MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR

MALIGNANCY
BY DR BASHIR AHMED DAR
ASSOCIATE PROFESSOR MEDICINE
CHINKI PORA SOPORE
KASHMIR
Email –drbashir123@gmail.com

MMMC Annual Night
Carol-I will always love you

The cell
• The cell contains nucleus
and in the nucleus are
chromosomes.

Chromosomes
Chromosomes are
the rod-
shaped, filamento
us
structures, which
become visible
during cell
division.

Chromosomes
• Chromosomes are
composed of thin
chromatin threads
• Each chromatin
thread in turn is
made of DNA.

Chromosomes
• A chromosome is about
0.004 mm long
• The DNA is about 4 cm long
• This is about 10 000 times
longer than the
chromosome
• So it has to twist like a
corkscrew and coil to fit
inside
• If you unraveled these
coils, you'd have a six-foot
long double strand of
deoxyribonucleic acid-DNA.

Chromosomes
• DNA is wrapped tightly
around histones and
coiled tightly to form
chromosomes

DNA
• DNA is made of
• Nucleotide = nitrogen base (purine or
pyrimidine) + phosphate group + pentose
sugar ( ribose or deoxyribose)
• They are units of DNA.

DNA Nucleotide
O
O=P-O
O
Phosphate
Group
N
Nitrogenous base
(A, G, C, or T)
CH2
O
C1
C4
C3 C2
5
Sugar
(deoxyribose)

RNA
• RNA is made of
• Nucleoside= nitrogen base(purine or
pyrimidine)+ pentose sugar(ribose), but
without phosphate group
• They are units of RNA.

DNA
• Nitrogenous base is in the centre and
phosphate and sugar at the legs of ladder.
• The ladder coils on itself to form double helix
structure.
• You've got six billion of these pairs of
nucleotides in each of your cells, and amongst
these six billion nucleotide pairs are roughly
30,000 genes.

DNA Double Helix
Nitrogenous
Base (A,T,G or C)
“Rungs of ladder”
“Legs of ladder”
Phosphate &
Sugar Backbone

Nitrogenous Bases
• PURINES
1. Adenine (A)
2. Guanine (G)
• PYRIMIDINES
3. Thymine (T)
4. Cytosine (C) T or C
A or G

Chargaff’s Rule
• Adenine must pair with Thymine
• Guanine must pair with Cytosine
• Their amounts in a given DNA molecule will be about
the same.
G CT A

DNA Double Helix
P
P
P
O
O
O
1
2
3
4
5
5
3
3
5
P
P
P
O
O
O
1
2 3
4
5
5
3
5
3
G C
T A

GENES
• Genes are segments of DNA which contain set
of instructions that decide what the organism
is like, how it survives, and how it behaves in
its environment
• Each person's DNA is different - this is what
makes each of us unique.

Genes
• Genes are the means by which a cell produces
proteins, each of which have a very specific
role.

Genes
• A mutated gene can cause overproduction of
a protein, underproduction of a protein, or
alteration of a protein that may be unable to
carry out its purpose.

Genes
• Oncogenes typically produce more of their
protein product when mutated, while tumor
suppressor genes typically produce less of
their protein product when mutated.

Your genes decide
• Whether you are tall or not
• The color of your hair
• The color of your skin
• Whether you are more likely to develop certain
diseases
• Whether you are good at sports
• How you respond to environmental triggers
• What you look like inside and out
• And so many other things

Genetic Diversity…
• Different arrangements
of NUCLEOTIDES in a
nucleic acid (DNA)
provides the key to
DIVERSITY among living
organisms.

Genes
• The particular order of the
bases is called the DNA
sequence. The sequence
gives the exact genetic
instructions needed to
create a particular organism
with its own unique traits.

Genes
• Specific sequence of bases also
carry the information needed for
constructing proteins.
• These proteins are produced
through process of transcription
,translation etc

Genes
• Proteins provide the structural
components of cells and tissues as
well as enzymes for essential
biochemical reactions. The human
genome is estimated to be made of
more than 30,000 genes.

MUTATIONS
• Loss of DNA
• Gain of DNA
• Changes in nucleotides
• Epigenetic effects

DAMAGE TO DNA OR MUTATIONS
• Any change in DNA
sequence of base
pairs

Because of Deletions A deletion could be as small as a single base or
as large as the gene itself.
• .

Insertions are mutations in which extra
base pairs are inserted into a new place
in the DNA. Because of insertion

A substitution is a mutation that
exchanges one base for another Or reciprocal translocation

In an inversion mutation, an entire
section of DNA is reversed. Because of inversion

• Errors may occur during
replication, transcription, or translation.

