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Neoplasia & cancer

Dr.Nafea Sami Al-Esawi

General pathology 2014
2nd stage students

What is neoplasia ?

Neoplasia is new, uncontrolled growth of cells that is not

under physiologic control .
Pathogenesis :
1-Process of new growth of cells ( not single step).
2-Induced by certain stimuli .
3-Leading to new features TRANSFORMED CELL
- Persistent & useless growth.
- Uncontrolled (autonomy growth)
- Immortality .
- Transplantability .
Any cell can be transformed growth Tumor

Carcinogenic factor, causes a cell to be transformed to a

neoplastic cell that is not controlled by normal body
Probably most transformed cells die because they are
too abnormal to function or are abnormal enough for the
body's immune system to destroy them.
However, if the factors promoting transformation
persist, a transformed cell may give rise to a clone that
does continue to grow resulting in neoplasia.


An abnormal mass of tissue the growth of which is

1-Virtually autonomous ( independent of
physiological growth stimuli ).
2-Exceeds that of normal tissue.
3-Uncoordinated with that of normal tissues (unlike
non neoplastic proliferations like (hyperplasia ,
regeneration, repair).
4-Persists in the same excessive manner after the
cessation of the stimuli which evoked the change
( the genetic alterations are passed down to the
progeny of tumor cells ).

Characteristics of Transformed Cells : ?

Clonality :All tumor cells are clonal : Monoclonal .

All tumor cells (the entire population of neoplastic cells

) within the individual tumor arise from a single cell
that has incurred genetic changes and hence the tumor
are said to be clonal .
All tumors ( benign & malignant ) composed of :
1-Clonal neoplastic cells ( parenchyma ):which determine
the tumor behavior and consequence.
2-Reactive stroma (connective tissue ,BVS , inflammatory
cells ) : provide framework for neoplastic cells growth
and nutrients for tumor growth & evolution .

Autonomous growth :The growth of neoplastic cells is

independent of growth factors ,regarding mechanism
operating inside normal cells.

Excessive growth :The excess may be evident in the

size of the outgrowth & duration of the proliferation .

Disorganized growth ( cytoarchitectural level ) :The

structures formed by tumor cells differ from the normal
tissue & don't fit into general organization scheme of
the normal body .


A disordered growth and maturation of an epithelium,

which is still reversible if the factors driving it are
eliminated .

1st is hypercellularity .
A - Nuclear changes :
1-Nuclear enlargement ( increase N/C ratio ).
2-Pleomorphism ( variation in size & shape of nuclei).
3-Hyperchromatism &chromatin irregularity .
4-Multinucleation ( unequal size multiple nuclei ).
5-Irregularity of nuclear membrane .
6-Prominent & giant & multiple nucleoli ( differ in size &
shape) .

B Cytoplasmic changes :
1-Scanty cytoplasm .
2-Variation in size & shape .
3-Cytoplasmic staining :
Deep orange in keratinized squamous cell carcinoma.
Basophilic in poorely differentiated carcinoma.
4-Cytoplasmic inclusion :melanin in malignant melanoma


In capillaries and postcapillary venules, T. media

may be replaced by cells called pericytes which
have contractile function and can proliferate and
differentiate after injury to new blood vessels .

Tunica adventitia
Consists of longitudinally oriented collagenous and
elastic fibers that become continuous with the
surrounded C.T.
Innervation of Blood vessels:

Bl. Vessels supplied by autonomic nervous system

that regulate their relaxation and contraction by
special neurotransmitters.


Is an increase in the size of a tissue or organ due to

increase number of constituent cells or increase in
the number of cells resulting in growth lesion.
Postpartum breast lobules undergo hyperplasia for
lactation is normal physiological process.
Endometrial hyperplasia in a postmenopausal
woman is abnormal .




An increase in organ size due to increase in cell size

without increase number of constituent cells .

Increase in skeletal muscle fiber size is a physiologic

response to exercise .
The cardiac hypertrophy is a pathologic response to
abnormally elevated blood pressure.:




Is the replacement of one matur adult cell type by

another one mature adult cell type .
It is a reversible process .
Metaplasia: an initial change from normal cells to a
different cell type (such as chronic irritation of cigarette
smoke causing ciliated pseudostratified columinar
epithelium to be replaced by squamous epithelium more
able to withstand the insult).
Consider a first step toward neoplasia in many sites in
the body ( bronchus , cervix , esophagues ) .


Benign tumor:

A benign neoplasm looks microscopically a lot like the

tissue of normal cells from which it originated, and its
general characteristics include:
Slow growth ( innocent ).
Resemblance to tissue of origin (well differentiated) .
Circumscription ( localize ).
Capsulation .
Lack of invasion .
Absence of metastases .
Prognosis : Good .


A malignant neoplasm is composed of:

1- Cells that look less like the normal cell of origin (

less differentiation ).
2- It has a higher rate of proliferation ( mitosis ).
3-It can potentially invade and destroyed the adjacent
structure .
4- It can metastasize .
Prognosis : poor :potentially lethal .


Tumors are classified by:

1-Histological :Cell of origin (epithelial or stromal ).
2- Clinical behavior of tumor :
Benign :good prognosis .
Malignant :potentially lethal .
Borderline : low grade malignant tumor
3- Gross Appearance of the tumor :localize or
4- Grade :Degree of differentiation & anaplasia .

Classification by origin naming :

EPITHELIAL CELL : Benign tumors of epithelial cells:

Adenoma: is term applied to a benign epithelial

neoplasm derived from glands, although they may or
may not form glandular structures.
On this basis, a benign epithelial neoplasm that arises
from renal tubular cells growing in the form of
numerous tightly clustered small glands would be
termed an adenoma, as would a heterogeneous mass
of adrenal cortical cells growing as a solid sheet.
-Tubular adenoma of colon .
-Follicular adenoma of thyroid .



Papilloma :
Term applied for benign tumor arising from surface
epithelium e.g skin or mucosal surface:
Grossly appear as finger like protrusion on surface or
warty projection on mucosa of hallow organ .
Microscopically :It is composed of finger-like
epithelial cell growing overlying fibrovascular core
(connective tissue with blood vessels) .
e.g Squamous papilloma of skin .
Squamous papilloma of larynx .
Transitional Papilloma of bladder.


Benign epithelial cystic tumors:

Cystadenoma :as adenoma with cystic
Papillary cystadenoma: as above ( adenoma +
cyst + but with papillary (finger like projection ).





