Neoplasia

• Neoplasia means “new growth”.

• A neoplasm is an abnormal mass of
tissue, the growth of which exceeds and is
in-coordinated with that of the normal
tissues and persists in the same excessive
manner after the cessation of stimuli which
evoked the change.
• Neoplasms are independent of physiologic
growth regulatory stimuli
• Oncology means study of tumors
• Dysplasia means the presence of cells of
an abnormal type within a tissue, which
may signify a stage preceding the
development of cancer.
• Is reversible
• Neoplasms can be benign or malignant
• Benign neoplasms behave in an innocent
fashion, remain localized and are
amenable to local surgical removal
• Cancer means crab like. They adhere to
any part that they seize in an obstinate
manner like a crab
• Term “malignant” is applied to a neoplasm
which can invade and destroy adjacent
structures & spread to distant sites
• Tumors are composed of two basic
components
1. Parenchyma made up of neoplastic cells
2. Supporting, host derived, non-neoplastic
stroma, made up of connective tissue,
blood vessels and host-derived
inflammatory cells
 Nomenclature
Benign Tumors: Their names are derived by
attaching suffix “oma” to the cell type from
which the tumor is arising eg. Fibroma,
chondroma.
Adenoma is a benign tumor arising from
glandular epithelium
Papilloma is c/o finger like fronds
Polyp is a mass projecting over a mucosaal
surface
 Malignant tumors:
• Arising from connective tissue are called
Sarcomas like fibrosarcoma,
chondrosarcoma, osteosarcoma
• Arising from epithelium are called
Carcinomas eg Adenocarcinoma,
Squamous cell CA and Transitional cell
CA
• Lymphoma, Mesothelioma, Melanoma and
Seminoma are malignant tumors
Hamartoma is a malformation and is  
composed of tissue elements normally
found at that site, but which are growing in
a disorganized mass.
 Characteristics of Benign &
Malignant Neoplasms
1. Differentiation and Anaplasia
• Differentiation means the extent to which
the tumor cells resemble the original cells
both anatomically and functionally
• Benign tumors are composed of cells
which closely resemble the normal cells
• Malignant tumors show wide range of
differentiation from well to undifferentiated
• Anaplasia is a condition in which cells
have poor cellular differentiation, losing
the morphological characteristics of
mature cells and their orientation with
respect to each other 
• The more rapidly growing and the more
anaplastic a tumor is, less likely it will have
a specialized functional activity
• Anaplastic cells also show pleomorphism,
large hyperchromatic nuclei, high N/C
ratio, tumor giant cells and atypical
mitosis.
• Dysplasia  refers to an epithelial anomaly
of growth and differentiation 
• Loss in uniformity of individual cells and in
their architectural orientation
• Display some pleomorphism,
hyperchromasia and mitosis
• CA in situ
2. Rate of Growth
• Malignant tumors generally grow at a
faster rate than benign neoplasms
• Rate of growth is influenced by blood
supply and pressure
• Rate of growth of malignant neoplasms
correlates with their level of differentiation
• Rarely carcinomas have disappeared due
to necrosis leaving behind mets
• Many tumors special cells called stem
cells which initiate and sustain the tumor
• Constitute a small population of cells
• Anticancer therapy which leaves behind
stem cells may not be effective
3. Local Invasion
• A benign neoplasm remains localized at its
site of origin
• Does not infiltrate, invade or metastasize
• Most benign tumors are encapsulated or
have a margin of cleavage around them
• But lack of capsule does not mean that
tumor is malignant
• Cancers infiltrate, invade and penetrate
into surrounding structures
• Do not develop capsules and grow in a
crab like manner necessitating a wide
margin of excision
• After metastasis, local invasion is the most
reliable feature of malignancy
4. Metastasis
• Development of secondary implants
discontinuous with the primary tumor
• Most authentic criterion of malignancy
• Capacity to metastasize varies from Basal
cell carcinoma to Osteosarcoma
• Generally larger and more anaplastic the
tumor, the more chance of metastasis
Methods of Metastasis
a) Spread by Seeding:
• When neoplasms invade a natural body
cavity eg ovarian cancers spread to
peritoneum but do not invade the
underlying tissues
• Medulloblastoma invade cerebral
ventricles and are spread via CSF
b) Lymphatic Spread:
• Carcinomas vs Sarcomas
• Carcinomas first spread to regional lymph
nodes
• Rarely spare the regional nodes and get
trapped in further lymph nodes—skip
metastasis OR cells may traverse all the
lymph nodes to reach the vascular
compartment via thoracic duct
• Sentinal lymph node
c) Hematogenous Spread:
• Favored pathway for sarcomas. May also
be used by carcinomas.
• Cancer cells gain entry into veins more
easily than arteries.
• Since portal blood flows to liver and caval
blood to lungs, these are frequent sites of
hematogenous mets.
• Cancers of thyroid & prostate spread into
vertebral veins and metastasize to
vertebrae
• Renal carcinomas invade renal vein and
grow in a snake like fashion uptill inferior
vena cava
 Cancer Epidemiology

