Neoplasia 2014-2015
Dr. Ban J. Qasim
Definition and Nomenclature
Neoplasia, literally means new growth. A neoplasm is defined as “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 the cessation of the stimuli which evoked the change." In common
medical usage, a neoplasm is often referred to as a tumor and the study of tumors is called
oncology.
Neoplasms are named according to:
 Histologic types : mesenchymal and epithelial
 Behavioral patterns : benign and malignant neoplasms
Thus, the suffix -oma denotes a benign neoplasm. Benign mesenchymal neoplasms originating from
muscle, bone, fat, blood vessel, nerve, fibrous tissue and cartilages are named as rhabdomyoma,
osteoma, lipoma, hemangioma, neuroma, fibroma and chondroma respectively.
Benign epithelial neoplasms are classified on the basis of cell of origin for example adenoma is the
term for benign epithelial neoplasm that form glandular pattern or on basis of microscopic or
macroscopic patterns for example visible finger like or warty projection from epithelial surface are
referred to as papillomas.
This nomenclature has, however, some exceptions:
(I) Nonneoplastic misnomers: hematoma, granuloma, hamartoma which is a malformation that
presents as a mass of disorganized tissue indigenous to the particular site. Example: Hamartoma of
the lung seen as a mass containing islands of cartilage, bronchi, and blood vessels, and choristoma
which is a congenital anomaly better described as a heterotopic rest of cells. For example, a small
nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa
of the stomach, duodenum, or small intestine.
(II) Malignant misnomers: melanoma, lymphoma, seminoma, glioma, hepatoma, and
mesothelioma.
Malignant tumors are collectively referred to as cancers. Malignant neoplasm nomenclature
essentially follows the same scheme used for benign neoplasm with certain additions. Malignant
neoplasms arising from mesenchymal tissues are called sarcomas (Greed sar =fleshy). Thus, it is a
fleshy tumour. These neoplasms are named as fibrosarcoma, liposarcoma, osteosarcoma,
hemangiosarcoma etc. Malignant neoplasms of epithelial cell origin derived from any of the three
germ cell layers are called carcinomas.
•
E.g. Ectodermal origin: epidermis of skin (squamous cell carcinoma, basal cell carcinoma)
•
Mesodermal origin: renal tubules (renal cell carcinoma).
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Dr. Ban J. Qasim
Endodermal origin: linings of the gastrointestinal tract (colonic carcinoma)
Carcinomas can be further classified:
•
Those producing glandular microscopic pattern are called adenocarcinomas and those
producing recognizable squamous cells are designated as squamous cell carcinoma.
•
Furthermore, whenever possible the carcinoma can be specified by naming the origin of the
tumour such as renal cell adenocarcinoma.
Tumors that arise from more than one tissue component:
•
Teratomas are composed of mature or immature cells or tissues derived from more than one
germ-cell layer and sometimes all three.Teratomas originate from totipotential stem cells such
as those normally present in the ovary and testis. Such cells have the capacity to differentiate
into any of the cell types found in the adult body (bone, epithelium, muscle, fat, nerve, and
other tissues).
•
Mixed tumors containing both epithelial and mesenchymal components. Examples include
pleomorphic adenoma of salivary gland and fibroadenoma of breast.
Characteristics of Benign and Malignant Neoplasms
The difference in characteristics of these neoplasms can be conveniently discussed under the
following headings:
1. Differentiation & anaplasia
2. Rate of growth
3. Local invasion
4. Metastasis
1. Differentiation and anaplasia
Differentiation refers to the extent to which parenchymal cells resemble comparable normal cells
both morphologically and functionally. Thus, in well-differentiated tumours ,cells resemble mature
normal cells of tissue of origin. Poorly- differentiated or undifferentiated tumours have primitive
appearing, unspecialized cells. In general, benign neoplasms are well differentiated. Malignant
neoplasms in contrast, range from well differentiated, moderately differentiated to poorly
differentiated types.
Malignant neoplasm composed of undifferentiated cells are said to be anaplastic, literally anaplasia
means to form backward.Morphology of anaplastic cell includes large pleomorphic; hyperchromatic
nucleus with high nuclear cytoplasmic ratio 1:1(normally 1:4 to 1:6). The cell usually reveals large
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nucleoli with increased and often abnormal mitoses. Tumour giant cells and frequent loss of
polarity of epithelial arrangements are encountered.
Dysplasia is a disorderly but non-neoplastic proliferation characterized by loss in the uniformity of
individual cells and in their architectural orientation. Dysplasia is encountered mainly in the
epithelia.
Features of dysplastic cells are:
1. Pleomorphic and with hyperchromatic nuclei and high N/C.
2. Mitotic figures are more abundant than usual.
3. Mitoses appear in abnormal locations within the epithelium. In dysplastic stratified squamous
epithelium, mitoses are not confined to the basal layers, where they normally occur, but may
appear at all levels and even in surface cells.