Malignant tumor of epithelial origin: Carcinoma

Squamous cell carcinoma : would denote a cancer in

which the tumor cells resemble stratified squamous
epithelium, arise in organs with squamous epithelial lining
:e.g. skin , mouth ,cervix, bronchus.etc
Adenocarcinoma :denotes a lesion in which the neoplastic
epithelial cells grow in glandular patterns , arise from
glandular origin, e.g.G.I.T. ,endometrium,breast, kidney,
thyroid..etc .
Transitional cell carcinoma :arise from epithelial lining of
urinary bladder.
Small cell carcinoma :arise from neuroendocrine
cells.(mainly in lung ,although can arise in other tissue &
organs ) , so it considered as systemic disease .

Squamous cell carcinoma , invasive





Mesenchymal (Stromal :connective tissue) cell origin :

1-Benign connective tissue tumors :
Named by tissue of origin with attached suffix oma
e.g. fibroma (fibrous tissue),.
lipoma (adipose tissue),
Chondroma (cartilage),
Lieomyoma (smooth muscle) etc.
Others ending by oma include
Granuloma:chronic inflammatory process.
Lymphoma :malignancy of lymphoid t.
Hamartoma:disorganized indogenous tissue,
Choristoma:hetropic rest of cellsetc .



2-Malignant connective tissue tumors: ( Sarcoma ) :
Prefix (origin)+ suffix (sarcoma) .
e.g. Bone :Osteosarcoma ,
Adipose tissue : Liposarcoma,
Blood vessels : Angiosarcoma,
Smooth muscle :Leiomyosarcoma,
Skeletal muscle :Rhabdomyosarcoma .
Cartilage : Chondrosarcoma .






*Some tumors have more than one paranchymal cell

type,these include tumors of Germ cell origin : able to
differentiate into 3germ layers (ectoderm , mesoderm &
1-TERATOMA : Term applied for tumor with recognized
mature or immature cells or tissue representive of more
than one germ cell layer & some time all three (ectoderm ,
mesoderm & endoderm).
May be benign or malignant.
Contain skin ,sebaceous& mucus glands ,hair ,cartilage,
bone, respiratory epithelium, glial tissue..etc.
Usual location is ovary or testes (contain totipotential
cells=primitive cells) .
Stroma ovarii: ovarian teratoma with predominant thyroid
tissue (may undergo pathological change , .


pleomorphic adenoma


2-Mixed tumors

These tumors differ from teratoma in that they

derived from one germ cell layer, and differentiate
into more than one paranchymal cell type e.g
Pleomorphic adenoma of salivary gland and
fibroadenoma of breast .




. of blood cells & lymphocytes :All tumors in this group

are malignant ( leukemia ,lymphoma , polycythemia rubra vera ).

Neural,glial cell&neural supporting structures tumor:

Like glioma , neuroblastoma &meningioma.

Germ cell tumors : This include seminoma , teratoma &

choriocarcinoma .

Tumors of primitive fetal origin :

Blastoma :(small primitive cells). e.g. Retinoblastoma
Nephroblastoma, Neuroblastoma, Medulloblastoma
Note : The great majority of these tumors are malignant.
Majority occur in infants & children


Non neoplastic masses :

1-Hamartoma : Tumor like malformation (mass or
nodule) in which there is abnormal mixing of
normal native tissue components of the organ ,either
in the form of change in quantity or arrangement of
tissue elements: e.g. Lung Hamartoma ,most
haemangioma, melanocytic nevi.: usually develop
during fetal development .
2-Choristoma : Mass composed of normal cells or
tissue found in a wrong location ( Ectopia) :
Different types of tissue, ectopic to the region. e.g.
Meckles Diverticulum,(ectopic pancreatic &gastric
tissue) , Salivary tissue in lymph nodes .
Both are present at birth & do not have malignant



Exceptions :Exception to above mentioned rules

include tumors that are always malignant such as :
Lymphoma: malignant tumor of lymphoid tissue .
Melanoma :malignant tumor of melanocytes .

Seminoma &dysgerminoma :tumor of primitive

germ cells.


How do benign tumor differ from malignant tumor

1-Differentiation & anaplasia: Extent to which the
transformed cells resemble their normal forebears
morphologically &functionally.
2-Rate of growth : Correlates in general with their level of
differentiation ( slowly=well diff *rapidly =poorly diff)
3-Local invasion : benign tumor remain localize.
Malignant tumor :grow by progressive infiltration, invasion,
destruction & penteration of surrounding normal tissue.


4-Distant metastases: development of secondary
implants in site that anatomically discontinous with
primary malignant tumor, possibly in remote tissue
(absolute feature of malignant tumor).
5-Gross features :
Benign : smooth , capsulated , uniform color.
Malignant: irregular , no capsule ,variegated color.


Benign versus malignant tumors


1- Differentiation:
This indicates the degree of resemblance of the tumor
cell to its cell of origin,functionally &morphologically.
- In most benign tumors constituent cell closely
corresponding to normal cells :e.g - Cells of a lipoma
may look exactly like normal fat cells.
- Malignant tumors display a range of differentiation,
which form the basis of tumor grading (well , moderate
, poorly) :
-Malignant tumor can be extremely well differentiated e.g. a well differentiated liposarcoma or anaplastic in
which tumor cells lack of differentiation .


Dysplasia : Abnormal growth (disorganization of tissue

structural &cytological) which may precede malignancy.

Disorder growth & maturation of cells that are not normal , but are
not obviously malignant .
Considered as precursor of invasive malignancy .
Process of gradual loss of differentiation .
Complete loss of differentiation ANAPLASIA
Differentiation features include functional &morphological:
- Formation of glands( morphology).
- Formation of squamous nest ( morphology).
- Production of keratin ( Functional ).
- Formation of mucin secretion (functional).
- Formation of osteoid ( functional).

Grading of colonic epithelial tumors


Poorly differentiated


Well differentiated

Anaplastic carcinoma

Cytological Features of Dysplasia

1-Increased nuclear size: N/C ratio(nuclear/cytoplasmic)

2- Pleomorphism :Variation in nuclear & cell size .

3-Loss of cell differentiating features (Giant cells & bizarre

cells with multiple nuclei ).

4- Hyperchromatism :Increased nuclear DNA content .

5-Mitosis: often numerous : increase proliferative activity &

distinctly atypical (tripolar ).

6-Celluarity :increase degree of cellularity ..

7-Loss of polarity in an epithelial surface (loss of orientation

&dissary of tissue architecture).

8-Prominent nucleoli.