1. Incidence of cancer in men has slightly

decreased due to decrease in incidence
of lung cancer
• Incidence of cancer in women has
decreased due to decrease in cancers of
uterine cervix, stomach & large bowel.
• Incidence of lung CA in women is
increasing
2. Geographical & Environmental Factors:
• Death rate for breast CA is 4-5X high in
USA and Europe as compared to Japan
• Death rate for CA stomach is 7X higher in
Japan as compared to USA
• HCC is much higher in Africa & south east
Asia as compared to USA
• Differences are due to environmental
rather than genetic causes
3. Age:
• In general frequency of cancer increases
with age.
• Most cancer deaths are between 55 and
75 years of age. Mostly due to mutations
• 10% deaths in children upto 15 years are
due to cancer as leukemia, CNS tumors,
soft tissue sarcomas bone sarcomas and
lymplomas
4. Heredity
a) Inherited cancer syndromes in which
inheritance of a single mutant gene
increases the risk of cancer eg
Retinoblastoma. 40% of these are
familial due to inherited tumor
suppressor gene which increases
chance by 10000X.
• Familial adenomatous polyposis: People
with inherited gene develop innumerable
polyps of colon with 100% chance of CA
b) Familial Cancers:
• Most cancers which occur sporadically
also have familial forms eg. CA breast,
colon, ovary and brain.
• Features of familial cancers are early age,
tumors in two or more close relatives and
multiple or bilateral tumors
c) Autosomal recessive syndrome of
Defective DNA repair:
• Small group of autosomal recessive
tumors eg. Xeroderma pigmentosa
5. Acquired Preneoplastic Disorders
• Persistent regenerative cell Replication as
in squamous cell CA in margin of chronic
skin fistula or long standing unhealed skin
wound
• Hyperplastic & dysplastic proliferations
eg. Endometrial CA in atypical
endometrial hyperplasia and broncho CA
in dysplastic bronchial mucosa of
cigarette smokers
• Chronic Atrophic Gastritis eg Gastric CA
in pernicious anemia
• Chronic ulcerative colitis with increased
incidence of colorectal CA
• Leucoplakia of oral cavity with increased
risk of squamous cell CA
• Villous adenoma of colon with high risk of
transformation into colorectal CA
The Molecular Basis of Cancer
• Cancer arises due to non lethal damage or
mutation to the genome
• These could be inherited or acquired by
environmental factors as chemicals,
radiation and viruses.
• Tumors arise from a single cell which has
been damaged ie they are monoclonal
• Principal target of genetic damage are:
1. Growth promoting proto-oncogenes
2. Growth inhibiting tumor suppressor genes
3.Genes which regulate Apoptosis
4.Genes involved in DNA repair
• The mutant alleles of proto-oncogenes are
called oncogenes
• Mutation of a single allele can cause
cellular transformation ie. They are
dominant
• Tumor suppressor genes are recessive
• Genes controlling Apoptosis may be
dominant or recessive
• Tumor progression ie ability to invade
tissues, metastasize and hormonal
responsiveness is due to multiple
mutations which accumulate in different
cells.
Changes in cell physiology which
cause malignancy
1.Self sufficiency in growth signals:
Proto-oncogenes and Oncogenes
Products of oncogenes are oncoproteins
• In normal cells a growth factor binds to its
receptor on cell membrane.
• Activates proteins on inner leaflet
• Transmission of signal to nucleus
• Initiation of DNA transcription
• Entry of cell into cell cycle
• Cancer cells acquire self sufficiency by
following methods
A) Growth Factors: Many cancer cells
acquire ability to synthesize growth factors
to which they are responsive eg GBM
secrete PDGF and express PDGF
receptor on cell membrane
• Some sarcomas produce TGF-alpha and
its receptor
B) Growth Factor Receptor: Some
oncogenes cause over expression of
growth factor receptors
• Mutant receptor proteins deliver
continuous signals to cells even in
absence of growth factors
• Over expression of normal receptors
• Example is over expression of EGF
receptor in squamous cell CA of lung
• HER2/NEU in 30% breast cancers
C) Signal Transducing proteins: These
causing signaling downstream of growth
factor receptors
• Examples are RAS & ABL
• 30% human tumors contain mutated RAS
• Shuttles between excited and quiescent
states
• Mutated proteins are active continuously
• ABL is translocated in chronic myeloid
leukemia
D) Nuclear transcription factors: Growth
autonomy can occur due to mutations in
genes which regulate transcription of DNA
• Example is MYC proto-oncogene. Controls
cell cycle. In normal cells level of MYC
proteins drops rapidly when cell cycle
begins.
• Mutated oncogene remains at high level
resulting in sustained proliferation
• Translocated in Burkitt lymphoma
• Amplified in Neuroblastoma
E) Cyclins and Cyclin dependent Kinases
• Cell cycle is tightly regulated by proteins
Cyclins and cyclin dependent kinases
(CDKs)
• More than 15 cyclins have been identified
• Of these D, E, A and B take important part
in cell cycle
• CDKIs halt cell cycle Of these p21, p27,
p57 and INK-4
• So these act as tumor suppressors
• Mutations or down regulation of CDKIs are
associated with many cancers as
pancreatic CA, oesophageal CA
2. Insensitivity to growth –Inhibitory signals
• Tumor suppressor genes apply brakes to
cell proliferation.
• Disruption of these genes make cells
refractory to growth inhibition and mimic
action of oncogenes
• Retinoblastoma (RB) gene is a cancer
suppressor gene
• 60% retinoblastomas are sporadic and
rest are familial
• RB gene & cell cycle

