neoplasia 2015.ppt

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Neoplasia & cancer

Dr.Nafea Sami Al Esawi

General pathology 2014

2

nd

stage students



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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

processes.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.

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Tumor:

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 ). 5



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 .6



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- Autonomous growth :The growth of neoplastic cells isindependent of growth factors ,regarding mechanismoperating inside normal cells.

Excessive growth :The excess may be evident in thesize of the outgrowth & duration of the proliferation .

Disorganized growth ( cytoarchitectural level ) :Thestructures formed by tumor cells differ from the normaltissue & don't fit into general organization scheme ofthe normal body .



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Dysplasia: A disordered growth and maturation of an epithelium,

which is still reversible if the factors driving it areeliminated .

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) . 9



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

.

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In capillaries and postcapillary venules, T. media

whichpericytesmay be replaced by cells called

have contractile function and can proliferate and

differentiate after injury to new blood vessels .

Tun ica advent i t ia

oriented collagenous andlongitudinallyConsists ofelastic fibers that become continuous with the

surrounded C.T.

•:Innervation of Blood vesselsBl. Vessels supplied by autonomic nervous system

that regulate their relaxation and contraction by

special neurotransmitters.



Hyperplasia: 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 .

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Hypertrophy:.

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.:

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.

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Metaplasia 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 ) .

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Benign tumor: A benign neoplasm looks microscopically a lot like the

tissue of normal cells from which it originated, and itsgeneral characteristics include:

Slow growth ( innocent ).

Resemblance to tissue of origin (well differentiated) . Circumscription ( localize ).

Capsulation .

Lack of invasion . Absence of metastases .

Prognosis : Good .

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: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 .

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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

(intermediate).

3- Gross Appearance of the tumor :localize or

infiltrative.

4- Grade :Degree of differentiation & anaplasia .



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naming : Classif ication by origin EPITHELIAL CELL : Benign tumors of epithel ial cel ls:

Adenoma : is term applied to a benign epithelial

neoplasm derived from glands, although they may ormay not form glandular structures.

On this basis, a benign epithelial neoplasm that arises

from renal tubular cells growing in the form ofnumerous tightly clustered small glands would betermed an adenoma, as would a heterogeneous mass

of adrenal cortical cells growing as a solid sheet.

-Tubular adenoma of colon .

-Follicular adenoma of thyroid .



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:PapillomaTerm 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-likeepithelial cell growing overlying fibrovascular core(connective tissue with blood vessels) .

e.g Squamous papilloma of skin .

Squamous papilloma of larynx .

Transitional Papilloma of bladder.

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Benign epithel ial cystic tumors:

Cystadenoma :as adenoma with cysticcomponents.Papil lary cystadenoma : as above ( adenoma +cyst + but with papillary (finger like projection ).

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Malignant tumor of epithelial or igin: Carcinoma

Squamous cell carcinoma : would denote a cancer in

which the tumor cells resemble stratified squamousepithelium, 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 ofurinary bladder.

Small cell carcinoma :arise from neuroendocrine

cells.(mainly in lung ,although can arise in other tissue &

organs ) , so it considered as systemic disease .



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Squamous cell carcinoma , invasive



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Mesenchymal (Stromal :connective tissue) cell origin :

1-Benign connective tissue tumors :

Named by tissue of origin with attached suffix – omae.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 cells…etc .



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.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 .

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*Some tumors have more than one paranchymal cell



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Some tumors have more than one paranchymal cell

type,these include tumors of Germ cell origin : able to

differentiate into 3germ layers (ectoderm , mesoderm &

endoderm).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 , .





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Teratoma pleomorphic adenoma

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Mixed tumors-2

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 andfibroadenoma of breast .

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

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

Neural,gl ial cell& neural supporting structures tumor: Like glioma , neuroblastoma &meningioma.

Germ cell tumors : This include seminoma , teratoma &

choriocarcinoma .

Tumors of pr imitive fetal or igin :

Blastoma :(small primitive cells). e.g. Retinoblastoma

Nephroblastoma, Neuroblastoma, Medulloblastoma

HepatoblastomaNote : The great majority of these tumors are malignant.