Severe Dysplasia / Anaplasia


Intraepithelial Neoplasia:
Dysplasia involving an epithelial surface
Low grade & High grade.
High grade dysplasia ,limited by intact epithelial
basement membrane CARCINOMA IN SITU.
Not all dysplasias progress to higher grade or
carcinoma in situ.
Not all carcinoma in situ progress to invasive CA.
Mild to moderate degrees of dysplasiacan be seen
in reactive & inflammatory lesions.
Dysplasia can regress.

Intraepithelial Neoplasia


Grade of tumor: Based on level of differention :

Grading :Is the attempt to assign a rough numerical value
( Score of differentiation ) to the extent of histological
deviation from the normal. 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.


2- Rate of growth:

Most cancers grow faster than benign tumors .

Rate of growth usually correlates with level of
May be rapid in some benign tumors .
Some tumors may shrink in size (lieomyoma & pituitary
Some malignant tumors may outgrow their blood
supply ( choriocarcinoma).i.e rapidly growing tumors
may develop areas of ischemic necrosis because outgrow
their blood supply .
Some cancers are hormone sensitive , their rate of
growth may be affected by variation in hormone level
associated with pregnancy , menapause like breast cancer

3- Local invasion :
Second most important feature distinguishing
malignant tumors after metastases.
Benign tumors frequently have a capsule.
Not all benign tumor are encapsulated
Malignant tumors progressively invade
(infiltrative ) & destroy surrounding normal
tissue: e.g. Breast cancer infiltrating
Basal cell carcinoma of skin infiltrating nerve

4- Metastasis :

Metastasis is the absolute criteria of malignancy .

Spread of malignant tumors to distant sites not
contigious with the main primary tumor ( secondary
deposit or metastatic foci ).
All tumors can potentially metastasize except
Metastasis is often proportionate to the size and grade
of the primary tumor
Routes of metastases:
2-Blood vessels.
3-Seeding within body cavities.

Lymph node with metastasis carcinoma


1- Lymphatic Spread :
Invasion of lymphatic vessels followed by spread of
tumor to regional lymph nodes , ultimately to other
sites in the body.
More characteristic in Carcinoma than sarcoma.
Not all enlarged lymph nodes located at the sites of
drainage of a malignancy signifies a metastasis
(immune response in form of lymphoid hyperplasisa
Spread follows the anatomical route of drainage
e.g. : - Breast cancer in upper outer quadrant
axillary L.N.
- Lung Carcinoma - Peribronchial hilar
Paratracheal lymph nodes.


Lymphatic channels with metsatatic carcinoma


2- Hematogenous spread :

Usually venous (veins are more readily ).

More characteristic of Sarcoma ,
although in later
stages of carcinoma they also use Blood Vessels.
Lung & liver are the commenest site of haematogenous
spread , because they receive dual circulation ( the
systemic &portal venous blood )respectively .
Other major sites are the bones & brain (well
vascularized organs with abundant blood supply).
Certain carcinomas invade veins early e.g.
RENAL Carcinoma renal vein IVA
Hepatocellular Carcinoma Portal &Hepatic v.


Fig 8-16 Main sites of hematogenous spread





3- Transcelomic spread :
By seeding of surface of cavity :Tumor cells enter
the cavities & floate in the serous fluid to attached
on the surface of peritoneal cavity .
Within peritoneal or pleural cavity
e.g.: - CA of upper lobe of lung to lower lobe.
- CA of stomach to ovary (krukenburge tumor).
- CA of ovary spread widely through peritoneal
surface (mucinous adenocarcinoma spread to
peritoneal cavity to give pseudomyxoma peritoni )
- CA of colon across peritoneum to S.I.& colon



Staging of Tumor :

This indicates the extent of spread of the tumor.

It based on correlating Clinical data ,investigative
procedures (radiological ) and pathological finding
appearance of tumor have to be used to assess it.
It depends on :
* Size of tumor (local infiltrations).
* Regional lymph node involvement.
* Metastases to distant organs .
Prove to be of greater clinical value, when compared
with grading ( more valuable for prognosis ).
Both staging & grading of tumors are valuable for the
1- Determination of prognosis.
2- Planning of therapy .

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
e.g.T1,N1, M0 ( Small tumor that has
metastasized to lymph nodes &distant site ).
---------------------------------- Others: AJC(American Joint Committee) staging
system (0-IV)
Dukes staging for colonic CA

TNM staging for carcinoma of breast


Tumor Therapy :
Staging, and to a less extent, grading, affect therapy :
1- Surgical excision .
2- Radiotherapy .
3- Chemotherapy .
4- Immunotherapy .
5- MULTIMODALITY of treatment .
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


Cancer epidemiology deals with the occurrence of tumors in
human populations , by study the incidence , prevalence &
mortality .Epidemiologist are trying to identify
environmental , genetic causes of cancer , thus contribute to
better diagnosis ,treatment and prevention .Epidemiology
data may point to a cause & effect relationship between a
cancer and potential carcinogen .
In Iraq males the comments cancers are those of lung ,
bladder , larynx , non Hodgkin lymphoma & leukemias .
In Iraq females , breast cancer , non Hodgkin lymphoma ,
leukemias , CNS tumors , lung cancers.


Incidence :is the number of new cases of a specific registered

over a specified period in a defined population .Incidence may
be related to ethnic &geographic differences in community .
Prevalence :Is the number of all cases of cancer both new &
old registered within a defined population at a given point in
Mortality : Is the number of deaths from a given form of cancer
during a specified period of time in defined population .

Increase incidence: lung carcinoma in female ( smoking)

:Prostate carcinoma (PSA test) : early DX.

:kaposi sarcoma : homosexual AIDS person.
Decrease incidence : gastric carcinoma ( food refrigeration).
:cervical carcinoma (pap smear preinvasive)


1-Epstein-Barr infection (EBV)-Burkitt

lymphoma &nasopharyngeal carcinoma.

2-Viral hepatitis B&C :Hepatocellular carcinoma

3-Humen papilloma virus : Uterine cervix

carcinoma .

4-AIDS (HIV) : Lymphoma &kaposi sarcoma.


1- Geographic location :
Esophageal CA -- High in Iran &north of iraq.
Gastric CA -- High in Japan
Skin CA------ High in New Zealand
Hepatocellular CA --- High in China &south east Asia.
Breast CA , Prostatic CA ,Colorectal CA ---- High in USA
2- Environment factors :Significantly affect the occurrence
of specific forms of cancers in different parts of the world.
* Diet: e.g :gastric cancers in Japan & USA.
* Occupation :e.g : anyline dye with bladder cancer.
* Sunlight e.g : melanoma in Australia .
* Personal habits e.g : cigarette with lung cancer.

