Neoplasia:

1. Definition:
 Neoplasia means “new growth”
 Neoplasm means “tumor/cancer”
 Cancer is generally defined as a malignant process of autonomus unregulated cells
proliferation with the ability to spread (metastasized) to distant sites.
 Cancer is a second leading cause of death in United States.
 Cancer is not said to be a disease but rather many disorders that share a profund growth
dysregulation.
 Some cancers such as Hodgkin Lymphoma are highly curable, whereas others such as
cancer of pancreas are virtually always fatal.
a) Cancer due to Genetic Mutation:
 It is a genetic disorder.
 Most pathogenic mutation are either induced by exposure of mutagens or occur as part of
aging.
 Cancer frequently show epigenetic changes, such as focal increase in DNA methylation
and alteration in histone modification.
 These genetic and epigenetic changes alter the expression and function of key genes that
regulate fundamental genetic process such as growth, survival and senescence.
b) Darwinian Selection:
 Genetic alteration in cancer cells are heritable i.e; being passed to daughter cell during
cell devision i.e; in result to Darwinian selection (survival of the fittest).
 Cells bearing mutation provide growth and survival advantage outcomplete their
neighbor and thus come to dominate the population initially these are conferred over
single cell and as a result all tumors are clonal.
 Here, Darwinian selection continuous to evolution of subclonal with more aggressive
properties and result to progression ( spread or onward movement of subclonal).

c) Hallmarks:
 The mutation and epigenetic alteration impart to cancer cell as set of properties that refer
to collectively as cancer hallmarks.
 These properties produce cellular phenotype that dictate natural history of cancer cell as
well as response to various therapies.
d) Tumor:
 Study of tumor is called oncology.
 It may be benign or malignant.
e) Benign:
 Benign neoplasm is mass of slow growing localized tumor.
 These do not invade surrounding tissues or cells or in other words spread to various site
is absent in these.
 Some kind of benign neoplasm is:
 Fibroma (fibrious tissue)
 Lipoma (under skin)
 Hemangioma ( blood vessels)
 These are removed by local surgical operate.
 These cells lack appropriate growth pattern.
f) Malignant:
 Malignant tumors are cancerous.
 These cells can grow and spread to other part of body.
 These are life threatening cases.
 These cancer cells grow very quickly and invade other cells.
 All this process is called metastasis.
 Theses involve some kind of malignant tumor are.
 Carcinoma(stomach, pancreases and lungs)
 Sarcoma (bone marrow)
 Germ-cells tumors (ovaries and testis)
 Blastoma (embryonic cells)
 Both malignant and benign tumors have two basic components i.e
 Parenchyma, made up of transformed or neoplastic cells.
 Non-neoplastic storma, made up of connective tissue, blood vessels and host derived
inflammatory cells
g) Mixed Tumor:
 Transformed cells in neoplasm whether benign or malignant resemble each other
consistant with their origin from a single transformed progenitor cell.
 In some unusual instances, tumor cells undergo dirgent differentiation creating so called
mixed tumor.
 Mixed tumor are monoclonal but progenitor cell have capability to differentiate down to
more than one clinge.
 Some examples are:
 Pleomorphic adenoma ( salivary glands)
 Fibroadenoma ( female breast)
 Teratpoma ( germ cell layer)

2. Anaplasia:
 Drived from Greek word which means “backward formation”
 Condition of cells with poor cellular differentiation, losing morphogical characteristics or in
other words we can say that these cells may 3 times bigger than nearby cells.