MUTATIONS OR DAMAGE TO DNA
Terminal
Deletion
Ring
Chromosome
Robertsonian
Translocation
Deletion Reciprocal
translocation
IsochromosomesInsertion Inversion
Duplication

MUTATIONS OR DAMAGE TO DNA
Nucleotide
Deletions
Nucleotide
Insertions
Nucleotide
Substitutions

• Before a cell divides, the DNA is checked to make
sure it has replicated correctly. (If DNA does not
copy itself correctly, a gene mutation occurs.

• A point mutation, or single base
substitution, is a type of mutation that causes
the replacement of a single base nucleotide
with another nucleotide of the genetic
material, DNA or RNA. Often the term point
mutation also includes insertions or deletions
of a single base pair.
• As was shown in previous slides.

• Point mutations that occur in non-coding
sequences are most often without
consequences, although there are exceptions.

• If the mutated base pair is in the promoter
sequence of a gene, then the expression of
the gene may change.

• An organism's DNA affects how it looks, how it
behaves, and its physiology for example
division of cells , growth etc. So a change in an
organism's DNA can cause changes in all
aspects of its life.
• Your DNA contains a set of instructions for
"building" a human. These instructions are
inscribed in the structure of the DNA molecule
through a genetic code.

• The sequence of these bases encodes
instructions. Some parts of your DNA are
control centers for turning genes on and
off, some parts have no function, and some
parts have a function that we don't
understand yet. Other parts of your DNA are
genes that carry the instructions for making
proteins — which are long chains of amino
acids. These proteins help build an organism.

• Somatic mutations occur in non-reproductive
cells and won't be passed onto offspring.
• The only mutations that matter to large-scale
evolution are those that can be passed on to
offspring. These occur in reproductive cells
like eggs and sperm and are called germ line
mutations.

• There are many types of mutations that
change not the protein itself but where and
how much of a protein is made. These types
of changes in DNA can result in proteins being
made at the wrong time or in the wrong cell
type. Changes can also occur that result in too
much or too little of the protein being made.

Carcinogen or Mutagen
• A carcinogen or
mutagen is any
substance or agent
that, damages or
alters cell DNA.

• A carcinogens may be
the initiator — the
agent that alters or
damages DNA, the
basic coding system
of cells.
• They may also be
promoters —
encouraging out-of-
control cell growth

Human viral pathogens
• Oncogenic RNA
Viruses, Oncogenic DNA
Viruses
• Retroviruses (HIV)
• Epstein-Barr viruses
• Herpesviruses-HSV-2
• HBV
• Papovaviruses
• Adenoviruses

• Ionizing radiation
• UV from the sun and
tanning lamps
• X-rays: medical and dental
• Radon, cosmic rays, and
gamma radiation

• Solar UV radiation is associated with skin
cancers – squamous CA, basal cell
CA, malignant melanoma, air-skinned and
elderly are susceptible

• Earlier use of X-rays caused skin
cancer, leukemia and papillary thyroid CA
• Radiotherapy causes radiation-induced
malignancy 10-30 yrs later – usually sarcomas
• Diagnostic X-rays are considered to have no
increased risk except in abdominal x-rays
which increase incidence of leukemia in the
fetus.

• Radioisotopes
• Osteosarcoma common among factory workers
who use radium-containing paints
• Radioactive mineral mining in Europe and USA
associated with lung cancer
• Thorium increases risk of liver cancer –
hepatocellular, angiosarcoma, cholangiocarcinom
a
• Radioactive iodine – increased risk of cancer 15-
25 years later.

• Nuclear Fallout
• Hiroshima, Nagasaki (atomic blasts), Marshall
islands (atmospheric testing of nuclear device
containing radioactive
iodine), Chernobyl, 1986.

• Nutritional deficiency (having antioxidant effect)
• Protein deficiency
• Carotenes and retinoid - deficiency
• Tocopherols - deficiency
• Selenium (glutathione peroxidase) - deficiency
• Zinc deficiency
• Flavanoids (enzyme inhibition) - deficiency
• Vit C deficiency
• Vit E deficiency
• High fat
• Low-fiber diet and colonic CA
• Fatty diet with breast ca
• Betel leaves with oral ca

• Industrial chemicals
• Exposure to pesticides
• Agricultural chemicals
• Asbestos
• vinyl chloride
• benzene
• Hydrocarbons in cigarette smoke
• Aflatoxin: fungal product
• Nitrosamines and amides
Converted to nitrites by gut
bacteria
• food preservatives
• food dyes

• Aromatic amines and azo
dyes
• Polycyclic aromatic
hydrocarbons
• Tobacco smoke
• benzene
• carbon tetrachloride
• vinyl chloride
• asbestos fibers
• pesticides
• dioxins

• Carcinogenic substances may be inhaled, absorbed
through the skin or even ingested in some cases. Effect
of carcinogenic chemicals used in industrial processes
is felt beyond the workplace
• Often water is contaminated and air is polluted by
carcinogens, causing additional cancers in surrounding
communities.
• The idea of carcinogens (in soot)was first put forward
in 1775 as doctors discovered a high incidence of
scrotal cancer among chimney sweeps in uk.