Majority occur in infants & children



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Non neoplastic masses :

1-Hamartoma : Tumor like malformation (mass or

nodule) in which there is abnormal mixing ofnormal native tissue components of the organ ,eitherin the form of change in quantity or arrangement oftissue elements: e.g. Lung Hamartoma ,most

haemangioma, melanocytic nevi.: usually developduring fetal development .

2-Choristoma : Mass composed of normal cells ortissue found in a wrong location ( Ectopia ) :

Different types of tissue, ectopic to the region. e.g.Meckle’s Diverticulum,(ectopic pancreatic &gastrictissue) , Salivary tissue in lymph nodes .

Both are present at birth & do not have malignant

potential



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E i b i d lE i



Exception to above mentioned rules:Exceptions

include tumors that are always malignant such as :

Lymphoma: malignant tumor of lymphoid tissue .

Melanoma :malignant tumor of melanocytes .

Seminoma &dysgerminoma :tumor of primitivegerm cells.

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How do benign tumor dif fer f rom malignant tumor

1-Differentiation & anaplasia: Extent to which the

transformed cells resemble their normal forebearsmorphologically &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.

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Benign versus malignant tumors



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Benign versus malignant tumors

:Differentiation-1



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:Differentiation - 1

- 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 .

Ab l h (di i i f iD l i



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: Abnormal growth (disorganization of tissueDysplasia 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



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Normaladenoma

Well differentiatedadenocarcinoma

Poorly differentiatedadenocarcinoma Anaplastic carcinoma

Cytological Features of Dysplasia



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Cytological Features of Dysplasia 1-I ncreased 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 polar ity in an epithelial surface (loss of orientation

&dissary of tissue architecture).

8-Prominent nucleoli .

Severe Dysplasia / Anaplasia



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Severe Dysplasia / Anaplasia

:I ntraepithel ial Neoplasia



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:I ntraepithel ial 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 “dysplasia”can be seen

in reactive & inflammatory lesions.

Dysplasia can regress.

Intraepithelial Neoplasia



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Intraepithelial Neoplasia

: Based on le el of differentionGrade of tumor



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:: Based on level of differentionGrade of tumor

Grading :Is the attempt to assign a rough numerical value

( Score of differentiation ) to the extent of histologicaldeviation 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.

:hRate of growt-2



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: h Rate of growt 2

Most cancers grow faster than benign tumors .

Rate of growth usually correlates with level of

differentiation.

May be rapid in some benign tumors .

Some tumors may shrink in size (lieomyoma & pituitary

adenoma). 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

:Local invasion-3



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:Local invasion 3

Second most important feature distinguishing

malignant tumors after metastases. Benign tumors frequently have a capsule.

Not all benign tumor are encapsulated

(lieomyoma)

Malignant tumors progressively invade

(infiltrative ) & destroy surrounding normal

tissue: e.g. Breast cancer infiltrating

skin,muscle.

Basal cell carcinoma of skin infiltrating nerve

:Metastasis-4



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: Metastasis 4

Metastasis is the absolute criteria of malignancy .

Spread of malignant tumors to distant sites not

contigious with the main primary tumor ( secondarydeposit or metastatic foci ).

All tumors can potentially metastasize except

BASAL CELL CA ., GLIAL TUMORS Metastasis is often proportionate to the size and grade

of the primary tumor

Routes of metastases:

1-Lymphatics. 2-Blood vessels.

3-Seeding within body cavities.

Lymph node with metastasis carcinoma



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Lymph node with metastasis carcinoma

:Lymphatic Spread1



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:Lymphatic Spread - 1

Invasion of lymphatic vessels followed by spread oftumor to regional lymph nodes , ultimately to othersites 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



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Lymphatic channels with metsatatic carcinoma

Hematogenous spread :2



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Hematogenous spread : - 2 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 ( thesystemic &portal venous blood )respectively .

Other major sites are the bones & brain (wellvascularized 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



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brain

lungs

boneliver

3- Transcelomic spread :



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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



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:Staging of Tumor



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: Staging of Tumor

This indicates the extent of spread of the tumor.

It based on correlating Clinical data ,investigative procedures (radiological ) and pathological findingappearance 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 cl inical 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 :



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Stag g Syste

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

e.g.T1,N1, M0 ( Small tumor that hasmetastasized to lymph nodes &distant site ).

-----------------------------------

Others: AJC(American Joint Committee) staging system (0-IV)

Duke’s staging for colonic CA

TNM staging for carcinoma of breast



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TNM staging for carcinoma of breast

:Tumor Therapy



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: 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 of5year or 10 year survival.

