Neoplasia E02 (MedLive by DR Priyanka)

NEOPLASIA
Dr. PRIYANKA SACHDEV, MD

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DEFINITION
•The term ‘neoplasia’ means new growth
•The new growth produced is called

‘neoplasm’ or ‘tumour`
•The branch of science dealing with the study

of neoplasms is called oncology
Dr. PRIYANKA SACHDEV
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• “A neoplasm is an abnormal mass of tissue,
the growth of which exceeds and is
uncoordinated with that of the normal tissues
and persists in the same excessive manner
even after cessation of the stimuli which
evoked the change.”

Neoplasm
An abnormal mass of tissue
➢The growth of which exceeds and is

uncoordinated with that of the normal tissues
➢Persists in the same excessive manner even
after cessation of the stimuli which evoked the
change.

{

Genetic regulators (genes)
Normal cell growth, 4 regulatory genes:
i) Proto-oncogenes are growth-promoting genes
ii) Anti-oncogenes or tumour suppressor genes are growth-

inhibiting or growth suppressor genes.
iii) Apoptosis regulatory genes control the programmed cell death.
iv) DNA repair genes regulate repair of DNA damage that has
occurred during mitosis and also control the damage to proto-
oncogenes and antioncogenes.
Genetic regulators (genes)
i) Proto-oncogenes are growth-promoting
genes
ii) Anti-oncogenes or tumour suppressor

genes are growth-inhibiting or growth
suppressor genes.
In cancer
i) Overstimulation of proto-oncogenes
ii) Inhibition of tumour-suppressor genes

In cancer

Activation of Proto-Oncogenes

Proto-oncogenes
•Proto-oncogenes were discovered by Harold
Varmus and Michael Bishop.
•Normal genes required for cell proliferation

• They act under proper physiological stimuli
• Without physiological stimuli they will be
silent and there is no replication.
Oncogenes
•Derived from mutation of proto-oncogenes

•
•When, due to mutation, proto- oncogenes
become autonomous ie. promote cell
growth without any physiological stimulus,
it acts as oncogene.
•Infact oncogene and protooncogene is
the same,
•In normal cell it acts as protooncogen

while in cancer cell it acts as oncogene

Proto-oncogenes (Normal genes required for cell
proliferation and differentiation)
Mutation
Oncogenes (Genes promoting autonomous cell growth in

cancer cells)
Oncoproteins (Proteins lacking regulatory control and

responsible for promoting cell growth)
Transformation of proto-oncogene to
oncogene occur by 3 mechanisms:
➢ Point mutations
➢Chromosomal translocations
➢Gene amplification
CLASSIFICATION
5 classes→
•i) Growth factors

•ii) Receptors of growth factors
•iii) Cytoplasmic signal transduction proteins
•iv) Nuclear transduction factors
•v) Cell regulatory proteins
RAS gene
•RAS protein is signal transducing protein
•Point mutation of RAS family genes is the

single most common abnormality of Proto-
oncogenes in human tumor.
2 scenarios
•Normally
•Mutation

NORMALLY

In Inactive state RAS proteins bind GDP
Growth factors
RAS proteins become activated by exchanging GDP for GTP
Activated RAS recruits RAF-1 and also activates PI3K
Mitosis
GTPase Activating Proteins (GAP)
GTP breaks into GDP
RAS Back to inactive state (Activated state is transient)

2 scenarios
•Normally
•Mutation

MUTATION

Mutation in the RAS gene
GTPase Activating Proteins (GAP) not working
GTPase acitivity cannot be increased
No breakdown of GTP
Permanent activation of RAS
Uncontrolled mitosis
Cancer
EXAMPLES

CLASSIFICATION
5 classes→
•i) Growth factors

•ii) Receptors of growth factors
•iii) Cytoplasmic signal transduction proteins
•iv) Nuclear transduction factors
•v) Cell regulatory proteins
ABL-BCR hybrid gene
• ABL gene is a protooncogene having

tyrosine kinase activity.

NORMALLY
•ABL gene → normal location on

chromosome 9
•BCR gene→normal location on

chromosome 22

IN TRANSLOCATION

ABL gene → normal location on chromosome 9
It is translocated to chromosome 22
It fuses with BCR gene (breakpoint cluster region)
Forms an ABL-BCR hybrid gene → Philadelphia chromosome on chromosome 22
This hybrid do an abnormal signal transduction even without growth factors
Cancer
EXAMPLE
•CML
•Now a days a specific tyosine kinase inhibitor

drug called imatinib is used in treatment of
CML
•This is an example of targeted drug therapy
MYC
•MYC gene is a protooncogene having
nuclear regulatory activity (transcriptional
activators).
•These are involved in carcinogenesis of

many cancers
NORMALLY
•MYC gene → normal location on

chromosome 8
• IG gene→normal location on
chromosome 14

IN TRANSLOCATION

MYC gene → normal location on chromosome 8
It is translocated to chromosome 14
It fuses with IG gene
Forms an MYC-IG hybrid gene
This hybrid has abnormal nuclear regulatory activity
Cancer
POLLS 1