4. There is considerable architectural disturbance .For example, the usual progressive maturation
of tall cells in the basal layer to flattened squames on the surface may be lost and replaced by a
disordered proliferation of basal cells.
The term dysplasia does not indicate cancer, and dysplasias do not necessarily progress to cancer.
•
•
Mild-to-moderate dysplasia that do not involve the entire thickness of epithelium may be
reversible, and with removal of the inciting causes, the epithelium may revert to normal.
Severe epithelial dysplasia (carcinoma in situ): dysplastic changes involve the entire thickness
of the epithelium without invasion of the basement membrane, a pre-invasive stage of cancer.
The better the differentiation of the cell, the more completely it retains the functional capabilities
found in its normal counterparts. Benign neoplasms and even well-differentiated cancers of
endocrine glands frequently elaborate the hormones characteristic of their origin. Welldifferentiated squamous cell carcinomas elaborate keratin, just as well-differentiated hepatocellular
carcinomas elaborate bile. The more rapidly growing and the more anaplastic a tumor, the less likely
it is to have specialized functional activity.
2. Rate of growth
Most benign tumours grow slowly whereas; most malignant tumours grow rapidly sometimes, at
erratic pace. Some benign tumours for example uterine leiomyoma increase in size during
pregnancy due to hormonal effects (estrogen) and regress after menopause. In general, the growth
rate of neoplasms correlate with their level of differentiation and thus, most malignant neoplasms
grow more rapidly than do benign neoplasms. Rapidly growing malignant tumors often contain
central areas of ischemic necrosis because the tumor blood supply, derived from the host, fails to
keep pace with the oxygen needs of the expanding mass of cells.
On occasions, cancers have been observed to decrease in size and even spontaneously disappear.
Examples include renal cell carcinoma, malignant melanoma, choriocarcinoma.
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3. Local invasion
Nearly all benign neoplasms grow as cohesive expansile masses that remains localized to their site
of origin and do not have the capacity to invade or metastasize to distant sites, as do malignant
neoplasms. Rims of fibrous capsules encapsulate most benign neoplasms. Thus, such encapsulations
tend to contain the benign neoplasms as a discrete, well-demarcated and easily movable mass that
can easily surgically enucleated.
Not all benign neoplasms are encapsulated. For example, the leiomyoma of the uterus is discretely
demarcated from the surrounding smooth muscle by a zone of compressed myometrium, but there
is no well-developed capsule. A few benign tumors are neither encapsulated nor discretely defined;
e.g, some vascular benign neoplasms (hemangioma of the dermis). Although encapsulation is the
rule in benign tumors, the lack of a capsule does not imply that a tumor is malignant.
The growth of malignant neoplasms is accompanied by progressive infiltration, invasion and
destruction of the surrounding tissue. Generally, they are poorly demarcated from the surrounding
normal tissue (and a well-defined cleavage plane is lacking).
The infiltrative mode of growth makes it necessary to remove a wide margin of surrounding normal
tissue (safe margin) when surgical excision of a malignant tumor is done. Surgical pathologists
carefully examine the margins of resected tumors to ensure that they are devoid of cancer cells
(clean margins). Next to the development of metastasis, invasiveness is the most reliable feature
that differentiates malignant from benign neoplasms.
Even though, malignant neoplasms can invade all tissues in the body, connective tissues are the
favoured invasive path for most malignant neoplasms, due to the elaboration of some enzymes such
as type IV collagnases & plasmin, which is specific to collagen of basement membrane. Several
matrix-degrading enzymes including glycosidase may be associated with tumour invasion. Arteries
are much more resistant to invasion than are veins and lymphatic channels due to its increased
elastic fibers contents and its thickened wall. Densely compact collagens such as membranous
tendons is also resistant to invasion. Cartilage is probably the most resistant of all tissues to
invasions and this is may be due to the biologic stability and slow turnover of cartilage.
Sequential steps in mechanisms of tumor invasion and metastasis:
1. Carcinoma in-situ
2. Malignant cell surface receptors bind to basement membrane components (e.g., laminin).
3. Malignant cell disrupt and invade basement membrane by releasing collagenase type IV and
other protease.
4. Invasion of the extracellular matrix
5. Detachment
6. Embolization
7. Survival in the circulation
8. Arrest
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Extravasation
Evasion of host defense
Progressive growth
Metastasis
Most carcinomas begin as localized growth confined to the epithelium in which they arise. As long as
these early cancers do not penetrate the basement membrane on which the epithelium rests such
tumour is called carcinoma in-situ. In those situations in which cancers arise from cell that are not
confined by a basement membrane, such as connective tissue cells, lymphoid elements and
hepatocytes, an in-situ stage is not defined.
4. Metastasis
It is defined as a transfer of malignant cells from one site to another not directly connected with it.
