|


Dr.H.M.Zahawi,FRC.Path

  
ð Definitions of terms used in neoplasia
ð Nomenclature of tumors
ð Characteristics of benign & malignant
tumors
ð Routes of metastasis
ð Epidemiology of CANCER
ð The molecular basis of neoplasia
ð Carcinogenesis
ð Tumor immunity
ð The clinical effects of tumors
ð Tumor grading and staging
ð The laboratory diagnosis of neoplasia
eneral terms used :

ð Neoplasm = New growth of cells producing a

mass
ð Benign neoplasm = Limited new growth
without invasion or spread
ð Malignant neoplasm = invasive growth that
also spreads
ð Carcinoma : Malignant tumor of epithelial cells
ð Sarcoma : Malignant tumor of connective tissue
cells
ð Lymphoma
ð Cancer is a general term for all
malignant growths of whatever type
ð Tumor may be used instead of
neoplasm but the term is not accurate
ð Oncology : study of cancer in all its
aspects
 |

ð 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
ð A neoplasm develops from a single
transformed cell !!!
 Features of transformed cells :

ð Persistent & useless

ð Uncontrolled growth *
ð Immortal
ð Transplantable
ð This cell may arise from :
ð Endoderm

ð Mesoderm

ð Ectoderm

ð Epithelial cells may arise from any

of the above
ð Connective tissue is from mesoderm
 

ð Cell of origin
ð Behavior of tumor : Benign or malignant

ð Appearance of the tumor: Solid/cystic

ð Degree of differentiation
  !!"
ð  Parenchymal cell
 Stromal ( supporting cell )

ð Degree & type of stromal cells may

contribute to the appearance of tumors

ð If there is stromal proliferation u hardness of

the tumor u Scirrhous tumor u Desmoplasia
e.g.carcinoma of breast, pancreasƦ..etc
ð If there is lack of many stromal cells, the
tumor may be soft or cystic.
ð This feature may be included in the name
of the tumor..e.gƦ
ð Cystadenoma of ovary
ð Poorly differentiated cystadenocarcinoma of
ovary
ð Moderately differentiated scirrhous
carcinoma of breastàààààà
! #$!% #
 & ' !
!( "&! 

ð Adenoma  glandular epithelium tumor

often producing a secretion e.g.
(mucin) which may be intraepithelial or
intraluminal
ð Papilloma ƛ epithelial tumor forming
finger like projections from epithelial
surface with a connective tissue core
ð Polyp ƛ a tumor projecting from the
mucosal surface of a hollow organ
Structure of Polyp
ð (!"&! 
 

ð Squamous cell carcinoma e.g. skin,mouth

cervix, bronchusƦ.etc

ð Adenocarcinoma from glandular origin,

e.g..I.T.,endometrium,breast, kidney,
thyroidƦ..etc
!%!!! (

!(
Named by tissue of origin with attached
suffix ƛ oma
e.g. fibroma, lipoma, chondromaƦetc

Not all endings (ƛ oma) are benign tumors

e.g. : granuloma,lymphoma, hamartoma,
choristomaƦetc
ð (!%!! 

)

Prefix (origin)+ suffix (sarcoma) e.g.
Osteosarcoma, liposarcoma, angiosarcoma
leiomyosarcoma, rhabdomyosarcomaƦ
ð !  !* +,,,
 -!$ 
ð 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 :
ð Teratomas ƛ 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
  )


ð May be benign or malignant depending

on structure, site, age, sex Ʀ.

ð Contain skin ,sebaceous & mucus

glands,hair,cartilage, bone, respiratory
epithelium, glial tissueƦ..etc.

ð Usual location is ovary or testes

 " %!! (

ð Blastoma : from immature tissue

ð May arise in kidney, liver, retinaƦetc
e.g. Retinoblastoma

ð The great majority of these tumors are

malignant & occur in infants & children
Some tumors have names that do not
conform with general rules :

ð Melanomas arise from nevus cells

ð Seminomas arise from testicular germ cells
ð Lymphomas arise from lymph nodes
ð Some tumors are named eponymously
e.g. Hodgkins disease, Wilmƞs tumorƦ.etc

ð Note : See table on page 176

!. / !|
 !
!"
ð 0 
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.
ð & 

Different types of tissue, ectopic to the

region.
e.g. Meckleƞs Diverticulum,
Salivary tissue in LN

Both are present at birth & do not become

malignant .
01$'!(2(
 $! 3

ð Differentiation & anaplasia

ð Rate of growth
ð Presence of capsule
ð Local invasion
ð Distant metastases
Benign versus malignant tumors
 1 Differentiation:
 This indicates the degree of resemblance
of the tumor cell to its cell of origin,
functionally & morphologically.
e.g ƛ

Cells of a lipoma may look exactly like

normal fat cells.