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A

A

A

All are growth promoting oncogenes
except -
• a) F GF
• b) TGF-a
• c) TGF-B
• d) PDGF

C

MYC gene is -
• a) Protein kinase inhibitor

• b) Growth factor inhibitor
• c) GTPase
• d) Transcription activator

D

Which of the following has tumor
promoting effect?
• a) BRAC
• b) RB
• c) MYC
• d) p16

C

In the MAPK pathway, the activation of
RAS is counteracted by
a) Protein kinase C
b) GTPase activating protein
c) Phosphatidyl inositol
d) Inositol triphosphate

B

False about proto oncogenes

D

Following are required for normal
growth exept

C

C

In cancer

2. INACTIVATION OF Tumour
sppressor genes
• Tumor suppressor genes are the genes whose
products down regulate the cell cycle and thus apply
brakes to cellular proliferation
• Normally tumour suppressor genes act by entering

the cell into G0 (resting) phase
• So, loss of function of tumor suppressor genes

results in uncontrolled cell proliferation and
carcinogenesis.
The mechanisms of loss of tumour
suppressor actions of genes are due to
1.Chromosomal deletions
2. Point mutations
CLASSIFICATION


RB gene
•Located on long arm (q) of chromosome 13

(chromosome 13q14)
•RB gene was the first tumor suppressor

gene to be discovered

NORMALLY

Growth inhibitors
Activates CDK inhibitors and inactivates cyclins and CDKS
Hypophosphorylation of RB
RB becomes active
forming an inactive complex with transcription factor EF-2
blocks cell division (no mitosis)

Growth factors
Activates cyclins and CDKS
Hyperphosphorylation of RB
RB becomes inactive
Dislocation of RB from transcription factor EF-2
Cell division (mitosis)

Mutation in RB→

Mutation in RB
Permanent inactivation of RB
Permanent Dislocation of RB from transcription factor EF-2
Abnormal Cell division (mitosis)
Cancer

ACTIVE RB gene →
• Active in hypophosphorylated state
• Prevents replication by forming an inactive complex with transcription
factor EF-2
• blocks cell division
• Inhibiting the cell cycle at G1 → S phase
INACTIVE RB gene→
• Phosphorylation of RB gene causes inactivation of RB gene
• Dissociation of RB from EF-2
• Activation of EF-2
• Cell replication
Mutation in RB→
Permanent inactivation of RB
•Retinoblastoma is associated with concept
of
1. Loss of Heterozygosity
2. Knudson's Two Hit Hypothesis

Knudson’s two hit hypothesis→
•Retinoblastoma develops when both

the normal alleles of the RB genes are
inactived

Familial/Hereditary retinoblastoma
•First genetic change (first hit) in RB gene is

inherited from an affected parent
•Second mutation (second hit) occurs in

postnatal life and both alleles are lost.

•In hereditary retinoblastoma, children are born
with one normal and one abnormal RB gene,
i.e. Heterozygous for RB gene.
•Mutation in normal RB gene results in loss of

heterozygosity (as both RB genes become
abnormal) and development of
retinoblastoma→ Loss of Heterozygosity
Sporadic/non- hereditary
retinoblastoma
•Both mutations (first and second hits)
occur postnataly

Familial retinoblastoma
• comprises 40% of cases
• bilateral.
• somatic cells inherit one mutant RB gene from a carrier parent (i.e.
germline mutation). The other mutation occurs after birth.
• Besides retinoblastoma, children inheriting mutant RB gene have 200 times
greater risk of development of other cancers eg osteosarcoma, breast,
colon and lungs.
Sporadic retinoblastoma
• constitutes 60% of cases
• unilateral.
• acquired both the somatic mutations in the two alleles after birth.
•Familial Retinoblastoma is also
associated with increased risk of
osteosarcomas.

REMEMBER
•Retinoblastoma is associated with

Concept of Loss of Heterozygosity as
well as Knudson’s Two Hit Hypothesis

• Retinoblastoma is the most common primary
intraocular malignancy of children.
• In the sporadic cases, both RB allelesare lost by

somatic mutations.