This is influenced by :Tumor Type e.g. Lung CA versus Lip CA

Tumor Grade & Stage.

Host reactions

:EPIDEM IOLOGY OF CANCER



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Cancer epidemiology deals with the occurrence of tumors inhuman populations , by study the incidence , prevalence &

mortality .Epidemiologist are trying to identifyenvironmental , genetic causes of cancer , thus contribute to

better diagnosis ,treatment and prevention .Epidemiologydata 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



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. 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

time.

Mortality : Is the number of deaths from a given form of cancer

during a specified period of time in defined population .I ncrease 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)

INFECTIONS & CANCER



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INFECTIONS & CANCER

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.

:Geographic location - 1



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g p

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

Significantly affect the occurrence:Environment factors - 2

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.

:Age-3



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:Age 3

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 chi ldren less than 5yearsAcute Leukemia ,Lymphoma , CNS Tumors

(retinoblastoma ,neuroblastoma),soft tissue Sarcomas

(rabdomyosarcoma).

Adolescence age tumors :Osteosarcoma , Ewing sarcoma

, Medulloblastoma .

Biphasic age incidence : Hodgkin lymphoma ( 20 & 60 ).

4- Hereditery :



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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 togenetic 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

mutant genes e.g. BRCA-1



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Gross appearance of familial polyposis. Entire large bowel was involved. Note the

fact that practically all of the polyps are small and sessile.

A i d P l ti diti



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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 proliferation1- 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 .

:the subsequent development of malignancy in benign tumors isNotequite uncommon (i.e most malignant tumors arise denovo).

However :there are few exceptions e.g .villous adenoma of colon often

Neoplasia & cancer



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Neoplasia & cancer

MOLECULAR BASIS OF CANCER

Dr.Nafea Sami Al Esawi

General pathology 2010

Al

–

anbar medical college

3

rd

stage medical students



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Cell cycle stages, also called phases, are thecomponents 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 athird gap phase, known as G0.

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http://www.wisegeek.com/what-is-a-metaphase.htm

http://www.wisegeek.com/what-is-an-anaphase.htm

http://www.wisegeek.com/what-is-an-anaphase.htm

http://www.wisegeek.com/what-is-a-metaphase.htm



The G1, S, and G2 stages are collectivelyknown as interphase. A cell in the G1 phase

is actively growing and undergoing the

metabolic changes that are required for cellsto divide. The G1 phase ends at the

restriction point, when the cell "decides" to

undergo division and moves on to the S

phase

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http://www.wisegeek.com/what-is-interphase.htm

http://www.wisegeek.com/what-is-interphase.htm



All of the cell's DNA is replicated during the synthesisphase 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 alongeach 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

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http://www.wisegeek.com/what-is-polymerase.htm

http://www.wisegeek.com/what-is-polymerase.htm



Cells prepare for mitosis during the secondgap stage. Special materials are required in

the cytoplasm of the cell in order for mitosis

to occur. The cell undergoes metabolicchanges during G2 in order to form these

cytoplasmic materials

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http://www.wisegeek.com/what-is-cytoplasm.htm

http://www.wisegeek.com/what-is-cytoplasm.htm



After G2, mitosis begins with the prophasestage. A structure known as the mitotic spindle

is formed during this phase. Another structure

called the centrosome duplicates itself, and theduplicates 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 spindleusing structures known as kinetochores. This

last step of prophase is sometimes further

divided into a stage called prometaphase 96

http://www.wisegeek.com/what-is-the-centrosome.htm

http://www.wisegeek.com/what-is-the-centrosome.htm



During metaphase, the chromosomes alignwith the metaphase plate to help the

chromosomes separate properly during

anaphase. Once the chromosomes arealigned, anaphase occurs as the

chromosomes separate and move to

opposite ends of the cell. The separated

chromosomes are called daughterchromosomes

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Telophase is the final phase of mitosis and ofthe cell cycle stages. The daughter

chromosomes each acquire their own nuclear

membranes, and the spindle fibers detachand 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

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Some researchers include a fifth phase of cellcycle stages. The G0 phase is inserted

between mitosis and G1. If cells enter the G0

phase, they are no longer growing. Theymay, however, become reactivated and enter

the G1 phase again

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During development from stem to fullydifferentiated, cells in the body alternately divide

(mitosis) and "appear" to be resting (interphase).