a) Feartures:
 Anaplastic cells often display the following morphologic features:
 Pleomorphism (i.e., variation in size and shape)
 Nuclear abnormalities, consisting of extreme hyperchromatism (dark-staining), variation in
nuclear size and shape, or unusually prominent single or multiple nucleoli. Enlargement of
nuclei may result in an increased nuclear-to-cytoplasmic ratio that approaches 1 :1 instead of
the normal 1: 4 or 1 : 6. Nucleoli may attain astounding sizes, sometimes approaching the
diameter of normal lymphocytes.
 Tumor giant cells may be formed. These are considerably larger than neighboring cells and may
possess either one enormous nucleus or several nuclei.
 Atypical mitoses, which may be numerous. Anarchic multiple spindles may produce tripolar or
quadripolar mitotic figures .
 Loss of polarity, such that anaplastic cells lack recognizable patterns of orientation to one
another. Such cells may grow in sheets, with total loss of communal structures, such as glands
or stratified squamous architecture.
3. Dysplasia:
 Literally means “disordered growth”.
 Encountered principally in epithelium
 When changes involve whole epithelium without spread to dermis – carcinoma in situ.
4. Local Invasion:
 Benign tumors are surrounded by a capsule, malignant tumors do not have capsule.
 That means malignant tumors invade the surrounding tissue

5. Metastasis:
 Pathogenic process in which larger cancer cells break and move to different parts of body
and leads to malignant tumors and also as by define benign neoplasm do not perform
metastasis.
6. Epidemiology:
 Epidemiology is the curing section and branch of science where incidence, disturbance, and
possible central of disease and other factors relating to health.
a) Environmental Factors:
 Environmental exposure appears to be dominant risk factor for many common cancer.
 Suggesting that a high fraction of cancer are potentially preventable like diet, smoking, and
alcohol consumption.
b) Cancer Incidence:
  Is a count among the raising cause of cancer and the death rate of patients due to
cancer.
c) Aging Factor:
 Frequency of cancer increase with age.
 Mostly death occur with the age of 55 and 75.
 This cancerous increase is the result of weakness in immunity and accumulation of
somatic mutation that drive emergency of malignant neoplasm.
 The cancerous rate of death is 10% which include lymphomas, soft tissue, and bone
sarcomere.
d) Acquired Predisposing Condition:
 It involves chronic inflammation, immunodeficiency states and precursor lesion.
 These create fertile soil for the development of malignant tumor.
 “Precursor Lesions” are localized disturbance of epithelial differentiation that are
associated with an elevated risk for developing carcinoma.
 These lesions include following:
 Squamous metaplasia and dysplasia of bronchial mucosa.
 Endometrial hyperplasia
 Leukoplakia of oral cavity
 Villous adenoma of colon
7. Cancer Gene:
 Genes that increase risk of cancer is genetic disease tumor cells differ from their normal
progenitors by genetic alteration that effect growth regulating gene.
 These exist in 2 classes:
 Oncogenes which function as positive growth regulator.
 Tumor Suppressor Gene which function as negative gene growth regulator.
a) Oncogenes:
 These have potential to cause cancer and are often mutated or expressed at high levels.
 This in case cause normal cells to undergo programmed cell death which result in critical
function alteration and malfunctioning.
b) Tumor Suppressor Gene:
 These are the cells that cause uncontrolled growth and enhance transformed phenotype
to develop normal alleles of tumor suppressor gene.
 8. Genetic Lesion In Cancer:
 The genetic changes that found in cancer vary from point mutation involving single
nucleotide to abnormalities large enough to produce gross changes in chromosomes
structure.
 These are classified as follow:
a) Driver Mutation:
 Mutation that alter function of cancer gene that directly contribute to development
or progression of given cancer.
b) Passenger Mutations:
 It greatly outnumber the driver mutations and are random and sprinkled throughout
the genome.
c) Point Mutation:
 It can either activate or inactivate protein product of affected gene depending upon
their precise position and consequences.
 A cardinal example is point mutation that convert RAS gene to cancer gene.
d) Gene Rearrangement:
 May be produced by chromosomal translocation and inversion.
 The translocation and inversion is associated with certain malignancies, particularly
neoplasm derived from hematopoietic cells and other kinds of mesenchymal cells.
e) Aneuploidy:
 It is defined as number of chromosomes that is not multiple of haploid state and not
a multiple of 23.
 It is remarkably common in cancer.
 In this human all have 45 or 47 chromosomes instead of 46.
f) MicroRNA and Cancer:
 These are endogenous, small non-coding RNAs that function in regulation of gene
expression.
 This influences numerous cancer relevant processes such as proliferation, cell cycle
and apoptosis.