•Retinoblastomas arising in the context
of germline mutations are often
bilateral.
•In addition, they may be associated with
pinealoblastoma (“trilateral”
retinoblastoma).
P53 gene
•p53 is a tumor suppressor gene.
•p53 gene is located on chromosome 17
•Guardian of genome
•Molecular policeman

•P53 is a tumour suppressor gene as
well as DNA repair gene

In cancer
i) Activation of proto-oncogenes
ii) Inactivation of tumour-suppressor genes
iii) Abnormal apoptosis regulatory genes
iv) Inactivation of DNA repair genes

NORMALLY

UV radiation (DNA damage)
P53 accumulate in cell
P21 GADD 45
Cell cycle arrest DNA repair
successful Unsuccesful
MDM-3 BAX
Degradation of p53 Apoptosis
•p53 acts through: CDK inhibitor p21
•p53 itself is not a CDK inhbitor

Mutation in p53

Cells with mutation or loss of p53
DNA damage
p53 dependent genes not activated
No cell cycle arrest

No DNA repair
Mutant cells→Expansion and additional mutations
Cancer

• When there is DNA damage due to irradiation, UV light or mutagenic
chemicals, there is rapid increase in p53 levels.
• p53 causes→
i) Cell cycle arrest:

• p-53 induces transcription of p21, a CDK inhibitor.
• p21 inhibit cyclin D-CDK-4 complex
• arrest of cell cycle in G1 phase.
• This allow time for DNA repair.
ii) DNA repair:
• inducing transcription of GADD 45 (growth arrest and DNA damage).
• GADD 45 encodes a protein that is involved in DNA repair.

If DNA damage is repaired successfully,
• p53 activate MDM-3
• MDM-3 induce degradation of p-53→ Relieve in cell cycle
block
If DNA damage cannot be successfully repaired,

• p53 induces apoptosis by inducing the activation of
apoptosis inducing gene BAX
• So p-53 prevents replication of cell with defective DNA
REMEMBER
•Non-mutated (wild type) p53 reduces

the chances of cancer.
•Mutated form is associated with cancer

• Sometimes individual may inherit one mutant p53
allele and the second acquired 'hit' may inactivate
the normal p53 allele.
• This later condition is called Li-Fraumeni syndrome
• Associated with development of sarcoma, breast

cancer, leukemia and brain tumors.

•Human papilloma virus (HPV) causes
inactivation of p53 through its E6 protein
• so,it is responsible for development of

cancer of anal and genital region.

•p73 (big brother of p53) and p63 are other
members of the family of p53 gene.
•p63 is esential for the differentiation of stratified

squamous epithelia.
•p73 has pro-apoptotic effects after DNA damage

induced by the chemotherapeutic agents
REMEMBER
•Overall → p-53
•Amongst Tumour suppressor genes→ p-53 is

involved most commonly
• Amongst Proto-oncogene → RAS is involved

most commonly

POLLS 2

An example of a tumour suppressor
gene is -
• a) myc
• b) EGFR
• c) ras
• d) Rb

D

A

A

A

C

A

D

B
Retinoblastoma is a prime example of a tumor which is
associated with loss of heterozygosity.
• Rb gene is a tumor suppressor gene located on chromosome 13
q14Q.
• Retinoblastoma develops when both the normal alleles of the
Rb gene are inactivated or altered.
• Familial retinoblastoma is associated with autosomal dominant
inheritance whereas the Rb gene is having autosomal recessive
inheritance.
A

C

D

Knudson two hit hypothesis is seen with
• (a) Melanoma
• (b) Retinoblastoma
• (c) Ulcerative colitis
• (d) Crohn disease

B

D

B

REVISION

In cancer

Activation of Proto-Oncogenes

RAS gene
•RAS protein is signal transducing
protein
•Point mutation of RAS family genes is

the single most common abnormality of
Proto-oncogenes in human tumor.
ABL-BCR hybrid gene
NORMALLY→
• ABL gene is a protooncogene having tyrosine

kinase activity.
• ABL gene → normal location on chromosome 9

• BCR gene→normal location on chromosome 22
MYC
•These are nuclear regulatory proteins

(transcriptional activators).
•These are involved in carcinogenesis of

many cancers

In cancer

Tumour sppressor genes

RB gene
•Located on long arm (q) of chromosome
13 (chromosome 13q14)
•RB gene was the first tumor suppressor

gene to be discovered

P53 gene
•p53 is a tumor suppressor gene.
•p53 gene is located on chromosome 17
•Guardian of genome
•Molecular policeman

P21 GADD 45
MDM-3 BAX
In cancer

3. Escaping Cell Death: Apoptosis
Regulating genes
Apoptosis in normal cell is guided by
1. Pro-apoptotic factors (BAD, BAX, BID

and p53)
2. Anti apoptosis factors (BCL2, BCL-X).

In cancer cells, the function of apoptosis is interfered due
to mutations in the above genes which regulate apoptosis in
the normal cell.

Mutation in apoptosis Regulating genes
1. Inactivation of proapoptotic factors(BAD, BAX, BID and p53)

2. Overactivation of antiapoptotic factors(BCL2, BCL-X)
Escaping Cell Death
Uncontrolled growth
Cancer
•Of these two pathways, it is the intrinsic
apoptotic pathway (sometimes referred
to as the mitochondrial pathway) that is
most frequently disabled in cancer.

Eg.
Normally
•chromosome 14 has immunoglobulin

heavy chain gene
•Chromosome 18 has bcl-2 gene.