Metastasis is the most reliable sign of malignancy. The invasiveness of cancers permits them to
penetrate in to the blood vessel, lymphatic and body cavities providing the opportunity for spread.
Most malignant neoplasms metastasize except few such as gliomas in the central nervous system,
and basal cell carcinoma (Rodent ulcer) in the skin. At the other extreme are osteogenic (bone)
sarcomas, which usually have metastasized to the lungs at the time of initial discovery. Organs least
favoured for metastatic spread include striated muscles and spleen.
Since the pattern of metastasis is unpredictable, no judgment can be made about the possibility of
metastasis from pathologic examination of the primary tumour. Approximately 30% of newly
diagnosed patients with solid tumours (excluding skin cancers other than melanoma) present with
metastasis in the studied populations.
Pathways of spread:
Dissemination of malignant neoplasm may occur through one of the following pathways.
1. Seeding of body cavities and surfaces (transcoelomic spread)
This seeding may occur wherever a malignant neoplasm penetrates into a natural “open field”.
Most often involved is the peritoneal cavity, but any other cavities such as pleural, pericardial, subarachnoid and joint spaces-may be affected.
Particular examples are krukenberg tumour that is a classical example of mucin producing signet
ring adenocarcinomas arising from gastrointestinal tract, pancreas, breast, and gall bladder may
spread to one or both ovaries and the peritoneal cavities.
The other example is pseudomyxoma peritonei which are mucus secreting adrocarcinomas arising
either from ovary or appendix. These carcinomas fill the peritoneal cavity with a gelatinous soft,
translucent neoplastic mass. It can also be associated with primaries in the gallbladder and
pancreas.
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2. Lymphatic spread
It is typical of carcinomas, whereas hematogenous spread is favored by sarcomas. There are
numerous interconnections, however, between the lymphatic and vascular systems, and so all forms
of cancer may disseminate through either or both systems. The pattern of lymph node involvement
follows the natural routes of drainage. Lymph nodes involvement in cancers is in direct proportion
to the number of tumour cell reaching the nodes. Metastasis to lymph nodes first lodge in the
marginal sinus and then extends throughout the node. The cut surface of this enlarged lymph node
usually resembles that of the primary tumour in colour and consistency. The best examples of
lymphatic spread of malignant neoplasm can be exemplified by breast carcinoma.
A "sentinal lymph node" is defined as the first lymph node in a regional lymphatic drainage that
receives lymph from a primary tumor. It can be stained by injection of blue dyes or radiolabelled
material. Biopsy of sentinal lymph nodes allows determination of the extent of spread of tumor, and
can be used to plan treatment. Skip metastasis may occur when local lymph nodes may be bypassed and occasionally found in lymph node distant from the site of the primary malignant
neoplasm. Skip metastasis occurs because of venous lymphatic anastomoses or because
inflammation or radiation has obliterated the lymphatic channels for example abdominal cancer
(gastric cancer) may be initially signaled by supra clavicular (Virchow’s node).
A clinical presence of enlarged lymph node is not necessarily synonymous with a metastasis. The
necrotic products of the neoplasm and tumor antigens often evoke reactive changes in the nodes,
such as enlargement and hyperplasia of the follicles (lymphadenitis) and proliferation of
macrophages in the subcapsular sinuses (sinus histiocytosis). Conversely, the absence of tumour
cells in reseated lymph nodes does not guarantee that there is no underlying cancer.
3. Hematogenous spread
Typical for all sarcomas and certain carcinomas- the spread appears to be selective with seed and
soil phenomenon. Lung & liver are common sites of metastasis because they receive the systemic
and venous out flow respectively. Other major sites of hematogenous spread include brain and
bones.
Certain carcinomas have a propensity to invade veins. Renal cell carcinoma often invades the renal
vein to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of
the heart. Hepatocellular carcinomas often penetrate portal and hepatic venous channels.
In the circulation, tumour cells form emboli by aggregation and by adhering to circulating leukocytes
particularly platelets. The site where tumour cell emboli lodge and produce secondary growth is
influenced by:
1. Vascular (and lymphatic) drainage from the site of the primary tumour.
2. Interaction of tumour cells with organ specific receptors
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3. The microenvironment of the tissue, example a tissue rich in protease inhibitors might be
resistant to penetration by tumour cells.
Anatomic localization of the neoplasm and pathways of venous drainage do not wholly explain the
systemic distributions of metastases. Some tumors show organ tropism or site-specific homing ,
probably due to expression of adhesion receptors whose ligands are expressed by the metastatic
site. For example:
 Prostatic carcinoma preferentially spreads to bone.
 Bronchogenic carcinomas tend to involve the adrenals and the brain
 Conversely, skeletal muscles, although rich in capillaries, are rarely involved by secondary
deposits.