This sequence of activities exhibited by cells iscalled 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.

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Interphase: Interphase generally lasts at least 12 to 24 hours inmammalian 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.

neuron).

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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 isready 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.

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Gap 2 (G2): During the gap between DNA synthesis andmitosis, 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. 103

http://www.cellsalive.com/mitosis.htm




Cancer cells reproduce relatively quickly inculture. In the Cancer Cell CAM compare the

length of time these cells spend in interphase to

that for mitosis to occur.

104

http://www.cellsalive.com/cam1.htm



http://www.cellsalive.com/cam1.htm



Cycle, Checkpoint Control and DNA Damage

Control of eukaryotic cell growth and division

involves molecular circuits known as

“checkpoints” that ensure proper timing ofcellular 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

tumorigenesis. 105



The G1/S checkpoint controls progression of cells throughthe 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 cyclin-

bound cyclin dependent kinases (CDK) in late G1 inducesdissociation 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 andChk1/2 kinases to block CDK activity, leading to cell cycle

arrest and DNA repair or cell death.

106



The G2/M checkpoint prevents cells containing damaged DNAfrom 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 M-

phase. Phosphorylation of p53 promotes dissociation betweenp53 and MDM2 and allows binding of the transcription factor to

DNA

107



The spindle checkpoint ensures properchromatid attachment prior to progression

from metaphase to anaphase. The SCF and

APC/C protein complexes play prominentroles, with APC-cdc20 initiating the entry into

anaphase by promoting ubiquitin-mediated

degradation of multiple substrates, including

cyclin B and the regulatory protein securin.

108




109

PROCESS ! : MULTISTEP Carcinogenesis is a

Molecular change Morphologic appearance

-Normal epithel ium Loss or mutation of APC locus

on chromosome 5q

-Hyperproli ferative Loss of DNA methylation

epithelium

-Earl y adenoma Mutation of RAS gene on 12p

-I nermediat adenoma Loss of tumor suppressor gene on 18 q

-Late adenoma Loss of RAS gene on 17p

-carcinoma

* * Each cancer must resul t from accumulations of mul tiple

mutations.




110

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

INVASION & METASTASES .

Multisteps Carcinogenesis (molecular basis of cancer)



111



Oncogenes :are cancer inducing genes derived from

cellular genes called protooncogenes



113

cellular genes called protooncogenes.

OncogenProtooncogenFunction

SISPDGFGrowth factor

ERB-B2EGF-ReceptorGrowth factor receptor

ABLTyrosine kinaseSignal transduction

MYCTranscription activatorDNA binding protein



: Methods of gene activation



115

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 Burkittlymphoma and chronic myelogenous leukemia.



116

Gene Amplification of N-MYC gene in Neuroblastoma:

N MYC present normally on 2p become amplified & seen either as



117

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 S lf ffi i i th i l ( O )



118

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 Enablerof malignancy).

5- Limitless replication potential (Telomeres :determinethe life of individual cell) i.e overcoming cellularsenescence .

6- Development of Sustained angiogenesis.7- Ability to invade & metastasize (new features acquired

during new mutations ).



119

Oncogenes:Genes that promote autonomaous cellgrowth 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

kinases).

Inhibitors of apoptosis.

1-Oncogenes :Classified by site of action

Genes in Neoplasia Transformation:(cancer associated genes )



120

Oncogenes coding for Growth Factors - 1

All normal cells require stimulation by growth factor



121

All normal cells require stimulation by growth factorto undergo proliferation .(Cell growth is stimulated

by Growth factors) Cancer cells acquire growth self-sufficiency by:

1-Ability to synthesize the same growth factors towhich they are responsive( persistent activation).

Platelet derived growth factor (PDGF) seen inglioblastomas .

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 GrowthFactor (TGF-)in sarcomas

Oncogenes coding for GF Receptors: - 2 Growth Factors integrate with membrane receptors



122

Growth Factors integrate with membrane receptors tyrosine kinase activity nucleus .

Mutant receptor proteins continuous mitogenicsignals to cells even in the absence of GF inenvironment.

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 & ovariancarcinoma .

