products. Uncoupling of
oncogene activities could result in uncontrolled growth and development of tumors.

Characteristics: Oncogene products are similar to growth factors, growth factor receptors,
protein tyrosine phosphate kinase (function in cell growth and proliferation), or GTP binding
proteins.

Function: Products of oncogenes function as regulators of DNA replication, gene transcription,

GTP binding factors, and protein phosphorylation.

Three families of oncogenes are described below-

1. The ras Gene Family :
The three genes of the ras family are H-ras, K-ras, and N-ras. These genes are activated owing
to a single point mutation in codons 12, 13, 59, and 61 in their p21 coding region. The H-ras
gene is the cellular homolog of the viral oncogene found in the Harvey strain of murine sarcoma
virus and has been associated with bladder, mammary, and lung carcinomas. The single base
changes that are found in these tumors are at codons 12 and 61; they result in single amino acid
changes from glycine to valine or aspartic acid, or from glutamine to leucine, in the peptide
sequence. The amino acid change in the transforming p21 results in a more rigid molecule rather
than the flexible hinge that allows the amino terminus to fold into the core of the normal p21
molecule. Normal p21 has GTP-binding GTPase activity and an amino acid sequence
homologous to signal transducing proteins coupled to specific cell surface receptors. Mutant p21
may not be able to hydrolyze GTP (GTPase activity) and hence not be able to modulate
intracellular signal transduction; the mutation in codon 12 results in loss of the ability of p21 to
bind GTP. Transfection of an estrogen-dependent breast carcinoma cell line with the mutant ras
converts it into an estrogen-independent line.

2. The C- myc and myc - like Gene Family :

C-myc is associated with the progression of cells from a resting state to a dividing state, i.e.
progression from G0 to G1 and maintenance of the potentially proliferative state. Thus, it is
associated with cell growth, division, and differentiation. The c-myc gene product is a nuclear
protein with DNA binding activity. It is activated in Burkitt's lymphoma by the chromosome
translocation (8;22). This translocation not only activates this gene but also results in the
overexpression of its product, pp62 (a phosphoprotein of MW 62,000) located in the nucleus.
The increased c-myc expression probably contributes to the high rate of proliferation observed in
these tumors.
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Another member of the myc gene family, N-myc, is amplified 75- to 500-fo1d in some
neuroblastoma lines. Amplification of this gene is most likely preceded by its translocation

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together with variable lengths of its flanking sequences. The degree of overexpression correlates
with the gene copy number. c-myc is reported not to be expressed in tumors that express N-myc.
As with c-myc, the N-myc gene product is associated with increased proliferation; proliferation
of neuroblasts prevents their differentiation.

3. The HER- 2/ neu Gene :

HER-2/neu (also called c-erb B2) was originally identified by transfecting DNA derived from
chemically induced rat neuro-glioblastomas into NIH/3T3 cells. It has partial sequence
homology but can be distinguished from the epidermal growth factor (EGF) receptor. This gene
is amplified in 25-30% of all human primary breast tumors. Amplification and overexpression
are associated with the stage of disease. It has also been shown to be associated with increased
mitotic fraction. If either overexpression or amplification conclusively demonstrates an increased
tumor growth fraction, then chemotherapeutic agents that are S phase-specific might be
efficacious in the treatment of these cancers. The normal HER-2/neu gene has been shown to
induce transformation in in vitro transfection studies. Cells transformed in this way express the
neu gene products at levels comparable to human breast and ovarian cancer cells. Data from
several groups suggest that the activation of this gene results in the stimulation of the
cytoplasmic receptor protein tyrosine kinase activity causing signal transduction into the cell that
ultimately results in increased cell growth.