3- Age :
In general , cancer incidence AGE : Cancers is most
common in those over 55 years of age( fact pointing that
cancer evolution requires multiple independent events,
apparently taking place over along period of time e.g.
prostatic carcinoma & lung carcinoma .
Certain cancers occur more in children less than 5years
Acute Leukemia ,Lymphoma , CNS Tumors
(retinoblastoma ,neuroblastoma),soft tissue Sarcomas
Adolescence age tumors :Osteosarcoma , Ewing sarcoma
, Medulloblastoma .
Biphasic age incidence : Hodgkin lymphoma ( 20 & 60 ).


4- Hereditery :
Hereditary play a role in the development of cancers even in the
presence of clearly defined environmental factor Usually well
defined inheritance & phenotype :
1-Inherited cancer syndromes:
- Familial Adenomatous Polyposis Coli & - MEN Syndrome
2- Autosomal recessive syndrome of defective DNA repair: - Xeroderma Pigmentos &- X linked immune deficiency:due to
genetic defect of nucleated excision enzyme lead to increase
susceptibility to UV irradiation .
3-Familial cancer :Familial clusters of specific forms of cancers,
but the transmission pattern is not clear (breast , colon ,brain &
ovary ). Younger age groups, multiple or bilateral, two or more
family members are affected. Some linked to inheritance of
genes e.g. BRCA-1


Familial adenomatous polyposis coli

Gross appearance of familial polyposis. Entire large bowel was involved. Note the
fact that practically all of the polyps are small and sessile.

Acquired Preneoplastic conditions :

These are certain clinical conditions that are associated with increased
risk for CA and most are related to rapid or abnormal cell proliferation
1- Endometrial Hyperplasia & endometrial adenocarcinoma
2- Cervical Dysplasia & Cervical CA &Bronchial dysplasia & lung CA
3- Liver Cirrhosis & Hepatocellular carcinoma .
4- Chronic healing process (skin squamous carcinoma & skin burn).
5- Ulcerative Colitis & Colorectal CA.
6- Villous Adenoma of colon & Colorectal CA.
7- Oral Leukoplakia & Squamous cell CA.
8-Atrophic gastritis & gastric CA.
9-Paget disease of bone & Osteosarcoma .
Note :the subsequent development of malignancy in benign tumors is
quite uncommon (i.e most malignant tumors arise denovo).
However :there are few exceptions e.g .villous adenoma of colon often

Neoplasia & cancer


Dr.Nafea Sami Al-Esawi

General pathology 2010
Al anbar medical college
3rd stage medical students


Cell cycle stages, also called phases, are the

components that make up a cell's life cycle.
There are four stages in a cell cycle, gap
phase 1 (G1), synthesis (S), gap phase 2
(G2), and mitosis (M). Mitosis is further
divided into four stages, prophase,
metaphase, anaphase, and telophase. Some
descriptions of cell cycle stages include a
third gap phase, known as G0.

The G1, S, and G2 stages are collectively

known as interphase. A cell in the G1 phase
is actively growing and undergoing the
metabolic changes that are required for cells
to divide. The G1 phase ends at the
restriction point, when the cell "decides" to
undergo division and moves on to the S


All of the cell's DNA is replicated during the synthesis

phase of cell cycle stages. During DNA synthesis, or
replication, special cell components separate the
double-stranded DNA helix into two single strands.
An enzyme called DNA polymerase then goes along
each template strand of DNA and builds on a second
strand to exactly copy the cell's original DNA. Other
enzymes in the cell check to make sure the DNA
was copied correctly. The end result of synthesis is
two exact double-stranded copies of the cell's
original DNA, called chromosomes

Cells prepare for mitosis during the second

gap stage. Special materials are required in
the cytoplasm of the cell in order for mitosis
to occur. The cell undergoes metabolic
changes during G2 in order to form these
cytoplasmic materials


After G2, mitosis begins with the prophase

stage. A structure known as the mitotic spindle
is formed during this phase. Another structure
called the centrosome duplicates itself, and the
duplicates move to opposite ends of the cell.
The chromosomes move toward a region of
the mitotic spindle called the metaphase plate,
and the centromeres attach to the spindle
using structures known as kinetochores. This
last step of prophase is sometimes further
divided into a stage called prometaphase


During metaphase, the chromosomes align

with the metaphase plate to help the
chromosomes separate properly during
anaphase. Once the chromosomes are
aligned, anaphase occurs as the
chromosomes separate and move to
opposite ends of the cell. The separated
chromosomes are called daughter

Telophase is the final phase of mitosis and of

the cell cycle stages. The daughter
chromosomes each acquire their own nuclear
membranes, and the spindle fibers detach
and disappear. Cell division is not complete,
however, until cytokinesis occurs and the cell
splits completely into two new cells. At this
point the cell cycle begins again with G1


Some researchers include a fifth phase of cell

cycle stages. The G0 phase is inserted
between mitosis and G1. If cells enter the G0
phase, they are no longer growing. They
may, however, become reactivated and enter
the G1 phase again


During development from stem to fully

differentiated, cells in the body alternately divide
(mitosis) and "appear" to be resting (interphase).
This sequence of activities exhibited by cells is
called the cell cycle.
Interphase, which appears to the eye to be a
resting stage between cell divisions, is actually a
period of diverse activities. Those interphase
activities are indispensible in making the next
mitosis possible.

Interphase: Interphase generally lasts at least 12 to 24 hours in

mammalian tissue. During this period, the cell is constantly
synthesizing RNA, producing protein and growing in size. By
studying molecular events in cells, scientists have determined
that interphase can be divided into 4 steps:
Gap 0 (G0), Gap 1 (G1), S (synthesis) phase, Gap 2 (G2). Gap
0 (G0): There are times when a cell will leave the cycle and quit
dividing. This may be a temporary resting period or more
permanent. An example of the latter is a cell that has reached
an end stage of development and will no longer divide (e.g.

Gap 1 (G1): Cells increase in size in Gap 1,

produce RNA and synthesize protein. An important
cell cycle control mechanism activated during this
period (G1 Checkpoint) ensures that everything is
ready for DNA synthesis. (Click on the
Checkpoints animation, above.)
S Phase: To produce two similar daughter cells,
the complete DNA instructions in the cell must be
duplicated. DNA replication occurs during this S
(synthesis) phase.