In follicular lymphoma
there is presence of translocation t (14:18)
which causes increased expression of bcl-2
thereby preventing apoptosis
protects lymphocytes from apoptosis and contributes to the survival of

transformed B cells.
Inducing the development of cancer.

In cancer

4. DNA Damage and Repair System
•DNA damage by exogenous factors (e.g.

by radiation, chemical carcinogens etc)
or during mitosis is repaired.
•p53 gene is held responsible for

detection and repair of DNA damage
DNA damage
If this system of DNA repair is defective
The defect in unrepaired DNA is passed to the next

progeny of cells
cancer results

NORMALLY p53

P21 GADD 45
MDM-3 BAX
REMEMBER
• The cell cycle has its own internal controls, called checkpoints.
There are two main checkpoints, one at the G1/S transition
and another at G2/M.
• In the G1/S checkpoint, cell-cycle arrest is mostly mediated

through p53, which induces the cell-cycle inhibitor p21.
• Arrest of the cell cycle by the G2/M checkpoint involves both

p53-dependent (via cyclin A/cdK-2) and independent (via cdc
25) mechanisms
Mutation in p53

Cells with mutation or loss of p53
DNA damage
p53 dependent genes not activated
No cell cycle arrest

No DNA repair
Mutant cells→Expansion and additional mutations
Cancer

Eg
•i) Hereditary non-polyposis colon cancer
(HNPCC or Lynch syndrome)
•ii) Ataxia telangiectasia (AT)
•iii) Xeroderma pigmentosum
•iv) Bloom syndrome.
•V) Fanconi anemia
Fanconi’s anemia
• Fanconi’s anemia is an autosomal recessive disease characterized by
1. progressive pancytopenia
2. increased risk of malignancy (solid tumors and AML)
3. congenital developmental anomalies like short stature, café au lait spots,
abnormalities affecting thumb, radius and genitourinary tract.
• Fanconi’s anemia is associated with BRCA gene.

• The Fanconi anemia proteins and BRCA proteins form a DNA-damage repair proteins
to correct intrastrand and interstrand DNA cross links induced by chemical cross-
linking agents.

•Hereditary non polyposis colon cancer
(HNPCC) is an autosomal dominant
condition caused by defective DNA repair
genes.
•All others are conditions associated with

defective DNA repair genes are autosomal
recessive
In cancer

Cancer: Multistep Theory
Multiple steps :
•Activation of Proto oncogenes
•Loss of tumour suppressor genes
•Inactivation of apoptotic mechanisms
•Escaping cellular ageing
• A classic example →adenoma-carcinoma

sequence in colorectal carcinoma
REMEMBER

POLLS.

B

A

D

C

C

C

CARCINOGENS AND
CARCINOGENESIS
•Carcinogenesis means mechanism of
induction of tumours
•Agents which can induce tumours are

called carcinogens

3 TYPES→
A. Chemical carcinogens
B. Physical carcinogens
C. Biologic carcinogens

A. CHEMICAL CARCINOGENESIS
Types of chemical carcinogens
➢Direct-acting carcinogens → induce cellular

transformation without undergoing any prior
metabolic activation
➢Indirect-acting carcinogens or
procarcinogens → require metabolic
conversion within the body so as to become
‘ultimate’ carcinogens
STAGES IN CHEMICAL
CARCINOGENESIS
3 stages→
➢Initiation
➢Promotion
➢Progression
Initiation of Carcinogenesis
1.Metabolic activation
2.Reactive electrophiles
3.Target molecules mutations
4.The initiated cell

1.Metabolic activation →
•Indirect-acting or procarcinogens require

to be activated in liver by the mono-
oxygenases of the cytochrome, P-450
system in ER

2. Reactive electrophiles
•Direct-acting carcinogens are intrinsically
electrophilic (electron deficient)
• Indirect-acting substances become electron-
deficient after metabolic activation i.e. they
become reactive electrophiles.
•Following this step, both types of chemical
carcinogens behave alike
•Reactive electrophiles bind to electron-rich
portions of DNA
3. Target molecules mutations
• Primary target of electrophiles is DNA
• Produces mutagenesis
➢Any gene may be the target molecule

➢Most frequently affected proto oncogene is RAS gene
mutation
➢Tumour suppressor gene is p53 gene mutation.
4. The initiated cell
The unrepaired damage produced in the DNA of
the cell becomes permanent and fixed only if
the altered cell undergoes at least one cycle of
proliferation.
•Results in transferring the change to the next

progeny of cells
•so that the DNA damage becomes permanent
and irreversible
STAGES IN CHEMICAL
CARCINOGENESIS
3 stages→
➢Initiation
➢Promotion
➢Progression
Promotion of Carcinogenesis
• Promoter carcinogens do not damage the
DNA per se and are thus not mutagenic
•But instead enhance the effect of initiators
•They cause clonal proliferation and expansion
of initiated (mutated) cells
•They do not produce sudden change.
• The change induced may be reversible.
•To produce tumour → initiator should
be followed by promoter

•Initiators cause irreversible DNA damage.
•Promoters cause reversible DNA damage.