• Viral oncogenesis :
Much of what is known about the genetic etiology of cancer is based on studies of retrovirus.
The viral genome consists of three main structural genes. The oncogenic potential of these
viruses is independent of the replicative genes. It has been determined that the oncogenic form of
the virus cannot replicate and that one of the original three genes has been replaced by a
transforming gene.
Examples of retroviruses that are important in the etiology of human disease are HTLVs
involved in the production of T cell leukemias and lymphomas, hairy cell leukemias and
lymphomas, and AIDS. In addition to retroviruses, hepadnaviruses (hepatotropic DNA viruses)
and papillomaviruses (DNA viruses) are also capable of inserting themselves into the cellular
genome and thereby altering gene expression. Epidemiologic evidence that the hepadnavirus
hepatitis B virus (HBV) is involved in the etiology of hepatocellular carcinoma (HCC) is
striking. The integration of the HBV into the host chromosome may lead to tumor induction
either by direct action of cellular oncogenes or by disrupting the function of tumor suppressor
genes.
Human papillomaviruses (HPV) have also been implicated as transforming viruses and have
been associated with precancerous lesions and invasive cervical cancers. Additional factors may
be required to produce cellular transformation. Like the hepadnaviruses, HPV 16 and HPV 18,
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which demonstrate a high risk for malignant progression, be integrated into the cellular
genomes of

Page | 22
invasive cancers. The transforming proteins of HPV 16 and HPV 18 bind pRB1 and p53, both of
which have been shown to participate in tumor suppression.

IMMUNOLOGIC BASIS OF CANCER :

The host's immune response to a tumor is assumed to be beneficial and therefore desirable. It is
the notion that the immune system surveys the body for aberrant changes, growths, or neoplasms
and mobilizes armies of immune lymphocytes or killer cells to attack and subdue the invasive
tumor.

• Immune Surveillance :

At the heart of immune surveillance is the concept that cancerous cells express tumor antigens
that can be recognized by different immune cell phenotypes. Tumor antigens fall into general
categories, which include many normal gene products that are turned on at inappropriate times or
appear on cell types that normally do not express those particular proteins.
For simplicity, any overexpressed, mutated, dysregulated, or rearranged gene product expressed
by a cancerous cell is considered a tumor antigen. Sometimes these are referred to as tumor-
specific transplantation antigens. These tumor antigens play a role in differentiating tumors as
being immunologically different from healthy tissue and allow the immune system to recognize
cancerous cells as “non-self.” A proto-oncogene is a normal gene that undergoes mutation to
allow increased expression.

• Immunofacilitaton :

Tumor growth and progression require or are dependent on a positive immune response, i.e. the
immune system encourages or fosters tumor growth and progression. Furthermore, this immunity
is unique for each tumor, and the tumor adjusts its immunogenicity to a level that is most
favorable to its growth. From this argument, it follows that immunosuppression may be as good
as or better than enhancement of the immune response for the treatment of malignancy.
The immunofacilitaton hypothesis warrants further consideration because of its possible impact
on the recently accelerated use and development of immunotherapies. Data supporting the
hypothesis of immunofacilitaton are that-
1. In immune restoration or titration experiments (by addition of varying numbers of
lymphocytes), a level of immunity existed that favored the formation of 3-
methylcholanthrene (MCA)induced tumors.
2. The growth of tumors in vivo and in vitro could be inhibited or facilitated by varying the
concentration of a specific antibody in the culture.

Page | 23
3. MCA-induction of tumors in adult mice could be favorably influenced by the autoimmune
state induced by 3-day neonatal thymectomy.
Thus, tumors that have undergone less progression are probably less malignant and more
homogeneous and are better treated by immunotherapy regimens. However, after progression has
been established, immunosuppression may be as beneficial as immunotherapy as enhancement of
immune response.