• Hormonal Oncogenesis & drugs (promotors)
• Promoters enhance proliferation of initiated cells. Expand
population of initiated cells
• Increase risk of additional mutations (during DNA synthesis)
• Oral Contraceptives
• Estrogens/ Progesterones/Androgens
• prolactin, thyroxin
• Phenobarbital
• Estrogen – breast ca,enodmetrial hyperplasia ->
endometrial cancer
• Diethylstilbestrol (DES) – vaginal and uterine ca

• Breakdowns in immunity
• Healthy immune system can target and destroy
cancer cells. When cancer cells have altered
proteins at its surface, cells are not destroyed.
Risk of cancer increases With age.
• HIV infection
• Immunosuppressant drugs
• Anxiety and depression

• Inflammation like
• Chronic hepatitis -> hepatocellular carcinoma
• Colitis -> colon cancer
• Osteomyelitis sinus tracts -> squamous cancer
• Chronic bronchitis -> lung cancer

• Genetic Oncogenesis (Role of Inheritance)
• Association with inherited diseases,Mendelian
Inheritance, Dominant or Recessive.
• Examples
• Retinoblastoma
• Wilm’s tumor
• Neurofibromatosis (type 1 von Recklinghausen’s disease)
• Multiple endocrine adenomatosis (MEN)
• Familial polyposis coli
• Nevoid basal cell carcinoma syndrome
• Syndromes of immunodeficiency

• Besides
• O2 free radicals DNA
damage
• Foreign bodies

Normal Cell/Mutated Cell
DNA of a normal cell DNA of mutated cell

Damage to p53 gene
• When DNA is damaged there might also occur
damage to p53 gene. Due to damage to p53
gene the DNA repair protein gets inactivated
and there fore does not repair DNA.

Damage to p53 gene
• p53 gene damage also leads to inhibition of
apoptosis. So that damaged cell if not repaired
would get killed and destroyed by immune
system & killer cells had there been no
damage to p53 gene.

APOPTOSIS
Programmed cell death
Orderly & normal cellular self destruction

APOPTOSIS: important in embryogenesis
Morphogenesis (eliminates excess cells):
Selection (eliminates non-functional cells):

APOPTOSIS: important in embryogenesis
Immunity (eliminates dangerous cells):
Self antigen
recognizing cell
Organ size (eliminates excess cells):

APOPTOSIS: important in adults
Maintains organ size and function:
Apoptosis
+ cell division
Cells lost by apoptosis are replaced by cell division
X

APOPTOSIS: Role in Disease
TOO MUCH: Tissue atrophy
TOO LITTLE: Hyperplasia
Neurodegeneration
Thin skin
etc
Cancer
Athersclerosis
etc

APOPTOSIS: Role in Disease
Cancer
Most cancer cells are defective in apoptotic response
(damaged, mutant cells survive)
High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins
===> CANCER

Immune Surveillance System
• Apoptosis normally eliminates aged and damaged
cells or excess cells that are not needed through
different mechanisms e.g through immune
surveillance system as follows
• through
• 1) Natural killer (NK) cells
• 2) Cytotoxic T-cells

• 3) B-cells :
• Tumor associated antigens stimulate
production of specific antibodies by host B-
cells
• These specific antibodies bind together on
tumor cell surface leading to destruction of
tumor through cytotoxic T-cells that kill IgG-
coated tumor cells

• Healthy immune system would target and
destroy mutated cells. But the mutated cells
have developed altered proteins at their cell
surfaces,neoantigens & tumor-associated
antigens. Therefore escape recognition and
destruction by immune system.(Failure of
Immune Surveillance)

• Risk of cancer increases: With age When an
immune system has been suppressed for a
long time , HIV infection, Immunosuppressant
drugs. Anxiety and depression

Mechanisms by which tumor escape immune defenses:
1) Reduced levels or absence of MHCI molecule on tumor so
that they can not be recognized by CTLs
2) Some tumors stop expressing the antigens
These tumors are called “antigen loss variants”
3) Production of immunosuppressive factors by tumor e.g.
transforming growth factor (TGF-β)
4) Tumor antigens may induce specific immunologic tolerance