 
)

Features of differentiation include :
ð Epithelial cells :
 formation of glands
 formation of keratin
 formation of secretionƦetc
ð Connective tissue cells :
 formation of osteoid
 presence of lipoblasts
 Striations in tumors of skeletal
muscleƦ.etc
6! !$($  &! !
|,4|  
 When a tumor cell loses its differentiation
it gradually gains features of
+5

ð It is a process of gradual loss of

differentiation

ð It is an abnormal growth which may

precede malignancy

ð Complete loss of differentiation  

|
#(6! !+#"

ð Increased nuclear size ,  N/C ratio

ð ïariation in nuclear & cell size :


)0
ð Loss of differentiating features
ð Increased nuclear DNA content
05 )0)

 6! !$#"!$ 

ð |! :Prominent, sometimes multiple

ð ( ! : Increased
ð ' !: may be present
ð " # : in an epithelial surface
Severe Dysplasia/ Anaplasia
 !"&!|!"

Dysplasia involving an epithelial surface

ð Low grade & High grade

ð High grade dysplasia ,limited by

epithelial basement membrane  
)|
|7
Intraepithelial Neoplasia
NOTE :

ð Not all dysplasias progress to higher

grade or carcinoma in situ.
ð Not all carcinoma in situ progress to
invasive CA
ð Some cases of dysplasia can regress
 2 Rate of growth

ð Rate of growth usually correlates with

level of differentiation
ð May be rapid in some benign tumors
ð Some tumors may shrink in size
ð Some malignant tumors may outgrow
their blood supply
Some tumor growths are semicontroled :
HORMONE DEPENDENCE :

ð This is through presence of receptors on surface

 Breast CA
 Thyroid CA
 Prostatic CA
X Local invasion & Encapsulation
ð Benign tumors frequently have a capsule
ð Malignant tumors progressively invade
& destroy surrounding tissue
e.g.Breast cancer infiltrating skin
Basal cell carcinoma face
infiltrating nerve
ð *!$" ! !
$(&(( 
 4 Metastasis :
ð Spread of malignant tumors to distant
sites not contigious with the main tumor
ð " $((
(#
ð All tumors can potentially metastasize
except BASAL CELL CARCINOMA
ð Metastasis is often proportionate to the
size and differentiation of the primary
tumor
)!!!

ð Lymphatics
ð Blood vessels
ð Seeding within body cavities/
Transcoelomic Spread
  #"&" !$
ð More characteristic in  
ð Spread follows the anatomical route of
drainage unless skip Ơmetastasesơ e.g.
ð Breast cancer in left upper upper
quadrant u Left axillary L.N.
ð In medial quadrant u internal mammary
chain u supraclavicular & infraclavicular
ð Lung Ca  Peribronchial u tracheobronchial
LNs u hilar LNs
ð IMPORTANT IN SURICAL RESECTION :

ð !#"&|$! :
ð First lymph node in the pathway of
a primary tumor.
ð Usually outlined by dye

ð Not all enlarged L.N.s indicate metastases

e.g. Reactive hyperplasia
Histiocytic infiltrate in sinuses
  0!(!" !$

ð Usually venous first following anatomical

drainage : Lung & Liver
ð More characteristic of Sarcoma ,but may
in occur in later stages of carcinoma
ð Certain carcinomas invade veins early
ð RENAL Carcinoma u renal veinu IïC
ð Hepatocellular Carcinoma uPortal &Hepatic v.
X  !" !$

ð Within peritoneal or pleural cavity e.g.:

ð CA of upper lobe of lung to lower

lobe
ð CA of stomach to ovary

ð CA of ovary tends to spread widely

through peritoneal surface

ð CA of colon across peritoneum to

S.I.& colon
 #+! !!'!1!!
'!(2(à !"

ð  |4| %4||

Welldifferentiated Anaplastic
Low mitotic index High mitotic index
Slow rowth Rapid growth
With capsule Infiltrative growth
No invasion without capsule
No metastases Invasion
Metastases
+ 

45| )
 a
à à
à à
 XX
ð X

 àà  X
ð a
 àà 
 àà
ð
 àà

 à 


ð


 àà
 àà 

ð 
  
   
àààààààààààààààààààààà à

  X
ð 
 àà
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ð X
ààààà
 X
ð X

  a
ð a

 à 

àà 
ð a
 
ð aa

àà
·
à  à
à  àà
à
à
à
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 à
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 à
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a
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ða

 àà 
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 #
ð
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ð

 
 

ð


àà  

à  ð 

 
ð X
  
   àààààààààààààààààX
àààà 
àààààààààààààà ð X

 à

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ð a
à
  X

ð a
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àààààààààààààààààaX

ð aX
àààà
àà


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

ð Nasopharyngeal CA
ð Cervical CA & Cancer of the penis
ð Burkitt Lymphoma
ð Multiple myeloma
ð Chronic lymphocytic leukemia
4!!"# "& !"'!
 