Hallmarks of Cancer:
 All cancer displays 8 fundamental changes in cell physiology, which are considered the hallmarks
of cancer.
 These changes are as follow;
 Self-sufficiency in growth signals
 Insensitivity to growth-inhibitory signals
  Altered cellular metabolism
 Evasion of apoptosis
 Limitless replicative potential ( immortality)
 Sustained angiogenesis
 Invasion and metastasis
 Evasion of immune surveillance
1. Self-sufficiency in Growth Signals:
 Many cancer cells acquired growth self-sufficiency by acquiring the ability to synthesize the
same growth factor to which they are responsive.
 Growth factor genes are over expressed to stimulate large section of GFs which stimulate cell
proliferation. E.g; many glioblastomas secrete PDGF and express the PDGF receptors and many
sarcomas make both TGF-a and its receptor interaction with stroma.
 Over expression of growth factor receptor can render cancer cells hyperresponsive to level of
the growth factor that would not normally trigger proliferation or mutation of growth factor
receptor e.g; epidermal growth factor (EGF) receptor family in squamous cell carcinomas of the
lung.
 ERBB1 the EGF receptor, is over expressed in 80% of squamous cell carcinoma of the lung, 50%
or more of glioblastomas and 80-100% of epithelial tumors of the head and neck.
 Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the absence of
the growth factor in the environment.
 Mutation in gene that encode various components of the signaling pathway downstream of
growth factor receptor.
 E.g; RAS protein:
RAS protein is the most commonly mutated proto-oncogene in human tumors. It’s a G protein
that relays a growth signal from growth factor receptor to a cascade of protein kinases. Many
RAS oncogene have a point mutation that leads to hyperactive version of RAS protein that can
issue signals on its own resulting in excessive cell division.
 ABL proto-oncogene tyrosin kinase activity that is dampened by internal negative regulatory
domains.
2. Insensitivity to Growth Inhibitory Signals:
 The mutation of normal growth suppressor anti-oncogene results in removal of the brakes for
growth; thus the inhibitory effect to growth cells is removed and the abnormal continues
unchecked.
 Oncogenes encode proteins that promote cell growth, the product of tumor suppressor genes
apply brakes to cell proliferation.
 Disruption of such genes renders cells refractory to growth inhibition and mimics the growth
promoting effects of oncogenes.
3. Evasion of cell Death:
 Apoptosis in normal cell is guided by cell death receptor, CD95, and other gene regulating
apoptosis and cancer pro-apoptotic factors ( BAD, BAX, p53) and apoptosis inhibitors ( BCL2,
BCL-X).
 In cancer cells, the function of apoptosis is interfered due to mutations in the above gene
which regulates apoptosis in the normal cells.
 Example; BCL2 gene mutation removes the apoptosis inhibitory control on cancer cells, thus
more live cells undergoing mitosis contributing to tumor growth e.g; in B-lymphoma. It is
also seen in many other human cancer such as that of breast, thyroid and prostate.
 MYC oncogene and p53 tumor suppressor gene also connected to apoptosis. While MYC
allows cell growth BCL2 inhibits cell death; thus MYC and BCL2 together allows cell
proliferation. Normally, p53 activates proapoptotic gene BAX but mutated p53 (I.e; absence
of p53) reduces apoptotic activity and thus allows cell proliferation.
 CD95 receptors are depleted in hepatocellular carcinoma and hence the tumor cells escape
apoptosis.
4. Limitless Replicative Potential:
 Cancer cells is most malignancies have markedly upregulated telomerase enzyme, and
hence telomerase length is maintained. Thus , cancer cells avoid aging, mitosis does not
slow down or cease, thereby immortalizing the cancer cells. In immortalized cancer cells ,
telomerase is usually reactivated and telomerase length is stabilized, allowing the cells to
proliferate indefinitely.
 In normal cells, which lack expression of telomerase, the shortened telomerase generated
by cell division eventually activate cell cycle checkpoints, leading to senescence and
placing a limit on the number of divisions a cell may undergo.