Comparison between benign and malignant tumors:
Benign Tumors
Malignant Tumors
Mode of growth
Expansion , remain localized
Infiltrates locally and metastasizes
Rate of growth
Slower
Faster
Histologic features
Similar to tissue of origin
May differ from tissue of origin
Nuclei are normal
enlarged, pleomorphic, hyperchromatic,
Cells uniform in size and shape
Prominent nucleoli
Increased mitotic activity, abnormal mitosis
Cellular pleomorphism in size and shape
Clinical effects
Local pressure effects
Local pressure and tissue destructive effects
Hormone secretion
Inappropriate hormone secretion/Paraneoplastic syndrome
Cured by adequate excision
Not cured by local excision because of metastasis
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Cancer Epidemiology
The only certain way to avoid cancer is not to be born, to live is to incur the risk.
In USA, one in five deaths is due to cancers. Over the years cancer incidence increased in males while it
slightly decreased in females because of screening procedures (cervical, breast..etc.). In the studied
populations, the most common cancer in males is bronchogenic carcinoma while breast carcinoma in
females. Most cancers in adults occur in those over 55 years of age.Children under 15 years of age
however, are susceptible to acute leukemia, central nervous system tumours, neuroblastoma, Wilm's
tumour, retinoblastoma and rhabdomyosarcoma. Acute leukemias and neoplasms of the central
nervous system accounts for about 60% of the deaths.
Geographic factors (geographic pathology):
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Specific differences in incidence rates of cancers are seen worldwide. For example,
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Stomach carcinoma - Japan
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Lung cancer - USA
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Skin cancer - New zeland & Australia
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Liver cancer - Ethiopia
Environmental factors (occupational hazards) include:
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Asbestos-----Lung cancer, mesothelioma
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Dietary fat and fiber content----- Colon cancer
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Vinyl chloride----Angiosarcoma of liver
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Benzene ---Leukemias
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Cigarette smoking-----Brochogenic carcinomas
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Venereal infection (HPV)--Cervical carcinoma
Premalignant disorders
A) Heredity premalignant disorders
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Inherited predisposition to cancer is categorized in to three groups:
1. Inherited cancer syndromes (autosomal dominant) with strong family history include:
a) Familial retinoblastomas: usually bilateral with a risk of a second cancer particularly osteogenic
sarcoma. A tumor suppressor gene (RB) is the basis for this carcinogenesis
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b) Familial adenomatous polyps of the colon: virtually all cases will develop carcinoma of the colon
by the age of 50.
Tumors within this group often are associated with a specific marker phenotype. There may be
multiple benign tumors in the affected tissue, as occurs in familial polyposis of the colon.
2. Familial cancers.
Evidence of familial clustering of cancer is documented. Examples: breast, ovarian, colonic, and brain
cancers.Features that characterize familial cancers include early age at onset, tumors arising in two or
more close relatives of the index case, and sometimes multiple or bilateral tumors.Familial cancers are
not associated with specific marker phenotypes. The transmission pattern of familial cancers is not clear.
3. Autosomal recessive syndromes of defective DNA repair.
Characterized by chromosomal or DNA instability. One of the best-studied examples is xeroderma
pigmentosum, in which DNA repair is defective.
B) Acquired preneoplastic disorders
1.Regenerative, hyperplasic and dysplastic proliferations are fertile soil for the origin of malignant
neoplasms.
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Endometrial hyperplasia - endometrial carcinoma
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Cervical dysplasia - cervical cancer
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Bronchial dysplasia - bronchogenic carcinoma
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Regenerative nodules - liver cancer
2. Certain non-neoplastic disorders may predispose to cancers.
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Chronic atrophic gastritis - gastric cancer
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Solar keratosis of skin - skin cancer
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Chronic ulcerative colitis - colonic cancer
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Leukoplakia of the oral cavity- squamous cell carcinoma
3. Certain types of benign neoplasms
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Large cumulative experiences indicate that most benign neoplasms do not become malignant.
However, some benign neoplasms can constitute premalignant conditions. For example:
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Villous colonic adenoma - Colonic cancer
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Molecular Basis of Cancer (Carcinogenesis)
Basic principles of carcinogenesis:
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The fundamental principles in carcinogenesis include:
1) Non-lethal genetic damage lies at the heart of carcinogenesis. Such genetic damage (mutation)
may be acquired by the action of environmental agents such as chemicals, radiation or viruses or it
may be inherited in the germ line.
2) The four classes of normal regulatory genes are:
A) The growth promoting proto-oncogenes
Proto-oncogenes: normal cellular genes whose products promote cell proliferation. Activation of
proto-oncogenes gives rise to oncogenes (cancer causing genes). Oncogenes: mutant versions of
proto-oncogenes that function autonomously (promote autonomous cell growth in cancer cells)
without a requirement for normal growth-promoting signals. Examples: RAS, MYC
Proto -oncogenes are activated by:

Point mutation

Chromosomal rearrangements: Translocation, Inversion

Gene amplification
Oncogenes are considered dominant because mutation of a single allele can lead to cellular
transformation.