ð Individual predisposition to disease

ð Individual response to environmental

agents

ð Individual response to drugs

ð FACTORS WHICH MAY PLAY A ROLE IN
THE INCIDENCE OF CANCER INCLUDE :
 4!( "& -

astric 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
ð CANCERS common in JORDAN include :

ðLung CA
ð Colorectal CA } MALES
ð Prostate CA


ð Breast CA

ð Colorectal CA } FEMALES
ð Lung CA

ð Lymphomas are also common

  % !

ð Diet
ð Occupation
ð Sunlight
ð Personal habits
 X (! :

ð In general , cancer incidence Ƽ AE

ð However , certain cancers occur
more in children
ð Acute Leukemia
ð Some Lymphoma
ð Some CNS Tumors
ð Bone &soft tissue Sarcomas
o 0! !$#
10% of tumors

ð Inherited Cancer Syndromes :

Presence of defined genetic abnormality,
usually AD, often specific phenotype e.g.
ð APC gene : Familial Adenomatous
Polyposis Coli
ð MEN1 & RET genes : MEN syndrome
ð NF1 & NF2 genes : Neurofibromatosis
ð RB gene : Retinoblastoma
ð Familial cancers : No specific phenotype
& multifactorial

ð Family members have higher incidence

to common cancers
 

|
 ) 
 
)5
ð Younger age groups, multiple or
bilateral, two or more family members
are affected.
ð Some linked to inheritance of mutant
genes e.g. )2)
)#$ !+|)!" 

ð Chromosomal & DNA instability

ð Best example :

XERODERMA PIMENTOSUM
 8 !$ !!"#$ !

ð 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
X Liver Cirrhosis & Hepatocellular
8 !$" !!"#$ !
!$

4 Chronic healing process

 Ulcerative Colitis & Colorectal CA
6 ïillous Adenoma & Colorectal CA
7 Leukoplakia & Squamous cell CA

 7)
6
| )
|!" ! (!!
!

ð roup of cells produced from a single

ancestral cell by repeated cellular
replication.
ð Thus they can be said to form a single
"clone".
ð 
|

|
 Principles :
ð Tumors arise from clonal growth of cells
that have developed mutations in four
classes of genes :
ð rowth promoting protooncogenes
ð rowth inhibiting tumor suppressor genes
ð enes regulating apoptosis
ð enes involved in DNA repair
ð More than one mutations in above result
in abnormal growth of cells
  (!!
7 )
 ,
Multistep Carcinogenesis :
 Steps in Neoplastic Transformation :
1Non lethal damageu TRANSFORMATION

2Cell Proliferation : initially Polyclonal u

MONOCLONAL CELLS

Xenetic instability of malignant phenotype u

cells with diverse features u progression of
tumor u INïASION & METASTASES
" ! 

ð Heterozygous
Xlinked marker:
6PD isoenzyme.
!!
&!! 9#( 
4:+; 
!
1""
!1&! !
&! !"
 !&9#(
 !!9#!
 -"!

ð Chronic myeloid leukemia (CML):

Philadelphia Chromosome (9:22 )
ð Multiple Myeloma u single immuno
globulin specific for the tumor.
ð T&B cell lymphomas : specific gene
rearrangement
ð Tumor Progression :

This is the stepwise accumulation of

mutations resulting in increasing
features of malignancy.
4 | ||

)|6
)
|
enes in Neoplastic Transformation:

!4!!
 Protooncogenes

ð Normal genes whose products

(Oncoproteins) promote cell growth

ð Oncogenes are mutant versions of proto

oncogenes that function autonomously
without normal signals
4!!$( ( 1& 
!$'#!
ð Arise from mutant protooncogenes

ð They are dominant genes.

ð They include :

ð rowth factors

ð Cell surface receptors

ð Signal transduction proteins

ð Nuclear transcription factors

ð Cell cycle proteins

ð Inhibitors of apoptosis
 
(!!$(4 1&6 
ð Normal Cell growth is stimulated by F
ð Platelet derived growth factor (PDF) seen
in glioblastomas
ð Fibroblast growth factor(FF)stomach CA
& melanomaƦƦetc
ð Transforming rowth Factor (TFY)in
sarcomas
ð Products of other oncogens (e.g.RAS) may
cause over expression of F
 
(!!$(4 1&6
)!!" 
ð F integrate with membrane receptors u
tyrosine kinase activity u nucleus
ð Mutant receptor u continuous signals even in
the absence of FƦ..OR
Normal but overexpressed u hypersensitive to
F
ð Epidermal F receptor family:
ERBB1 in 80% of sq.CA lung
ERBB2 ( HER 2 NEU) in 2X0% of breast
& ovarian CA 
ð Increase = POOR PRONOSIS
 X
(!!( $

