MOLECULAR BASISof CANCER

NON-lethal genetic damage A tumor is formed by the clonal

expansion of a single precursor cell (monoclonal)

Four classes of normal regulatory genes PROTO-oncogenes Oncogenes Oncoproteins DNA repair genes Apoptosis genes

Carcinogenesis is a multistep process

CARCINOGENESIS

Carcinogenesis is a multistep process at both the phenotypic and the genetic levels.

It starts with a genetic damage: Environmental

Chemical Radiation Viral

Inhereted

Carcinogenesis

Genetic damage lead to “ mutation” single cell which has the genetic damage

undergoes neoplastic prliferation ( clonal expansion) forming the tumor mass

TRANSFORMATION &PROGRESSION

Self-sufficiency in growth signals Insensitivity to growth-inhibiting

signals Evasion of apoptosis Defects in DNA repair: “Spell checker” Limitless replicative potential:

Telomerase Angiogenesis Invasive ability Metastatic ability

Carcinogenesis

Remember the cell cycle !! Binding of a growth factor to its receptor on

the cell membrane Activation of the growth factor receptor

leading to activation of signal-transducing proteins

Transmission of the signal to the nucleus Induction of the DNA transcription Entry in the cell cycle and cell division

6

4. NuclearProteins:

TranscriptionFactors

5. Cell GrowthGenes

3. CytoplasmicSignal Transduction

Proteins

1. Secreted Growth Factors

2. Growth Factor Receptors

Functions of Cellular Proto-Oncogenes

Regulation of G1/S cell cycle transition

Cell cycle arrest at G1/S (in response to DNA damage or other stressors) is medicated through which gene?

p53 (levels of p53 under negative regulation by MDM2 and p14 ARF)

Normal CELL CYCLE Phases

INHIBITORS: Cip/Kip, INK4/ARFTumor (really growth) suppressor

genes: p53

cyclins and cyclin-dependent kinases

-cyclins are only expressed at specific stages of the cell cycle

-cyclin-dependent kinases are expressed constitutively, but must bind cyclins for

activation; phosphorylation of target proteins essential for progression through

cell cycle

Carcinogenesis

5- Cyclins and cyclins- dependent kinases (CDKs) Progression of cells through cell cycles is

regulated by CDKs after they are activated by binding with cyclins

Mutations that dysregulate cyclins and CDKs will lead to cell proliferation …e.g. Cyclin D genes are overexpressed in breast,

esophagus and liver cancers. CDK4 is amplified in melanoma and sarcomas

Carcinogenesis

RB gene exists in “ active “ and “ inactive” forms

If active will stop the advancing from G1 to S phase in cell cycle

If cell is stimulated by growth factors inactivation of RB gene brake is released cells start cell cycle …G1 SM …then RB gene is activated again

13Hanahan and Weinberg, Cell 100: 57, 2000

Apoptosis

Oncogenes

Tumor Suppressor

Inv. and MetsAngiogenesis

Cell cycle

Four classes of normal regulatory genes PROTO-oncogenes Oncogenes Oncoproteins DNA repair genes Apoptosis genes

Carcinogenesis is a multistep process

15

ONCOGENES

Oncogenes are mutated forms of cellular proto-oncogenes.

Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.

ONCOGENES Are MUTATIONS of NORMAL

genes (PROTO-oncogenes)Growth FactorsGrowth Factor ReceptorsSignal Transduction Proteins

(RAS)Nuclear Regulatory ProteinsCell Cycle Regulators

Oncogenes code for Oncoproteins

Mutations that confer these properties fall into two categories

Oncogene : a cancer-causing gene that has been

mutated to cause an increase in activity, or the activity becomes constitutive,

or a new activity is acquired. -a mutation in a single allele is sufficient to

transform cells (dominant). -originally identified as viral proteins that

resembled normal human proteins. -the term "proto-oncogene" refers to the

normal protein that has not been mutated

tumor Suppressor gene Mutation of tumor

suppressor gene cause a loss offunction.

-mutations are required in both alleles to transform cells (recessive)

19

Class I: Growth Factors

Class II: Receptors for Growth Factors and Hormones

Class III: Intracellular Signal Transducers

Class IV: Nuclear Transcription Factors

Class V: Cell-Cycle Control Proteins

Five types of proteins encoded by proto-oncogenes participate in

control of cell growth:

1

2

3

4

4 types of genetic mutations that contribute to cancer

Categories of oncogenes A. Growth factors -generally not directly involved

transformation, but increased expression seen as part of

an autocrine loop due to changes in other steps in the same pathway

growth factor receptors

-They are transmembrane proteins with an external ligand binding domain and an

internal tyrsosine kinase domain. -oncogenic mutations can result in

dimerization and activation in the absence of

ligand -more commonly, increased activity is a

result of overexpression of receptors

Growth factor receptors

They are transmembrane proteins with an external ligand binding domain and an

internal tyrsosine kinase domain. -Oncogenic mutations can result in

dimerization and activation in the absence of

ligand -More commonly, increased activity is a

result of overexpression of receptors.

signal transducers

-Activated directly or indirectly by growth factor receptors

-Activation of signal transducers triggers a phosporylation cascade that ultimately

results in changes in gene expression at the transcriptional level.

-mutations in RAS , a GTPase, are the most common oncogenic

abnormality in tumors -failure to hydrolyze GTP locks RAS in its

active form.

Transcription factors

-Transcription factors contain DNA binding domains.

Sequences Regulate expression of genes essential

for passage through the cell cycle, or regulation of apoptosis.

-

CategoryPROTO- Oncogene

Mode of Activation

Associated Human Tumor

GFsPDGF-β chain SIS Overexpression Astrocytoma

OsteosarcomaFibroblast growth factors

HST-1 Overexpression Stomach cancer

INT-2 Amplification Bladder cancer

Breast cancerMelanoma

TGFα TGFα Overexpression Astrocytomas

Hepatocellular carcinomas

HGF HGF Overexpression Thyroid cancer

CategoryPROTO- Oncogene

Mode of Activation

Associated Human Tumor

GF ReceptorsEGF-receptor family

ERB-B1 (ECFR)

Overexpression Squamous cell carcinomas of lung, gliomas

ERB-B2 Amplification Breast and ovarian cancers

CSF-1 receptor FMS Point mutation Leukemia

Receptor for neurotrophic factors

RET Point mutation Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas

PDGF receptor PDGF-R Overexpression Gliomas

Receptor for stem cell (steel) factor

KIT Point mutation Gastrointestinal stromal tumors and other soft tissue tumors

CategoryPROTO- Oncogene

Mode of Activation

Associated Human Tumor

Signal TransductionProteins

GTP-binding K-RAS Point mutation Colon, lung, and pancreatic tumors

H-RAS Point mutation Bladder and kidney tumors

N-RAS Point mutation Melanomas, hematologic malignancies

Nonreceptor tyrosine kinase

ABL Translocation Chronic myeloid leukemia

Acute lymphoblastic leukemia

RAS signal transduction

BRAF Point mutation Melanomas

WNT signal transduction

β-catenin Point mutation Hepatoblastomas, hepatocellular carcinoma

CategoryPROTO- Oncogene

Mode of Activation Associated Human

TumorNuclear Regulatory Proteins

Transcrip.activators

C-MYC Translocation Burkitt lymphoma

N-MYC Amplification Neuroblastoma, small cell carcinoma of lung

L-MYC Amplification Small cell carcinoma of lung

2) Activation Growth-Promoting OncogenesWhich signal transduction pathway is continuously activated by mutant RAS?

MAP kinase pathway

Point mutations of ras are seen in what % of all human malignancies?

15-20%

MYC It is a protooncogene Found on Chromosome 8 Member of Myc protein family

Includes N-myc and L-myc

C-MYC

Normal Roles

Main functions: Cell proliferation Apoptosis

The MYC protein can either activate or repress the transcription of other genes.

Activated by MYC are growth-promoting genes, including cyclin

dependent kinas (CDKs), Genes repressed by MYC THE CDK inhibitors (CDKIs)

Dysregulation of MYC promotes TUMORIGENESIS by increasing expression of genes that promote proliferation in turn inactivates the inhibitors.

c-Myc and Cancer: Burkitt’s Lymphoma

c-Myc was first discovered in lymphoma patients

Reciprocal translocation from chromosome 8 to chromosome 14

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.92

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BurkittLymphoma.html

c-Myc and Cancer: Burkitt’s Lymphoma

Rare but extremely aggressive cancer Predominantly affects children in Southern

Africa Solid tumor of B lymphocytes High tendency to spread to CNS, bone

marrow, other blood elements

http://www.brown.edu/Courses/Digital_Path/systemic_path/female/burkitt.htmlhttp://tmcr.usuhs.mil/tmcr/chapter41/clinical.htm

c-Myc and Cancer

Over-expressed in 70% of all human cancers

Translocated in 90% of all Burkitt’s lymphoma cases 90% of gynecological cancers 80% of breast cancers 70% of colon cancers

Contributes to more than 70,000 cancer deaths annually in the U.S.

REMEMBER

Translocation in Burkitt lymphoma, a B cell tumor. (t9:22)

Amplified in breast, colon, lung, and many other cancers;

Amplified in N-MYC NEUROBLASTOMAS L-MYC small cell cancers of

lung.

Tumor supressor gene

. Tumor suppressor were originally identified as inherited mutations that confer a

predisposition to cancer (familial form).

Inactivation of tumor suppressors can occur Sporadically -sequential inactivation of both alleles in somatic

cells You may hear the term haploinsufficiency , which refers to inactivation of a single allele contributing to malignancy. -usually not the initiating event, but exacerbating. Viral inactivation -HPV expresses proteins that inhibit Rb and p53

function.

Tumor Suppressor genes

RB gene P53 gene APC/Beta Catenin INK4/ARF locus TGF beta pathway NF-1 NF-2 VHL WT-1Caderins

RB gene

It is a tumor suppressor gene It is located on chromosome 13 It regulates G1 /S transition

phase. It occurs in active

hypophosphorylated and inactive hyperphosphorylaed state

RB gene

A Loss of RB function confers a predisposition to retinoblastoma.

occurs in both the familial form (early onset)

and sporadic form.

Retinoblastoma

Red reflex Leukocoria

Knudson, in 1974, proposed two-hit hypothesis, which in molecular terms can be stated as follows:

1. Two mutations (hits) are required to produce retinoblastoma. Both of the normal

alleles of the RB locus must be inactivated (hence the two hits) for the development of retinoblastoma.

2.In familial cases, children inherit one defective copy of the RB gene in the germ line; the other copy is normal. Retinoblastoma develops when the normal RB gene is

lost in retinoblasts as a result of somatic mutation.

3.In sporadic cases, both normal RB alleles are lost by somatic mutation in one of the retinoblasts.

The end result is the same: a retinal cell that has lost both of the

normal copies of the RB gene becomes cancerous.

Why Retinoblastoma is autosomal dominant?

Retinoblastoma families only a single somatic mutation is required for expression of the disease,.

Loss of heterozygosity(LOH)

In hereditary retinoblastoma, an affected child inherits one defective Rb allele together with one normal gene. This is heterozygous state.

It is not associated with changes in the retina because 50% of the Rb gene product is sufficient to prevent

the development of retinoblastoma. If the remaining normal Rb allele is inactivated by

deletion or mutation, the loss of its suppressor function leads to the appearance of a neoplasm.

This genetic process is referred to as loss of heterozygosity.

The importance of Rb lies in its regulation of

the G1/S checkpoint

loss of normal cell cycle control leads to malignant transformation

the four key regulators of the cell cycle (CDKN2A, cyclin D,CDK4, Rb) is mutated in most human cancers.

Functional deletion of RB

Human papillomavirus(HPV) produce E7 protein and the protein E7 binds to the hypophosphorylated form of Rb in place of E2F leading to uncontrolled growth.

SPORADIC (Non-hereditary)

Unilateral, unifocal. 60% of all cases. Present later. Children of the

affected are normal. Chromosomal

anomaly is a somatic mutation. Relatives have a low

risk of RB development

FAMILIAL (Hereditary)

85% bilateral, multifocal. 40% % of all cases. Present earlier. Children of the affected

have 45% chance of inheritance.

Chromosomal anomaly is a Germline mutation.

Autosomal dominant with high penetrance.

The median age at presentation is 2 years, although the tumor may be present at birth.

Clinical features poor vision,

strabismus, A whitish hue to

the pupil ("cat's eye reflex"),

pain and tenderness in the eye.

P53

The TP53 gene which encodes p53 resides on the short arm of chromosome 17.

In healthy unstressed cells,

p53 is short half life (20 min)

It undergo destruction by MDM2.

IT HAS DIFFERENT NAMES “GUARDIAN OF THE

GENOME.” GATE KEEPER.

MOLECULAR POLICE MAN.

When cell is stressed, When ever there is a DNA Damage ATM (ataxia telangiectasia mutated) are

activated. These activated complexes release P53

from MDM2 and increase its half-life and

enhance its ability to drive the transcription of target genes. Hundreds of genes whose transcription is triggered by p53 have been found.

Functions of P53

1.Temporary cell cycle arrest. 2.permanent cell cycle arrest 3.Triggering of programmed

cell death (termed apoptosis). 4.p53 plays a central role in

maintaining the integrity of the genome.

P53 is activated by the following

.DNA damage by irradiation, chemicals,

uv light and Free radicle injury and senescence.

Inactivation of P53

Point mutationsMDM2 –degrade P53E6 protein-From HPV

p53-mediated cell cycle arrest in response to DNA damage in

The late G1 phase and is caused mainly by p53-dependent

transcription of the CDKI gene CDKN1A (p21)belongs to KIP/CIP group of CDKI.

P53 induces expression of DNA damage repair genes to reapir the damaged DNA.

p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic transformation by pro-apoptotic genes such as BAX.

70% of human cancers have a defect in P53 gene, Most commonly in Breast , colon and lung

cancer

Li-Fraumeni syndrome.

Less commonly, some patients inherit a mutant TP53 allele The disease is called the

Li-Fraumeni syndrome.

patients with Li-Fraumeni syndrome develop tumors at a younger age and may develop multiple primary tumors.

25-fold greater chance of developing a malignant tumor by age 50 in a person with mutant single allele.

sarcomas, breast cancer, leukemia, brain tumors, and

carcinomas of the adrenal cortex. patients with Li-Fraumeni syndrome develop tumors at a younger

age and may develop multiple primary tumors.

1: Failure of DNA Repair (acquired)

Normal function of p53 is to upregulate activity of which 2 genes to allow repair of DNA?

p21

GADD45

Summary

p53 inhibits G1 progression only in response to DNA damage

-normally p53 is very unstable, due to proteolytic degradation triggered by mdm2

.p53 is phosphorylated in response to DNA damage; mdm2 no longer binds p53

-p53 upregulates expression of p21, which in turn inhibits G1/S CDKs.

c. In response to excessive DNA damage, p53 can trigger apoptosis

Tumor (really “GROWTH”) suppressor genes

TGF-β COLON E-cadherin STOMACH NF-1,2 NEURAL TUMORS APC/β-cadherin GI, MELANOMA SMADs GI RB RETINOBLASTOMA P53 EVERYTHING!! WT-1 WILMS TUMOR p16 (INK4a) GI, BREAST BRCA-1,2 BREAST KLF6 PROSTATE

Evasion of APOPTOSIS

BCL-2 p53 MYC

DNA REPAIR GENE DEFECTS

DNA repair is like a spell checker HNPCC (Hereditary Non-Polyposis

Colon Cancer [Lynch]): TGF-β, β-catenin, BAX

Xeroderma Pigmentosum: UV fixing gene

Ataxia Telangiectasia: ATM gene Bloom Syndrome: defective helicase Fanconi anemia

LIMITLESS REPLICATIVE POTENTIAL

TELOMERES determine the limited number of duplications a cell will have, like a cat with nine lives.

TELOMERASE, present in >90% of human cancers, changes telomeres so they will have UNLIMITED replicative potential

TUMOR ANGIOGENESIS Q: How close to a blood vessel must a cell

be? A: 1-2 mm

Activation of VEGF and FGF-b

Tumor size is regulated (allowed) by angiogenesis/anti-angiogenesis balance

TRANSFORMATION

GROWTHBM INVASION

ANGIOGENESISINTRAVASATIONEMBOLIZATION

ADHESIONEXTRAVASATIONMETASTATIC GROWTH

etc.

Invasion Factors

Detachment ("loosening up") of the tumor cells from each other

Attachment to matrix components

Degradation of ECM, e.g., collagenase, etc.

Migration of tumor cells

METASTATIC SUPPRESSOR GENES?

NM23 KAI-1 KiSS

CHROMOSOME CHANGESin CANCER

TRANSLOCATIONS and INVERSIONS

Occur in MOST Lymphomas/Leukemias

Occur in MANY (and growing numbers) of NON-hematologic malignancies also

Malignancy Translocation Affected Genes

Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34

    bcr 22q11

Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21

    MLL 11q23

  (6;11)(q27;q23) AF6 6q27

    MLL 11q23

Burkitt lymphoma (8;14)(q24;q32) c-myc 8q24

    IgH 14q32

Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13

    IgH 14q32

Follicular lymphoma (14;18)(q32;q21) IgH 14q32

    bcl-2 18q21

T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc 8q24

    TCR-α 14q11

  (10;14)(q24;q11) Hox 11 10q24

    TCR-α 14q11

Ewing sarcoma (11;22)(q24;q12) Fl-1 11q24

    EWS 22q12

Carcinogenesis is “MULTISTEP” NO single oncogene causes cancer

BOTH several oncogenes AND

several tumor suppressor genes must be involved

Gatekeeper/Caretaker conceptGatekeepers: ONCOGENES and

TUMOR SUPPRESSOR GENES

Caretakers: DNA REPAIR GENES Tumor “PROGRESSION”

ANGIOGENESIS HETEROGENEITY from original single cell

Carcinogenesis:

Initiation/Promotion concept: BOTH initiators AND promotors are needed NEITHER can cause cancer by itself

INITIATORS (carcinogens) cause MUTATIONS

PROMOTORS are NOT carcinogenic by themselves, and MUST take effect AFTER initiation, NOT before

PROMOTORS enhance the proliferation of initiated cells

Q: WHO are the usual suspects?

Inflammation?

Teratogenesis?

Immune Suppression?

Neoplasia? Mutations?

A: The SAME 3 that are

ALWAYS blamed! 1) Chemicals 2) Radiation 3) Infectious Pathogens

CHEMICAL CARCINOGENS:INITIATORS

DIRECT β-Propiolactone Dimeth. sulfate Diepoxybutane Anticancer drugs

(cyclophosphamide, chlorambucil, nitrosoureas, and others)

Acylating Agents 1-Acetyl-imidazole Dimethylcarbamyl

chloride

“PRO”CARCINOGENS

Polycyclic and Heterocyclic Aromatic Hydrocarbons

Aromatic Amines, Amides, Azo Dyes

Natural Plant and Microbial Products Aflatoxin B1 Hepatomas Griseofulvin Antifungal Cycasin from cycads Safrole from sassafras Betel nuts Oral SCC

CHEMICAL CARCINOGENS:INITIATORS

OTHERS Nitrosamine and amides (tar,

nitrites) Vinyl chloride angiosarcoma in

Kentucky Nickel Chromium Insecticides Fungicides PolyChlorinated Biphenyls (PCBs)

CHEMICAL CARCINOGENS:PROMOTORS

HORMONES PHORBOL ESTERS (TPA), activate

kinase C PHENOLS DRUGS, many

“Initiated” cells respond and proliferate FASTER to promotors than normal cells

RADIATION CARCINOGENS

UV: BCC, SCC, MM (i.e., all 3)

IONIZING: photons and particulate Hematopoetic and Thyroid (90%/15yrs)

tumors in fallout victims Solid tumors either less susceptible or

require a longer latency period than LEUK/LYMPH

BCCs in Therapeutic Radiation

VIRAL CARCINOGENESIS

HPV SCC EBV Burkitt Lymphoma HBV HepatoCellular Carcinoma

(Hepatoma) HTLV1 T-Cell Malignancies KSHV Kaposi Sarcoma

H. pylori CARCINOGENESIS

100% of gastric lymphomas (i.e., M.A.L.T.-omas)

Gastric CARCINOMAS also!

HOST DEFENSES

IMMUNE SURVEILLENCE

CONCEPT

CD8+ T-Cells NK cells MACROPHAGES ANTIBODIES

How do tumor cellsescape immune surveillance?

Mutation, like microbes

↓ MHC molecules on tumor cell surface Lack of CO-stimulation molecules, e.g.,

(CD28, ICOS), not just Ag-Ab recognition

Immunosuppressive agents Antigen masking Apoptosis of cytotoxic T-Cells (CD8),

i.e., the damn tumor cell KILLS the T-cell!

Effects of TUMOR on the HOST

Location anatomic ENCROACHMENT HORMONE production Bleeding, Infection ACUTE symptoms, e.g., rupture,

infarction METASTASES

CACHEXIA Reduced diet: Fat

loss>Muscle loss Cachexia: Fat loss AND

Muscle loss TNF (α by default) IL-(6) PIF (Proteolysis Inducing

Factor)

Cancer Cachexia

Progressive weakness, loss of appetite, anemia and profound weight loss (>20%)

Often correlates with tumor mass & spread

Etiology includes a generalized increase in metabolism and central effects of tumor on hypothalamus

Probably related to macrophage production of TNF-a

Paraneoplastic Syndromes

Due to Products released by tumor Cushing’s Syndrome

Adrenal, Lung Ca – ACTH Inappropriate ADH syndrome

(Hyponatremia) – lung ca Hypothalamic tumors (vasopressin) Hypercalcemia – Ca is the common cause.

– lung. Hypoglycemia - insulin or insulin like

activities Fibrosarcoma, Cerebellar hemangioma.

PARA-Neoplastic Syndromes Endocrine (next)

Nerve/Muscle, e.g., myasthenia w. lung ca.

Skin: e.g., acanthosis nigricans, dermatomyositis

Bone/Joint/Soft tissue: HPOA (Hypertrophic Pulmonary OsteoArthropathy)

Vascular: Trousseau, Endocarditis Hematologic: Anemias Renal: e.g., Nephrotic Syndrome

ENDOCRINECushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance

  Pancreatic carcinoma  

  Neural tumors  

Syndrome of inappropriate antidiuretic hormone secretion

Small cell carcinoma of lung; intracranial neoplasms

Antidiuretic hormone or atrial natriuretic hormones

Hypercalcemia Squamous cell carcinoma of lungParathyroid hormone-related protein

(PTHRP), TGF-α, TNF, IL-1

  Breast carcinoma  

  Renal carcinoma  

  Adult T-cell leukemia/lymphoma  

  Ovarian carcinoma  

Hypoglycemia Fibrosarcoma Insulin or insulin-like substance

  Other mesenchymal sarcomas  

  Hepatocellular carcinoma  

Carcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin

  Pancreatic carcinoma  

  Gastric carcinoma  

Polycythemia Renal carcinoma Erythropoietin

  Cerebellar hemangioma  

  Hepatocellular carcinoma  

GRADING/STAGING

GRADING: HOW “DIFFERENTIATED” ARE THE CELLS?

STAGING: HOW MUCH ANATOMIC EXTENSION? TNM

Which one of the above do you think is more important?

Grading & Staging of Tumor

Grading – Cellular Differentiation (Microscopic)

Staging – Progression or Spread (clinical)

TNM: Staging of tumor:

WELL?(pearls)

MODERATE?(intercellular bridges)

POOR?(WTF!?!)

GRADING for Squamous Cell Carcinoma

ADENOCARCINOMA GRADINGLet’s have some FUN!

LAB DIAGNOSIS BIOPSY CYTOLOGY: (exfoliative) CYTOLOGY: (FNA, Fine

Needle Aspirate)

IMMUNOHISTOCHEMISTRY

Categorization of undifferentiated tumors

Leukemias/Lymphomas Site of origin Receptors, e.g., ERA,

PRA

TUMOR MARKERS.

Prostatic Carcinoma-Bone Lung Carcinoma-Adrenals &

Brain Neuroblastoma-Liver & Bone Less common sites

of metastases include skin, muscle thyroid,

breast….etc.

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

Effects of tumor on body

Location of tumor is of importance 1- Mass effect by pressing on vital areas e.g. airway, intestine , BV, brain, nerve  obstruction, infarction , paralysis…etc  2- Local destruction of epithelial surface

or BV ulceration , bleeding , infection3-

Hormonal activity

CANCER CACHEXIA

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

Reduced food intake but high metabolic rate

Possibly due to release of cytokines by tumor cells & macrophages

Para neoplastic syndrome

Systemic symptoms that can't be explained by effects of local or distant spread of tumor

or hormones appropriate to tumor tissue. Due to ectopic production of hormones or

other factors They may precede the tumor or mimic

metastases They occur in about10%-15%of malignant

tumors.

DIAGNOSIS

History & clinical examination Radiographic techniques 1- X ray 2CT scan 3- MRI 4-Ultrasound 5-Laboratory tests : general & specialized

This is very important as many cancers a recurable if they are diagnosed early.

Specific symptoms should be followed upe.g. Abnormal bleeding Change of voice Change in a nevus Abnormal lump in breast

 An ulcer that does not heal……etc.  

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

Screening for genetic mutations in familial cancers.

Cytological methods :

Study of cells :- Smear- FNA, Brush, Fluid tapping…etc  Papanicolaou stain (PAP)often used. False(+), False (-)- A negative report

does not exclude malignancy, repeat- Advise biopsy, even if (+ )

1-Morphological Methods :

Biopsy of tissue: Needle & core biopsy , Endoscopic Biopsy, or open surgical biopsy

Frozen Section (Rapid technique) Paraffin Section ( 36-48 hrs. or longer ) H&E, Special histochemical stains stains)

or by IMMUNOHISTOCHEMICALMethods

Tumor markers represent biochemical indicators of the presence of a tumor.

Their uses are to I - Confirm diagnosis. II -Determine the response to treatment . III - Detect early relapse. Present in serum or urine. Many are present in normal & tumor

tissue, so they are not very specific but their level is important.

Types of tumor marker

Hormones Human Chorionic Gonadotrophic

Hormone( HCG)Elevated levels are seen in

Pregnancy& Gestational Trophoblastic Disease 

 Calcitonin useful in diagnosis of some thyroid carcinomas

 

Oncofetal antigens

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

 Colorectal CA & Pancreatic CA   Alpha Fetoprotein (AFP):Cirrhosis :

Elevated Hepatocellular carcinoma : Extremely high

ISOENZYMES

Prostatic Acid Phosphatase ( PAP ) levels seen in Metastatic prostatic

CA Useful in :  Staging prostatic CA   Assessment of prognosis Response to th

erapy.

Several mucins

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

hepatobiliary CA