B) Tumor suppressor genes
Its physiologic role is to regulate cell growth; however, the inactivation of cancer suppressor genes is
the key event in carcinogenesis.
Examples of tumour suppressor genes include: RB, p53, APC and NF-1&2 genes.
Both normal alleles of tumor suppressor genes must be inactivated for transformation to occur
(recessive).
C) Genes that regulate apoptosis
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Genes that prevent or induce programmed cell death are also important variables in the cancer
equation. These genes include:
•
bcl-2 that inhibits apoptosis whereas, others such as bax, bad, and bcl-x5 promote programmed
cell death. Genes that regulate apoptosis may be dominant as are protooncogenes or may
behave as cancer suppressor genes (recessive in nature)
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D) Genes that regulate DNA repair
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Inability to DNA repair can predispose to mutations in the genome and hence, to neoplastic
transformations.
3) Carcinogenesis is a multifactorial process at both the phenotypic and genotypic levels.
Types of carcinogenesis:
A large number of agents cause genetic damages and induce neoplastic transformation of cells. They
fall into the following three categories:
A. Chemical carcinogenesis
B. Radiation carcinogenesis
C. Viral carcinogenesis
A) Chemical carcinogenesis
Hundreds of chemicals have been shown to be carcinogenic.
Steps involved in chemical carcinogenesis
1.
An appropriate dose of a chemical carcinogenic agents to a cell results in the formation of
initiation –promotion sequence. Initiation causes permanent DNA damage (mutation) which is
rapid and irreversible.
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2. However, initiation alone is not sufficient for tumour formation and thus, promoters can induce
tumours in initiated cells, but they are non-tumourogenic by themselves.
3. Furthermore, tumours do not result when a promoting agent is applied before the initiating
agent.
In contrast to the effects of initiators, the cellular changes resulting from the application of promoters
do not affect DNA directly and are reversible.
4. Promoters render cells susceptible to additional mutations by causing cellular proliferation.
Examples of promoters include phorbol ester, hormones, phenols and drugs.
Chemical carcinogenic agents fall into two categories
1. Directly acting compound
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These are ultimate carcinogens and have one property in common:
•
They are highly reactive electrophiles (have electron deficient atoms) that can react with
nucleophilic (electron-rich) sites in the cell. This reaction is non-enzymatic and result in the
formation of covalent adducts (addition products) between the chemical carcinogen and a
nucleotide in DNA.
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Electrophilic reactions may attack several electron-rich sites in the target cells including DNA,
RNA, and proteins.
•
They are important because some of them are cancer chemotherapeutic drugs (e.g., alkylating
agents).
•
They evoke later a second form of cancer, usually leukemia.
2. Indirect acting compounds (or pro-carcinogens)
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Requires metabolic conversion in vivo to produce ultimate carcinogens capable of transforming
cells.
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Most known carcinogens are metabolized by cytochrome p-450 dependent monooxygenase.
•
These chemical carcinogens lead to transformation of cells by causing mutations of oncogenes,
tumor suppressor genes and genes that regulate apoptosis.
Some of the most potent indirect chemical carcinogens:
1. The polycyclic hydrocarbons:
They are formed in the high-temperature combustion of tobacco in cigarette smoking. These products
are implicated in the causation of lung cancer in cigarette smokers.
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Dr. Ban J. Qasim
Polycyclic hydrocarbons may also be produced from animal fats during the process of broiling
meats and are present in smoked meats and fish.
2. The aromatic amines and azo dyes:
β-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily
exposed workers in the aniline dye and rubber industries.
3. Naturally occurring agent:
Aflatoxin B1 is produced by some strains of Aspergillus, a mold that grows on improperly stored
grains and nuts. There is a strong correlation between this contaminant and the incidence of
hepatocellular carcinoma in some parts of Africa and the Far East.
4. Vinyl chloride, arsenic, nickel, chromium, and insecticides are potential carcinogens in the
workplace and about the house.
5.Nitrites used as food preservatives cause nitrosylation of amines contained in the food. The
nitrosoamines that are formed are suspected to be carcinogenic.
B) Radiation carcinogenesis
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Radiant energy whether in form of ultraviolet (UV) sun light or ionizing electromagnetic (X rays
and gamma (δ ) rays) and particulates (α, β, protons and neutrons) radiation can transform and
induce cancer in both humans and experimental animals.
Two types of radiation injuries are recognized:
1) Ultraviolet rays (UV light)
•
UV rays are examples of non-ionizing radiation that cause vibration and rotation of atoms in
biologic molecules.
•
UV rays induce an increased incidence of squamous cell carcinoma, basal cell carcinoma and
possibly malignant melanoma of skin.