ð RAS & non receptor ABL

ð RAS action:
m
m
4+ 4uproliferation




 m

ð Mutations in APs(|6):|! ' 
ð Commonest oncogen mutation
ð Point mutations in codon 12, 1X are present
in GX0% of cancers, specially CA pancreas &Colon
 | !!" !$
# !<!( 
ð Normal ABL is located in nucleus where it
promotes apoptosis
ð Chronic myeloid leukemia : Mutation
9:22 translocation u BCR ABL gene
ð This new gene is retained in cytoplasm
where it has tyrosine kinase activity u
cell proliferation
ð New action is Proliferation +No Apoptosis
 o|!   "6 
ð DNA transcription regulated by genes e.g.
MYC*, JUN, FOSƦ.etc.
ð In normal :MYC protein + DNA u Activation
of Cyclin Dependant Kinases ( CDKƞs)
uinitiation of cell cycle u MYC
ð MYC mutation u sustained activation
ð Examples :
ð Dysregulation of MYC present in Burkittƞs
lymphoma (t8:14)
ð Breast ,colon, lung CA & neuroblastoma
  #2#+!"!$=
>! !(!!#!"&!

ð Family of proteins that control entry of

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





 


 



 


2
 
      2  
  !"#
$% 
ð 1" ( "

 Cyclin D family u CDK4 & CDK6 at

1 u S phase checkpoint
 Cyclin BCDK1 activate 2 uM transition
ð Activity of CDK/ Cyclin regulated by
CDK inhibitors
ð Non selective wide inhibition :
p21, p27 and p7
ð Selective effect on cyclinD/CDK4 &
cyclinD/CDK6 :
p1, p16, p18, and p19
 Cyclin/CDK/RB function

ð 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
ð Mutations that disregulate activity of
cyclins & CDKs cell proliferation
Examples :
ð Cyclin D is overexpressed in breast,

liver, & esophageal cancers

ð Amplification of CDK4 gene present in

melanoma, sarcomas, glioblastoma

  ! "" ! 4!!

ð rowth inhibitory pathway by:

* Regulate cell cycle : Rb gene

* Regulate cycle & apoptosis: P X
* Block F signals: TF˜
* APC regulates ˜catenin

ð Cancer suppressor genes are recessive

genes which may be lost in familial or
sporadic cases.
  )(!!

ð First studied in Retinoblastoma:

ð Called RB gene

ð Both copies of gene must be lost

for neoplastic transformation to occur

ð This is called loss of heterozygosity
 Retinoblastoma :
ð Autosomal dominant hereditary disease
ð May be sporadic
ð In familial, patients carry one mutation in
their genome
ð No tumor develops unless two alleles
in 1Xq14 become mutant (two hit theory)
ð $incidence of bilateral Retinoblastoma
and $ osteosarcoma
Inheritance of Retinoblastoma
 Mode of action of RB gene:

ð RB exists in active nonphosphorylated

& inactive phosphorylated forms.
ð Active RB binds to transcription factors
(E2F) u NO TRANSCRIPTION
ð CyclinD/CDK4, and cyclinE/CDK2
phosphorylate RB.
ð Inactive RB releases transcription factor
E2F u TRANSCRIPTION (1 u S phase )
ð Many oncogenic DNA viruses may act
similarly by inactivating RB
2
 
      2  
  !"#
$% 
  X
ð 70% of tumors show homozygous loss of
pX
ð pX is a negative regulator of cell cycle,
present in low levels with short half life
MDM2 protein which targets it for
destruction
ð Called Ɲuardian of the enomeƞ OR
(Policeman) preventing genetically damaged
cells from progressing through new cycle.
 Mode of activation & action :
ð PX senses DNA damage through various
sensors e.g. ATM protein
ð PX is activated by anoxia, or DNA
damage and accumulates in cell with long
half life after release of MDM2
ð Activated pX
ð Transcription of CDKI(p21) cell cycle arrest
at 1
ð Transcription of ADD4 ( repair gene)
ð pX is a regulator of apoptosis
ð More time for repair u Normal
ð Failed repairu Apoptosis or Senescence
(permanent cell cycle arrest)

ð ˜ xed mutat
 u |


Action of pX
PX may show the following :

ð Acquired mutation in many cancers

e.g. colon, breast, lung , leukemiaƦetc
ð Inherited mutation in Li  Fraumeni S.
sarcoma, leukemia, breast carcinom
and gliomas Ʀ.. etc
ð May be blocked by some DNA viruses
producing viral induced cancers
X 46˜

ð Antiproliferative activity:
 regulation of RB pathway at 1 by
action on some cyclins & CDKs
 blocks F signals

ð Mutational inactivation of TF ˜

components seen in 100% of pancreatic
carcinoma & the majority of colonic CA
 o (!!
Cytoplasmic protein , acts as an adhesion
molecule by regulating level of
˜! in cytoplasm
*  ˜!  $&! 
Result u intercellular adhesion
·  ˜! u nucleus
Result u stimulates proliferation
ð Individuals with inherited one mutant
allele of APC develop 100s to 1000s of
adenomatous polyps in their 2nd.
Xrd.decade of life
ð Additional mutations u colonic carcinoma
ð 100%  risk in familial polyposis coli
ð 7080% of sporadic colonic carcinoma
show mutant APC
 X %"" :
ð Mutations in genes involved in programmed
cell death which regulate mitochondrial
permeability promoting or suppressing
apoptosis.
*;>" !"! !'#
 ;*&'"! !'#
0X#" ! !(!&!'!
ð BCL2 prevents apoptosis, prolonging life.
ð Activated by translocation (18:14)
Follicular B cell Lymphoma
o! !""!!! ! 