5) Tumor cells have an inherent defect in antigen
processing and presentation
6) Blocking of receptors on T-cells by specific antigen
antibodies complex (after shedding of tumor Ag)
prevents them from recognizing and attacking tumor
cells
7) Antigens on the surface of tumors may be masked by
sialic acid-containing mucopolysaccharides
8) Immune suppression of the host as in transplant
patients who show a higher incidence of malignancy

2. Normal Chemical Signals tell Normal cell
when to start and stop dividing.

Damage to p53 gene
• Two genes involved in apoptosis are the tumor
suppressor gene p53 and the bcl-2 proto
oncogene.
• Tumor-suppressor genes p53, function like
brakes, keep cell numbers in check .

Control of the Cell Cycle
• Cell division or Mitosis goes through several
stages such as
• Prophase
• Metaphase
• Anaphase
• Telophase
• and Cytokinesis

• Then the cell enters Interphase, which is an
intervening stage at which the cell prepares
for the next cell division or goes into resting
phase where the cells undergo differentiation
to specific cell type.

• Interphase consists of sub-stages such as G1, S
and G2; where, G stands for the gap in
knowledge

• The G1 phase is----preparatory phase for DNA
replication.
• The S-phase is for DNA replication and repair if
needed
• and G2 stage is a preparatory phase for M-
phase(Mitosis)

Cell cycle checkpoints
• The major checkpoints lie in between G1 and
S phase and G2 and M-phase and another
control point exists within the M-phase events
at anaphase.

• Cell cycle checkpoints are biochemical
signaling pathways that sense damage to the
DNA structure or impaired chromosome
function and elicit complex cellular repair
responses.

• These checkpoints rapidly induce cell cycle
delay, generally at the G1, S, and G2
checkpoints, allowing time for the activation
of DNA repair mechanisms.

• The checkpoints also maintain cell cycle arrest
while the repair takes place and initiate cell
cycle progression once repair is complete . If
the DNA cannot be repaired adequately, the
cell then undergoes permanent cell cycle
arrest and apoptosis.

Function of check points
• Can DNA synthesis begin?
• Has DNA synthesis been completed correctly?
And go for mitosis
• Are all chromosomes attached to spindle?
• Can sister chromatids separate correctly?

• Damage to p53 also causes disturbance in
proof reading of DNA prior to replication at G1
phase of mitosis.(failure at check point)
• Cancer cells lose normal restraints for
replication of damaged DNA and G1/S
progression of cells with damaged DNA

• If cell receives “GO” signal, it divides
• By Internal signals: cell growth (size), cell
nutrition
• By external signals: “growth factors”
• If cell does not receive signal, it exits cycle &
switches to G0 phase, non-dividing, working
state

Other mechanisms for controlling progress
through the cell cycle are
Length of Telomeres
Chemical Signals from within and outside
the cell

Chemical Signals that Control the Cell Cycle
1. Cyclin and Kinase
-proteins that initiate mitosis
-requires buildup of cyclin to pair with kinase
2. Hormones
-chemical signals from specialized glands
that stimulate mitosis
3. Growth Factors
-chemical factors produced locally that stimulate
mitosis

Failure to Stop at
Cell Cycle Checkpoints
Mutation in a gene that
usually slows the cell
cycle
Rate of cell division is
accelerated.
Failure to pause for
DNA repair
Faulty DNA leads to
unregulated cell growth.
Loss of control over
telomere length
Cancer cells have
telomerase, an enzyme
that elongates telomeres.
Cells continue to divide
after 50 mitoses.

• Incorrectly repaired DNA, however, continues
to replicate, leading to accumulation of the
mutation and, thus, elevated cancer risk.
Studies have shown that mutations in cell
cycle control genes, such as p53 and p21, are
directly linked to chromosomal aberrations
and genomic instability

• Mutation is thus passed on to daughter cells
that results in Successive accumulation of
mutations.

1st & 2nd Mutations
• The genetically altered
cells have, over time,
reproduced unchecked,
crowding out the
surrounding normal
cells. The growth may
contain one million cells
and be the size of a
pinhead. At this point
the cells continue to
look the same as the
surrounding healthy
cells.

Contact Inhibition: (density-dependent
inhibition of growth)
• Two or more normal cells come in contact
with each other, they tend to stop dividing
and form a single layer or sheet of cells called
a confluent monolayer.
• Cancer cells will continue to grow and pile up
on top of each other even after forming the
monolayer.

• Normally cells attach to each other by various
cell junctions so that they are fixed in place
• Communicate with each other via Growth
Factors
• But all such things are lost when cell is
mutated.
• In other words cells Escape Regulations.