Increase expression = POOR PROGNOSIS

Oncogenes in Signal Transduction: - 3



123

g g

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 signalsfor cell proliferation.

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

GDP GTP

Point mutations in RAS are present in 30% of all cancers, specially pancreatic & GIT cancer

Active RAS

GTPase activating prot.(GAP)

: Non receptor associated tyrosineAction of ABL

kinase signal transmission



124

kinase signal transmission

Normal ABL (proto-oncogene has tyrosine kinase

activity )is located in nucleus where it promotesapoptosis of cells that suffer DNA damage .

Chronic myeloid leukemia : Mutation ( 9:22translocation ) BCR- ABL hybrid gene .

This new hybrid gene is retained in cytoplasm whereit has tyrosine kinase activity cell proliferation.

Action is Proliferation + Absent Apoptosis.



: Dependent Kinases - Cyclins & Cyclin - 5 Cancers may become autonomous if the genes that



126

Cancers may become autonomous if the genes thatderives the cell cycle become dysregulated by mutations

or amplification . Cyclins bind to CDKs, activating them.

Cyclin D family CDK4 & CDK6 at G1 S phasecheckpoint.

Activity of CDK/Cyclin regulated by CDK inhibitors

Cyclin D overexpressed in breast, liver, & esophagealcancers

Amplif ication of CDK4 gene present in melanoma,sarcomas, glioblastoma .

2- Cancer Suppressor Genes:-



127

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 infamilial 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 )genewith B-catenin pathway :



128

): RetinoblastomaRb gene ( - 1 Rb role is regulating the G1 S check point of cell



129

Rb role is regulating the G1 S check point of cellcycle.

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 I nactive pRb releases transcription factors TRANSCRIPTION ( of genes whose products arerequired for S phase of cell cycle ) , so drive the cell to

proliferation.

This is a trigger the cell cycle at G1 phase pushing cellinto S phase

:Retinoblastoma Example :



130

Autosomal dominant hereditary disease.

May be sporadic. Patients carry one mutation in their genome .

No tumor develops unless two alleles in 13q14

become mutant (Knudson’s two hit theory).

Patients have high incidence of Retinoblastoma and

osteosarcoma.

I nher itance (pathogenesis )of Retinoblastoma

T t ti f RB l 13 14 l d t l ti



131

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 celldivides non stop.



132

Two hit hypothesis of oncogenesis

Summary Cyclin/CDK/RB function

L f l ll l t l i t l t



133

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



: 53Mode of Action of PT Normal PT53 binds to DNA (maintain the integrity of genome .



135

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 , leukemia…etc

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 upregulation of targeted gene i.e. faulty PT53 molecules allow cell withdamaged DNA (mutant DNA)to survive & replicate :

P21-CDK inhibitor Arrest cell at G1.

GADD45-DNA repair requir DNA damage

53 Action of PT



136

These are genes involved in programmed cell death ,promoting

3- Apoptosis Genes :



137

or suppressing this process.

BAX, 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 themfrom 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

These repair errors in:DNA M ismatch repair genes - 2

-



138

pp g

pairing of nucleotides during cell division .

e.g. G+T instead of A+T .a.) (HNPCC).ColonicConpolyposis NereditaryH(

These genes are not oncogenic but allow mutation in

other genes in normal cell cycle .

BRCA -1 in familial breast cancer & ovarian CABRCA –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.

These are specialized structures (nucleotide repeats )at the

5- Telomeres (Cellular senescence)



139

These are specialized structures (nucleotide repeats )at theend of chromosomes which are shortened after each celldivision till eliminated when the cell stop dividing (thisreach to point whereby loss of telomere lead to an end-end fusion of chromosome during mitosis wheretelomerase 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 cellshave the ability to reactivate this enzyme ) so contributeto immortalization of cancer cells by prevention ofnaturally programmed shortening of the telomere.

:TUMOR PROGRESSION

Despite the fact that most malignant cells are



140

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

Invasion

Metastases Rate of generation of these clones differs in individual

tumors e.g. Osteosarcoma versus Seminoma

:Tumor Progression



141

BIOLOGY OF METASTASES



142

How does a cell

metastasize ? 1-First step is :

PRESENCE OF A

CELL CAPABLE OF

UNDERGOING THE PROCESS

OF METASTASES

!2-Development of sustained

angiogenesis3-Ability to invade & metastasize



I I ABIL I TY TO INVADE & METASTASISE



144

1- Invasion through the (ECM) :

E-cadher in is an intercel lular adhesion molecule

Inactivation detachment of tumor cells

Brought about by laminin & integrin receptors to basementmembrane & ECM

i-Detachment (loosening )of tumor cells

ii- Attachment of tumor cells to matrix components



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

Invasion of the circulation (intravasation):Adhesion to



146

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 ).