ð 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.
ð Shortening is prevented by TELOMERASE
ð Active in stem cells, not in somatic cells
ð Majority of cancers  telomerase
 4!'#$!$!!%!
+|)!" 4!!

ð Repair mutations in other genes

ð Persons with inherited mutations in
these genes are at $ risk for cancer
ð These include :
1 Nucleotide excision repair genes
ð Damage by Uï light . Defective in
Xeroderma igmentosum
ð Damage by ionizing radiation
ð Drugs e.g. nitrogen mustard
 )!" (!!!$

2Mismatch repair genes : These repair

errors in pairing of nucleotides during
cell division
e.g. +T instead of A+T
0| ?
(0ereditary |on"olyposis olonic a.)
 )!" (!!!$ 

X BRCA 1 & BRCA2

80% familial breast cancer & ovarian CA
BRCA ƛ2 in breast CA in both sexes,
e.g: prostate,ovary, pancreas, stomach CA

ð Rarely inactivated in sporadic cases.

: +!%!"!!$((!! -

ð Tumors remain small or in situ

( <12mm.diameter) without angiogenesis
Angiogenesis Ƽ Antiangiogenesis
Angiogenic Switch
ð Controlled by hypoxia which induces
angiogenic factors by tumor cells
ð HypoxiaInduced Factor(HIF1Y) u ïEF
ð RAS mutation u  ïEF
ð Proteases from tumor or stroma  ïEF
 Anti Angiogenesis :
ð ïHL protein can destroy HIF1 Y u No
ïEF so ïHL acts as tumor suppressor
ð erm line mutation of ïHL u hereditary
renal CA , hemangiomas in CNSƦƦetc
ð Antiangiogenic factors : e.g.

PX u antiangiogenic thrombospondin

ð Inactivation of PX u angiogenesis

  vascular density = Poor prognosis

  '#%$!2!9!

ð 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 Ʀetc
ð Rate of generation of these clones differs
in individual tumors e.g.
Osteosarcoma versus Basal Cell Carcinoma
Metastatic Pathway:
!! 1"&!
  %

ð Loosening of intercellular junctions

ð Attachment
ð Degradation of ECM
ð Migration

ð   $!
 !&% 

 +!&! !
Inactivation of ECadherin OR
activation of ˜ cateninu detachment of
tumor cells
 Loss of function ECadherin in many CAs 
 +!( $ '#" !! :e.g.
Matrix Metalloproteinase (MMPs)
Cathepsin D
Type Iï collagenase
 Result of digestion of ECM u Cleavage products
of matrix have chemotactic activity for more
tumor cells
X &! ! to matrix
components by laminin & integrin
receptors to basement membrane & ECM
o (  !
Tumor derived cytokines e.g.
Autocrine motility factor
   $! :

 %&! 
Adhesion to endotheliumu retraction of
endothelium u vessel
 <'#|>!, some escape by
formation of a thrombus
X "!  
Adhesion to endotheliumu retraction of
endothelium u escape to tissue
 60|67 |  
6
  3
ð Anatomical Location
ð Complimentary adhesion molecule
between tumor cells & target organs
ð Chemoatractants liberated by target
organs
ð Protease inhibitors present in certain
tissues
 -"! "0(
ð Prostatic Carcinoma u Bone
ð Lung Carcinoma u Adrenals & Brain

ð Neuroblastoma u Liver & Bone

Less common sites of metastases include

skin,muscle thyroid,breastƦ.etc.
Spleen , Cartilage , Heart are almost
never involved by metastatic tumours.
 !" (!!#'!
1!$(!!#2&(#

ð Each cancer must result from

accumulation of multiple mutations,
in many genes including those in
apoptosis & senescence

ð EXAMPLE :
Different ene Lesions :

ð  mainly in RAS

ð !$  mainly in
hematopoietic tumors:
9;22 , 8;14 , 14;18
& rare in solid tumors :Ewing Sarcoma
ð 4!!" :
Neuroblastoma : NMYC
Breast carcinoma : HER2/NEU
ð & $!!: More
in nonhematopoietic & solid tumors
e.g. Retinoblastoma 1Xq band14
also several in colorectal CA

ð & ! ( :

( Aneuploidy)