• Immunodeficiency Syndromes & Tumor Formation :

Individuals with acquired and congenital immunodeficiency syndromes have been reported to
have an increased incidence of certain malignancies relative to normal individuals. It has been
postulated that the breakdown or absence of immune surveillance in these states permits the
formation and growth of tumors because of a ubiquitous environmental, microbial, or
carcinogenic agent. In these patients, including immunosuppressed transplant recipients, tumors
are restricted to a few types such as ultraviolet-induced skin cancers, (tumors of the
lymphoreticular system - lymphomas and leukemias and Kaposi's sarcoma.
In HIV-1-infected individuals, Kaposi's sarcoma is a common clinical feature, previously this
relatively rare form of skin cancer has been seen primarily in elderly males of Mediterranean
origin. Other tumors associated with HIV-1-infected individuals are squamous cell carcinoma of
the oral cavity, cloacogenic carcinoma of the rectum, non-Hodgkin's lymphoma, and acute and
chronic leukemias.
These tumors may result from the transformation of cells by viruses such as Epstein-Barr virus
(EBV) and cytomegalovirus (CMV). Coupled with other events such as oncogene activation or
overproduction of growth factors, these cells could attain a proliferative advantage and aid in
tumor formation.
Two-thirds of X-linked lymphoproliferative syndrome-affected males develop infectious
mononucleosis that is associated with high morbidity and mortality. These patients are
specifically immunologically deficient in their ability to respond to EBV. and they develop
extranodal non- Hodgkin's lymphoma of the Burkitt type or become hypogammaglobulinemic or
both. Because of their specific inability to destroy the EBV-infected, transformed B cells. these
cells continue to proliferate and invade virtually all organs; the activated but ineffective killer
cells (T and NK) cause widespread damage to the organism owing to nonspecific cell-mediated
cytotoxicity. The result is immune dysregulation and dysfunction.

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CHAPTER 04
CARCINOGENESIS
Carcinogenesis refers to the study of the origin of cancer. In a broad sense, epidemiologic studies
are performed to corroborate clinical observations. Investigations in biological systems can be
performed to reproduce these observations to determine the steps involved in the conversion of
normal cells to malignant cells.

IDENTIFICATION OF SUSCEPTIBLE INDIVIDUAL :

Pharmacogenetics is the study of the heritable basis for idiosyncratic responses to xenobiotics,
including clinically prescribed agents as well as other foreign substances.
Several polymorphisms have been associated with malignancy in humans, three of which involve
differences in the expression of cytochrome P-450 genes. Cytochrome P-450 polymorphisms
associated with lung cancer susceptibility

CLASSIFICATION OF CARCINOGENS :
Chemical carcinogens can be classified into two general categories based on the ability of
compounds to bind to DNA.
• Genotoxic: Compounds that bind to DNA are termed genotoxic.
• Epigenetic: Compounds that are carcinogenic but have no evidence of DNA binding are
termed, epigenetic.

Genotoxic carcinogens :
Genotoxic carcinogen refers to the type of carcinogen that can bind to DNA.
Some common properties of genotoxic compounds :
• Genotoxic compounds are more readily detected.
• Short-term assays for detecting genotoxic agents are inexpensive and reliable indicators
of the potential carcinogenicity of such compounds. The principle of such tests is the
ability of this class of compounds to cause a mutation.
• Most genotoxic carcinogens are small molecules with a molecular weight of less than
500. The ultimate reactive species are generally electrophilic.

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Classification of genotoxic agents :
a) Direct acting: Direct-acting carcinogens are active at the site of application.
b) Pro-carcinogen: Pro-carcinogens require metabolic activation. Pro-carcinogens may be
metabolized by one organ and transported to a second site for the final step in activation.
Also within the category of genotoxic carcinogens are inorganic compounds that do not directly
bind to DNA but cause alterations in normal DNA replication.

Carcinogen Metabolism :
1. Polycyclic Aromatic Hydrocarbons:
The metabolism of PAHs is complex, but for some compounds such as benzo[a]purine, the
details of metabolism have been determined. Benzo[a]purine serves as a prototype PAH owing to
widespread distribution in the environment, ease of detection of the parent compound and
metabolites, and ready availability of metabolite standards.

2. Aromatic Amines:
In general, aromatic amines and amides are activated by N-hydroxylation and detoxified by ring-
hydroxylation. N-hydroxylation further metabolic activation steps to ultimate reactive
metabolites including sulfate esterification, de-acetylation, or acyl transfer.