Gap 2 (G2): During the gap between DNA synthesis and

mitosis, the cell will continue to grow and produce new
proteins. At the end of this gap is another control checkpoint
(G2 Checkpoint) to determine if the cell can now proceed to
enter M (mitosis) and divide.
Mitosis or M Phase: Cell growth and protein production stop
at this stage in the cell cycle. All of the cell's energy is
focused on the complex and orderly division into two similar
daughter cells. Mitosis is much shorter than interphase,
lasting perhaps only one to two hours. As in both G1 and
G2, there is a Checkpoint in the middle of mitosis
(Metaphase Checkpoint) that ensures the cell is ready to
complete cell division. Actual stages of mitosis can be
viewed at Animal Cell Mitosis.

Cancer cells reproduce relatively quickly in

culture. In the Cancer Cell CAM compare the
length of time these cells spend in interphase to
that for mitosis to occur.


Cycle, Checkpoint Control and DNA Damage

Control of eukaryotic cell growth and division
involves molecular circuits known as
checkpoints that ensure proper timing of
cellular events. Passage through a checkpoint
from one cell cycle phase to the next requires a
coordinated set of proteins that monitor cell
growth and DNA integrity. Uncontrolled cell
division or propagation of damaged DNA can
contribute to genomic instability and


The G1/S checkpoint controls progression of cells through

the restriction point (R) into the DNA synthesis S-phase.
During G1, the tumor suppressor Rb binds and inhibits
transcription factor E2F. Phosphorylation of Rb by cyclinbound cyclin dependent kinases (CDK) in late G1 induces
dissociation of Rb and permits E2F-mediated transcription
of S-phase-promoting genes. Responding to upstream
signals, INK4 and Kip/Cip family inhibitors control CDK
activity and prevent entry into S-phase. DNA damage
activates response pathways through ATM/ ATR and
Chk1/2 kinases to block CDK activity, leading to cell cycle
arrest and DNA repair or cell death.

The G2/M checkpoint prevents cells containing damaged DNA

from entering mitosis (M). Activated CDK1 (cdc2) bound to
cyclin B promotes entry into M-phase. Wee1 and Myt1 kinases
and cdc25 phosphatase competitively regulate CDK1 activity;
Wee1 and Myt1 inhibit CDK1 and prevent entry into M-phase,
while cdc25 removes inhibitory phosphates. DNA damage
activates multiple kinases that phosphorylate kinases Chk1/2
and tumor suppressor protein p53. Chk1/2 kinases stimulate
Wee1 activity and inhibit cdc25C, preventing entry into Mphase. Phosphorylation of p53 promotes dissociation between
p53 and MDM2 and allows binding of the transcription factor to

The spindle checkpoint ensures proper

chromatid attachment prior to progression
from metaphase to anaphase. The SCF and
APC/C protein complexes play prominent
roles, with APC-cdc20 initiating the entry into
anaphase by promoting ubiquitin-mediated
degradation of multiple substrates, including
cyclin B and the regulatory protein securin.



Carcinogenesis is a MULTISTEP PROCESS !:
Morphologic appearance
Molecular change
-Normal epithelium
Loss or mutation of APC locus
on chromosome 5q
Loss of DNA methylation
-Early adenoma
Mutation of RAS gene on 12p
-Inermediat adenoma
Loss of tumor suppressor gene on 18 q
-Late adenoma
Loss of RAS gene on 17p

**Each cancer must result from accumulations of multiple



1-Non lethal genetic damage (mutation: irreversible
alteration of DNA ): TRANSFORMATION inherited in
germ line or acquired (radiation, chemicals, virus ,etc).
2-Involvement of normal regulatory genes that involved in
cell replication & death .
3-The tumor mass is the result of clonal expansion of single
precursor (progenitor ) cell . (Cell Proliferation ) initially
Polyclonal Monoclonal :most of malignant tumors are
monoclonal i.e. result from transformation of a single cells.
4-Progression of tumor cells inducing new features : i.e
become heterogeneous cells with different capability for

Multisteps Carcinogenesis (molecular basis of cancer)


Genes involved in cell replication &death

1-Genes encoding growth factors , growth factor
receptors , signals proteins involved in various
steps of cell division.
2-Genes regulating apoptosis (programmed cell
death ).
3-Genes of tumor suppression genes family.
4-Genes of DNA repair enzyme .


Oncogenes :are cancer inducing genes derived from

cellular genes called protooncogenes.


Protooncogen Oncogen

Growth factor



Growth factor receptor EGF-Receptor


Signal transduction

Tyrosine kinase


DNA binding protein

Transcription activator MYC


Outline of Gene Action :


Methods of gene activation :

1- Point mutation .

2- Chromosomal translocation.

3- Gene amplification.

4- Gene deletion .
Result : Change in structure or quantity of gene
product ( functional proteins).


*Chromosomal Translocation &associated oncogenes in Burkitt

lymphoma and chronic myelogenous leukemia.


Gene Amplification of N-MYC gene in Neuroblastoma:

N-MYC present normally on 2p , become amplified & seen either as
extra chromosomal double minutes or as a chromosomally
integrated homogenous staining region (HSR)


Changes necessary for malignant phenotype :

1- Self sufficiency in growth signals ( Oncogenes ).
2- Insensitivity to growth inhibitory signals ( Suppressors).
3- Evasion of apoptosis (programmed cell death :i.e.
immortality of neoplastic cells)
4- Genetic instability ( Accumulation of mutation Enabler
of malignancy).
5- Limitless replication potential (Telomeres :determine
the life of individual cell) i.e overcoming cellular
senescence .
6- Development of Sustained angiogenesis.
7- Ability to invade & metastasize (new features acquired
during new mutations ).

1-Oncogenes :Classified by site of action

Oncogenes:Genes that promote autonomaous cell
growth in cancer cells. These are usually dominant
genes & include:
Growth factors.
Cell surface growth factor receptors.
Signal transduction proteins.
Nuclear transcription factors.
Cell cycle proteins (cycline &cyclin-dependent
Inhibitors of apoptosis.

Transformation:(cancer associated genes ) Genes in Neoplasia


1-Oncogenes coding for Growth Factors

All normal cells require stimulation by growth factor
to undergo proliferation .(Cell growth is stimulated
by Growth factors)
Cancer cells acquire growth self-sufficiency by:
1-Ability to synthesize the same growth factors to
which they are responsive( persistent activation).
Platelet derived growth factor (PDGF) seen in
glioblastomas .
Fibroblast growth factor(FGF)-stomach Carcinoma.
2-Overexpresion of growth factor genes. (TGF).
Products of other oncogens (e.g.RAS) may cause
over expression of GF e.g. Transforming Growth
Factor (TGF-)in sarcomas


2-Oncogenes coding for GF Receptors:

Growth Factors integrate with membrane receptors

tyrosine kinase activity nucleus .
Mutant receptor proteins continuous mitogenic
signals to cells even in the absence of GF in
Or normal but overexpressed (amplifications )
hypersensitive to GF.
Epidermal GF receptor family:
ERBB1 in 80% of sq.CA lung
ERBB2 ( HER 2 ) in 25-30% of breast & ovarian
carcinoma .
Increase expression = POOR PROGNOSIS


3- Oncogenes in Signal Transduction:

Most of these are located in the inner leaflet of plasma membrane where they
receive signals from outside the cell & transmit them to the nucleus.
RAS action: Active RAS in turn activates down-stream regulators of
proliferation (kinase mitogenic cascade) which flood the nucleus with signals
for cell proliferation.