HORMONE DEPENDENCE : : - Some tumor

cells are hormone dependant for growth. This is through presence

of receptors on surface e.g- Breast CA , Thyroid CA , Prostatic

CA

-Some genes may be important in metastases :

- nm 23in breast CA ,- KAI -1in prostatic CA , - KiSS in

Melanoma

Examples of Tropism ( Homing ) Prostatic Carcinoma Bone



147

Lung Carcinoma Adrenals & Brain

Neuroblastoma Liver & BoneLess common sites of metastases include skin,muscle

thyroid,breast….etc.

*Spleen & Cartilage are almost never involved by

metastatic tumours.WHAT INFLUENCES SI TE OF METASTASES ?

1-Anatomical Location

2-Complimentary adhesion molecule between

tumor cells & target organs. 3-Chemoatractants liberated by target organs.

4-Protease inhibitors present in certain tissues.

CARCINOGENIC AGENTS : Chemical Mutagenes are detected & graded by the AMES TEST

Factors influencing carcinogenesis include :



148

g g

- Genetic susceptibility

- Sex & hormonal status- Diet

Chemical carcinogens act by inducing ras mutation

Some strong chemicals act as Initiator & Promoter

1- CHEMICAL CARCINOGENS :

Direct Carcinogens -

Directly produce damage without prior metabolic conversion

Indirect Carcinogens- (Procarcinogen)

Metabolic conversion in liver bycytochrome P-450 dependent mono-

oxygenases ultimate carcinogen

: Action of chemical carcinogens

Initiator - Chemical inducing irreversible



149

g

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



150

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 CA…etc.

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

2- PHYSICAL CARCINOGENS : 1- U-V light : - Effect depends on intensity of exposure

& quantity of melanin

Production of pyrimidine dimers in DNA MUTATION in ras p 53



151

- 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- I onizing 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

3- VIRAL CARCINOGENESIS :

A - DNA Vi ruses :Vi rus have DNA transforming genes (E6,E7)inactivate suppressor genes, activates cyclins, & inhibit



152

inactivate suppressor genes, activates cyclins, & inhibitapoptosis.

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 Vi rus

* BURKITT’S LYMPHOMA , * B CELL LYMPHOMA

* HODGKIN’S LYMPHOMA, * NASOPHARYNGEAL CA

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 C-

MYC by translocation : BURKITT’S Lymphoma (t 8:14)

- In endemic cases Malaria & Malnutrition may play a role in immunity ( Lost T cell control ).

Pathogenesis of Burkitt Lymphoma



153

3- HBV ( Hepatitis B Virus )

Chronic liver disease Cirrhosis



154

HEPATOCELLULAR CA

Action :* Cell proliferation mutation* HBV encodes Hbxprot. growth

promoting genes

*Hbx binds to p 53 Inactivates suppressorfunction.

*Aflatoxin in endemic areas

(HBC is similar to above but no X-protein)

4 - HHV-8 ( KSHV ) Kaposi Sarcoma in AIDS

RNA virus tumors :



155

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 ) proliferationPOLYCLONAL MONOCLONAL LEUKEMIA

HTLV-1-induced T-cell leukemia/lymphoma

HTLV-1 infects many T cells and



156

initially causes polyclonal

proliferation by autocrine andparacrine 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



157

First described as a cause for peptic ulcer

Plays a role in etiology of gastric CA & gastric

lymphoma

LYMPHOMA :

Chronic gastritis mucosal lymphoid follicles reactiv

polyclonal B cells monoclonal B cells LYMPHOM

CARCINOMA :

Chronic gastritis Gastric atrophy intestinalmetaplasia dysplasia Gastric Carcinoma

CANCERS --ASSOCIATED CARCINOGEN



158

CA LUNG Smoking.

CA CERVIX Sexual transmision of HPV.

CA BLADDER Rubber Industry.