Prepare to
divide

Cells
mature
• G1 to S is a crucial step. Once cells cross
G1 checkpoint they have to complete
mitosis.
• Signals acting here determine whether cell
will enter cell cycle, exit it and differentiate
or die.
• RB plays a key role at this point.
• It shuttles between active
(hypophoshorylated) and inactive
(hyperphosphorylated) form
• Loss of normal cycle control is basis of
malignant transformation
• Most human cancers are associated with
mutations of one of the 4 regulator genes
namely CDKIs, cyclin D, CDK4 and RB
gene.
• Many oncogenic viruses as HPV encode
proteins which bind to RB gene and
inactivate it
 p53 Gene: Guardian of the Genome
• P53 is a tumor suppressor gene and is
mutated in many cancers.
• It prevents neoplastic transformation by 3
mechanisms
1. Activation of temporary cell cycle arrest–
quiescence
2. Induction of permanent cell cycle arrest–
senescence
3.Triggering of Apoptosis
• In healthy non stressed cells p53 has a short
life of 20 minutes
• It is destroyed by binding to a protein MDM2
• When cell is stressed by damage to its DNA,
p53 is modified, released from MDM2 and is
activated.
• The cell cycle is halted temporarily in late G1
phase.
• P53 also stimulates DNA repair mechanisms
• This pause gives time for DNA to repair itself.
• If DNA damage is repaired, p53 induces
formation of MDM2 which destroys p53
and releases the pause in G1 phase.
• If DNA is not repaired, p53 induces a
permanent cell cycle arrest (senescence)
by activation of p53, RB gene and CDKIs
OR
• P53 induces apoptosis by pro apoptotic
genes like BAX
• With homologous loss of p53, DNA
damage goes unrepaired, mutations
become fixed in dividing cells and
neoplastic transformation begins.
• More than 70% human cancers show
mutations of p53 genes including the top
killer cancers namely lung, colon and
breast.
• Rarely p53 mutation is inherited
• These people have a 35 fold great chance
of developing cancer by age of 50 years
• P53 is inactivated by hepatitis B & Epstein
Barr viruses
3. Evasion of Apoptosis
• Mutation of genes regulating apoptosis
can lead to neoplastic change in cells
• Cancer cells can avert apoptosis in a
number of ways:
1. Decreased level of CD95
2. Increased level of FLIP in tumor cells
3. Over expression of anti apoptotic BCL2
due to t(14;18) translocation thus
protecting tumor cells from apoptosis
4. p53 mutations
4. Limitless Replicative Potential
• Most human cells have capacity of 60-70
divisions
• After this they lose the capacity of mitosis
and enter senescence.
• This is due to shortening of Telomeres
• Cancer cells evade telomere shortening
and acquire potential of limitless
replications
5. Development of Sustained Angiogenesis
• Tumors cannot grow more than 1-2mm in
diameter without formation of new blood
vessels.
• Cancer cells stimulate neo-angiogenesis in
which new vessels sprout from existing
capillaries or vaculogenesis in which
endothelial cells are recruited from bone
marrow
• Newly formed endothelial cells produce
growth factors which promote tumor cells
• Also required for Metastasis
• Angiogenic switch ie production of
angiogenic factors and loss of angiogenic
inhibitors is necessary for tumor
enlargement
• Induced by hypoxia
• p53 stimulates anti-angiogenic molecules
Thrombospondin-1
• Loss of p53 induces angiogenesis
• Proteases produced by tumor cells or
stromal cells can also result in
angiogenesis or inhibit it.
6. Ability to Invade and Metastasize
A) Invasion of Extracellular Matrix