Mutant RAS is trapped in its activated GTP bind form & cell

proliferation continue.

Active RAS


GTPase activating prot.(GAP)

Point mutations in RAS are present in 30% of all cancers, specially

pancreatic & GIT cancer


Action of ABL : Non receptor associated tyrosine

kinase signal transmission
Normal ABL (proto-oncogene has tyrosine kinase
activity )is located in nucleus where it promotes
apoptosis of cells that suffer DNA damage .
Chronic myeloid leukemia : Mutation ( 9:22
translocation ) BCR- ABL hybrid gene .
This new hybrid gene is retained in cytoplasm where
it has tyrosine kinase activity cell proliferation.
Action is Proliferation + Absent Apoptosis.


4-Nuclear (DNA)Transcription Factors :

Growth autonomy (mitotic cycles ) may occur as a

consequence of mutations affecting genes that regulate
DNA transcription , these include MYC, JUN, FOS.etc.
MYC protein + DNA Activation of Cyclin Dependant
Kinases (derive cells into cell cycle).
CDKs cell cycles MYC
MYC mutation over expression & sustained activation.
t(8:14)in Burkitts lymphoma: cause dysregulation of MYC
gene .
Amplification of MYC in :Breast ,colon,lung CA&
neuroblastoma .

5-Cyclins & Cyclin-Dependent Kinases :

Cancers may become autonomous if the genes that

derives the cell cycle become dysregulated by mutations
or amplification .
Cyclins bind to CDKs, activating them.
Cyclin D family CDK4 & CDK6 at G1 S phase
Activity of CDK/Cyclin regulated by CDK inhibitors
Cyclin D overexpressed in breast, liver, & esophageal
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: PT 53
* Block GF signals: TGF-
APC regulates -catenin
APC gene loss in APC & mutated in colon carcinoma.
-Cancer suppressor genes are recessive genes which may be lost in
familial or sporadic cases or mutated .

APC gene exert antiproliferative effect it is cytoplasmic

protein that regulate intracellular level of -catenin .
-catenin :is transcription activation factor (TcF) of growth
promoting genes ( Cyclin D1 , MYC).

Action of APC (adenomatous polyposis coli )gene

with B-catenin pathway:


1- Rb gene (Retinoblastoma ):

Rb role is regulating the G1 S check point of cell

Rb exists in active nonphosphorylated & inactive
phosphorylated forms.
Normal Active pRb binds to transcription factors
NO TRANSCRIPTION( of genes whose products are
required for S phase of cell cycle).
Mutated Inactive pRb releases transcription factors
TRANSCRIPTION ( of genes whose products are
required for S phase of cell cycle ) , so drive the cell to
This is a trigger the cell cycle at G1 phase pushing cell
into S phase

Example : Retinoblastoma :

Autosomal dominant hereditary disease.

May be sporadic.
Patients carry one mutation in their genome .
No tumor develops unless two alleles in 13q14
become mutant (Knudsons two hit theory).
Patients have high incidence of Retinoblastoma and


Inheritance (pathogenesis )of Retinoblastoma

Two mutation of RB locus on 13q14 lead to neoplastic

proliferation of retinal cells (two hit theory).
In familial form all somatic cells inherit on mutant RB gene
from a carrier parent: i.e inherited 1st hit.
The second mutation affect RB locus in one of retinal cells
after birth: i.e acquired 2nd hit .
In sporadic form , both mutation at RB locus are acquired
by retinal cells after birth.
Rb mutation renders the protein inactive , thus the cell
divides non stop.


Two hit hypothesis of oncogenesis


Summary 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
- RB
- CDK inhibitors



PT 53 PT53 is tumor suppressor gene , play important role

as guardian of the genome .

PT53 is a negative regulator of cell cycle, normally present
in low levels with short half life.
Non functioning mutants PT 53 have long half life
&accumulate in cell.
PT 53:Called molecular policeman of the cell preventing
genetically damaged cells from progressing through new
PT 53 have antiproliferative effect & regulate apoptosis.


Mode of Action of PT 53 :

Normal PT53 binds to DNA (maintain the integrity of genome .

P 21 & GADD45 Transcription Delay
*More time for repair Normal

*Failed repair APOPTOSIS(by activation of BAX gene)

*Fixed mutation (mutant PT 53) NEOPLASIA
Acquired mutation in many cancers :
e.g.colon, breast, lung , leukemiaetc
Inherited mutation in Li - Fraumeni S.
sarcoma, leukemia,breast&brain CA..etc
May be blocked by some DNA viruses .
Damaged DNA PT53 activated & bind to DNA cause transcription up
regulation of targeted gene i.e. faulty PT53 molecules allow cell with
damaged DNA (mutant DNA)to survive & replicate :

P21-CDK inhibitor Arrest cell at G1.

GADD45-DNA repair requir DNA damage


Action of PT53


3- Apoptosis Genes :

These are genes involved in programmed cell death ,promoting

or suppressing this process.
BCL-2 , BCL-x , BAD..etc
BCL-2 prevents apoptosis, i.e.prolonging cell life.
Activated by translocation (18:14 ): Low grade B cell
Lymphoma .

4- DNA Repair Genes :

*Repair mutations in other genes, preventing them
from continuing in further cell cycles.
*Defective DNA repair= Genomic Instability &
Enabler of Malignancy .These include :
1- Nucleotide excision repair genes :
* Damage by U-V light . Defective in genes encode

for certain enzyme involve in DNA synthesis:

Xeroderma Pigmentosum


2-DNA Mismatch repair genes : These repair errors in

pairing of nucleotides during cell division .
e.g. G+T instead of A+T .
(Hereditary Nonpolyposis Colonic Ca.) (HNPCC).
These genes are not oncogenic but allow mutation in
other genes in normal cell cycle .
BRCA -1 in familial breast cancer & ovarian CA
BRCA 2 in breast CA in both sex ,e.g: prostate, ovary,
pancreas, stomach CA.
Both above are important in repairing breaks in DNA but
are rarely inactivated in sporadic cases.