•
Risk factors for developing UV rays related disorders depend on:
1. Type of UV rays – UV type B
2. Intensity of exposure
3. Quality of light absorbing protective mantle of melanin in the skin. Ex. Australians in
Queensland.
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UV rays’ effects on cell nucleus are:
1. The carcinogenesis of UV type B rays is attributable to its formation of pyrimidine dimmers in
DNA
2. However, UV rays can also cause inhibition of cell division, inactivation of enzymes, induction of
mutation and sufficient dose kill cells.
3. As with other carcinogens, UVB also cause mutations of oncogenes and tumour suppressor
genes .Mutant forms of p53 and ras genes have been detected.
2) Ionizing radiation
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Ionizing radiations are of short wave length and high frequency which can ionize biologic target
molecules and eject electrons.
•
Electromagnetic and particulate radiations in forms of therapeutic, occupational or atomic
bomb incidents can be carcinogenic.
•
Occupational hazards include:
a)
Many of the pioneers in the development of roentgen rays develop skin cancers.
b) Miners for radioactive elements developed lung cancer.

Therapeutic irradiations have been documented to be carcinogenic:
Thyroid cancer may result from childhood & infancy irradiation (9%), and in adults taken radiation
therapy for spondylitis may lead to acute leukemia year later.

In atomic bonds dropped in Hiroshima and Nagasaki initially principal cancers were acute and
chronic mylogenous leukemias after a latent of about 7 years as well as increased incidence of
solid tumours such as breast, colon, thyroid and lung cancers.
In humans, there is a hierarchy of vulnerability of radiation-induced cancers. Most frequent are the
leukemia except CLL, which almost never follow radiation injury.
Cancer of the thyroid follows closely but only in the young. In intermediate category are cancers of
the breast, lungs, and salivary glands.In contrast, skin, bone and gastrointestinal tract are relatively
resistant to radiation induced neoplasia.
C) Viral and microbial carcinogenesis
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Large groups of DNA and RNA viruses have proved to be oncogenic and there is an association
between infections by the bacterium Helicobacter Pylori and gastric adenocarcinoma and
lymphoma.
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1) DNA oncogenic viruses
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a) Transforming DNA virus forms stable associations with the host cell genome.
•
b) Those viral genes that are transcribed early (early genes, E1-E7) in the viral life cycle are
expressed in the transformed cells.
This group includes:
•
Human Papilloma Virus (HPV)
•
Epstein Barr Virus (EBV)
•
Hepatitis B Virus (HBV)
1.Human Papillomavirus (HPV)
•
Genetically distinct types of HPV have been identified. Low-risk HPVs (1, 2, 4, and 7) cause
benign squamous papillomas (warts) in humans and (6, 11) cause genital warts.
•
High-risk HPVs (e.g., 16 and 18) cause squamous cell carcinoma of the cervix.
•
The oncogenic potential of HPV can be related to products of two early viral genes, E6 and E7
which bind to p53 and RB, respectively, neutralizing their function.
•
E6 and E7 from high-risk HPV have higher affinity for their targets than E6 and E7 from low-risk
HPV.
2. Epstein-Barr Virus
EBV has been implicated in the pathogenesis of:
1) Burkitt lymphomas
2)
Lymphomas in immunosuppressed individuals with HIV infection or organ transplantation
3) Hodgkin lymphoma
4) Nasopharyngeal carcinoma

All except the nasopharyngeal cancers are B-cell tumors.

In immunologically normal individuals either remains asymptomatic or develops infectious
mononucleosis.

In regions of the world where Burkitt lymphoma is endemic (Africa), concomitant (endemic)
malaria or other infections impair immune competence, allowing sustained B-cell proliferation
and eventually development of lymphoma with occurrence of additional mutations such as t(8 ;
14), leading to activation of the MYC gene.
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3. Hepatitis B and Hepatitis C Viruses
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Between 70% and 85% of hepatocellular carcinomas are due to infection with HBV or HCV.
•
The oncogenic effects of HBV and HCV are multifactorial including chronic inflammation,
hepatocellular injury, compensatory hepatocyte regeneration (proliferation), and production of
reactive oxygen species that can damage DNA.
Oncogenic RNA Viruses

Human T-cell leukemia virus-1 (HTLV-1) is the only oncogenic retrovirus in humans. HTLV-1 is
associated T-cell leukemia/lymphoma, endemic in Japan.

HTLV-1 has tropism for CD4+ T cells. Human infection requires transmission of infected T cells
via sexual intercourse, blood products, or breastfeeding. Leukemia develops only in about 3% to
5% of infected individuals after a long latent period of 20 to 50 years.
•
HTLV-1 initially causes polyclonal T cells proliferation. Inactivation of tumor suppressor genes
such as p53 leads to secondary mutations and ultimately, a monoclonal T-cell
leukemia/lymphoma results.