Result : Change in structure or quantity of gene

product
ene Amplification :
)|
4 |4 |
 0 )|
4 | 

ð Direct Carcinogens 
Directly produce damage without prior
metabolic conversion
ð Indirect Carcinogens (Procarcinogen)
Metabolic conversion in liver by
cytochrome P40 dependent mono
oxygenasesu ultimate carcinogen
 Action of chemical carcinogens :
ð Initiator  Chemical inducing irreversible
DNA damage
ð Promoter Augment effect of initiator by
promoting cell growth
e.g. phorbol ester (PTA) activate signal
transduction or F secretion , hormones,
saccharine Ʀ..etc
ð 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 u CA Lung
X Aromatic Amines & Azo dyes : Rubber &
Food Industry e.g.
˜ naphthylamineu Bladder CA
 Chemical carcinogens ( Continued)

4 Nitrosamines : Endogenous or food

preservatives e.g.astric & Colon CAƦetc.

 Aflatoxin B1 : Naturally occurring

carcinogen present in fungus.
Aspergillus flavus u Hepatocellular CA
$!&! (!

ð Chemical carcinogens contain highly

reactive electrophil groups that combine to
DNA, RNA, or proteins producing mutations
ð enes commonly affected are
RAS & PX
ð May be very specificƝ Signature Mutationƞ
ð Some strong chemicals act as Initiator &
Promoter e.g. polycyclic hydrocarbon
  05)|
4 | -
ð Uï light :
 Effect depends on intensity of exposure
& quantity of melanin
 Production of pyrimidine dimers in
DNA u MUTATION in RAS , P X
 Failed repair u Skin CA
 Skin cancer includes :
Squamous Cell CA
Basal Cell CA
Melanoma
ð Ionizing Radiation:

 Explosions  Leukemia after 7 yrs.

Latent period u Breast,colon, thyroid,
lung CA
 Therapeutic exposure u Thyroid CA,
Leukemia
 Mechanism:Free radical injury u
Mutations in RAS, RB. PX
ð Asbestos fiber inhalation :
Mesothelioma & Lung CA
 X ))|
4 |  -
 +| ! :

 00" 
Benign squamous papilloma (wart)
groups 1,2,4 & 7
* Low risk groups (6, 11) u
enital Squamous Cell Papilloma
* High risk group ( 16, 18 ) u
Squamous Cell CA in cervix, vulva,
perianal & oropharyngeal regions
Mode of Action :
ð HPï have transforming early genes
(E6,E7) inactivate suppressor genes
ð E6 acts on pXuno apoptosis
ð E7 ubinds to E2F ublocks Rb action &
activates cyclins, & inhibit CDKI
ð High risk groups have a stronger affinity
of early genes to E2F
ð Result uCell proliferation
    '!  

ð BURKITTƞS LYMPHOMA **
ð B CELL LYMPHOMA
ð HODKINƞS LYMPHOMA subset
ð NASOPHARYNEAL CA

ð Post transplant lymphoma

ð CNS Lymphoma in AIDS patients

 Mode of action in Burkittƞs Lymphoma :
ð EBï has LMP1 gene receptor for B lymphocytes

ð Induce B cell proliferation

ð Prevents apoptosis by activating BCL2

ð Controlled POLYCLONAL B proliferationu

Infectious Mononucleosis
ð Dysregulation of c myc by translocation :
BURKITTƞS Lymphoma (t 8:14)
ð Malaria & Malnutrition may play a role in
immunity ( Lost T cell control ).
ð In endemic cases EBï is identified in tumor cells
In Nasopharyngeal Carcinoma :

ð LMP 1 is expressed on epithelial cells

activating cell proliferation
========================
ð LMP 1 also activates pro angiogenic
factors
ð Both in Burkitt Lymphoma &
Nasopharyngeal Carcinoma other
environmental factors play a role
 X00!" 

Multifactorial oncogenic effect but mainly

Immunologically mediated chronic liver
diseaseÈu Cirrhosis uHepatocellular CA in
70 8% Action :* Cell proliferation Èu
mutation
* HBï encodes Hbxprot. u
growth promoting genes
*Hbx binds to p X u
Inactivates suppressor function
(HCï is similar but HCï core Protein)

(!)| !

ð HTLï1 induces Leukemia /Lymphoma

ð Transmitted sexually,blood or milk

$! :
ïirus * gene attaches to T cells:
ð Produce cytokines +receptor u autocrine
stimulation u proliferation
ð Suppresses action of TPX &CDKI

POLYCLONALu MONOCLONAL u LEUKEMIA

 0!'! "#  (!!