•The chemical which acts as both initiator as
well as promotor is called complete
carcinogen.

STAGES IN CHEMICAL
CARCINOGENESIS
3 stages→
➢Initiation
➢Promotion
➢Progression
Progression of Carcinogenesis
•Progression of cancer is the stage when
mutated proliferated cell shows phenotypic
features of malignancy.
•Initiated cell proliferate rapidly and in this

process acquires more and more mutations

TESTS FOR CHEMICAL
CARCINOGENICITY
AMES’ TEST
•Evaluates the ability of a chemical to
induce mutation in the mutant strain of
Salmonella typhimurium that cannot
synthesise histidine.

• Such strains of mutant Salmonella typhimurium are
incubated with the potential carcinogen
• If the chemical under test is mutagenic, it will induce

mutation in the mutant strains of S. typhimurium in the
functional histidine gene
• It will be reflected by the number of bacterial colonies

growing on histidine-free culture medium

•Sir Percival Pott demonstrated the
increased incidence of scrotal skin
cancer in chimney workers exposed to
chemical soot.

3 TYPES→

B. PHYSICAL CARCINOGENESIS
B. PHYSICAL CARCINOGENESIS
1. Radiation→ ultraviolet light and

ionising radiation
2. Non-radiation physical agents→

injuries

RADIATION CARCINOGENESIS
•ULTRAVIOLET LIGHT
•IONISING RADIATION

ULTRAVIOLET LIGHT
•source → sunlight
• skin cancers—squamous Cell carcinoma,
basal cell carcinoma and melanoma.
•Basal cell carcinoma is the most common

cancer due to excessive UV light exposure.

• has three subtypes
1. UV-A is 320-400 nm
2. UV-B is 280- 320 nm
3. UV-C is 200 - 280 nm
• UV-C gets filtered by ozone layer

• UV-B is the most carcinogenic UV ray to reach the
earth
(UV-B is Bad for humans as it causes cancers)
Mechanism
Exposure to UV rays
Pyrimidine dimers in DNA
Mutation in oncogenes and tumor suppressor

genes
Cancer
RADIATION CARCINOGENESIS
•ULTRAVIOLET LIGHT
•IONISING RADIATION

IONISING RADIATION
• Source→ x-rays, y rays , α rays, β particles
• Cancers→
1. All forms of leukaemias (except chronic lymphocytic
leukaemia CLL),
2. Cancers of the thyroid (most commonly papillary carcinoma)
3. skin, breast, ovary, uterus, lung, myeloma, and salivary glands
• Maximum sensitivity is at G2 stage

Mechanism
Exposure to ionizing radiation
dislodge ions from water
formation of highly reactive free radicals
DNA damage
Cancer

NON-RADIATION PHYSICAL
CARCINOGENESIS
Mechanical injury to the tissues →
•i) Stones in the gallbladder→ cancer

•ii) Healed scars following burns → cancer

REMEMBER
➢CLL is the only leukemia NOT associated

with ionizing radiation exposure.

REMEMBER
• The most radiosensitive cell in the blood is the lymphocytes
• The least radiosensitive cell in the blood is the platelets
• DNA is the most sensitive intracellular organelle to radiation.

3 TYPES→

C. BIOLOGIC CARCINOGENESIS
VIRAL CARCINOGENESIS
•Based on their nucleic acid content,

oncogenic viruses 2 types→
1. DNA oncogenic viruses

2. RNA oncogenic viruses or retroviruses
1. Mode of DNA viral oncogenesis
➢Replication The virus may replicate in the host cell with
consequent lysis of the infected cell and release of
virions→ cell death
➢Integration The viral DNA may integrate into the host

cell DNA → induction of mutation→neoplastic
transformation of the host cell

Mode of RNA viral oncogenesis
• RNA oncogenic viruses are retroviruses i.e.
they contain the enzyme reverse
transcriptase (RT)

The viral envelope fuses with the plasma membrane of the host cell
Reverse transcriptase acts as template to synthesise ss of matching viral

DNA
It is then copied to form complementary DNA resulting in ds viral DNA

(provirus)
The provirus is integrated into the host cell genome producing ‘transformed
host cell’
Integration of the provirus brings about replication of viral components
Assembled and released by budding

Human Papillomavirus (HPV)
• At least 70 genetically distinct types of HPV have been identified.
• Low risk HPV (e.g., 1, 2, 4, and 7) cause benign squamous

papillomas (warts) in humans.
• High-risk HPVs (e.g., types 16 and 18) cause squamous cell

carcinomas of the cervix, anogenital region, and head and neck
• These cancers are sexually transmitted diseases, caused by

transmission of HPV

Integration interrupts the viral DNA
overexpression of the oncoproteins E6 and E7
E6 E7
TERT + p53- p21- RB-
Increased telomerase expression