Helicobacter pylori

H. pylori infection has been implicated in both gastric adenocarcinoma and MALT lymphoma.

The mechanism of H. pylori-induced gastric cancers is multifactorial, including chronic
inflammation, gastric cell proliferation, and production of reactive oxygen species that damage
DNA.

H. pylori infection leads to polyclonal B-cell proliferations and that eventually a monoclonal B-
cell tumor (MALT lymphoma) emerges as a result of accumulation of mutations.
Clinical aspects of neoplasia
Although malignant tumors are of course more threatening than benign tumors, any tumor, even a
benign one, may cause morbidity and mortality.
Effects of Tumor on Host
(1) Location and impingement on adjacent structures: Location is crucial in both benign and
malignant tumors. A small (1-cm) pituitary adenoma can compress and destroy the surrounding normal
gland and give rise to hypopituitarism. A small carcinoma within the common bile duct may induce fatal
biliary tract obstruction.
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2) Functional activity such as hormone synthesis or the development of paraneoplastic syndromes:
Hormone production is seen with benign and malignant neoplasms arising in endocrine glands.
Adenomas and carcinomas of the adrenal cortex elaborate aldosterone. Such hormonal activity is more
likely with a well-differentiated benign tumor than with carcinoma.
Paraneoplastic Syndromes: are symptom complexes that occur in patients with cancer caused by
ectopic production of hormones or hormone -like substances not indigenous to the tissue of origin .They
occur in 10% to 15% of patients with cancer, and are important to recognize for several reasons:
1. They may represent the earliest manifestation of an occult neoplasm.
2. They may cause significant clinical problems and may be lethal.
3. They may mimic metastatic disease and affect treatment.
•
The paraneoplastic syndromes are diverse and are associated with many different tumors most
often lung and breast cancers and hematologic malignancies.
The most common syndromes are:
A) Hypercalcemia in cancer patients is multifactorial, but the most important mechanism is the
synthesis of a parathyroid hormone-related protein (PTHrP) by tumor cells as in squamous cell
carcinoma of lung .Hypercalcemia resulting from skeletal metastases is not a paraneoplastic
syndrome.
B) Cushing syndrome is usually related to ectopic production of ACTH or ACTH-like polypeptides by
cancer cells, as occurs in small-cell cancers of the lung.
C) Hypercoagulability leading to migratory thrombophlebitis (Trousseau syndrome) as in
pancreatic carcinoma and nonbacterial thrombotic endocarditis in advanced cancers.
D) Clubbing of the fingers and hypertrophic osteoarthropathy in patients with lung carcinomas.
Sometimes one tumor induces several syndromes concurrently. For example, bronchogenic
carcinomas may elaborate ACTH, antidiuretic hormone, parathyroid hormone and other bioactive
substances.
(3) Bleeding and infections: when the tumor ulcerates through adjacent surfaces.
(4) Benign or malignant neoplasms that protrude into the gut lumen may cause intussusception and
intestinal obstruction or infarction.
(5) Cancer Cachexia: Many cancer patients suffer progressive loss of body fat and lean body mass,
profound weakness, anorexia, and anemia, referred to as cachexia (wasting). There is some
correlation between the size and extent of spread of the cancer and the severity of the cachexia.
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Dr. Ban J. Qasim
The basis of metabolic abnormalities is not fully understood; however, Tumor Necrosis Factor
(TNF) produced by macrophages and possibly by some tumour cells is the cause of the wasting
that accompanies cancer rather than reduced food intake.
Grading and Staging of Cancer
•
Grading and staging of cancer are necessary for making accurate prognosis and treatment
protocols. For instance, the results of treating extremely small, highly differentiated thyroid
adenocarcinomas that are localized to the thyroid gland are likely to be different from those
obtained from treating highly anaplastic thyroid cancers that have invaded the neck organs.
•
The grading of a cancer is the estimate of its aggressiveness or level of malignancy based on the
cytologic differentiation of tumor cells and the number of mitoses within the tumor.
•
Grading is based on the idea that behavior and differentiation are related, with poorly
differentiated tumors having more aggressive behavior. The cancer may be classified as grade I,
II, III, or IV, in order of increasing anaplasia (well-differentiated, moderately differentiated,
poorly differentiated and undifferentiated or anaplastic).
•
Criteria for the individual grades vary with each form of neoplasia. In some instances to
descriptive characterizations are added (e.g., "well-differentiated adenocarcinoma with no
evidence of vascular or lymphatic invasion" or "highly anaplastic sarcoma with extensive
vascular invasion").
•
Staging of cancers is based on the size of the primary lesion, its extent of spread to regional
lymph nodes, and the presence or absence of metastases. This assessment is usually based on
clinical and radiographic examination (computed tomography (CT) and magnetic resonance
imaging (MRI))and in some cases surgical exploration. Staging has proved to be of greater
clinical value than grading.