• Cancer cells do not respond to crowding; loss
of contact inhibition
• Leads to a disorganized mass

Interaction of a Cell at Risk
with a Carcinogen Can Produce
an Initiated Cell
• An initiated cell is the first step in
formation of a tumor
• For an initiated cell to become a
tumor both the Promotion and
Progression stages have to occur
• The larger the number of initiated
cells the higher the breast cancer
risk
Cells
at
Risk

Initiation Promotion Progression
•Mutation
•Cancer Gene
•Proliferation
•Independence
•Mutation
•Invade & Spread
Stages of Cancer Formation
Unspecialized
Cell
Initiated
Cell
Benign
Tumor
Malignant
Tumor
Latency Period, 20 years or more

Third mutation
• Not all mutations that lead to cancerous cells result in the cells
reproducing at a faster, more uncontrolled rate. For example, a
mutation may simply cause a cell to keep from self-destructing.
All normal cells have surveillance mechanisms that look for
damage or for problems with their own control systems. If such
problems are found, the cell destroys itself.
Over time and after many cell divisions, a third mutation may
arise. If the mutation gives the cell some further advantage, that
cell will grow more vigorously than its predecessors and thus
speed up the growth of the tumour.

Fourth mutation
• The new type of cells grow rapidly, allowing for more
opportunities for mutations. The next mutation paves
the way for the development of an even more aggressive
cancer.
At this point the tumour is still contained as has not
broken basement membrane –carcinoma in situ.

Breaking through the membrane
• The newer, wilder cells created by another mutation are able
to push their way through the epithelial tissue's basement
membrane, which is a meshwork of protein that normally
creates a barrier. The invasive cells in this tumour are no
longer contained.
At this point the cancer is still too small to be detected.

Angiogenesis
• Often during the development of earlier stages of the tumour, or
perhaps by the time the tumour has broken through the
basement membrane (as pictured above), angiogenesis takes
place. Angiogenesis is the recruitment of blood vessels from the
network of neighbouring vessels.
• Without blood and the nutrients it carries, a tumour would be
unable to continue growing. With the new blood
supply, however, the growth of the tumour accelerates; it soon
contains thousand million cells and, now the size of a small
grape, is large enough to be detected as a lump

Invasion and dispersal
• The tumour has now invaded the tissue beyond the basement
membrane.
Individual cells from the tumour enter into the network of
newly formed blood vessels, using these vessels as highways
by which they can move to other parts of the body. A tumour
as small as a gram can send out a million tumour cells into
blood vessels a day.

Tumour cells
travel - metastasis
• What makes most
tumours so lethal is
their ability to
metastasize -- that
is, establish new
tumour sites at other
locations throughout
the body.
Secondary tumours.
• Metastasis is now
underway, as tumour
cells from the original
cancer growth travel
throughout the body.
Most of these cells will
die soon after entering
the blood or lymph
circulation.

Metastasis
• To form a secondary tumour, a tumour cell needs to leave the
vessel system and invade tissue. The cell must attach itself to
a vessel's wall. Once this is done, it can work its way through
the vessel and enter the tissue.
Although perhaps less than one in 10,000 tumour cells will
survive long enough to establish a new tumour site, a few
survivors can escape and initiate new colonies of the cancer.

Changes observed when a normal tissue
culture cell is transforming to a tumor
• Changes observed when a normal tissue cell
is transforming to a tumour are as follows.
• 1. Alterations in the nucleus
• 2. Plasma membrane related abnormalities
• 3. Adherence abnormalities
• 4. Growth and division abnormalities
• 5. Defective differentiation

• 6. Inability to undergo apoptosis following
DNA damage
• 7. Anaplasia: Loss of differentiation, meaning
literally “without form”
• 8. Cell division fixes the mutation in daughter
cells
• 9. hyperplasia and stimulate growth
• 10.loose control over the cell division process
• 11.do not adhere to each other
• 12.do not resemble normal cells
• 13.do not carry out functions of normal cells

• Dysplasia
• Abnormal change in the size, shape, and
organization of cells in a tissue
• Often an early step toward cancer
• Microscopic characteristics of cancer cells
• Behave differently from normal cells
• they are precancerous stages and turn into
cancer

Growth Factors Regulate When Cells Divide

NORMAL CELL
Growth factor
Growth factor receptor
Signal transduction
Activation of
transcription
cytoplasm
nucleus

Relationship between gene products of
proto oncogene
Growth factors eg IGF
Growth factor receptors
Eg erb-2, ret
Signal transducing
factors
Eg cytoplasmic
kinases
DNA binding proteins
concerned with
transcription
cell cycle
proteins eg
cyclin D

NEOPLASTIC CELLS
Increased
In growth
factor
Increased
In growth
factor
receptors
Increased in
signal
transduction
Increase in
activation of
transcription

Length of Telomeres
Telomeres are structures
at the ends of
chromosomes that
shorten with each cell
division. After 50
divisions, the shortened
length of telomeres
causes mitosis to stop.
telomeres

Summary
• Cancer develops through four definable
stages:
• initiation
• promotion
• progression
• and malignant conversion.