• UV radiation (DNA damage)
P21 GADD 45
MDM-3 BAX
REMEMBER

Epstein-Barr Virus (EBV)
•Burkitt lymphoma
•subset of Hodgkin lymphoma (lymphocyte
depleted)
•Nasopharyngeal carcinoma
•Some gastric carcinomas
•T-cell lymphoma
•Natural killer (NK) cell lymphoma.
•Nasopharyngeal cancer is the only T cell
malignancy amongst the cancers caused
by EBV

EBV causes infection of epithelial cells of oropharynx and B- cells because of
the presence of CD21 molecule on the surface of these cells.
LMP-1 gene present in the EBV integrate with human DNA
Activation of NF-kB and JAK/STAT signaling pathways
promoting B-cell survival and proliferation (This increases the chances of B-

cell lymphoma)
Acquisition of t(8;14)translocation
Burkitt lymphoma
REMEMBER
•In the case of Burkitt lymphoma, it seems that
EBV is not directly oncogenic
•But by acting as a polyclonal B-cell mitogen,

it sets the stage for the acquisition of the
(8;14) translocation that ultimately produce a
full-blown cancer.

BACTERIA
• H. pylori is the first bacterium classified as a
carcinogen.
• H. pylori infection is implicated in the genesis of
1. Gastric adenocarcinomas
2. Gastric lymphomas.

• The gastric lymphomas are of B-cell origin and are called
MALT lymphomas (marginal zone-associated lymphomas)
because the transformed B cells normally reside in the
marginal zones of lymphoid follicles.
• H. pylori infection results in the formation of H. pylori-

reactive T cells, which cause polyclonal B-cell
proliferations.
• The MALT lymphoma is associated with t(11;18)

translocation.
3 TYPES→

POLLS 3

A

A

•a. EBV
•b. HHV-8
•c. CMV
•d. Kaposi sarcoma

A

A

D

BACTERIA
• H. pylori is the first bacterium classified as a
carcinogen.
• H. pylori infection is implicated in the genesis of
1. Gastric adenocarcinomas
2. Gastric lymphomas.

• The gastric lymphomas are of B-cell origin and are called
MALT lymphomas (marginal zone-associated lymphomas)
because the transformed B cells normally reside in the
marginal zones of lymphoid follicles.
• H. pylori infection results in the formation of H. pylori-

reactive T cells, which cause polyclonal B-cell
proliferations.
• The MALT lymphoma is associated with t(11;18)

translocation.
B

D

C

B

• has three subtypes
1. UV-A is 320-400 nm
2. UV-B is 280- 320 nm
3. UV-C is 200 - 280 nm
• UV-C gets filtered by ozone layer

• UV-B is the most carcinogenic UV ray to reach the
earth
(UV-B is Bad for humans as it causes cancers)
C

A

D

REMEMBER
➢CLL is the only leukemia NOT associated

with ionizing radiation exposure.

C

D

B

Mechanism
Exposure to UV rays
Pyrimidine dimers in DNA
Mutation in oncogenes and tumor suppressor

genes
Cancer
B

REMEMBER
• The most radiosensitive cell in the blood is the lymphocytes
• The least radiosensitive cell in the blood is the platelets
• DNA is the most sensitive intracellular organelle to radiation.

CLINICAL FEATURES
CLINICAL FEATURES
•A. LOCAL EFFECTS
•B. SYSTEMIC MANIFESTATIONS

A. LOCAL EFFECTS
➢Compression→ Some benign tumours due to
their critical location, have more serious
consequences e.g. pituitary adenoma
➢Mechanical obstruction Benign and malignant
tumours in the gut may produce intestinal
obstruction.
➢Tissue destruction Malignant tumours infiltrate
and destroy the vital structures
➢Infarction, ulceration, haemorrhage
B. SYSTEMIC MANIFESTATIONS
1.Cacer cachexia
2.Fever
3.Tumour lysis syndrome
4.Paraneoplastic syndrome

1.CANCER CACHEXIA
•Due to anorexia and increased nutritional

demands of the tumour.
•Certain cytokines such as tumour necrosis

factor a (TNF-a), IL-1 and INF-g play a
contributory role in cachexia

2. FEVER
•Exact mechanism of tumour-associated

fever is not known
•Probably the tumour cells themselves
elaborate pyrogens.