 In cells that have disable checkpoints, DNA repair pathways are inappropriately activated
by shortened telomerase, leading to massive chromosomal instability and mitotic crisis.
 Tumor cells reactive telomerase, thus staving off mitotic catastrophe and achieving
immortality.
5. Development of Sustained Angiogenesis:
 Cancer cells (and large benign tumors) can stimulate neoangiogenesis during which new vessels
sprout from previously existing capillaries or in some cases, vassculogenesis in which endothelial
cells are recruited from the bone marrow.
 Neovascularisation supplies needed nutrients and oxygen and newly formed endothelial cells
stimulate the growth of adjacent tumor cells by secreting growth factors such as insulin like
growth factor, PDGF and granulocytes macrophages colony-stimulating factors.
 Promoters of tumor angiogenesis – VEGF ( released from genes in the paerenchymal tumor
cells)and basic fibroblast growth factors (bFGF).
 Anti-angiogenesis factors inhibiting angiogenesis include thrombospondin-1 ( also produced by
tumor cells themselves), angiostatin, endostatin and vasculoststin. Mutated form of p53 gene in
both alleles in various cancers results in removal of anti-angiogenic role of thrombospondin-1
thus favouring continued angiogenesis.
6. Ability to Invade and Metastasize:
 Invasion-metastasis cascade, which include local invasion, intravasation into blood and
lymph vessels, transit through the vasculature, extravasation from the vessels, formation of
micrometastases, and growth of micrometastastases into macroscopic tumors.
a) Invasion of Extracellular Matrix:
 ECM is made of collagen, glycoprotein and involves the basement membrane and the
interstitial connecting tissue.
 Tumor cells must first penetrate the bm and then the interstitial connective tissue in the
following sequence
 Detachment of tumor cells from each other – cells are adhered to each other by adhesion
molecules like E-cadherins. These are down regulated and the cells become loose.
 Attachment to matrix components – tumor cells binds to laminin and fibronrctin through
receptors.
 Degradation of ECM – tumors cells secrete proteolytic enzymes that degrade the matrix and
create passage ways.
 Migration of tumor cells
b) Vascular Dissemination and Homing:
 Tumors cells from emboli in circulation by aggregation and by adhering to lymphoid cells and
platelets.
 These tumors emboli adhere to the endothelium, then extravagate and form a metastatic
deposit.
7. Reprogramming Energy Metabolism:
 Cancer cells shift their glucose metabolism away from the oxygen- hungry but efficient
mitochondria to glycolysis. This phenomenon is called the Warburg effect and also known as
aerobic glycolysis. E.g; Burkitt lymphoma.
 Oncogenes and tumors suppressor that favour cell growth, such as TP53, PTEN and Akt( an
intermediary in RAS signaling) stimulate glucose uptake by affecting glucose transporter
proteins and favour aerobic glycolysis.
 Tumor cells that adapt this altered metabolism are able to divide more rapidly and outpace
competing tumor cells that do not.
8. Evasion of Immune Surveillance:
 Tumor cells can be recognized by the immune system as non-self and destroyed.
  Antitumor activity is mediated by predominantly cell- mediated mechanisms. Tumor antiges
are presented on the cells surface by MHC class I molecules and are recognized by CD8+
CTLs.
 The different classes of tumor antigens include product of mutated gene, overexpressed or
aberrantly expressed proteins, and tumor antigens produced by oncogenic viruses.
 Immunosuppressed patient have an increased risk for the development of cancer,
particularly types caused by oncogenic DNA viruses.
 In immunocompetent patients, tumors may avoid the immune system by several
mechanisms including selective outgrowth of antigen-negative variants, loss or reduced
expression of histocompatibility molecules, and immunosuppression mediated by the
expression of certain factors (e.g.; TGF-beta, PD-1ligands) by tumor cells.
 Antibodies that overcome some of these mechanisms of immune evasion are now
approved for the treatment of patients with advanced forms of cancer.