5- Telomeres

(Cellular senescence)

These are specialized structures (nucleotide repeats )at the

end of chromosomes which are shortened after each cell
division till eliminated when the cell stop dividing (this
reach to point whereby loss of telomere lead to an endend fusion of chromosome during mitosis where
telomerase enzyme lost gradually) and may play a role in
determining the life of individual cells.
This shortening is prevented by TELOMERASE (which
absent in most somatic cells ) .
Majority of cancers telomerase activity (tumor cells
have the ability to reactivate this enzyme ) so contribute
to immortalization of cancer cells by prevention of
naturally programmed shortening of the telomere.


Despite the fact that most malignant cells are

monoclonal in origin , by the time they become clinically
evident , their constituent cells are extremely
hetrogenous ( result frome multiple mutations ).
Tumors may generate clones with different phenotypic
features, leading to a more aggressive nature e.g.
Non antigenic growth
Rate of generation of these clones differs in individual
tumors e.g. Osteosarcoma versus Seminoma

Tumor Progression :



How does a cell

metastasize ?
1-First step is : PRESENCE OF A
2-Development of sustained
3-Ability to invade & metastasize


I- ANGIOGENESIS : ( Angiogenic switch ):

Angiogenic switch :terminate the early tumor stages of
vascular quiescence include:
1-Increase production of angiogenic factors induce new
sprouting of vessels necessary for tumor growth > 12mm.diameter (e.g. FGF ,VEGF,TNF, PDGF, EGF
RAS mutation & Hypoxia Inducing factor promote VEGF
2-loss of Anti-angiogenic factors : e.g. thrombospondin,
angiostatin, endostatin
TP53 antiangiogenic thrombospondin
- loss of PT53 (mutation ) vascular density = Poor
prognosis .


1- Invasion through the (ECM) :

i-Detachment (loosening )of tumor cells

E-cadherin is an intercellular adhesion molecule
Inactivation detachment of tumor cells

ii- Attachment of tumor cells to matrix components

Brought about by laminin & integrin receptors to basement
membrane & ECM


iii- Degradation of BM by proteolytic enzymes :

- Metalloproteinase ( type IV collagenase)

Cathepsin D.
Protease .

iv- Movement through the interstitial tissue(locomotion)

-Degraded basement membrane .
- Tumor derived cytokines e.g. Autocrine motility factor
- Cleavage products of matrix (collagen & laminin )& GF
(ILGF)have chemotactic activity for more tumor cells.
-Stromal cells produce paracrine effectors of cell motality
(HGF) which bind receptors on tumor cells .

2- Metastases(vascular dissemination &homing of tumor cells)

Invasion of the circulation (intravasation):Adhesion to
endothelium retraction of endothelium vessel
Attack by NK cells, some escape by formation of a thrombus
Escape from circulation :Adhesion to endothelium retraction of
endothelium escape to tissue (extravasation ).
- Some tumor
cells are hormone dependant for growth. This is through presence
of receptors on surface e.g- Breast CA , Thyroid CA , Prostatic
-Some genes may be important in metastases :
- nm 23in breast CA ,- KAI -1in prostatic CA , - KiSS in

Examples of Tropism ( Homing )

Prostatic Carcinoma Bone

Lung Carcinoma Adrenals & Brain
Neuroblastoma Liver & Bone
Less common sites of metastases include skin,muscle
*Spleen & Cartilage are almost never involved by
metastatic tumours.
1-Anatomical Location
2-Complimentary adhesion molecule
tumor cells & target organs.
3-Chemoatractants liberated by target organs.
4-Protease inhibitors present in certain


Chemical Mutagenes are detected & graded by the AMES TEST
Factors influencing carcinogenesis include :
- Genetic susceptibility
- Sex & hormonal status
- Diet
Chemical carcinogens act by inducing ras mutation
Some strong chemicals act as Initiator & Promoter

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

metabolic conversion


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.
4- Nitrosamines : Endogenous or food preservatives e.g.
Gastric & Colon CAetc.
5- Aflatoxin B1 : Naturally occurring carcinogen present in
fungus. Aspergillus flavus Hepatocellular CA.

1- 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-Ionizing Radiation:
- Present in environment
- 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. PT53
3-Asbestos fiber inhalation : Mesothelioma & Lung CA


A - DNA Viruses :Virus have DNA transforming genes (E6,E7)
inactivate suppressor genes, activates cyclins, & inhibit
1- HPV : Human Papilloma Virus
* Low risk groups (6, 11) Squamous Cell Papilloma
(wart ).
* High risk group ( 16, 18 ) Squamous Cell CA in cervix.
2- EBV : Ebstein Barr Virus
Mode of action :
Receptors for virus on B cells Activated B cells Polyclonal
Proliferation, under T cell control ,
- MONOCLONAL B proliferation due to deregulation of CMYC by translocation :
BURKITTS Lymphoma (t 8:14)
- In endemic cases Malaria & Malnutrition may play a role in
immunity ( Lost T cell control ).

Pathogenesis of Burkitt Lymphoma


3-HBV ( Hepatitis B Virus )

Chronic liver disease Cirrhosis
Action :* Cell proliferation mutation
* HBV encodes Hbxprot. growth
promoting genes
*Hbx binds to p 53 Inactivates suppressor
*Aflatoxin in endemic areas
(HBC is similar to above but no X-protein)
4- HHV-8 ( KSHV ) Kaposi Sarcoma in AIDS


RNA virus tumors :

HTLV-1 induces Leukemia /Lymphoma in humans

Transmitted sexually,blood or milk

- Mode of action :
Target cells are CD4+ T cells which have receptors for
the virus tax gene (transforming agent ) proliferation


HTLV-1-induced T-cell leukemia/lymphoma

HTLV-1 infects many T cells and
initially causes polyclonal
proliferation by autocrine and
paracrine pathways triggered by
TAX gene. Simultaneously, TAX
neutralizes growth inhibitor signals
by affecting TP53 and
CDKN2A/p16 genes. Ultimately, a
monoclonal T-cell
leukemia/lymphoma results when
one proliferating T cell suffers
additional mutations.


Helicobacter in carcinogenesis

First described as a cause for peptic ulcer

Plays a role in etiology of gastric CA & gastric
Chronic gastritismucosal lymphoid follicles reactive
polyclonal B cells monoclonal B cells LYMPHOMA
Chronic gastritis Gastric atrophy intestinal
metaplasia dysplasia Gastric Carcinoma


CA LUNG Smoking.
CA CERVIX Sexual transmision of HPV.
CA BLADDER Rubber Industry.
CA LIVER Aflatoxin & HBV infection
CA THYROID Radiation.