3. Nitrosamines:
N-nitrosamines are metabolized by cytochrome P-450 enzymes (CYP2El, CYP2A3). Both alkyl
and cyclic nitrosamines are carcinogenic, and organo-tropism is a major characteristic of this
class of compounds. A key step in the metabolic activation of this class of chemical carcinogens
appears to be alpha hydroxylation. Nitrosamines derived from nicotine are found in tobacco and
tobacco combustion products. The ultimate reactive species of nitrosamines are alkylating
agents.

DNA Binding & Repair :

• Binding: A key step in the carcinogenic process is the covalent modification of DNA by
genotoxic carcinogens. Most genotoxic carcinogens (or their active metabolites) are
electrophilic and can bind to bases in DNA that have many nucleophilic sites.
This covalent binding to DNA presents a unifying concept whereby structurally diverse
chemicals share a common fate.
The binding of compounds to DNA can result in decreased fidelity of DNA synthesis, leading to
mutated protein products. Two examples of such an action are the deletion of a base, leading to a

Page | 26
frameshift mutation, and disruption of the normal hydrogen bonding between strands of DNA,
which can lead to a base pair substitution.

• Repair: A DNA base that is covalently bound to a carcinogen can be removed by the DNA
repair system, thus restoring the normal gene sequence. Several factors that determine the
efficiency of DNA repair include the size of the compound that is covalently linked (a methyl
group, compared to a fused ring structure), whether the covalent bond lies in a coding or
control region, and the three-dimensional orientation of the carcinogen-DNA adduct.

EPIGENETIC CARCINOGENS :
Carcinogens for which there is no evidence for genotoxicity are considered to be epigenetic.
Possible mechanisms of action include -
1. Chronic tissue injury
2. Alteration of immune system function
3. Hormonal alterations
• Compounds that enhance tumor incidence also fall into the epigenetic category. Two such
examples are co-carcinogens and tumor promoters.
• Co-carcinogens are compounds that increase tumor yield when administered concurrently
with compounds of known carcinogenic potential. Tumor promoters are compounds that
increase the tumor yield when administered after a genotoxic agent.

Solid- State Carcinogens :

The most widely studied carcinogen in this category is asbestos. The physical size and
composition of the particles are important in determining the carcinogenic potential.
Tumor promoter :
A tumor promoter is a type of compound that increases tumor yields after the administration of a
genotoxic agent.
Tumor promoters have been best characterized in a mouse skin painting model. Using this
animal model, specific stages of tumor promotion have been identified. Phoebe esters,
particularly 12 phoebe acetate (TPA), hydrogen peroxide, etc.

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 CHAPTER 05
DIAGNOSIS & MANAGEMENT OF CANCER

PRINCIPLES OF CANCER DIAGNOSIS :

The biologic and clinical hallmark of cancer is a disturbance of tissue growth in the host, most
often distinguished by expansion of the aberrant tissue, invasion into local tissues, dissemination
to distant sites, and ultimately death of the host as a consequence of the perturbations of normal
organ function. Although this behavior seems chaotic and uncontrolled, uniform progress of
malignant growth through these stages seems shared by most of the phenomena characterized as
“cancer.” It is the uniformity of behavior which directs the diagnostic and therapeutic approach
to the cancer patient and which is reflected in the following principles-

1. Obtain Histopathologic Evidence of Malignancy:

Histopathologic confirmation of the presence of cancer is a principle that should remain
inviolate. The diagnosis of cancer is such a stigmatizing fact that its presence should be
unequivocally assured. At moments of diagnostic doubt, seeking additional opinions from
recognized experts is a common and frequently useful pursuit. Additionally, when potentially
disabling, disfiguring, or life-threatening treatment is envisioned for the patient, the diagnosis of
malignant disease should be assured before treatment commences.