CA LIVER Aflatoxin & HBV infection

CA THYROID Radiation.

ANGIOSARCOMA of LiverPlastic(PVC).

MESOTHELIOMA Asbestose.

TUMOR IMMUNOLOGY:



159

Tumor Antigens :Tissue specific Ag (peptide of mutant gene),tissue associatedAg (glycoprotein), viral, Oncofetal ( AFP , CEA)…..etc

Anti tumor Host Mechanisms :

1- Sensitized Cytotoxic T lymphocytes (directed against T-Cell defined tumor Ag).

2- Natural Killer cells may kill tumor cells without previous sensitization lyse a wide range of tumors .

3- Macrophages activated by IFN- to secrete TNF- whichis lytic to tumor cells.

4- Humoral mechanisms .





- Cancer Cachexia :



162

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

adipocytes.

4 - Paraneoplastic Syndrome :

Symptoms that not directly related to the primary tumor or

i i l b i f h i di h



163

its metastasis or elaboration of hormones indigenous to the

tissue from which the tumor arose . Syndrome that can’t 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.

PARANEOPLASTIC SYNDROMES : 1- Ectopic hormone production (endocinopathy )

ACTH ADH Parathormonelike polypeptide



164

ACTH, ADH,Parathormonelike polypeptide,

Insulin like GF, erythropoietin .2- Coaggulative abnormalities & hematologic syndromes

Venous thrombosis, Erythrocytosis,

Eosinophilia, Thrombocytosis,

Autoimmune hemolytic anemia…etc3- 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



165

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

endocarditis.

Colonic Adenocarcinoma Acanthosis nigricans

TUMOR MARKERS & CANCER

These are tumor derived or associated antigens enzyme



166

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 notvery specific but their level is important.

Types of Tumor Markers

1- Hormones :

H Ch i i G d t hi H ( HCG)



167

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 CAthyroid.

ACTH :ectopic production in small cell carcinoma.

2- Oncofetal Antigens :

Carcinoembryonic Antigen ( CEA ) : in fetal tissue &



168

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- I soenzymes :

Prostatic Acid Phosphatase ( PAP )



169

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- Specif ic Proteins :

Immunoglobulins secreted in Multiple Myeloma &

NHL . Prostate -specific antigen ( PSA ) :

Present in epithelium of prostatic ducts.* BPH & Prostatic CA .

* Level correlates with stage

LABORATORY DIAGNOSIS OF CANCER

1- Cytological methods : Cytological diagnosis dependth id tifi ti f f t f l i i ll



170

on the identification of features of anaplasia in cells

exfoliated , aspirated or brushed . Study exfoliated cells :

- FNA: for superfacial, palpable mass (breast mass ) ordeep 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 cervicaldysplasia.

Natural exfolative cytology :for urine , sputum- False(+), False (-)

- A negative report does not exclude malignancy

- Advise biopsy !

: H istological methods - 2

Biopsy of tissue: Needle Biopsy , Endoscopic Biopsy,



171

Biopsy of tissue: Needle Biopsy , Endoscopic Biopsy,Open Biopsy.

Frozen Section (Rapid technique & rapid diagnosis duringoperation): Define the lesion & surgical margins ofexcision .

Paraffin Section ( 36-48 hrs. or longer ).

3 -Immunocytochemistry

:Staining by use of monoclonal AB directed against variouscomponents in cell

May help in diagnosis of undifferentiated cancers or helpin identifying source of a metastatic tumor.e.g.Cytokeratin Carcinoma

Common leukocyte antigenLymphoma

S 100 Melanoma

:Electron microscopy - 4 For recognition of desmosomes (epithelial tumors ) , or

neurosecretory granules ( neuroendocrine tumors)….etc.



172

5- F low cytometry :

For measuring DNA content , detecting diploid versusaneuploid tumors….etc.

Correlates with rate of growth

&prognosis(aneuploidy=poor). 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(malignant).

:EARLY DI AGNOSIS of CANCER

This is very important as many cancers are curable if theydi d l



173

are diagnosed early.

Specific symptoms should be followed upe.g. Abnormal bleeding ( GIT , uterine ).

Change of voice

Change in a nevusAbnormal lump in breast

An ulcer that does not heal……etc.

Specif ic procedures :

- Self examination of the breast .

- Mammography of 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.

neoplasia 2015.ppt

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