Tumor Antigens :
Tissue specific Ag (peptide of mutant gene),tissue associated
Ag (glycoprotein), viral, Oncofetal ( AFP , CEA)..etc
Anti tumor Host Mechanisms :
1- Sensitized Cytotoxic T lymphocytes (directed against TCell defined tumor Ag).
2- Natural Killer cells may kill tumor cells
previous sensitization lyse a wide range of tumors .
3- Macrophages activated by IFN- to secrete TNF- which
is lytic to
tumor cells.
4- Humoral mechanisms .

Immune surveillance :
Supportive evidence :
1- Patients with congenital immune
deficiency have
200 timesrisk of cancer.
2- Immunosuppressed patients have
increased rates
of cancers , specially
-Tumors may escape immune surveillance by :
1- Selection of antigen-negative variants .
2-Loss or reduced expresion of histocompatibility
antigens ,thus become less susceptible to cytotoxic TCell lysis .
3-Tumor induced immunosuppression.

Effect of NEOPLASIA on the body :

1- Mass effect by pressing on vital area
e.g.airway, intestine , BV, brain,nerve
obstruction, infarction , paralysisetc
2- Local destruction of epithelial surface or BV
ulceration , bleeding , infection .
3- Functional activity in certain tumors.
4- Cancer cachexia .
5- Paraneoplastic syndrome.


- Cancer Cachexia :

Wasting syndrome characterized by anorexia , loss of

body fat ,with marked weakness,anemia & fever.
Possibly due to :
1- Release of cachectin ( TNF and IL-1) by
macrophages & some tumor cells.
2- Loss of appetite.
3- Metabolic changes leading to reduced synthesis &
storage of fats & increased mobilization of fatty acids from


4 - Paraneoplastic Syndrome :
Symptoms that not directly related to the primary tumor or
its metastasis or elaboration of hormones indigenous to the
tissue from which the tumor arose .
Syndrome that cant be explained by the effects of either
local or distant spread of tumor or by hormones indigenous
to cell of origin.

They may precede the tumor or mimic metastases.

They occur in about 10% of malignant tumors.



1- Ectopic

hormone production (endocinopathy )

ACTH, ADH,Parathormonelike polypeptide,

Insulin like GF, erythropoietin .
2- Coaggulative abnormalities & hematologic syndromes
Venous thrombosis, Erythrocytosis,
Eosinophilia, Thrombocytosis,
Autoimmune hemolytic anemiaetc
3- Neurological abnormalities (encephalopathy ).
4- Skin changes ( acanthosis nigricans )& Myopathy .
5- Malabsorption in up to 50% of cases
6- Nephrotic syndrome .
7-hypertrophic osteoarthropathy & finger clubbing .

Some Paraneoplastic Syndromes :

Small Cell CA lung ACTH , ADH, Bone

changes,nervous system disorders
Squamous Cell CA lung Hypercalcemia
Pancreatic & lung CA Deep vein thrombosis.
Breast CA Hypercalcemia (lytic bone metastases).
Hepatic & Renal CA Polycythemia
Pancreatic, Gastric CA Carcinoid S.
Advanced Cancers Nonbacterial thrombotic
Colonic Adenocarcinoma Acanthosis nigricans


These are tumor derived or associated antigens , enzyme ,
cytoplasmic proteins and hormons that can be detected in
blood or other body fluid.
-Tumor markers represent biochemical indicators of the
presence of a tumor.
Their uses are to :
I - Confirm diagnosis (not for primary 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
- testicular tumors
- pregnancy
- Gestational Trophoblastic Disease :
Hydatidiform Mole , Choriocarcinoma

Calcitonin useful in diagnosis of Medullary CA

ACTH :ectopic production in small cell carcinoma.


2- Oncofetal Antigens :
Carcinoembryonic Antigen ( CEA ) : in fetal tissue &
some malignancies - Colorectal CA & Pancreatic CA .

CEA value in detected tumor burden in colorectal cancer

& in detecting recurrences after surgery
-Alpha Fetoprotein (AFP:produced by fetal yolk sac&liver
-Normal 15 g / L
- Cirrhosis 200-300 g / L
- Hepatoma 400g / L
-Non seminomatous testicular germ cell tumor.
Less consistent elevation may be seen in some non
neoplastic conditions (alcoholic hepatitis
,cirrhosis,ulcerative colitis ).

3- Isoenzymes :

Prostatic Acid Phosphatase ( PAP )

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

Neuron -specific enolase :

Small Cell CA of lung & Neuroblastoma.
4- Specific Proteins :
Immunoglobulins secreted in Multiple Myeloma &

Prostate -specific antigen ( PSA ) :

Present in epithelium of prostatic ducts.
* BPH & Prostatic CA .
* Level correlates with stage.


1- Cytological methods : Cytological diagnosis depend
on the identification of features of anaplasia in cells
exfoliated , aspirated or brushed .
Study exfoliated cells :
- FNA: for superfacial, palpable mass (breast mass ) or
deep mass under u/s control ( liver mass) .
Brush cytology : like bronchial tree brush .
Fluid tapping : aspirated pleural effusion & ascetis.
PAP often used for early detection of cervical
Natural exfolative cytology :for urine , sputum
- False(+), False (-)
- A negative report does not exclude malignancy
- Advise biopsy !

2- Histological methods :
Biopsy of tissue: Needle Biopsy , Endoscopic Biopsy,
Open Biopsy.
Frozen Section (Rapid technique & rapid diagnosis during
operation): Define the lesion & surgical margins of
excision .
Paraffin Section ( 36-48 hrs. or longer ).
: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 Melanoma

4- Electron microscopy :
For recognition of desmosomes (epithelial tumors ) , or
neurosecretory granules ( neuroendocrine tumors).etc.
5- Flow cytometry :
For measuring DNA content , detecting
diploid versus
aneuploid tumors.etc.
Correlates with rate of growth
Useful in the diagnosis of Lymphoma (identification of cell
surface Ag).
DNA-probe analysis (molecular diagnosis):
diagnosis of malignant neoplasm by detection of polyclonal
(benign) B&T-Cell proliferation from monoclonal



This is very important as many cancers are curable if they
are diagnosed early.
Specific symptoms should be followed up
e.g. Abnormal bleeding ( GIT , uterine ).
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 of breast .
- 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.


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