Requires 4 stages:
1)Detachment of tumor cells from each other
• Normal cells are bound to each other by
E-cadherins. This function is lost in
cancers by inactivation of E-cadherin due
to mutations or activation of beta-catenin
2) Degradation of ECM (BM & interstitial CT)
• Proteolytic enzymes are produced
• Are secreted by tumor cells or stromal
cells (fibroblasts, inflammatory cells) in
response to tumor.
• Proteases include Metalloproteinases
(MMPs) & Cathepsin D
• Many cancers show increase in MMP
levels
• Use of protease inhibitors as
chemotherapeutic agents.
 3) Attachment to novel ECM components
• In malignant tumors the matrix is modified
in different ways which promote invasion
and metastasis
• Cleavage of basement membrane proteins
like Laminin by MMPs unfolds special sites
which bind to tumor cells and help them to
migrate
 4) Migration of tumor cells
• Is a complex procedure involving many
receptors and signaling proteins
• Most cytokines are derived from tumor
cells having autocrine function
• Others are chemotactic for tumor cells
• Thus signaling between tumor cells and
stromal cells can promote or prevent
spread.
 B) Vascular Dissemination & Homing of
Tumor Cells
• Inside the blood vessels tumor cells travel
singly or in form of emboli by aggregating
to WBCs and platelets
• As emboli they are protected from host
immune cells
• Finally extravasate by binding to
endothelium and egressing through
basement membrane into another organ
or tissue
What determines the site of Metastasis?
• Many tumors metastasize to that organ
which represents the first capillary bed
they come across in circulation
• Tumor spread is also determined by
adhesion molecules expressed by tumor
cells which have ligands on endothelium of
target organs
• Tumor cells also show chemotaxis towards
certain chemokines. So spread to tissues
expressing those chemokines
 Etiology of Cancer
• Cancer is caused due to damage to DNA
• What inflicts this damage?
A. Chemical Carcinogens:
1. Direct Acting Agents
• Do not require metabolic conversion to
carcinogens
• Are weak carcinogens
• Some are used as chemotherapeutic drugs
eg Alkylating agents
2. Indirect Acting Agents
• Require metabolic conversion to actual
carcinogens eg tobacco combustion in
cigarettes cause formation of benzo
pyrene & other carcinogens
• Polycyclic hydrocarbons– present in
smoked meat
• Hydrocarbons contain epoxides which
combine to DNA and RNA
• Aromatic amines: Beta –Nahpthylamine
caused bladder cancer in people working
with aniline dyes
• Aflatoxin B1--- a fungus which grows on
improperly stored food, is related with
HCC
• Azo dyes, vinyl chloride, insecticides and
fungicides are carcinogens
• Nitrites used as food preservatives form
Nitrosamines which are thought to be
carcinogens
 Mechanism of Action of Chemical
Carcinogens:
• Attach to DNA and cause mutations
• Most likely affected genes are p53, RAS.
• Carcinogenicity of many cancers is
enhanced by administration of initiator
chemical carcinogen followed by
promoters as hormones, phenols and
some drugs
• Initiator is mutagenic and promoter
induces cell proliferation.
3. Radiation Carcinogenesis
• Oncogenic properties of ionizing radiation
are due to its mutagenic effect
• Cause chromosome breakage (most
common), translocations & point mutations
• UV rays cause melanomas, squamous cell
CA and Basal cell CA
• Mostly affects fair skinned people
• Some DNA damages are repaired by
nucleotide excision repair pathways
• Extensive damage overwhelms this
4. Viral & Microbial Oncogenesis
a) Oncogenic RNA Viruses
• Human T cell leukemia virus-1 causes T
cell leukemia and affects CD4 cells
• HTLV-1 virus encodes for TAX protein
• Causes formation of cytokines and their
receptors on infected T cells
• Results in autocrine and paracrine
signaling loops and T cell proliferation
 b) Oncogenic DNA Viruses
• Human Papillomavirus infection acts as
loss of tumor suppresser gene, activates
cyclins, inhibits apoptosis and opposes
cellular senescence
Is the cause of Squamous Cell CA of cervix
and 20% oropharyngeal cancers.
• Epstein-Barr Virus causes Burkitt
lymphoma, lymphoma in
immunosuppressed people and
nasophryngeal CA
• Hepatitis B and C viruses are linked with
HCC. Is the result of persistent
inflammation, injury and repair
• Helicobacter pylori implicated in gastric CA
and MALT lymphoma