•
Two methods of staging are currently in use:
1) TNM system (T, primary tumor; N, regional lymph node involvement; M, metastases)
In the TNM system, T1, T2, T3, and T4 describe the increasing size of the primary lesion; N0, N1, N2,
and N3 indicate progressively advancing node involvement; and M0 and M1 reflect the absence or
presence of distant metastases.
2) AJC (American Joint Committee) system: the cancers are divided into stages 0 to IV,
incorporating the size of primary lesions and the presence of nodal spread and of distant metastases.
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Laboratory Diagnosis of Cancer
1) Morphologic Methods
•
Clinical data are so valuable for optimal pathologic diagnosis. The specimen must be adequate,
representative, and properly preserved.
•
Several sampling approaches are available, including :
A) Excisional or incisional biopsy : When excision of a lesion is not possible as in a large mass, incisional
biopsy is taken by selection of an appropriate site avoiding the non- representative margins and the
necrotic center.
B) Frozen-section: This method, in which a sample is quick-frozen and sectioned, permits histologic
evaluation within minutes .It is useful in determining the nature of a lesion or in evaluating the regional
lymph nodes in a patient with cancer for metastasis.
C) Fine-needle aspiration cytology (FNA) : It involves aspiration of cells from a mass, followed by
cytologic examination of the smear. It is used most commonly with palpable lesions affecting the breast,
thyroid and lymph nodes. In deeper structures, such as the liver, it can be performed with imaging
techniques guidance.
D) Cytologic (Papanicolaou) smears: This approach is widely used for the discovery of carcinomas of
the cervix, lung and bladder; and for the identification of tumor cells in abdominal, pleural and
cerebrospinal fluids. Neoplastic cells are less cohesive than others and so are shed into fluids or
secretions. The shed cells are evaluated for features of malignancy.
2) Immunocytochemistry: is a powerful adjunct to routine histology, by detection of antigen using
specific monoclonal antibodies. It is useful in the differential diagnosis between undifferentiated
carcinoma and large-cell lymphoma by detection of cytokeratin. Also detection of estrogen receptors in
breast cancers indicates good prognosis and response to hormonal therapy.
3) Flow cytometry: is used routinely in the classification of leukemias and lymphomas. In this method,
fluorescent antibodies against differentiation antigens (CD markers) are used to obtain the phenotype of
malignant cells (B-cell or T-Cell).
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4) Tumor Markers: Biochemical assays for tumor markers in the blood is not used for the definitive
diagnosis of cancer; however, they assist in the diagnosis and are useful in determining the effectiveness
of therapy or the appearance of a recurrence. The most commonly used tumor markers are:
A) Prostatic specific antigen (PSA): it is one of the most used and most successful tumor markers in
clinical practice. Prostatic carcinoma can be suspected when elevated levels of PSA are found in the
blood. However, PSA test has low specificity and low sensitivity because PSA levels also may be elevated
in benign prostatic hyperplasia and there is no PSA level that ensures that a patient does not have
prostate cancer.
B) Carcinoembryonic antigen (CEA) and α-fetoprotein are oncofetal antigens or embryonic antigens.
They are expressed during embryogenesis but not in normal adult tissues.
Carcinoembryonic antigen (CEA) is elaborated by carcinomas of the colon, pancreas, and stomach.
Α-fetoprotein, which is produced by hepatocellular carcinoma, yolk sac tumor, and teratoma.
Unfortunately, like PSA, CEA and α-fetoprotein assays lack both specificity and sensitivity required
for the early detection of cancers. They can be produced by a variety of non-neoplastic conditions as
well. They are still particularly useful in the detection of recurrences after excision. With successful
resection of the tumor, these markers disappear from the serum; their reappearance almost always
signifies the beginning of the end.
Molecular Diagnosis
Molecular techniques are used for the diagnosis of tumors and for predicting their behavior.
1) Diagnosis of malignancy: polymerase chain reaction (PCR) is used for the detection of T-cell receptor
or immunoglobulin genes and this allows distinction between monoclonal (neoplastic) and polyclonal
(reactive) proliferations.
2)Prognosis and behavior. Certain genetic alterations are associated with a poor prognosis, and
determines the patient's subsequent therapy. Example amplification of oncogene HER-2/NEU in breast
cancers which can be detected by fluorescence in situ hybridization (FISH) and PCR methods.
3) Detection of minimal residual disease: For example, detection of BCR-ABL fusion gene by PCR gives a
measure of residual disease, in patients treated for chronic myeloid leukemia.
4) Diagnosis of hereditary predisposition to cancer: Detection of germ-line mutation of tumor
suppressor genes, such as BRCA1 may useful in screening for patients at risk of developing breast
cancers and to consider prophylactic surgery .
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