Genomic instability as an enabler of malignancy:

 Individuals with inherited mutations of gene involved in DNA repair systems are at greatly
increased risk for the development of cancer.
 Patients with HNPCC syndromes have defects in the mismatch repair system, leading to
development of carcinomas of the colon. These patients genomes show microsatellite instability
 , characterized by changes in length of short tandem repeating sequence throughout the
genome.
 Patients with xeroderma pigmentosum have a defect in the nucleotide excision repair pathway.
They are at increased risk for the development of skin cancer in sites exposed to sunlight
because of an inability to repair pyrimidine dimmers induced by UV light.
 Syndrome involving defects in the homologous recombination DNA repair system constitute a
group disorders – bloom syndrome, ataxia- telangiectasia, and Fanconi anemia – that are
characterized by hypersensitivity to DNA damaging agents, such as ionizing radiations. BRCA1
and BRCA2 which are mutated in familial breast cancers, also are involved in homologous DNA
repair.
 Mutations incurred in lymphocytes expressing gene products that induce genomic instability
( RAG1, RAG2, AID) are important in the pathogenesis of lymphoid neoplasm.

Carcinogenic Agents:
These agents are classified as:

1. Chemical
2. Radiant Energy
3. Microbial Products

Chemical Carcinogens:

Certain chemicals, including benzene, beryllium, asbestors, vinyl chloride and arsenic are
known as carcinogens.They have been found to cause cancer in human.
1. Direct Acti ng Agents:

 Require no metabolic conversion to become carcinogenic.

 Most are weak carcinogens but some are important because they are cancer chemotherapeutic
drugs (e.g; alkylating agents) used in regimens that may cure certain types of cancer (e.g;
Hodgkin lymphoma).
 The associated risk for induced cancer is low, but its existence dictates judicious use of such
agents.

2. Indirect Acti ng Agents:

 Chemicals that requires metabolic conversion to become active carcinogens (ultimate

carcinogen).
 Some of the most potent indirect chemical carcinogens are polycyclic hydrocarbons (present in
fossil fules). E.g; benzo[a]pyrene formed during the combustion of tobacco are implicated in
the causation of lung cancer.
 Most of the known carcinogens are metabolized by cytochrome P-450 dependent mono-
oxygenases.
 The genes that encode these enzymes are polymorphic, and the activity and inducibility of these
enzymes vary significantly among individuals.
 Because these enzymes are essential for the activation of procarcinogens, the susceptibility to
the carcinogenesis is related in part to the particular polymorphic variants that an individual
inherits.
 Thus, it may be possible to assess cancer risk in a given individual by genetic analysis of such
enzyme polymorphisms.

3. Mechanism of Action Of Chemical Carcinogens:

 Because malignant transformation results from maturations, most chemical initiating agents
target DNA and are mutagenic.
 There is no single or unique alteration associated with cancer initiation nor there is any
apparent predisposition for initiator to cause mutation in particular genes.
 Presumably, mutations occur throughout the genome and cells that by chance suffer damage to
the “usual suspects”, oncogenes and tumor suppressors such as RAS and TP53, gain a potential
selective advantage and are risk for subsequent transformation.
 This is not to say that mutations induced by carcinogens occur in an entirely random fashion.
 Because of their chemical structures, some carcinogens interact preferentially with particular
DNA sequences or bases and thus produce mutations that are clustered at “hotspots” or that
are enriched for particular base substitutions.

4. Promoti on of Chemical Carcinogenesis :

 Promoters are chemical agents that are not mutagenic, but which stimulate cell proliferation.
 In tissues that are normally quiescent, such as the liver, the mitogenic stimulus may be provided
by the initiating agent. This occurs if the carcinogenic initiator is toxic and kills a large number of
cells, thereby stimulating regeneration of the surviving cells.
 Application of promoters leads to proliferation and clonal expansion of initiated (mutated) cells.
 Radiation Carcinogens:
 Radiant energy in the form of the UV rays of sunlight, radiographs, nuclear fission, radionuclides
is carcinogen.
 Unprotected miners of radioactive elements have a 10-folds increased incidence of lung cancer.

1. Ionizing Radiati on:

 The oncogenic properties of ionizing radiation are related to its mutagenic effects; it cause
chromosome breakage, chromosomal rearrangement such as translocation and inversions, and
less frequently point mutation.
 Biologically, double stranded DNA breaks seem to be the most important form of DNA damage
caused by radiation.

