NEOPLASIA

(2010-2011)

Dr.H.M.Zahawi,FRC.Path
OBJECTIVES
Definitions of terms used in neoplasia
Nomenclature of tumors
Characteristics of benign & malignant
tumors
Routes of metastasis
Epidemiology of CANCER
The molecular basis of neoplasia
Carcinogenesis
Tumor immunity
The clinical effects of tumors
Tumor grading and staging
The laboratory diagnosis of neoplasia
General terms used :
Neoplasm = New growth of cells producing a
mass
Benign neoplasm = Limited new growth
without invasion or spread
Malignant neoplasm = invasive growth that
also spreads
Carcinoma : Malignant tumor of epithelial cells
Sarcoma : Malignant tumor of connective tissue
cells
Lymphoma



Cancer is a general term for all
malignant growths of whatever type
Tumor may be used instead of
neoplasm but the term is not accurate
Oncology : study of cancer in all its
aspects

NEOPLASM :

Abnormal mass of tissue, the growth of
which EXCEEDS and is UNCOORDINATED
with that of of the normal tissues, and
PERSISTS in the same manner even
AFTER CESSATION of the stimulus which
produced the change
A neoplasm develops from a single
transformed cell !!!



Features of transformed cells :

Persistent & useless
Uncontrolled growth *
Immortal
Transplantable




This cell may arise from :
Endoderm
Mesoderm
Ectoderm

Epithelial cells may arise from any
of the above
Connective tissue is from mesoderm



Classification of Tumors :

Cell of origin
Behavior of tumor : Benign or malignant
Appearance of the tumor: Solid/cystic
Degree of differentiation



Structure of neoplasms :
- Parenchymal cell
- Stromal ( supporting cell )

Degree & type of stromal cells may
contribute to the appearance of tumors

If there is stromal proliferation hardness of
the tumor Scirrhous tumor Desmoplasia
e.g.carcinoma of breast, pancreas..etc
If there is lack of many stromal cells, the
tumor may be soft or cystic.
This feature may be included in the name
of the tumor..e.g
Cystadenoma of ovary
Poorly differentiated cystadenocarcinoma of
ovary
Moderately differentiated scirrhous
carcinoma of breast

Serous cystadenoma of ovary

Scirrhous Carcinoma of breast
Benign Epithelial tumors :
Adenoma - glandular epithelium tumor
often producing a secretion e.g.
(mucin) which may be intraepithelial or
intraluminal
Papilloma epithelial tumor forming
finger like projections from epithelial
surface with a connective tissue core
Polyp a tumor projecting from the
mucosal surface of a hollow organ

Structure of Polyp

Malignant epithelial tumor :
Carcinoma

Squamous cell carcinoma e.g. skin,mouth
cervix, bronchus.etc

Adenocarcinoma from glandular origin,
e.g.G.I.T.,endometrium,breast, kidney,
thyroid..etc
Connective tissue cell origin :


Benign :
Named by tissue of origin with attached
suffix oma
e.g. fibroma, lipoma, chondromaetc

Not all endings ( oma) are benign tumors
e.g. : granuloma,lymphoma, hamartoma,
choristomaetc
Malignant connective tissue tumors:


SARCOMA :
Prefix (origin)+ suffix (sarcoma) e.g.
Osteosarcoma, liposarcoma, angiosarcoma
leiomyosarcoma, rhabdomyosarcoma
Some tumors are MIXED !!!
Mixed Tumors :
Tumors derived from a single germ cell layer
that differentiates into more than one cell type.
e.g. mixed tumor of salivary gland,
Fibroadenoma of breast
OR :
Teratomas made of a variety of parenchymal
cell types that derive from more than one germ
cell layer formed by totipotent cells that are able
to form ectoderm, endoderm & mesoderm


TERATOMA :

May be benign or malignant depending
on structure, site, age, sex .

Contain skin ,sebaceous & mucus
glands,hair,cartilage, bone, respiratory
epithelium, glial tissue..etc.

Usual location is ovary or testes


Tumors of primitive fetal origin :


Blastoma : from immature tissue
May arise in kidney, liver, retinaetc
e.g. Retinoblastoma

The great majority of these tumors are
malignant & occur in infants & children


Some tumors have names that do not
conform with general rules :

Melanomas arise from nevus cells
Seminomas arise from testicular germ cells
Lymphomas arise from lymph nodes
Some tumors are named eponymously
e.g. Hodgkins disease, Wilms tumor.etc

Note : See table on page 176
Some tumors are NOT true
neoplasms
Hamartoma :
Tumor like malformation in which there
is abnormal mixing of normal components
of the organ ,either in the form of change
in quantity or arrangement of tissue
elements.
e.g. Lung Hamartoma.


Choristoma :

Different types of tissue, ectopic to the
region.
e.g. Meckles Diverticulum,
Salivary tissue in LN

Both are present at birth & do not become
malignant .


How do benign & malignant
tumors differ?
Differentiation & anaplasia
Rate of growth
Presence of capsule
Local invasion
Distant metastases
Benign versus malignant tumors
- This indicates the degree of resemblance
of the tumor cell to its cell of origin,
functionally & morphologically.
e.g

Cells of a lipoma may look exactly like
normal fat cells.



1- Differentiation:
LIPOMA LIPOSARCOMA
Features of differentiation include :
Epithelial cells :
- formation of glands
- formation of keratin
- formation of secretionetc
Connective tissue cells :
- formation of osteoid
- presence of lipoblasts
- Striations in tumors of skeletal
muscle.etc

Well formed glandular architecture
No acini ! SIGNET CELLS


- When a tumor cell loses its differentiation
it gradually gains features of
DYSPLASIA

It is a process of gradual loss of
differentiation

It is an abnormal growth which may
precede malignancy

Complete loss of differentiation =
ANAPLASIA



Cytological Features of Dysplasia
Increased nuclear size , | N/C ratio
Variation in nuclear & cell size :
PLEOMORPHISM
Loss of differentiating features
Increased nuclear DNA content
HYPERCHROMATISM

Features of dysplasia (continued) :-

Nucleoli :Prominent, sometimes multiple
Mitotic figures : Increased
Abnormal mitoses: may be present
Loss of polarity : in an epithelial surface

Severe Dysplasia/ Anaplasia
Intraepithelial Neoplasia

Dysplasia involving an epithelial surface
Low grade & High grade
High grade dysplasia ,limited by
epithelial basement membrane =
CARCINOMA IN SITU


Intraepithelial Neoplasia
NOTE :
Not all dysplasias progress to higher
grade or carcinoma in situ.
Not all carcinoma in situ progress to
invasive CA
Some cases of dysplasia can regress

Rate of growth usually correlates with
level of differentiation
May be rapid in some benign tumors
Some tumors may shrink in size
Some malignant tumors may outgrow
their blood supply
2- Rate of growth
Some tumor growths are semicontroled :
HORMONE DEPENDENCE :


This is through presence of receptors on surface

- Breast CA
- Thyroid CA
- Prostatic CA

Benign tumors frequently have a capsule
Malignant tumors progressively invade
& destroy surrounding tissue
e.g.Breast cancer infiltrating skin
Basal cell carcinoma face
infiltrating nerve
*Second most important feature
distinguishing malignant tumors
3- Local invasion & Encapsulation
Spread of malignant tumors to distant
sites not contigious with the main tumor
Most important in diagnosing
malignancy
All tumors can potentially metastasize
except BASAL CELL CARCINOMA
Metastasis is often proportionate to the
size and differentiation of the primary
tumor

4- Metastasis :
Routes of metastases :

Lymphatics
Blood vessels
Seeding within body cavities/
Transcoelomic Spread
1- Lymphatic Spread :
More characteristic in Carcinoma
Spread follows the anatomical route of
drainage unless skip metastases e.g.
Breast cancer in left upper upper
quadrant Left axillary L.N.
In medial quadrant internal mammary
chain supraclavicular & infraclavicular
Lung Ca - Peribronchial tracheobronchial
LNs hilar LNs
IMPORTANT IN SURGICAL RESECTION :

Sentinal Lymph Node :
First lymph node in the pathway of
a primary tumor.
Usually outlined by dye

Not all enlarged L.N.s indicate metastases
e.g. Reactive hyperplasia
Histiocytic infiltrate in sinuses
2- Hematogenous spread :

Usually venous first following anatomical
drainage : Lung & Liver
More characteristic of Sarcoma ,but may
in occur in later stages of carcinoma
Certain carcinomas invade veins early
RENAL Carcinoma renal vein IVC
Hepatocellular Carcinoma Portal &Hepatic v.


3- Transcoelomic spread:
Within peritoneal or pleural cavity e.g.:
CA of upper lobe of lung to lower
lobe
CA of stomach to ovary
CA of ovary tends to spread widely
through peritoneal surface
CA of colon across peritoneum to
S.I.& colon



BENIGN vs MALIGNANT


Anaplastic
High mitotic index
Rapid growth
Infiltrative growth
without capsule
Invasion
Metastases

Well-differentiated
Low mitotic index
Slow Growth
With capsule
No invasion
No metastases

Summary : Differences between
benign & malignant neoplasms
EPIDEMIOLOGY of CANCER

2006 Estimated US Cancer Cases*
*Excludes basal and squamous cell skin cancers and in situ
carcinomas except urinary bladder.
Source: American Cancer Society, 2006.
Men
720,280
Women
679,510
31% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Non-Hodgkin
lymphoma
4% Melanoma of skin
3% Thyroid
3% Ovary
2% Urinary bladder
2% Pancreas
22% All Other Sites
Prostate 33%
Lung & bronchus 13%
Colon & rectum 10%
Urinary bladder 6%
Melanoma of skin 5%
Non-Hodgkin 4%
lymphoma
Kidney 3%
Oral cavity 3%
Leukemia 3%
Pancreas 2%
All Other Sites 18%

2006 Estimated US Cancer Deaths*
Men
291,270
26% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkin
lymphoma
3% Uterine corpus
2% Multiple myeloma
2% Brain/CNS
23% All other sites
Lung & bronchus 31%
Colon & rectum 10%
Prostate 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4%
bile duct
Esophagus 4%
Non-Hodgkin 3%
lymphoma
Urinary bladder 3%
Kidney 3%
All other sites 23%


Incidence may be related to ethnic &
geographic differences in community :

Nasopharyngeal CA
Cervical CA & Cancer of the penis
Burkitt Lymphoma
Multiple myeloma
Chronic lymphocytic leukemia
Genetic polymorphism is responsible
for :
Individual predisposition to disease

Individual response to environmental
agents

Individual response to drugs


FACTORS WHICH MAY PLAY A ROLE IN
THE INCIDENCE OF CANCER INCLUDE :
1- Geographic location :


Gastric CA -- High in Japan
Skin CA------ High in New Zealand
Hepatocellular CA --- High in Africa,China
Breast CA ---- High in USA
Prostatic CA ---- High in USA
Colorectal CA ----High in USA
Nasopharyngeal CA--- Far East
Burkitt Lymphoma ----- Africa




CANCERS common in JORDAN include :

Lung CA
Colorectal CA } MALES
Prostate CA
---------------------------------------------
Breast CA
Colorectal CA } FEMALES
Lung CA
Lymphomas are also common

2- Environment :

Diet
Occupation
Sunlight
Personal habits


3- Age :

In general , cancer incidence AGE
However , certain cancers occur
more in children
Acute Leukemia
Some Lymphoma
Some CNS Tumors
Bone &soft tissue Sarcomas

4- Heredity :
5-10% of tumors

Inherited Cancer Syndromes :
Presence of defined genetic abnormality,
usually AD, often specific phenotype e.g.
APC gene : Familial Adenomatous
Polyposis Coli
MEN1 & RET genes : MEN syndrome
NF1 & NF2 genes : Neurofibromatosis
RB gene : Retinoblastoma

Familial cancers : No specific phenotype
& multifactorial

Family members have higher incidence
to common cancers
- CA of COLON
- CA of BREAST
- CA of OVARY
Younger age groups, multiple or
bilateral, two or more family members
are affected.
Some linked to inheritance of mutant
genes e.g. BRCA-1 & BRCA-2

AR syndromes of DNA Repair :
Chromosomal & DNA instability
Best example :

XERODERMA PIGMENTOSUM
5- Acquired Preneoplastic Syndromes

These are associated with increased risk for CA
and most are related to rapid or abnormal cell
proliferation .

1- Endometrial Hyperplasia & carcinoma
2- Cervical Dysplasia & Cervical CA
Bronchial dysplasia & lung CA
3- Liver Cirrhosis & Hepatocellular

Acquired preneoplastic syndromes
(continued)

4- Chronic healing process
5- Ulcerative Colitis & Colorectal CA
6- Villous Adenoma & Colorectal CA
7- Leukoplakia & Squamous cell CA





MOLECULAR BASIS OF
CANCER
Neoplasms arise from a single clone
of cells :
Group of cells produced from a single
ancestral cell by repeated cellular
replication.
Thus they can be said to form a single
"clone".
MONOCLONAL
Principles :
Tumors arise from clonal growth of cells
that have developed mutations in four
classes of genes :
Growth promoting proto-oncogenes
Growth inhibiting tumor suppressor genes
Genes regulating apoptosis
Genes involved in DNA repair
More than one mutations in above result
in abnormal growth of cells


Carcinogenesis is a
MULTISTEP PROCESS !
Multistep Carcinogenesis :
Steps in Neoplastic Transformation :
1-Non lethal damage TRANSFORMATION

2-Cell Proliferation : initially Polyclonal
MONOCLONAL CELLS

3-Genetic instability of malignant phenotype
cells with diverse features progression of
tumor INVASION & METASTASES






Heterozygous
X-linked marker:
G6PD isoenzyme.
In females
heterozygous for
G6PD, normal
tissues contain
two populations of
cells whereas
their neoplasms
are homozygous
for one isoenzyme
Monoclonal proliferation
Clinical Examples :
Chronic myeloid leukemia (CML):
Philadelphia Chromosome (9:22 )
Multiple Myeloma single immuno-
globulin specific for the tumor.
T&B cell lymphomas : specific gene
rearrangement

Tumor Progression :

This is the stepwise accumulation of
mutations resulting in increasing
features of malignancy.
GENES IN NEOPLASTIC
TRANSFORMATION
Genes in Neoplastic Transformation:
Outline of Gene Action :
Proto-oncogenes
Normal genes whose products
(Oncoproteins) promote cell growth

Oncogenes are mutant versions of proto-
oncogenes that function autonomously
without normal signals
Arise from mutant proto-oncogenes
They are dominant genes.
They include :
Growth factors
Cell surface receptors
Signal transduction proteins
Nuclear transcription factors
Cell cycle proteins
Inhibitors of apoptosis


1-Genes coding for growth :
Classified by site of action
1-Oncogenes coding Growth Factors
Normal Cell growth is stimulated by GF
Platelet derived growth factor (PDGF)
seen in glioblastomas
Fibroblast growth factor(FGF)-stomach CA
& melanomaetc
Transforming Growth Factor (TGF-o)in
sarcomas
Products of other oncogens (e.g.RAS) may
cause over expression of GF
2-Oncogenes coding Growth Factor
Receptors
GF integrate with membrane receptors
tyrosine kinase activity nucleus
Mutant receptor continuous signals even in
the absence of GF..OR
Normal but overexpressed hypersensitive to
GF
Epidermal GF receptor family:
ERBB1 in 80% of sq.CA lung
ERBB2 ( HER 2 NEU) in 25-30% of breast
& ovarian CA ---
Increase = POOR PROGNOSIS
3- Oncogenes in Signal Transduction:
RAS & non receptor ABL
RAS action:

GDP GTP proliferation


Mutations in GAPs(NF1):Neurofibromatosis
Commonest oncogen mutation
Point mutations in codon 12, 13 are present
in >30% of cancers, specially CA pancreas &Colon

Active RAS
GTPase activity by (GAP)
Action of ABL : Non receptor associated
tyrosine kinase signal transmission
Normal ABL is located in nucleus where it
promotes apoptosis
Chronic myeloid leukemia : Mutation
9:22 translocation BCR- ABL gene
This new gene is retained in cytoplasm
where it has tyrosine kinase activity
cell proliferation
New action is Proliferation +No Apoptosis
4-Nuclear Transcription Factors :
DNA transcription regulated by genes e.g.
MYC*, JUN, FOS.etc.
In normal :MYC protein + DNA Activation
of Cyclin Dependant Kinases ( CDKs)
initiation of cell cycle +MYC
MYC mutation sustained activation
Examples :
Dysregulation of MYC present in Burkitts
lymphoma (t8:14)
Breast ,colon, lung CA & neuroblastoma

5- Cyclins & Cyclin Dependant
Kinases regulate Cell Cycle phases

Family of proteins that control entry of
the cells at specific stages of cell cycle
( D, E, A, B.etc.)
Level of a specific cyclin increases at a
specific stage, then decreases rapidly
after the cell departs that stage
Function by phosphorylating certain
proteins ( e.g.RB protein)
Cyclins bind to CDKs, activating them



G2
(Labile cells)
G0
(Stable
cells)
(Permenant
cells)
G0
G1
S
M
CELL CYCLE PHASES
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 5 November 2007 08:09 AM)
2007 Elsevier
Two important groups :

- Cyclin D family CDK4 & CDK6 at
G1 S phase checkpoint
- Cyclin B-CDK1 activate G2 M transition

Activity of CDK/ Cyclin regulated by
CDK inhibitors
Non selective wide inhibition :
p21, p27 and p57
Selective effect on cyclinD/CDK4 &
cyclinD/CDK6 :
p15, p16, p18, and p19


Cyclin/CDK/RB function
Loss of normal cell cycle control is
central to malignant transformation&
at least one of the following is mutated in
most human cancers :
- Cyclin D
- CDK 2, CDK 4, CDK 6
- CDK inhibitors
- RB
Mutations that disregulate activity of
cyclins & CDKs cell proliferation
Examples :
Cyclin D is overexpressed in breast,
liver, & esophageal cancers
Amplification of CDK4 gene present in
melanoma, sarcomas, glioblastoma


Growth inhibitory pathway by:

* Regulate cell cycle : Rb gene
* Regulate cycle & apoptosis: P 53
* Block GF signals: TGF-|
* APC regulates |-catenin

Cancer suppressor genes are recessive
genes which may be lost in familial or
sporadic cases.


2- Cancer Suppressor Genes:-
1- RB gene :
First studied in Retinoblastoma:
Called RB gene
Both copies of gene must be lost
for neoplastic transformation to occur
This is called loss of heterozygosity


Retinoblastoma :
Autosomal dominant hereditary disease
May be sporadic
In familial, patients carry one mutation in
their genome
No tumor develops unless two alleles
in 13q14 become mutant (two hit theory)
incidence of bilateral Retinoblastoma
and osteosarcoma

Inheritance of Retinoblastoma
Mode of action of RB gene:
RB exists in active nonphosphorylated
& inactive phosphorylated forms.
Active RB binds to transcription factors
(E2F) NO TRANSCRIPTION
CyclinD/CDK4, and cyclinE/CDK2
phosphorylate RB.
Inactive RB releases transcription factor
E2F TRANSCRIPTION (G1 S phase )
Many oncogenic DNA viruses may act
similarly by inactivating RB


Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 5 November 2007 08:09 AM)
2007 Elsevier
2- P 53
70% of tumors show homozygous loss of
p53
p53 is a negative regulator of cell cycle,
present in low levels with short half life
MDM2 protein which targets it for
destruction
Called Guardian of the Genome OR
(Policeman) preventing genetically damaged
cells from progressing through new cycle.


Mode of activation & action :
P53 senses DNA damage through various
sensors e.g. ATM protein
P53 is activated by anoxia, or DNA
damage and accumulates in cell with long
half life after release of MDM2
Activated p53
Transcription of CDKI(p21) cell cycle arrest
at G1
Transcription of GADD45 ( repair gene)
p53 is a regulator of apoptosis




More time for repair Normal
Failed repair Apoptosis or Senescence
(permanent cell cycle arrest)

Fixed mutation NEOPLASIA
Action of p53
P53 may show the following :
Acquired mutation in many cancers
e.g. colon, breast, lung , leukemiaetc
Inherited mutation in Li - Fraumeni S.
sarcoma, leukemia, breast carcinom
and gliomas .. etc
May be blocked by some DNA viruses
producing viral induced cancers
3- TGF-|
Antiproliferative activity:
- regulation of RB pathway at G1 by
action on some cyclins & CDKs
- blocks GF signals

Mutational inactivation of TGF- |
components seen in 100% of pancreatic
carcinoma & the majority of colonic CA
4- APC gene
Cytoplasmic protein , acts as an adhesion
molecule by regulating level of
|-catenin in cytoplasm
* APC--- |-catenin --- E-Cadherin
Result intercellular adhesion
* Mutant APC -- |-catenin nucleus
Result stimulates proliferation

Individuals with inherited one mutant
allele of APC develop 100s to 1000s of
adenomatous polyps in their 2
nd
.-
3
rd
.decade of life
Additional mutations colonic carcinoma
100% || risk in familial polyposis coli
70-80% of sporadic colonic carcinoma
show mutant APC
Mutations in genes involved in programmed
cell death which regulate mitochondrial
permeability promoting or suppressing
apoptosis.
BAX, BAK promote permeability
BCL-2 , BCL-XL inhibit permeability
BH3-only protein regulates the ballance
BCL-2 prevents apoptosis, prolonging life.
Activated by translocation (18:14)
Follicular B cell Lymphoma
3- Evasion of Apoptosis :


These are specialized structures at the
end of chromosomes which are
shortened after each division and may
play a role in determining the life of
individual cells.
Shortening is prevented by TELOMERASE
Active in stem cells, not in somatic cells
Majority of cancers | telomerase

4-Limitless replication potential(Telomeres)

Repair mutations in other genes
Persons with inherited mutations in
these genes are at risk for cancer
These include :
1- Nucleotide excision repair genes
Damage by U-V light . Defective in
Xeroderma Pigmentosum
Damage by ionizing radiation
Drugs e.g. nitrogen mustard



5- Genomic instability due to defective
DNA Repair Genes
Repair genes (continued)

2-Mismatch repair genes : These repair
errors in pairing of nucleotides during
cell division
e.g. G+T instead of A+T
( HNPCC).
(Hereditary Nonpolyposis Colonic Ca.)

Repair genes ( continued) :
3- BRCA -1 & BRCA-2
80% familial breast cancer & ovarian CA
BRCA 2 in breast CA in both sexes,
e.g: prostate,ovary, pancreas, stomach CA

Rarely inactivated in sporadic cases.
Tumors remain small or in situ
( <1-2mm.diameter) without angiogenesis
Angiogenesis Antiangiogenesis
Angiogenic Switch
Controlled by hypoxia which induces
angiogenic factors by tumor cells
Hypoxia-Induced Factor(HIF-1o) VEGF
RAS mutation | VEGF
Proteases from tumor or stroma | VEGF


6- Development of Sustained Angiogenesis :
Anti- Angiogenesis :
VHL protein can destroy HIF-1 o No
VEGF so VHL acts as tumor suppressor
Germ line mutation of VHL hereditary
renal CA , hemangiomas in CNSetc
Anti-angiogenic factors : e.g.
P53 antiangiogenic thrombospondin
Inactivation of P53 angiogenesis
- | vascular density = Poor prognosis

Tumors may generate clones with different
phenotypic features, accumulate
mutations, leading to a more aggressive
nature e.g.
Non antigenic growth , Increase rate of growth,
Invasion, Metastases etc
Rate of generation of these clones differs
in individual tumors e.g.
Osteosarcoma versus Basal Cell Carcinoma
7- Ability to invade & metastasize
Metastatic Pathway:

Metastases occurs in two phases :

1- Invasion :
Loosening of intercellular junctions
Attachment
Degradation of ECM
Migration

2- Vascular dissemination

1- Mechanism of invasion of ECM :
1- Detachment of tumor cells
Inactivation of E-Cadherin OR
activation of | catenin detachment of
tumor cells
- Loss of function E-Cadherin in many CAs -
2- Degradation of ECM by proteases :e.g.
Matrix Metalloproteinase (MMPs)
Cathepsin D
Type IV collagenase


- Result of digestion of ECM Cleavage products
of matrix have chemotactic activity for more
tumor cells

3- Attachment of tumor cells to matrix
components by laminin & integrin
receptors to basement membrane & ECM

4- Migration of tumor cells :
Tumor derived cytokines e.g.
Autocrine motility factor




2- Vascular dissemination :

1- Invasion of the circulation :
Adhesion to endothelium retraction of
endothelium vessel
2- Attack by NK cells, some escape by
formation of a thrombus
3- Escape from circulation :
Adhesion to endothelium retraction of
endothelium escape to tissue
WHAT INFLUENCES SITE OF
METASTASES ?
Anatomical Location
Complimentary adhesion molecule
between tumor cells & target organs
Chemoatractants liberated by target
organs
Protease inhibitors present in certain
tissues
Examples of Tropism ( Homing )
Prostatic Carcinoma Bone
Lung Carcinoma Adrenals & Brain
Neuroblastoma Liver & Bone
Less common sites of metastases include
skin,muscle thyroid,breast.etc.
Spleen , Cartilage , Heart are almost
never involved by metastatic tumours.

Each cancer must result from
accumulation of multiple mutations,
in many genes including those in
apoptosis & senescence

EXAMPLE :
Steps in carcinogenesis may be
followed genetically & histologically :
Different Gene Lesions :
Point mutation mainly in RAS
Balanced translocation mainly in
hematopoietic tumors:
9;22 , 8;14 , 14;18
& rare in solid tumors :Ewing Sarcoma
Gene amplification :
Neuroblastoma : N-MYC
Breast carcinoma : HER2/NEU


Chromosomal deletions: More
in nonhematopoietic & solid tumors
e.g. Retinoblastoma 13q band14
also several in colorectal CA

Chromosomes loss or gain :
( Aneuploidy)

Result : Change in structure or quantity of gene
product

Gene Amplification :


CARCINOGENIC AGENTS




Direct Carcinogens -
Directly produce damage without prior
metabolic conversion
Indirect Carcinogens- (Procarcinogen)
Metabolic conversion in liver by
cytochrome P-450 dependent mono-
oxygenases ultimate carcinogen



- CHEMICAL CARCINOGENS :

Action of chemical carcinogens :
Initiator - Chemical inducing irreversible
DNA damage
Promoter -Augment effect of initiator by
promoting cell growth
e.g. phorbol ester (PTA) activate signal
transduction or GF secretion , hormones,
saccharine ..etc
No tumor develops unless the promoter
is applied AFTER the initiator.
Classes of Chemical Carcinogens :
1- Alkylating Agents : Direct, used in
chemotherapy of cancer may induce
Leukemia
2- Polycyclic Hydrocarbons : Indirect & very
strong e.g.cigarette smoke CA Lung
3- Aromatic Amines & Azo dyes : Rubber &
Food Industry e.g.
| naphthylamine Bladder CA
Chemical carcinogens ( Continued)
4- Nitrosamines : Endogenous or food
preservatives e.g.Gastric & Colon CAetc.

5- Aflatoxin B1 : Naturally occurring
carcinogen present in fungus.
Aspergillus flavus Hepatocellular CA


Mode of action in chemical Carcinogens


Chemical carcinogens contain highly
reactive electrophil groups that combine to
DNA, RNA, or proteins producing mutations
Genes commonly affected are
RAS & P53
May be very specific Signature Mutation
Some strong chemicals act as Initiator &
Promoter e.g. polycyclic hydrocarbon



U-V light :
- Effect depends on intensity of exposure
& quantity of melanin
- Production of pyrimidine dimers in
DNA MUTATION in RAS , P 53
- Failed repair Skin CA
- Skin cancer includes :
Squamous Cell CA
Basal Cell CA
Melanoma


2- PHYSICAL CARCINOGENS :
Ionizing Radiation:

- Explosions | Leukemia after 7 yrs.
Latent period | Breast,colon, thyroid,
lung CA
- Therapeutic exposure | Thyroid CA,
Leukemia
- Mechanism:Free radical injury
Mutations in RAS, RB. P53
Asbestos fiber inhalation :
Mesothelioma & Lung CA


A - DNA Viruses :


Benign squamous papilloma (wart)
groups 1,2,4 & 7
* Low risk groups (6, 11)
Genital Squamous Cell Papilloma
* High risk group ( 16, 18 )
Squamous Cell CA in cervix, vulva,
perianal & oropharyngeal regions



3- VIRAL CARCINOGENESIS :

1- HPV-Human Papilloma Virus

Mode of Action :
HPV have transforming early genes
(E6,E7) inactivate suppressor genes
E6 acts on p53no apoptosis
E7 binds to E2F blocks Rb action &
activates cyclins, & inhibit CDKI
High risk groups have a stronger affinity
of early genes to E2F
Result Cell proliferation








BURKITTS LYMPHOMA **
B CELL LYMPHOMA
HODGKINS LYMPHOMA subset
NASOPHARYNGEAL CA
-----------------------------------------
Post transplant lymphoma
CNS Lymphoma in AIDS patients




2- EBV : Ebstein Barr Virus

Mode of action in Burkitts Lymphoma :
EBV has LMP1 gene- receptor for B lymphocytes

Induce B cell proliferation
Prevents apoptosis by activating BCL2

Controlled POLYCLONAL B proliferation
Infectious Mononucleosis
Dysregulation of c- myc by translocation :
BURKITTS Lymphoma (t 8:14)
Malaria & Malnutrition may play a role in +
immunity ( Lost T cell control ).
In endemic cases EBV is identified in tumor cells



In Nasopharyngeal Carcinoma :
LMP 1 is expressed on epithelial cells
activating cell proliferation
========================
LMP 1 also activates pro- angiogenic
factors
Both in Burkitt Lymphoma &
Nasopharyngeal Carcinoma other
environmental factors play a role




Multifactorial oncogenic effect but mainly
Immunologically mediated chronic liver
disease Cirrhosis Hepatocellular CA in
70 -85% Action :* Cell proliferation
|mutation
* HBV encodes Hbxprot.
growth promoting genes
*Hbx binds to p 53
Inactivates suppressor function
(HCV is similar but HCV core Protein)


3-HBV ( Hepatitis B Virus )

B- Oncogenic RNA Viruses :

HTLV-1 induces Leukemia /Lymphoma
Transmitted sexually,blood or milk
Mode of action :
Virus TAX gene attaches to T cells:
Produce cytokines +receptor autocrine
stimulation proliferation
Suppresses action of TP53 &CDKI
POLYCLONAL MONOCLONAL LEUKEMIA





First described as a cause for peptic ulcer
Multifactorial etiology in gastric CA & gastric
lymphoma ( MALT lymphoma )
Immune mediated gastric damage with FR
Occurs in only 3% after a long latent period
H.pylori contains (Cag A)genes GF
Cell proliferation
Helicobacter pylori in carcinogenesis
Mode of action :
LYMPHOMA :
Chronic gastritis mucosal lymphoid
follicles reactive polyclonal B cells
monoclonal B cells Malt lymphoma
CARCINOMA :
Chronic gastritis atrophy intestinal
metaplasia dysplasia Gastric
Carcinoma
CANCERS --ASSOCIATED CARCINOGEN


CA LUNG Smoking
CA CERVIX Sexual transmission of HPV
CA BLADDER Rubber Industry
CA LIVER Aflatoxin & HBV infection
CA THYROID Radiation
ANGIOSARCOMA of Liver Plastic(PVC)
MESOTHELIOMA Asbestos



TUMOR IMMUNOLOGY
What is Immune Surveillance ?
Normal immunity present to protect
against development of tumors
Evidence ?
When there is no immunity More
Cancers
Patients with congenital immune
deficiency have 200 times |risk of
cancer & immunosuppressed patients
have increased rates of cancers
(Lymphoma)
Explanation of failed survailance
This may be lost during tumor
progression
There may be acquired
immunosuppression produced by
oncogenic agents




Anti tumor Host Mechanisms :
1- Sensitized Cytotoxic T lymphocytes

2- Natural Killer cells may kill tumor cells
without previous sensitization.

3- Macrophages activated by IFN- may
destroy tumor cells

4- Humoral AB mechanisms

Tumor Antigens :
Tumors share MHC with normal cells

Tumor specific & Tumor Associated AGs
may be helpful in diagnosis & follow up of
some tumors
Therefore, they may act as tumor markers


Specific & Associated Tumor AG:
1- Products of mutant oncogenes & tumor
suppressor genes e.g. RAS protein
2- Mutant proteins induced by chemical
and radiation induced tumors
3- Overexpressed normal cellular proteins
or aberrantly expressed e.g. :
Tyrosinase in melanoma
Cancer Testes Genes : MAGE-1(melanoma..)
HER-2 in CA breast
4- Tumor AG produced by oncogenic
viruses in HPV & EBV infection

5- Oncofetal AG: Carcinoembryonic AG
(CEA) in colon and o fetoprotein in
liver CA
6- Several mucins: MUC-1 in breast CA
and CA-125, CA-19-9 in ovarian CA
7- Cell Type- specific differentiation
AG in B lymphomas (CD10&CD20)



Clinical Aspects of Neoplasia
Effects of tumors on body:
Location of tumor is of importance
1- Mass effect by pressing on vital areas
e.g.airway, intestine , BV, brain,nerve
obstruction, infarction , paralysisetc
2- Local destruction of epithelial surface
or BV ulceration , bleeding , infection
3- Hormonal activity


4 - Cancer Cachexia :

Wasting syndrome characterized by
anorexia , loss of body fat & weight,with
marked weakness,anemia & fever.

Reduced food intake but high metabolic
rate

Possibly due to release of cytokines by
tumor cells & macrophages


5 - Paraneoplastic Syndrome :

Systemic symptoms that cant be explained
by effects of local or distant spread of tumor
or hormones appropriate to tumor tissue.
Due to ectopic production of hormones or
other factors
They may precede the tumor or mimic
metastases
They occur in about 10%-15% of
malignant tumors.

Types of Paraneoplastic Syndromes :
Endocrinopathies e.g hyperglycemia,
hypoglycemia, Cushings S..etc
Nerve & Muscle Syndromes e.g
myasthenia gravis
Dermatologic disorders
Osseous & Articular changes
Vascular & hematological changes
Nephrotic syndrome
Well Known Examples of Paraneoplastic
Syndromes
Small Cell CA lung ACTH , ADH, Bone
changes,nervous system disorders
Squamous Cell CA lung & Breast CA
Parathormone related &othersHypercalcemia
Pancreatic & lung CA clotting factors Deep
vein thrombosis
N.B. Hypercalcemia is commonly produced by lytic
bone metastases

examples (continued)

Hepatic & Renal CA Polycythemia
Pancreatic, Gastric CA Carcinoid S.
Advanced Cancers Nonbacterial
thrombotic endocarditis.
Colonic Adenocarcinoma Acanthosis
nigricans
Grading & Staging of Tumors :
Must be documented for all malignant
tumours :
To quantify the aggressiveness of
tumor
To outline mode of therapy
To compare different modes of therapy
To give an approximate prognosis
Prognosis :
This indicates the final outcome of the
disease in terms of 5year or 10 year
survival.
This is influenced by :
Tumor Type e.g. Lung CA versus Lip CA
Tumor Grade & Stage
Host reactions

Grade of tumor: Based on level of
differention :
This indicates the degree of resemblance
of tumor cells to cell of origin and is
always based on microscopic
criteria.
Grade I : Well differentiated tumor
Grade II :Moderately differentiated tumor
Grade III : Poorly differentiated tumor
Grade IV : Anaplastic tumor

STAGE of Tumor :
This indicates the extent of spread of the
tumor.
Clinical ,investigative procedures and
pathological appearance of tumor have to
be used to assess it.
It depends on :
* Size of tumor
* Regional lymph node involvement
* Metastases to distant organs

TNM Staging System :
T : Size and extent of primary tumor(1-4)
N : Presence and extent of lymph node
involvement ( 0-3)
M : Presence or absence of distant
metastasis ( X0-1)
e.g.T1,N1, M0
-----------------------------------
Others : American Joint Committee
staging system ( AJC) Stage 0-IV
- Dukes staging for colonic CA
- Lymphoma Staging system
And many more.etc
Staging is more important than grading
because it affects treatment


CANCER DIAGNOSIS
General Outline :
History & clinical examination
Radiographic techniques
i- X ray
ii- CT scan
iii- MRI
iv- Ultrasound
Laboratory tests : general & specialized




1- Cytological methods :
Study of cells :
- Smear
- FNA, Brush, Fluid tappingetc
Papanicolaou stain (PAP) often used.
False(+), False (-)
- A negative report does not exclude
malignancy, repeat
- Advise biopsy, even if (+ )

1-Morphological Methods :
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2005 Elsevier
Normal PAP smear of Cervix
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2005 Elsevier
Dysplastic Epithelial Cells (PAP smear)
2- Histological methods :

Biopsy of tissue:
Needle & core biopsy , Endoscopic Biopsy,
or open surgical biopsy
Frozen Section (Rapid technique)
Paraffin Section ( 36-48 hrs. or longer )
H&E, Special histochemical stains e.g.
( PAS, CONGO RED, PERLs stains) or by
IMMUNOHISTOCHEMICAL Methods






3- Immunocytochemistry

Staining by use of monoclonal AB directed
against various components in cell may
help in diagnosis of undifferentiated
cancers or help in identifying source of a
metastatic tumor. e.g.
Cytokeratin Carcinoma
Common leukocyte antigenLymphoma
S 100 Neural tissue, melanocytic lesions
Desmin, Vimentin Sarcoma




Undifferentiated Tumor
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2005 Elsevier
Cytokeratin for epithelial cells indicating Carcinoma

Undifferentiated Malignant tumor

Desmin Positive for connective tissue indicating Sarcoma
4-Electron microscopy :
For recognition of desmosomes , or
neurosecretory granules.etc.

5- Flow Cytometry :
For measuring DNA content , detecting
diploid versus aneuploid tumors.etc.
Correlates with rate of growth & prognosis
Useful in the diagnosis & classification of
Lymphoma & Leukemia



Used to identify tumor associated
enzymes, hormones , antigens etc

These are useful as markers for
diagnosis of a tumor OR for assessing
the progress of a known tumor
2- Biochemical Assays :
Tumor markers represent biochemical
indicators of the presence of a tumor.

Their uses are to :
I - Confirm diagnosis.
II -Determine the response to treatment .
III - Detect early relapse.
Present in serum or urine.
Many are present in normal & tumor tissue,
so they are not very specific but their level
is important.
Types of Tumor Markers

1- Hormones :
Human Chorionic Gonadotrophic Hormone
(| HCG)
Elevated levels are seen in Pregnancy
& Gestational Trophoblastic Disease
Calcitonin useful in diagnosis of some
thyroid carcinomas
Ectopic hormones in paraneoplastic S.not used

2- Oncofetal Antigens :

Carcinoembryonic Antigen ( CEA ) :
in fetal tissue & some malignancies
Colorectal CA & Pancreatic CA

Alpha Fetoprotein (AFP) :
Cirrhosis : Elevated
Hepatocellular carcinoma : Extremely high


3- Isoenzymes :


Prostatic Acid Phosphatase ( PAP )

| levels seen in Metastatic prostatic CA
Useful in : * Staging prostatic CA
* Assessment of prognosis
* Response to therapy.



4- Specific Proteins :

Immunoglobulins secreted in
Multiple Myeloma
Prostate -specific antigen ( PSA ) :
Present in epithelium of prostatic ducts.
* | Prostatic hyperplasia &
* ||| in Prostatic CA
* Level correlates with Stage of CA

5- Several mucins

MUC-1 in breast CA
CA-125 in ovarian CA
CA-19-9 in pancreatic & hepatobiliary CA


Methods used include :
PCR (Polymerase Chain Reaction)
FISH (Fluorescent In Situ Hybridization)
Used to detect gene rearrangement,
translocations, amplificationsetc
BCR-ABL Chronic Myeloid Leukemia
Monoclonal proliferation of B or T cells
13q 14 deletion in Retinoblastoma.
3- Molecular Diagnosis :
For prognosis : gene amplification
HER- 2 NEU in breast carcinoma
N-MYC in neuroblastoma
Detection of residual disease in
chronic myeloid leukemia (BCR-ABL)
Detection of genes of hereditary
cancer e.g BRCA-1 in breast cancer










BE AWARE OF CANCER !!!
EARLY DIAGNOSIS of CANCER :
This is very important as many cancers are
curable if they are diagnosed early.
Specific symptoms should be followed up
e.g. Abnormal bleeding
Change of voice
Change in a nevus
Abnormal lump in breast
An ulcer that does not healetc.


Specific procedures :

- Self examination of the breast
- Mammography
- Serial PAP smears for the cervix
- Serial sputum cytology in smokers
- Serial urine cytology in some cases,
e.g. bilharziasis, workers in rubber
Screening for genetic mutations in familial
cancers.