ð First described as a cause for peptic ulcer

ð Multifactorial etiology in gastric CA & gastric
lymphoma ( MALT lymphoma )
ð Immune mediated gastric damage with FR
ð Occurs in only X% after a long latent period
ð H.pylori contains (Cag A)genes uF u
Cell proliferation
 Mode of action :
ð LYMPHOMA :
Chronic gastritis umucosal lymphoid
follicles u reactive polyclonal B cells u
monoclonal B cells u Malt lymphoma
ð CARCINOMA :

Chronic gastritis u atrophy u intestinal

metaplasia u dysplasia u astric
Carcinoma
CANCERS ASSOCIATED CARCINOEN

ð CA LUN u Smoking
ð CA CERïIX uSexual transmission of HPï
ð CA BLADDER u Rubber Industry
ð CA LIïER u Aflatoxin & HBï infection
ð CA THYROID u Radiation
ð ANIOSARCOMA of Liver u Plastic(PïC)
ð MESOTHELIOMA u Asbestos
7
)7|

45
 6&! %!! å

ð Normal immunity present to protect

against development of tumors
ð Evidence å
ð When there is no immunity More
Cancers
ð Patients with congenital immune
deficiency have 200 times risk of
cancer & immunosuppressed patients
have increased rates of cancers
(Lymphoma)
 -"!$ %!
ð This may be lost during tumor
progression
ð There may be acquired
immunosuppression produced by
oncogenic agents
 0!&
1 Sensitized Cytotoxic T lymphocytes

2 Natural Killer cells may kill tumor cells

without previous sensitization.

X Macrophages activated by IFN> may

destroy tumor cells

4 Humoral AB mechanisms
  (!

ð Tumors share MHC with normal cells

ð Tumor specific & Tumor Associated As

may be helpful in diagnosis & follow up of
some tumors
ð Therefore, they may act as tumor markers
 "!2!$ 4
ð 1 Products of mutant oncogenes & tumor
suppressor genes e.g. RAS protein
ð 2 Mutant proteins induced by chemical
and radiation induced tumors
ð X Overexpressed normal cellular proteins
or aberrantly expressed e.g. :
ð Tyrosinase in melanoma
ð Cancer Testes enes : MAE1(melanoma..)
ð HER2 in CA breast
ð 4 Tumor A produced by oncogenic
viruses in HPï & EBï infection

ð  Oncofetal A: Carcinoembryonic A

(CEA) in colon and Y fetoprotein in
liver CA
ð 6 Several mucins: MUC1 in breast CA
and CA12, CA199 in ovarian CA
ð 7 Cell Type specific differentiation
A in B lymphomas (CD10&CD20)
"!|!"
 ! '$#
ðLocation of tumor is of importance
1 Mass effect by pressing on vital areas
e.g.airway, intestine , Bï, brain,nerve
u obstruction, infarction , paralysisƦetc
2 Local destruction of epithelial surface
or Bï u ulceration , bleeding , infection
X Hormonal activity
  Cancer Cachexia :

ð Wasting syndrome characterized by

anorexia , loss of body fat & weight,with
marked weakness,anemia & fever.

ð Reduced food intake but high metabolic

rate

ð Possibly due to release of cytokines by

tumor cells & macrophages
   Paraneoplastic Syndrome :

ð Systemic symptoms that canƞt be explained

by effects of local or distant spread of tumor
or hormones appropriate to tumor tissue.
ð Due to ectopic production of hormones or
other factors
ð They may precede the tumor or mimic
metastases
ð They occur in about 10%1% of
malignant tumors.
Types of Paraneoplastic Syndromes :

ð Endocrinopathies e.g hyperglycemia,

hypoglycemia, Cushingƞs SƦ..etc
ð Nerve & Muscle Syndromes e.g
myasthenia gravis
ð Dermatologic disorders
ð Osseous & Articular changes
ð ïascular & hematological changes
ð Nephrotic syndrome
 Well Known Examples of Paraneoplastic
Syndromes
ð Small Cell CA lung uÈ ACTH , ADH, Bone
changes,nervous system disorders
ð Squamous Cell CA lung & Breast CA u
Parathormone related &othersuHypercalcemia
ð Pancreatic & lung CA uclotting factors uDeep
vein thrombosis
ð N.B. Hypercalcemia is commonly produced by lytic
bone metastases
 examples (continued)

ð Hepatic & Renal CA u Polycythemia

ð Pancreatic, astric CA u Carcinoid S.
ð Advanced Cancers u Nonbacterial
thrombotic endocarditis.
ð Colonic Adenocarcinoma u Acanthosis
nigricans
4 $(2(( 

Must be documented for all malignant

tumours :
ð To quantify the aggressiveness of
tumor
ð To outline mode of therapy

ð To compare different modes of therapy

ð To give an approximate prognosis

 (
ð This indicates the final outcome of the
disease in terms of #!  
#! 
 %%.
ð This is influenced by :
 #"! e.g. Lung CA versus Lip CA
 4 $!2(!
0 !
 4 $! : Based on level of
differention :
This indicates the degree of resemblance
of tumor cells to cell of origin and is
1# '!$ "
 ! ?
ð rade I : Well differentiated tumor

ð rade II :Moderately differentiated tumor

ð rade III : Poorly differentiated tumor

ð rade Iï : Anaplastic tumor

 4  
ð This indicates the extent of spread of the
tumor.
ð Clinical ,investigative procedures and
pathological appearance of tumor have to
be used to assess it.
ð It depends on :
* Size of tumor
* Regional lymph node involvement
* Metastases to distant organs
 |((#!