3. TUMOUR LYSIS SYNDROME
•Caused by extensive destruction of a large

number of rapidly proliferating tumour
cells

Tumor lysis syndrome is associated
with
1. Burkitt lymphoma
2. Acute lymphoblastic leukemia (ALL)
3. Chronic tumors (CLL)
4. uncommonly solid tumors

• Characterised by →
1. Hyperuricaemia(due to increased turnover of nucleic

acids).Hyperuricemia can cause uric acid precipitation in the
kidney causing acute renal failure.
2. Hyperkalaemia (due to release of the most abundant
intracellular cation potassium)
3. Hyperphosphataemia (due to release of intracellular phosphate)
4. Hypocalcaemia (due to complexing of calcium with the elevated
phosphate)

4. PARANEOPLASTIC SYNDROME
•A group of conditions developing in patients
with advanced cancer which are neither
explained by direct and distant spread of the
tumour
•About 10 to 15% of the patients with advanced

cancer develop paraneoplastic syndromes
• Sometimes PNS may be the earliest
manifestation of a latent cancer.
• Most common tumor associated with paraneoplastic syndrome is
small cell carcinoma of lung
• Hypercalcemia is the most comon paraneoplastic syndrome. Most

commonly it is caused by parathyroid hormone related peptide
• Cushing’s syndrome is most common endocrinopathy. It is usually

due to production of ectopic ACTH by small cell carcinoma
lung(most common), carcinoid tumor (neuroendocrine tumor),
pancreatic tumor (islet cell tumor), and medullary carcinoma of
thyroid.

POLLS 4

A

A

B

B

C

DIAGNOSIS OF CANCER
DIAGNOSIS OF CANCER
1.Histological method
2.Cytological method
3.Histochemistry and Cytochemistry
4.Immunohistochemistry (IHC)
5.Electron microscopy
6.Tumour markers
7.Others
1. HISTOLOGICAL METHODS
•The tissue must be fixed in 10% formalin

for light microscopic examination
✓Paraffin embedded technique

✓Frozen section

i) Paraffin-embedding technique
•10% formalin fixed tissue
•Processed through a tissue processor having an
overnight cycle
•Embedded in molten paraffin wax for making
tissue blocks.
•These blocks are fine-sectioning into 3-4 μm
sections using rotary microtome
•Stained with haematoxylin and eosin (H & E)
•Examined microscopically.
ii) Frozen section
• Procedure is generally carried out when the patient is
undergoing surgery
• Unfixed tissue is used
• Tissue is embedded in ice instead of paraffin wax , so called as
frozen section
• Cryostat machine is used
• Tissue is Sectioned
• Rapid H & E or toluidine blue staining.
• Frozen section is a rapid intraoperative diagnostic procedure
for tissues before proceeding to a major radical surgery

DIAGNOSIS OF CANCER
6.Tumour markers
7.Others
2. CYTOLOGICAL METHODS
• 2 types →
• study of cells shed off into body cavities (exfoliative

cytology)
• study of cells by putting a fine needle into the

lesion (fine needle aspiration cytology FNAC).

•Cell morphology and nuclear features is
well seen
•Cell architecture is not seen
•Less invasive and more cost effective

than histology
DIAGNOSIS OF CANCER
6.Tumour markers
7.Others
3. HISTOCHEMISTRY AND
CYTOCHEMISTRY

DIAGNOSIS OF CANCER
6.Tumour markers
7.Others
4. IMMUNOHISTOCHEMISTRY
(IHC)
•Immunohistochemistry is a method of
analyzing and identifying cell types based
on binding of antibodies to specific
components of the cell.

• Antibody, which is specific for an antigen of a
particular tissue, is labled with a probe (coloured
marker) and is run on the tissue specimen obtained
from a biopsy.
• If the tissue has that particular antigen, then

antibody will get attached to the tissue and the
labled antibody can be seen under a microscope.

IHC

DIAGNOSIS OF CANCER
6.Tumour markers
7.Others
5. ELECTRON MICROSCOPY
• Ultrastructural examination of tumour cells
• A few general features

i) Cell junctions, their presence and type.
ii) Cell surface, e.g. presence of microvilli.
iii) Cell shape and cytoplasmic extensions.
iv) Shape of the nucleus and features of nuclear membrane.
v) Nucleoli, their size and density.
vi) Cytoplasmic organelles—their number is generally reduced.
vii) Dense bodies in the cytoplasm
DIAGNOSIS OF CANCER
6.Tumour markers
7.Others
6. TUMOUR MARKERS (BIOCHEMICAL
ASSAYS)
•Some tumor produce or elicite the production of

markers that can be measured in the serum or
urine or other body fluids.
•Tumor markers are biochemical indicators of

the presence of a tumor.
•Markers may be cell surface antigen,
enzymes, hormones, tumor associated
protein, or oncofetal antigens.