2. UV Sunlight:
  Exposure to UV rays derived from the sun, particularly in fair-skinned individuals, is associated
with an increased incidence of squamous cells carcinoma, basal cell carcinoma, and melanoma
of the skin.
 The degree of risk depends on the type of UV rays, the intensity of exposure, and the quantity of
the light absorbing “protective mantle” of melanin in the skin.
 UV light has several biological effects on cells.
 Of particular relevance to carcinogenesis is the ability to damage DNA by forming pyrimidine
dimmers.
 This type of DNA damage is repaired by the nucleotide excision repair pathway.
 With extensive exposure to UV light, the repair system may be overwhelmed and skin cancer
results.

Microbial Carcinogens:
 Only few viruses have been linked with human cancer.

1. Oncogenic RNA Virses:

 Only one human retrovirus, human T-cell leukemia virus type-1 (HTLV-1) is firmly implicated in
the pathogenesis of cancer in humans.
 HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL)
 Similar to the human immunodeficiency virus, which cause AIDS, HTLV-1 has tropism for CD4+T
cells, and hence this subset of T cells is the major target for neoplastic transformation.
 Human infection requires transmission of infected T cell via sexual intercourse, blood products,
or breastfeeding.
 HTLV-1 genome contains the gag, pol, env and longterminal-repeat regions typical of all
retroviruses, but in contrast to other leukemia viruses,it contains another gene referred to as
tax.
 Several aspects of HTLV-1 is transforming activity are attributable to Tax, the protein product of
this gene.
 Tax contributes to the acquisition of several cancer hallmarks in the following ways:

a) Increased Pro-growth Signaling and Cell Survival:

 Tax interacts with P13K and thereby stimulates AKT (protein Kinase B) these kinases participate
in the cascade that promotes both cell survival and metabolic alterations that enhance cell
growth.
 Tax also directly up regulates the expression of cyclin D2 and represses the expression of
multiple CDK inhibitors, changes that promote cell cycle progression.
 Finally, Tax can activate the transcription factor NF-KB, which promotes the survival of many cell
types, including lymphocytes.

b) Increased Genomic Instability:

 By interfering with DNA-repair functions and inhibiting cell cycle checkpoints activated by DNA
damage.

2. Oncogenic DNA Viruses:

Five DNA viruses- HPV, Epstein-Barr (EBV), Kaposi sarcoma herpesviruse (KSHP, also called
human herpesirus-8 [HHV-8]), a polyoma virus called Merkel cell virus, and hepatitis B virus
(HBV)- have been implicated in the causation of human cancer.

3. Human Papillomavirus:

 Sources of genetically distinct types of HPV have been identified.

 Some types (e.g; 1,2 ,4 and 7) cause benign squamous papillomas (warts) in human.
 In contrast, high-risk HPVs (e.g; types 16 and 18) cause several cancers, particularly squamous
cell carcinoma of the cervix and anogenital region, particularly tumors arising in the tonsil
mucosa.

a) Oncogenic Acti vity of E6:

 The E6 protein binds to and mediate the degradation of p53 and also stimulates the expression
of TERT, the catalytic subunits of telomerase, which you will recall contributes to the
immortalization of cells.
 E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types.

b) Oncogenic Acti vity of E7:

 The E7 proteins has effect that complement those of E6, all of which are centered on speeding
cells through the G1-S cell cycle checkpoints.
 It binds to the RB protein and displaces the E2F transcription factors that are normally
sequested by RB, promoting progression through the cell cycle.
 As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB
than do E7 proteins from low-risk HPV types.
 E7 also inactivates the CDK inhibitors p21 and p27.Finally, E7 proteins from high- risk HPVs (type
16, 18, and 31) also binds and presumably activates cyclin E and A.