Summary
• The first stage, initiation in which DNA
damage takes place
• If repair does not take place will lead to
promotion phase in which mutated cell is
stimulated to grow and divide faster and
becomes a population of cells.

Summary
• During progression, there is further growth
and expansion of the tumor cells over normal
cells and leads then further mutations in
daughter cells until conversion occurs and cell
does not resemble normal cell at all but
becomes a tumor cell

Summary
• In a 2000 article by Hanahan and
Weinberg, the biological properties of
malignant tumor cells were summarized as
follows

Summary
• Acquisition of self-sufficiency in growth
signals, leading to unchecked growth.
• Loss of sensitivity to anti-growth signals, also
leading to unchecked growth.
• Loss of capacity for apoptosis, in order to
allow growth despite genetic errors and
external anti-growth signals.

Summary
• Loss of capacity for senescence, leading to
limitless replicative potential (immortality)
• Acquisition of sustained
angiogenesis, allowing the tumor to grow
beyond the limitations of passive nutrient
diffusion.

Summary
• Acquisition of ability to invade neighbouring
tissues, the defining property of invasive
carcinoma.
• Acquisition of ability to build metastases at
distant sites

Classification of bronchogenic
carcinoma

carcinoma
• Correct classification of lung cancer cases are
necessary to assure that lung cancer patients
receive optimum management

carcinoma
• There are two types of lung cancers
• 1.Non-small cell lung cancer
• 2.Small cell lung cancer

Non-small cell lung cancer
• Consist of three subtypes
• Squamous cell (epidermoid) carcinoma
• Adenocarcinoma (previously called
bronchioloalveolar carcinoma)
• Large cell (undifferentiated) carcinoma

Non-small cell lung cancer
• The cells in these subtypes differ in
size, shape, and chemical make-up when
looked at under a microscope. But they are
grouped together because the approach to
treatment and prognosis (outlook) are very
similar.

Squamous cell (epidermoid)
carcinoma
• These cancers start from squamous
cells, which are flat cells that line inside of the
airways in the lungs.

carcinoma
• Squamous cell
carcinoma usually starts
in one of the larger
airways.
Therefore, these tumors
tend to be located in
the central area(middle)
of the lung near the
bronchus.

carcinoma
• This form of NSCLC has decreased in
frequency over the past three decades, but is
still the most common form of lung cancer
among men who are current or former
smokers or over age 65 years of both sexes.

Adenocarcinoma of lung
• Adenocarcinoma is a cancer of an epithelium
that originates in glandular tissue.
Adenocarcinoma of the lung tends to stain
mucin positive as it is derived from the mucus
producing glands of the lungs.

• Similar to other adenocarcinoma, if this tumor
is well differentiated (low grade) it will
resemble the normal glandular structure.

• Poorly differentiated adenocarcinoma will not
resemble the normal glands (high grade) and
will be detected by seeing that they stain
positive for mucin (which the glands produce).

• This cancer usually is seen
peripherally in the lungs, as
opposed to small cell lung
cancer and squamous cell lung
cancer, which both tend to be
more centrally located,

• Generally, adenocarcinomas grow more slowly
than the other subtypes.

• Adenocarcinoma is a non-small
cell lung carcinoma, and as
such, it is not as responsive to
radiation therapy as is small cell
lung carcinoma, but is rather
treated surgically, for example
by pneumonectomy or
lobectomy.

• The solitary appearance of this neoplasm
suggests that the tumor is primary rather than
metastatic.

• Adenocarcinoma is the
most common form of
lung cancer found in
women, and is often
found in non-smokers.

• Most common type of lung cancer among all
Asians.
• Appears to be increasing in young, non-
smoking women.

• Lung adenocarcinoma has been increasing in
recent years, whereas another form of non-
small cell lung cancer, squamous cell
carcinoma, has been decreasing. It is thought
by some that the addition of filters to
cigarettes allows smoke to be inhaled more
deeply into the lungs where adenocarcinoma
occurs.