•Many of these products are produced by
normal body cells too
•thus the biochemical estimation of the
product in blood reflects total substance and
not by the tumour cells alone.
•So lack sensitivity as well as specificity
•Use as an adjunct to the pathologic diagnosis
and for prognostic and therapeutic purposes
The ideal tumor marker should be
✓ Present only in tumor cells

✓ Specific for the organ and type of tumor
✓ Assessable in the sera of all patients with the same
type of tumor
✓ Assessable in the serum at the very beginning of
tumor development
✓ Concentrations in the serum should correlate with
the tumor burden

Clinical applications
*Screening in general population
*Diagnosis in symptomatic patients
*Estimating tumor volume
*Prognostic indicator of disease progression
*Monitoring responses to therapy
*Detecting the recurrence of cancer

α-fetoprotein
• Glycoprotein
• Synthesized by fetal yolk sac and liver
• It is structurally and genetically related to albumin
• Normal value →< 10 μg/L

1. Specific and ideal marker for hepatocellular

carcinoma, and non-seminomatous germ cell
tumours of the testis.
2. Certain non-neoplastic conditions e.g. in hepatitis,

cirrhosis, toxic liver injury and pregnancy.

➢Serum levels correlates with the size of tumors
➢Useful in screening in high risk areas
➢Useful in determining prognosis and in the monitoring of therapy for

hepatocellular carcinoma
➢Level is a prognostic indicator of survival
➢Elevated levels >10 μg/L as well as serum bilirubin >2mg/dL are

associated with shorter survival time

Carcinoembryonic Antigen
(CEA)
• glycoprotein
• synthesized normally in fetal life by yolk sac, fetal liver
and fetal GIT.
Normal value
1. non smokers 3 μg/L
2. smokers 5 μg/L
1. Most useful marker in the colorectal

carcinoma, in cancers of the
gastrointestinal tract, pancreas and breast.
2. certain non-neoplastic conditions e.g. in

ulcerative colitis, Crohn’s disease, hepatitis
and chronic bronchitis.
➢CEA levels correlates with the stage of the disease
➢28% of Duke stage A
➢45% of Duke stage B
➢Pretreatment levels are prognostic of the development of

metastasis
➢Successful therapy: levels decline

➢Remission : levels stable
➢Rising levels: indicates recurrence
➢Lead time : level rise to clinical recurrence is 5month

•CEA lacks sensitivity as well as
specificity, hence cannot be used to
confirm the diagnosis

Human chorionic gonadotropin
(HCG)
•It is a placental hormone synthesized by
syncytiotrophoblasts.

•It is glycoprotein with two subunits (dimer):
1. α-subunit
2. β-subunit.

• But only the β subunit of HCG is typically measured as a
tumour marker because of specificity of the β subunit.
• The β subunit of HCG has unique sequences that are not

shared with other human glycoprotein hormones.
• α- HCG is not used as tumour marker because α unit of the

FSH, LH and TSH are identical. So there can be cross
reactivity between a subunits of these hormone.

•HCG (p-HCG) is raised in gestational

trophoblastic disease (hydatidiform
moles), gonadal germ cell tumor
(embryonal carcinoma,
choriocarcinoma), and pregnancy.

POLLS 5

B

B

D

A

A

C

B

B

D

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NEOPLASIA

Dr. PRIYANKA SACHDEV, MD

•The new growth produced is called

•The branch of science dealing with the study

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

➢The growth of which exceeds and is

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

i) Proto-oncogenes are growth-promoting genes

ii) Anti-oncogenes or tumour suppressor genes are growth-

iii) Apoptosis regulatory genes control the programmed cell death.

ii) Anti-oncogenes or tumour suppressor

ii) Inhibition of tumour-suppressor genes

Dr. PRIYANKA SACHDEV

ii) Inhibition of tumour-suppressor genes

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

•Normal genes required for cell proliferation

•Derived from mutation of proto-oncogenes

•In normal cell it acts as protooncogen

Dr. PRIYANKA SACHDEV

Oncogenes (Genes promoting autonomous cell growth in

Oncoproteins (Proteins lacking regulatory control and

•i) Growth factors

•Point mutation of RAS family genes is the

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

RAS proteins become activated by exchanging GDP for GTP

Activated RAS recruits RAF-1 and also activates PI3K

GTPase Activating Proteins (GAP)

GTP breaks into GDP

RAS Back to inactive state (Activated state is transient)

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

GTPase Activating Proteins (GAP) not working

GTPase acitivity cannot be increased

Permanent activation of RAS

Dr. PRIYANKA SACHDEV

•i) Growth factors

• ABL gene is a protooncogene having

Dr. PRIYANKA SACHDEV

•ABL gene → normal location on

•BCR gene→normal location on

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

It fuses with BCR gene (breakpoint cluster region)

Forms an ABL-BCR hybrid gene → Philadelphia chromosome on chromosome 22

This hybrid do an abnormal signal transduction even without growth factors

•Now a days a specific tyosine kinase inhibitor

•These are involved in carcinogenesis of

•MYC gene → normal location on

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

It fuses with IG gene

Forms an MYC-IG hybrid gene

This hybrid has abnormal nuclear regulatory activity

Scan or Click to watch Scan or Click to watch

Dr. PRIYANKA SACHDEV