4. Epstein- Barr Virus:

 EBV, a member of the herpesvirus family, was the first virus linked to a human tumors, Burkitt
Lymphoma.
a. Burkitt Lymphoma
b. B-cells lymphomas in immunosuppressed individuals (particularly in those with HIV infection
or undergoing immunosuppressive therapy after organ or bone marrow transplantation).
c. A subset of Hodgkin Lymphoma.
d. Nasopharyngeal and some gastric carcinomas etc.
 EBV infects B lymphocytes and possibly epithelial cells of the oropharynx.
 The virus uses the complement receptor CD21 to attach to and infect B cells.
 The infection of B cells is latent.
 One EVB gene, latent membrane protein-1 (LMP-1) acts as oncongene.
 LMP-1 behaves like a constitutively active CD40 receptor, a key recipient of helper T-cells signals
that stimulates B-cell growth.
 LMP-1 activates the NF-KB and JAK/STAT signaling pathways and promotes B-cells survival and
proliferation, all of which occurs autonomously (i.e; without T- cells or other outside signaling)
in EBV –infected B-cells.
 Concurrently, LMP-1 prevents apoptosis by activating BCL2.
 In addition, the EBV genome contains a gene encoding a viral cytokine, Vil-10. This viral cytokine
can prevent macrophages and monocytes from activating T cells and is required for EBV-
dependent transformation of Bcells.
 In nonendmic areas, 80% of tumors are unrelated to EBV, but virtually all endemic and sporadic
tumors possess the (8;14) or other translocations that dysregulate MYC.
 Thus, although sporadic Burkitt lymphomas are triggered by mechanisms other than EBV, they
appear to develop through similar oncogenic pathways.
 In summary, in the case of Burkitt lymphoma, it seems that EBV is not directly oncongenic but
by acting as a polyclonal B-cells mitogens, it sets the stage for the acquisition of the (8;14)
translocation and other mutations that ultimately produce a full blown cancer.
 The role played by EBV is more direct in EBV-positive B-cell lymphoma in immunosuppressed
patients.

a) Nasopharyngeal Carcinoma:

 It is also associated with EBV infection. This tumor is endemic in southern China, in some parts
of Africa and in the Inuit population of the Arctic.
 In contrast to Burkitt lymphoma, 100% of nasopharyngeal carcinoma obtained from all parts of
the world contain EBV.
 The structure of all viral genome is identical (clonal) in all of the tumor cells within individuals
tumors, excluding the possibility that EBV infection occurred after tumor development.
 The uniform association of EBV with nasopharyngeal carcinoma suggests that EBV has a central
role in the genesis of tumor.
 But ( as with Burkitt lymphoma) the restricted geographic distribution indicates that genetic or
environmental cofactors, or both also contributes to tumor development.
  Unlike Burkitt lymphoma, LMP-1 is expressed in nasopharyngeal carcinoma cells and as in B
cells, activates the NF-KB pathway. NF-KB in turn upregulates the expression of factors such as
VEGF, FGF-2, MMP9, and COX2 that may contribute to oncogenesis.

5. Hepatitis B and Hepatitis C Viruses:

• Between 70% and 85% of hepatocellular carcinomas worldwide are due to infection with HBV or
HCV.
• The oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be
immunologically mediated chronic inflammation, with hepatocellular injury,stimulation of
hepatocyte proliferation, and production of reactive oxygen species that can damage DNA.
• The HBx protein of HBV and the HCV core protein can activate a variety of signal transduction
pathways that also may contribute to carcinogenesis.

6. 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 immunologically
mediated chronic inflammation,stimulation of gastric cell proliferation, and production of
reactive oxygen species that damage DNA. H. pylori pathogenicity genes,such as CagA, also may
contribute by stimulating growth factor pathways.
• It is thought that 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, malaginant tumors are of course more threatening than benign tumor, morbidity and
mortality may be associated with any tumor, even a benign one.
 Both tumors cause problems because of:
 Location and impingement on adjacemt structures
 Functional activity such as hormones synthesis, or the development of paraneoplastic
syndromes
 Bleeding and infarctions when the tumor ulcerates through adjacent surfaces
 Symptoms that result from rupture or infarction
  Cachexia or wasting
1. Effects of Tumor on Host:
 Location : Pituitary Tumors (pressure)
Gut Tumors (obstruction)
 Functional Activity: Endocrine Tumors
 Bleeding: Skin, melena, hematuria
 Infection: Ulcerated Tumors
 Symptoms: Due to rupture or infractions
a) Cancer Cachexia:
 Loss of body fats and lean body mass, accompanied by profound weakness,
anorexia, and anemia.
 It is not caused by nutritional demands of the tumors.
 Patients with cancer, calories expenditure remains high and basal metabolic rate is
increased, despite reduce food intake.
b) Paraneoplastic Syndromes:
 Symptoms complexes in cancer bearing patients, unexplained by local or distant
spread of tumor, or release of hormones indigenous to tissue from which the tumor
arose
 Seen in 10-15% of patients with cancer
 Important to recognize:
 May represent an occult neoplasm
 May be lethal
 May mimic metastatic disease
 It includes:
Endocrinopathies ( Crushing syndrome, hypercalcemia, hypoglycemia)
Nerve and muscle syndrome ( Myasthenia, disorders of central and peripheral nervous
system)
Dermatological disorders ( Acanthosis nigricans, dermatomyositis)
2. Grading and Staging of Cancer:
 A method to assess clinical aggressiveness of a given neoplasm and its extent and spread in
individual patient.
 Necessary for making an acute prognosis.
 Needed for comparing results of various treatment protocols.