ð T : Size and extent of primary tumor(14)

ð N : Presence and extent of lymph node
involvement ( 0X)
ð M : Presence or absence of distant
metastasis ( X01)
e.g.T1,N1, M0

ð Others : American Joint Committee
staging system ( AJC) Stage 0Iï
 Dukeƞs staging for colonic CA
 Lymphoma Staging system
And many moreƦƦ.etc
ð Staging is more important than grading
because it affects treatment
| ) +4|

4!! 
!

ð History & clinical examination

ð Radiographic techniques
i X ray
ii CT scan
iii MRI
iv Ultrasound
ð Laboratory tests : general & specialized
 Ô
 



1 Cytological methods :
ð Study of cells :

 Smear
 FNA, Brush, Fluid tappingƦetc
Papanicolaou stain (PAP) often used.
False(+), False ()
 A negative report does not exclude
malignancy, repeat
 Advise biopsy, even if (+ )
|
 


 
2
 
      2 &2
 '&('!"#
$% 
2       

2
 
      2 &2
 '&('!"#
$% 
 2 Histological methods :

ð Biopsy of tissue:
Needle & core biopsy , Endoscopic Biopsy,
or open surgical biopsy
ð Frozen Section (Rapid technique)
ð Paraffin Section ( X648 hrs. or longer )
ð H&E, Special histochemical stains e.g.
( PAS, CONO RED, PERLƞs stains) or by
IMMUNOHISTOCHEMICAL Methods
 X Immunocytochemistry

ð 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.
ð Cytokeratinu Carcinoma
Common leukocyte antigenuLymphoma
S 100u Neural tissue, melanocytic lesions
Desmin, ïimentin u Sarcoma
Undifferentiated Tumor
  
 

        
  
2
 
      2 &2
 '&('!"#
$% 
Undifferentiated Malignant tumor
+!%! !%!!$( 
 4Electron microscopy :
ð For recognition of desmosomes , or
neurosecretory granulesƦ.etc.

 Flow Cytometry :
ð For measuring DNA content , detecting

diploid versus aneuploid tumorsƦ.etc.

ð Correlates with rate of growth & prognosis

ð Useful in the diagnosis & classification of

Lymphoma & Leukemia
  &!#

ð Used to identify tumor associated

enzymes, hormones , antigens Ʀ etc

ð 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.

ð Their uses are to :

I  Confirm diagnosis.
II Determine the response to treatment .
III  Detect early relapse.
ð Present in serum or urine.
ð Many are present in normal & tumor tissue,
so they are not very specific but their level
is important.
 #"!  <! 

 0 ! 
ð Human Chorionic onadotrophic Hormone

(˜ HC)
Elevated levels are seen in Pregnancy
& estational Trophoblastic Disease
ð Calcitonin useful in diagnosis of some

thyroid carcinomas
ð Ectopic hormones in paraneoplastic S.not used
 
!(!

ð Carcinoembryonic Antigen ( CEA ) :

in fetal tissue & some malignancies ƛ
Colorectal CA & Pancreatic CA

ð Alpha Fetoprotein (AFP) :

Cirrhosis : Elevated
Hepatocellular carcinoma : Extremely high
 X !9#!

ð Prostatic Acid Phosphatase ( PAP )

 levels seen in Metastatic prostatic CA

Useful in : * Staging prostatic CA
* Assessment of prognosis
* Response to therapy.
 o "! ! :

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

ð MUC1 in breast CA
ð CA12 in ovarian CA
ð CA199 in pancreatic & hepatobiliary CA
 X ! +(

ð Methods used include :

ð PCR (Polymerase Chain Reaction)
ð FISH (Fluorescent In Situ Hybridization)
ð Used to detect gene rearrangement,
translocations, amplificationsƦetc
ð BCRABL Chronic Myeloid Leukemia
ð Monoclonal proliferation of B or T cells
ð 1Xq 14 deletion in RetinoblastomaƦ.
ð For prognosis : gene amplification
ð HER 2 NEU in breast carcinoma
ð NMYC in neuroblastoma
ð Detection of residual disease in
chronic myeloid leukemia (BCRABL)
ð Detection of genes of hereditary

cancer e.g BRCA1 in breast cancer

 6) 
6| ),,,
 )5+4|
| )

This is very important as many cancers are

curable if they are diagnosed early.
ð 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 healƦƦetc.
ð 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
ð Screening for genetic mutations in familial
cancers.