• Because lung adenocarcinoma often begins in
the outer parts of the lungs, well-known
symptoms of lung cancer such as a chronic
cough and coughing up blood may be less
common until later in the disease.

• Seen here is the multifocal
variant

• that appears grossly as a
pneumonic consolidation.
• Most of the upper lobe toward
the right has a pale tan to grey
appearance.

• Microscopically, the bronchioloalveolar
carcinoma is composed of columnar cells that
proliferate along the framework of alveolar
septae. The cells are well-differentiated. These
neoplasms in general have a better prognosis
than most other primary lung cancers.

Large cell (undifferentiated)
carcinoma
• It may appear in any
part of the lung. It tends
to grow and spread
quickly, which can make
it harder to treat.

carcinoma
• The cells of large cell
carcinoma (LCC) are the
largest of the various
types of NSCLC. The
cells are generally
highly undifferentiated
or immature in
appearance.

carcinoma
• Some experts believe these tumors represent
adenocarcinomas or squamous cell
carcinomas that are so undifferentiated as to
be unrecognizable.

carcinoma
• The prognosis for large cell carcinoma is
generally less favorable than for other forms
of NSCLC.

OTHER CANCERS IN THE LUNGS
• There are other types of non-epithelial
cancers that arise in the lungs. They are all
relatively uncommon compared to SCLC and
NSCLC.

OTHER CANCERS IN THE LUNGS
• Examples of these cancers include
• Carcinoid tumors, malignant pleural
mesotheliomas, fibrosarcomas, and
leiomyosarcomas. The lungs are also a
frequent location for metastatic tumors from
other locations in the body.

SMALL (OAT) CELL CARCINOMA
• Small (Oat) cell
carcinoma accounts for
about 20-30% of all lung
cancers
• It has, in the past, been
called oat cell cancer
because the cells
resemble oat grains.

• when seen under a
microscope the cells
appear small round or
oval, or shaped like oat
grains.

• it is thought to originate from neuroendocrine
cells (APUD cells) in the bronchus called
Feyrter cells (named for Friedrich Feyrter)
• Hence, they express a variety of
neuroendocrine markers, and may lead to
ectopic production of hormones like ADH and
ACTH that may result in paraneoplastic
syndromes and Cushing's syndrome.

• The tumor cells cause increased secretion of
adrenocorticotropic hormone (a hormone
from the adrenal gland), causing Cushing’s
disease, which is characterized by a puffy face,
weight gain, hump on the lower neck, or
elevated blood sugar levels.

• Antidiuretic hormone, also secreted by these
tumor cells, lead to water retention and low
sodium, which(SIADH)can cause confusion.
Small cell carcinoma antibodies also can cause
weakness by the tumor-producing antibodies
against normal tissues (autoantibodies).

• Small cell lung cancer is a neuroendocrine
carcinoma that exhibits aggressive behavior, rapid
growth, early spread to distant sites, exquisite
sensitivity to chemotherapy and radiation, and
frequent association with distinct paraneoplastic
syndromes.
• The cancer spreads easily because of the constant
flow of blood and lymph through the lungs. The
fluids can carry cancer cells to the other
lung, lymph nodes, and organs outside of the
chest.

• There is usually early involvement of the hilar
and mediastinal lymph nodes.

• Prognosis
• In limited-stage disease, median survival with
treatment is 14–20 months, and about 20% of
patients with limited-stage small-cell lung
carcinoma live 5 years or longer.

• The prognosis is far worse in extensive-stage
small-cell lung carcinoma, with
treatment, median survival is just 8–13
months, and only 1–5% of patients with
extensive-stage small-cell lung carcinoma
treated with chemotherapy live 5 years or
longer.

• Approximately half of all individuals diagnosed
with Lambert-Eaton myasthenic syndrome
(LEMS) will eventually be found to have a
small-cell carcinoma of the lung.

• Arising centrally in this
lung and spreading
extensively is a small
cell anaplastic (oat cell)
carcinoma. The cut
surface of this tumor
has a
soft, lobulated, white to
tan appearance.

• The tumor seen here has
caused obstruction of the
main bronchus to left
lung so that the distal
lung is collapsed. Oat cell
carcinomas are very
aggressive and often
metastasize widely before
the primary tumor mass
in the lung reaches a large
size.

• Here is an oat cell
carcinoma which is
spreading along the
bronchi. The speckled
black rounded areas
represent hilar lymph
nodes with metastatic
carcinoma.

• These neoplasms are
more amenable to
chemotherapy than
radiation therapy or
surgery, but the
prognosis is still poor.
Oat cell carcinomas
occur almost exclusively
in smokers.