2. Make Use of Clinical Leads Likely to Provide the Highest Dividends:

If an abnormal and suspect lesion is detected by physical examination, radiologic examination, or
other technique, useful diagnostic evidence may be obtained by a direct approach to the suspect
lesion. For example, if a rectal mass is palpated, slight liver enlargement is present, and the
patient complains of dysphagia, diagnostic efforts should be devoted to the rectal mass as the
most likely source of useful material; evaluation of the liver and dysphagia by other studies may
await the characterization of the more obvious lesion. Furthermore, if the existing data suggest
multiple possible sources of malignancy, pursue those possibilities suggested by the patient’s
symptoms or signs.
[

3. Review Previous Biopsy Slides of Resected Malignant or Nonmalignant Tissues:

If the clinical behavior of a patient’s malignant or nonmalignant condition is atypical or brings
into doubt the initial diagnosis, a review of the original tissue in light of the clinical perspective
may provide new insight and revision of the histopathologic diagnosis. For example, a patient
thought to be afflicted with an aggressive lymphoma who fails to enter a durable remission and
suffers from recurrent lymphoma over a long period despite multiple aggressive therapeutic
attempts may be found to have an incurable indolent lymphoma upon review of the original
pathologic material.
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4. Obtain a Second Opinion:
Many malignancies provide the examining pathologist diagnostic challenges that may be
resolved in the hands of individuals experienced in the evaluation of large numbers of rare
diseases or critical differential diagnostic subtleties. Obtaining a second opinion is a fact of life
in all disciplines of medicine and should not be resisted when sought. If the diagnosis is not
straightforward and requires increasingly sophisticated techniques (special stains, electron
microscopy, etc.) or if tissue for analysis is extremely limited, additional input should be sought
from individuals with experience in the review of difficult diagnostic dilemmas.

CANCER STAGING :
Staging codifies the description of cancer states to enhance communication of cancer data
between institutions, practitioners, and monitoring or treatment organizations. The most
commonly accepted staging methods reflect a cancer biology dogma that is well entrenched,
namely, an untreated primary cancer increases in size progressively, eventually manifests
dissemination to lymph nodes, and ultimately manifests metastatic spread to distant anatomic
sites. TNM staging system is the most commonly proposed system. Tumor growth (T), spread
to primary or regional lymph nodes (N), and metastatic dissemination (M) are the events in
the natural history of cancer that this system seeks to define. This process of staging may utilize
only clinically derived parameters (physical examination, radiologic procedures, and blood and
serum data) or surgically/ pathologically derived parameters (histopathologic examination of
surgically resected tissues). Occasionally, the grade of a tumor (its differentiation or “degree of
malignancy”) is utilized in the further stage grouping of cancer.

APPROACH TO EARLY CANCER :

The patient who presents to a physician promptly after detection of early evidence of cancer is
the patient most likely to reap the benefits of early, aggressive, and intelligent application of
modern cancer diagnosis and care. Well-defined steps to ensure the patient the chance for
eradication of this disease-
1. Obtain histopathologic evidence of cancer: This step is critical to the primary management
of cancer. Although the first evidence of cancer often occurs at its site of origin, such an
assumption is not a dependable one. Yet the assumption that a clinical sign of malignant
disease is sufficient to proceed with further diagnostic or therapeutic procedures in the
absence of confirming histopathologic evidence is hazardous; such procedures may
carry a risk of

Page | 29
 disability, deformity, or death that can be rationalized only if cancer is unequivocally
documented.
2. Establish the extent of primary cancer: The extent of primary cancer (its size, its location,
the extent to which it locally invades other structures) is of prognostic importance and is a
determinant of the type of primary therapy appropriate to the disease. These are two of the
functions of cancer staging. Evaluate nodal and distant sites for evidence of metastases
consistent with natural history of cancer.
3. Obtain multidisciplinary evaluation: The major evolutionary advance made in the
management of cancer in the last 20 years has been the multidisciplinary treatment approach.
The simultaneous or rapid sequential administration of two or more anticancer maneuvers
may be rewarded by objective improvement in time-to-relapse, disease-free survival, and
overall survival, the common measures of therapeutic effect in cancer treatment. Adjuvant
radiation therapy or chemotherapy seeks to eradicate that undetectable residue of cancer
inadequately retrieved by surgery, either local advancement of the cancer unencompassed by
the surgical procedure.
4. Apply primary therapy aggressively: It cannot be overemphasized that the primary
management of a cancer when first detected is the best and may be the only opportunity for
cure. Most cancers are extremely sensitive to small changes in dosage, responding
beneficially to maximum treatment effects but manifesting disappointing therapeutic
outcomes following minor attenuation of treatment aggressiveness.
5. Evaluate the Need for Adjuvant Therapy: The rationale for follow-up therapy after
primary management of cancer has been alluded to. Such therapy intends to attempt
eradication of residual tumor soiling the resected or irradiated primary site or to destroy
microscopic lymphatic or blood-borne deposits of cancer at sites distant from the primary
tumor. Risks of recurrent or metastatic cancer may be inferred from tumor size, the presence
of regional lymph node metastases in the resected specimen, histopathologic differentiation
of the cancer, symptoms, or elevation of blood-borne tumor markers.

APPROACH TO ADVANCED CANCER :

The condition of advanced cancer generally reflects a disease that is incurable and may lead to
death. However, this realization should not paralyze the patient’s or the clinician’s commitment
to aggressive management of the disease. The rationale for maintaining an aggressive and upbeat
approach to advanced disease includes the following:

Page | 30
1. A few cancers are curable in the advanced or metastatic state (testis cancer, gestational
trophoblastic cancers, osteogenic sarcoma, Hodgkin’s disease, intermediate- and high-grade
non-Hodgkin’s lymphoma).
2. Although published reports of the treatment outcome or natural history of advanced cancers
suggest a disturbingly short median, mean, or 2- to 5-year survival, survival distributions
may have very long tails. Not all patients with a given advanced cancer may experience
prompt disability or demise. Such patients may enjoy long holidays from active treatment or
durable asymptomatic periods during disease stability.
[

3. Although treatment statistics may suggest discouragingly low response rates for a treatment
regimen, very brief response duration, or survival advantages no different from those of
minimal or no treatment, the opportunity for any response, no matter how small, may be
accepted easily by the advanced cancer patient.
4. Despite evidence of advanced or metastatic cancer at the time of diagnosis of the primary
disease, exploiting opportunities to remove relatively limited advanced disease may rarely be
accompanied by the cure of the disease, durable remission, or enhanced freedom from the
onset of cancer-induced symptoms.

Approach to advanced cancer-

 Obtain histopathologic confirmation of the first recurrence of cancer and any recurrences
widely separated in time.

 In the newly recurrent cancer patient, restage noninvasively all symptomatic sites and all
sites commonly known to harbor metastases.

 Actively treat advanced cancer no matter how dismal the treatment statistics. Corollary:
Obtain second opinions about treatment for advanced cancer

CANCER SCREENING :
The ultimate control of cancer will be the result of a combination of cancer prevention, risk
reduction, and early detection. Efforts at primary prevention seek to forestall the biological onset
of malignancy by altering host susceptibility or by removing etiologic agents from contact with
the host. Secondary prevention, or screening, on the other hand, seeks to detect the disease at a
preclinical stage in the asymptomatic host, at a time when it is presumably most treatable.
Widespread application of a screening test requires a demonstration of benefit from early
detection, and certain criteria must be fulfilled to identify those cancers that are suitable for
screening. The burden of suffering associated with a particular cancer must be sufficient, in
terms both of prevalence and morbidity and mortality, to warrant the risks and costs associated

Page | 31
with a

Page | 32
screening program. The screening test itself must fulfill certain standards. For widespread
application in a population, a test must be safe, convenient, acceptable to the public, and
relatively low in cost. In addition to being feasible, it must be accurate and reliable.
Accuracy refers to the sensitivity and specificity of a test, i.e. its ability to detect the maximum
number of true cases without falsely labeling others with positive tests. Reliability is the
capacity of a test to give the same results on repeat examinations.

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 CHAPTER 6
TREATMENT OF CANCER

SIGNS & SYMPTOMS OF CANCER :

Symptoms and signs of cancer depend on the type of cancer, where it is located, and/or where
the cancer cells have spread. For example, breast cancer may present as a lump in the breast or as
nipple discharge while metastatic breast cancer may present with symptoms of pain (if spread to
bones), extreme fatigue (lungs), or seizures (brain). A few patients show no signs or symptoms
until the cancer is far advanced.
Some warning signs and/or symptoms that a cancer patient may be show, and which should
prompt a person to seek medical attention are-
1. Change in bowel or bladder habits.
2. A sore throat that does not heal.
3. Unusual bleeding or discharge (for example, nipple secretions or a "sore" that will not
heal that oozes material).
4. Thickening or lump in the breast, testicles, or elsewhere.
5. Indigestion (usually chronic) or difficulty swallowing.
6. Obvious change in the size, color, shape, or thickness of a wart or mole.
7. Nagging cough or hoarseness.
Other signs or symptoms may include the following:

1. Unexplained loss of weight or loss of appetite.

2. A new type of pain in the bones or other parts of the body that may be steadily
worsening, or come and go, but is unlike previous pains one has had before.
3. Persistent fatigue, nausea, or vomiting.
4. Unexplained low-grade fevers may be either persistent or come and go.
5. Recurring infections that will not clear with usual treatment.

TREATMENT OF CANCER :
There are many types of cancer treatment. The type of treatment that one receives will depend on
the type of cancer one has and how advanced it is. Some people with cancer have only one
treatment. However, most people have a combination of treatments, such as surgery with
chemotherapy and/or radiation therapy.

Page | 34
SURGERY :
Surgery is a procedure in which a surgeon removes cancer from the body.
• Biopsy and lymph node sampling
• Sentinel nodes
• De-bulking surgery –remove most of the tumor
• Palliative surgery – relief of symptoms

RADIATION THERAPY :
Radiation therapy is a type of cancer treatment that uses high doses of radiation to kill cancer cells
and shrink tumors.
• Radiation eradicates cancer without excessive toxicity.
• It also avoids damage to normal structures.
• Ionizing radiations damage the cancer cell’s DNA.

CHEMOTHERAPY :
• Chemotherapy is a type of cancer treatment that uses drugs to kill cancer cells.
• In chemotherapy, nonselective cytotoxic drugs are used, that target vital cellular
machinery or metabolic pathways critical to both malignant and normal cell growth and
replication.
• The goal of chemotherapy is to eliminate enough tumor cells so the body’s defense can
eradicate any remaining cells.

Compartments of chemotherapy:
1: Cells undergoing mitosis and cytokinesis.
2: Cells capable of entering the cell cycle in the G1 phase.
3: Cells not dividing or have irreversibly left the cell cycle.
Cells in compartment 3 will die a natural death.

IMMUNOTHERAPY TO TREAT CANCER :

Immunotherapy is a type of cancer treatment that helps the immune system fight cancer.
Theoretically, antitumor responses can selectively eliminate cancer cells while sparing normal
cells.
Page | 35
 • Immune memory is long-lived.
• Numerous immunologic mechanisms are capable of rejecting different types of cancer.
• Biologic response modifiers (BRMs)
Other forms of immunotherapy are-
• Interferon administration
• Antigens
• Effector cell lymphokines
• Monoclonal antibodies

TARGETED THERAPY :
Targeted therapy is a type of cancer treatment that targets the changes in cancer cells that help
them grow, divide, and spread.

HORMONE THERAPY :
Hormone therapy is a treatment that slows or stops the growth of breast and prostate cancers that
use hormones to grow.
• Receptor activation or blockage
• Interferes with cellular growth and signaling

STEM CELL TRANSPLANT :

Stem cell transplants are procedures that restore blood-forming stem cells in cancer patients who
have had theirs destroyed by very high doses of chemotherapy or radiation therapy.

PRECISION MEDICINE :
Precision medicine helps doctors select treatments that are most likely to help patients based on a
genetic understanding of their disease.

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