Grading:

 Based on degree of differentiation of tumor cells and in some tumors number of mitosis and
architectural features
 Well differentiated (grade I)
  Moderately differentiated (grade II)
 Poorly differentiated ( grade III)
 Undifferentiated (grade IV)

Staging:

 Based on the size of primary lesion, extent of spread to regional lymphnodes, extent of blood-
born metastases.
 American joint committee for cancer staging uses TNM classification system:
 T0-T4 (primary tumor)
 N0-N3 (regional lymphnode involvement)
 M0-M2 (metastases)
3. Laboratory Diagnosis of Cancer:

Histological Method:

 Type of specimen:
Excisional, incisional and wide-bore needle
 Optimal Requirements:
Clinical data
Specimen must be adequate, representative and properly preserved (formalin)
 Additional Techniques:
Refrigeration (Hormones, receptors, molecular analysis)
“Quick frozen section” diagnosis for determining the nature of lesion (benign or malignant) and
evaluating the margins of an exercised cancer for completeness of excision.

Cytologic Method:

 Type of sample:
Fine needle aspiration , used in readily palpable lesion ( breast, thyroid, lymphnodes)
Deep seated structures advantage ( least invasive, rapidly performed, avoid surgery. Its risks)
 Smear
Type of sample:
Surface epithelium
Cavity fluid ( abdomen, pleura, joint, pericardium, subarachnoid)

Immiunohistochemistry:

 Specific antibodies for identification of cell products or surface markers

 Utility in ;
Categorization of undifferentiated cancer, leukemias, and lymphomas
Determination of site of origin of metastatic tumor
 Detection of molecules that have prognostic or therapeutic significance

Flow Cytometry:

 Measurement of membrane antigens and DNA content of tumor cells

 Used in identification and classification of lymphomas and leukemias

Tumor Markers:

 Biochemical assays for tumor associated markers in body fluids (blood, stool, sputum, saliva,
urine) for
Detection of cancer
Determination of the effectiveness of therapy
Detection of cancer recurrence
 Type of marker:
Hormones ( trophoblastic and testicular tumors), Calcitonin (thyroid)
Oncofetal Antigens (a-fetoprotein= liver cell carcinoma, testicular germ cell tumors)
Carcinoembryonic Antigen ( carcinomas of colon, pancreas, lung, stomach)

Molecular Diagnosis:

 For diagnosis of cancer

Differentiation between monoclonal (neoplastic) and polyclonal ( reactive) proliferations in
lymphomas
Detection of specific translocation in hematopoietic neoplasm and sarcomas
 Prognosis of cancer
 Detection of minimal residual disease ( leukemias, lymphomas)
 Diagnosis of hereditary predisposition to cancer
Detection of these mutated alleles may allow for screening programs in form of prophylactic
surgery and counseling of relatives at risk eg; mutations in tumor suppressor genes- BRCA1,
BRCA2

Molecular Profiling of Tumors:

 DNA microarray technology:

Measuring expression of all gene simultaneously
 Proteomics :
Obtain profile of proteins contained in tissues, serum or other body fluids.