• This is the microscopic
pattern of a small cell
anaplastic (oat cell)
carcinoma in which
small dark blue cells
with minimal cytoplasm
are packed together in
sheets.

Pulmonary Hamartoma
• Here are two examples
of a benign lung
neoplasm known as a
pulmonary hamartoma.

Pulmonary Hamartoma
• These uncommon
lesions appear on chest
radiograph as a "coin
lesion" that has a
differential diagnosis of
granuloma and localized
malignant neoplasm.

Pulmonary Hamartoma
• They are firm and
discreet and often have
calcifications in them
that also appear on
radiography. Most are
small (less than 2 cm).

Metastatic carcinoma
• Multiple variably-sized
masses are seen in all
lung fields. These tan-
white nodules are
characteristic for
metastatic carcinoma.

Metastatic carcinoma
• Metastases to the lungs are
more common even than
primary lung neoplasms
simply because so many
other primary tumors can
metastasize to the lungs.
Even the hilar nodes in this
photograph demonstrate
nodules of metastatic
carcinoma. The nodules are
usually in the periphery and
do not cause major
obstruction.

Mesothelioma
• The dense white
encircling tumor mass is
arising from the visceral
pleura and is a
mesothelioma. These
are big bulky tumors
that can fill the chest
cavity.

Mesothelioma
• The risk factor for
mesothelioma is
asbestos exposure.

Signs symptoms of bronchogenic
carcinoma

carcinoma
• Persistent cough
• Persistent haemoptysis
• Persistent wheeze & stridor
• Persistent dyspnea

carcinoma
• Pneumonitis fever productive cough
• Chest pain from pleural or chest wall
involvement
• Symptoms of lung abcess from tumour
cavitation

carcinoma
• Haematogenous,lymphatic or direct spread to
pleura resulting in malignant pleural effusion
• Superior vena caval obstruction resulting in
superior vena caval syndrome
• Tracheal obstruction leading to stridor and
dyspnea

carcinoma
• Oesophageal obstruction leading to dysphagia
• Recurrent laryngeal nerve involvement with
resultant hoarsness of voice and bovine cough
• Phrenic nerve involvement resulting in
diaphragmatic paralysis and dyspnea

carcinoma
• Sympathetic chain involvement leading to
horner's syndrome(pancosts tumour)
• Direct extension to chest wall resulting in rib
pain and pathological fractures, intercostal
neuralgia
• T1 involvement
• Pericardial and cardiac involvement with
resultant cardiac temponade,arrythemias or
cardiac failure

Metastasis to other organs
• Brain metastasis with neurological deficits
• Bone metastasis
• Bone marrow involvement with pancytopenia
• Liver metastasis
• Lymph node metastasis
• Metastasis to spinal cord & cord compression

Paraneoplastic syndrome(Result from
peptide secretion of tumour)
• Endocrine
• SIADH-Syndrome of inappropriate secretion of
antidiuretic hormone
• resulting in hyponatremia,cushings
syndrome, ectopic production of parathyroid
hormone resulting in hypercalcaemia and
hypophosphatemia

• Neuromuscular
• Eaton Lambert syndrome, peripheral
neuropathy,cerebellar degeneration, cortical
degeneration,polymyositis

• Skeletal
• Clubbing ,hypertrophic pulmonary
osteoarthropathy

• Haematological
• Migratory venous
thrombophelbitis(Trousseaus
syndrome),DIC,anaemia,granulocytosis or
pancytopenia

• Cutaneous
• Dermatomyositis,acanthosis nigricans
• Renal
• Nephrotic syndrome,glomerulonaphritis
• and many more

Investigations
• x ray chest
• May show opacity,cavitation,effusion,collapse or
consolidation
• Unilateral enlargement at hilum ,glandular
enlargement
• Mediastinal widening due to mediastinal
involvement
• etc etc

Investigations
• Cytological examination of the following may be
positive for malignant cells
• Sputum
• Bronchial brushing
• Bronchial washings
• Percutaneous needle aspiration biopsy of
peripheral tumour
• Fine needle aspiration of lymph node, skin or
liver

Investigations
• CT SCAN(computed tomography) of chest and
abdomen
• is an important investigation for staging
• Evaluation of tumour size
• CT guided biopsy
• To assess response to treatment

Investigations
• Bronchoscopy
• For visualisation and biopsy of intrabronchial
tumour
• Collection of bronchial washings

Other investigations
• Scalene node biopsy
• Mediastonoscopy
• Pleural aspiration and biopsy
• Barium swallow
• Ultrasound abdomen
• Bone scans
• Bone marrow biopsy
• CT brain
• Whole body scan spine etc
• Then all other routine tests and full blood count

MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR

MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR

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MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR