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, chondroma…etc

Not all endings (– oma) are benign tumors

e.g. : granuloma,lymphoma, hamartoma,
choristoma…etc
 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, retina…etc
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, Wilm’s 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. Meckle’s 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
 :Differentiation -1
- 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.
LIPOMA LIPOSARCOMA
Features of differentiation include :
 Epithelial cells :
- formation of glands
- formation of keratin
- formation of secretion…etc
 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 -2
 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
Some tumor growths are semicontroled :
HORMONE DEPENDENCE :

 This is through presence of receptors on surface

- Breast CA
- Thyroid CA
- Prostatic CA
 Local invasion & Encapsulation -3
 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
 4- Metastasis :
 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
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
Summary : Differences between
benign & malignant neoplasms
 BENIGN vs MALIGNANT

 Well-differentiated  Anaplastic
 Low mitotic index  High mitotic index
 Slow Growth  Rapid growth
 With capsule  Infiltrative growth
 No invasion without capsule
 No metastases  Invasion
 Metastases
EPIDEMIOLOGY of CANCER
 2006 Estimated US Cancer Cases*
Prostate 33% 31% Breast


Lung & bronchus 13% 12% Lung & bronchus



Colon & rectum 10% 11% Colon & rectum



Urinary bladder 6% 6%
 Uterine corpus
Melanoma of skin 5%  4% Non-Hodgkin
Non-Hodgkin4% lymphoma
lymphoma
4%
 Melanoma of skin
Kidney 3%
 3% Thyroid
Oral cavity 3%
Leukemia 3%
 3% Ovary

Pancreas 2% 2%
 Urinary bladder
All Other Sites 18% 2%
 Pancreas
22% All Other Sites


*Excludes basal and squamous cell skin cancers and in situ Men Women
carcinomas except urinary bladder.
Source: American Cancer Society, 2006.
720,280 679,510
2006 Estimated US Cancer Deaths*
26% Lung & bronchus
Lung & bronchus 31%
Colon & rectum 10% 15% Breast


Prostate 9% 10% Colon & rectum



Pancreas 6%  6% Pancreas
Leukemia 4%  6% Ovary
Liver & intrahepatic 4%
bile duct
 4% Leukemia
Esophagus 4%  3% Non-Hodgkin
lymphoma
Non-Hodgkin 3%
lymphoma  3% Uterine corpus
Urinary bladder 3%  2% Multiple myeloma
Kidney 3%  2% Brain/CNS
All other sites 23% 23%
 All other sites

Men Women
291,270 273,560
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
Monoclonal proliferation

 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
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
1-Genes coding for growth :
Classified by site of action
 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-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
& melanoma……etc
 Transforming Growth Factor (TGF-)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:
Active RAS
GDP GTP proliferation

GTPase activity by (GAP)

 Mutations in GAPs(NF1):Neurofibromatosis
 Commonest oncogen mutation
 Point mutations in codon 12, 13 are present
in 30% of cancers, specially CA pancreas &Colon
 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 ( CDK’s)
initiation of cell cycle  MYC
 MYC mutation  sustained activation
 Examples :
 Dysregulation of MYC present in Burkitt’s
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
 CELL CYCLE PHASES

S
G1

G0
G0 (Labile cells)

(Stable G2
cells)

(Permenant M
cells)
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© 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

2- Cancer Suppressor Genes:-

 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.
 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
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© 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 , leukemia…etc
 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 2nd.-
3rd.decade of life
 Additional mutations  colonic carcinoma
 100%  risk in familial polyposis coli
 70-80% of sporadic colonic carcinoma
show mutant APC
 3- Evasion of Apoptosis :
 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
4-Limitless replication potential(Telomeres)

 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
5- Genomic instability due to defective
DNA Repair Genes

 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
 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.

6- Development of Sustained Angiogenesis :
 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-1)  VEGF

 RAS mutation   VEGF

 Proteases from tumor or stroma  VEGF

 Anti- Angiogenesis :
 VHL protein can destroy HIF-1   No
VEGF so VHL acts as tumor suppressor
 Germ line mutation of VHL  hereditary

renal CA , hemangiomas in CNS……etc

 Anti-angiogenic factors : e.g.

P53  antiangiogenic thrombospondin

 Inactivation of P53  angiogenesis

-  vascular density = Poor prognosis

 7- Ability to invade & metastasize

 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
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.

 Steps in carcinogenesis may be
followed genetically & histologically :
 Each cancer must result from
accumulation of multiple mutations,
in many genes including those in
apoptosis & senescence

 EXAMPLE :
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
- CHEMICAL CARCINOGENS :

 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
 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

 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 CA…etc.

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
 2- PHYSICAL CARCINOGENS :
 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
 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
 3- VIRAL CARCINOGENESIS :
A - DNA Viruses :

1- HPV-Human
Benign Papilloma
squamous papilloma (wart) Virus
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
Mode of Action :
 HPV have transforming early genes
(E6,E7) inactivate suppressor genes
 E6 acts on p53no 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
 2- EBV : Ebstein Barr Virus

 BURKITT’S LYMPHOMA **
 B CELL LYMPHOMA
 HODGKIN’S LYMPHOMA subset
 NASOPHARYNGEAL CA
-----------------------------------------
 Post transplant lymphoma

 CNS Lymphoma in AIDS patients

 Mode of action in Burkitt’s 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 :
BURKITT’S 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
 3-HBV ( Hepatitis B Virus )

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)
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

 Helicobacter pylori in carcinogenesis

 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
 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  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 , paralysis…etc
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 can’t 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, Cushing’s 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 &othersHypercalcemia
 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
- Duke’s 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-Morphological Methods :

1- Cytological methods :
 Study of cells :

- Smear
- FNA, Brush, Fluid tapping…etc
Papanicolaou stain (PAP) often used.
False(+), False (-)
- A negative report does not exclude
malignancy, repeat
- Advise biopsy, even if (+ )
Normal PAP smear of Cervix
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Dysplastic Epithelial Cells (PAP smear)
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 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, PERL’s 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 antigenLymphoma
S 100 Neural tissue, melanocytic lesions
Desmin, Vimentin  Sarcoma
Undifferentiated Tumor
tokeratin for epithelial cells indicating Carcino
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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

 2- Biochemical Assays :

 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
 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
 3- Molecular Diagnosis :
 Methods used include :
 PCR (Polymerase Chain Reaction)
 FISH (Fluorescent In Situ Hybridization)
 Used to detect gene rearrangement,
translocations, amplifications…etc
 BCR-ABL Chronic Myeloid Leukemia
 Monoclonal proliferation of B or T cells
 13q 14 deletion in Retinoblastoma….
 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 heal……etc.
 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.