Pathology, Lecture 10, Neoplasia 1l2u5g

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Dr.H.M.Zahawi,FRC.Path

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Definitions of used in neoplasia Nomenclature of tumors Characteristics of benign & malignant tumors Routes of metastasis Epidemiology of CANCER The molecular basis of neoplasia Carcinogenesis Tumor immunity The clinical effects of tumors Tumor grading and staging The laboratory diagnosis of neoplasia

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Neoplasm = New growth of cells producing a

mass Benign neoplasm = Limited new growth without invasion or spread Malignant neoplasm = invasive growth that also spreads ð ð

Carcinoma : Malignant tumor of epithelial cells Sarcoma : Malignant tumor of connective tissue cells ð Lymphoma

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Cancer is a general term for all malignant growths of whatever type Tumor may be used instead of neoplasm but the term is not accurate Oncology : study of cancer in all its aspects

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Abnormal mass of tissue, the growth of which EXCEEDS and is UNCOORDINATED with that of of the normal tissues, and PERSISTS in the same manner even AFTER CESSATION of the stimulus which produced the change

A neoplasm develops from a single transformed cell !!!

Features of transformed cells : ð ð ð ð

Persistent & useless Uncontrolled growth * Immortal Transplantable

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This cell may arise from : ð Endoderm ð Mesoderm ð Ectoderm Epithelial cells may arise from any of the above Connective tissue is from mesoderm



Cell of origin ð Behavior of tumor : Benign or malignant ð Appearance of the tumor: Solid/cystic ð Degree of differentiation ð

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Parenchymal cell Stromal ( ing cell ) Degree & type of stromal cells may contribute to the appearance of tumors If there is stromal proliferation u hardness of the tumor u Scirrhous tumor u Desmoplasia e.g.carcinoma of breast, pancreasƦ..etc

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If there is lack of many stromal cells, the tumor may be soft or cystic. This feature may be included in the name of the tumor..e.gƦ ð ð

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Cystadenoma of ovary Poorly differentiated cystadenocarcinoma of ovary Moderately differentiated scirrhous carcinoma of breastàààààà

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

Structure of Polyp

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(!"&! Squamous cell carcinoma e.g. skin,mouth cervix, bronchusƦ.etc Adenocarcinoma from glandular origin, e.g..I.T.,endometrium,breast, kidney, thyroidƦ..etc

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!( Named by tissue of origin with attached suffix ƛ oma e.g. fibroma, lipoma, chondromaƦetc Not all endings (ƛ oma) are benign tumors e.g. : granuloma,lymphoma, hamartoma, choristomaƦetc

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) Prefix (origin)+ suffix (sarcoma) e.g. Osteosarcoma, liposarcoma, angiosarcoma leiomyosarcoma, rhabdomyosarcomaƦ

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Tumors derived from a single germ cell layer that differentiates into more than one cell type. e.g. mixed tumor of salivary gland, Fibroadenoma of breast OR : Teratomas ƛ made of a variety of parenchymal cell types that derive from more than one germ cell layer formed by totipotent cells that are able to form ectoderm, endoderm & mesoderm

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May be benign or malignant depending on structure, site, age, sex Ʀ. Contain skin ,sebaceous & mucus glands,hair,cartilage, bone, respiratory epithelium, glial tissueƦ..etc. Usual location is ovary or testes

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Blastoma : from immature tissue May arise in kidney, liver, retinaƦetc e.g. Retinoblastoma The great majority of these tumors are malignant & occur in infants & children

Some tumors have names that do not conform with general rules :

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Melanomas arise from nevus cells Seminomas arise from testicular germ cells Lymphomas arise from lymph nodes Some tumors are named eponymously e.g. Hodgkins disease, Wilmƞs tumorƦ.etc Note : See table on page 176

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0 Tumor like malformation in which there is abnormal mixing of normal components of the organ ,either in the form of change in quantity or arrangement of tissue elements. e.g. Lung Hamartoma.

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Different types of tissue, ectopic to the region. e.g. Meckleƞs Diverticulum, Salivary tissue in LN Both are present at birth & do not become malignant .

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Differentiation & anaplasia Rate of growth Presence of capsule Local invasion Distant metastases

Benign versus malignant tumors

1 Differentiation:

This indicates the degree of resemblance of the tumor cell to its cell of origin, functionally & morphologically. e.g ƛ Cells of a lipoma may look exactly like normal fat cells.



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Features of differentiation include : ð

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Epithelial cells : formation of glands formation of keratin formation of secretionƦetc Connective tissue cells : formation of osteoid presence of lipoblasts Striations in tumors of skeletal muscleƦ.etc

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When a tumor cell loses its differentiation it gradually gains features of +5 It is a process of gradual loss of differentiation It is an abnormal growth which may precede malignancy Complete loss of differentiation   |

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Increased nuclear size , N/C ratio ïariation in nuclear & cell size : )0

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Loss of differentiating features

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Increased nuclear DNA content 05 )0)

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|! :Prominent, sometimes multiple

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Severe Dysplasia/ Anaplasia

!"&!|!" Dysplasia involving an epithelial surface ð Low grade & High grade ð High grade dysplasia ,limited by epithelial basement membrane   )||7

Intraepithelial Neoplasia

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Not all dysplasias progress to higher grade or carcinoma in situ. Not all carcinoma in situ progress to invasive CA Some cases of dysplasia can regress

2 Rate of growth ð

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Rate of growth usually correlates with level of differentiation May be rapid in some benign tumors Some tumors may shrink in size Some malignant tumors may outgrow their blood supply

Some tumor growths are semicontroled : HORMONE DEPENDENCE :

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This is through presence of receptors on surface Breast CA Thyroid CA Prostatic CA

X Local invasion & Encapsulation ð ð

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Benign tumors frequently have a capsule Malignant tumors progressively invade & destroy surrounding tissue e.g.Breast cancer infiltrating skin Basal cell carcinoma face infiltrating nerve

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4 Metastasis : ð

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Spread of malignant tumors to distant sites not contigious with the main tumor " $(( (# All tumors can potentially metastasize except BASAL CELL CARCINOMA Metastasis is often proportionate to the size and differentiation of the primary tumor

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Lymphatics Blood vessels Seeding within body cavities/ Transcoelomic Spread

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More characteristic in Spread follows the anatomical route of drainage unless skip Ơmetastasesơ e.g. ð

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Breast cancer in left upper upper quadrant u Left axillary L.N. In medial quadrant u internal mammary chain u supraclavicular & infraclavicular Lung Ca Peribronchial u tracheobronchial LNs u hilar LNs

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IMPORTANT IN SURICAL RESECTION :

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First lymph node in the pathway of a primary tumor. Usually outlined by dye

Not all enlarged L.N.s indicate metastases e.g. Reactive hyperplasia Histiocytic infiltrate in sinuses

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Usually venous first following anatomical drainage : Lung & Liver More characteristic of Sarcoma ,but may in occur in later stages of carcinoma Certain carcinomas invade veins early ð ð

RENAL Carcinoma u renal veinu IïC Hepatocellular Carcinoma uPortal &Hepatic v.

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Within peritoneal or pleural cavity e.g.: ð CA of upper lobe of lung to lower lobe ð CA of stomach to ovary ð CA of ovary tends to spread widely through peritoneal surface ð CA of colon across peritoneum to S.I.& colon

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Welldifferentiated Low mitotic index Slow rowth With capsule No invasion No metastases

%4|| Anaplastic High mitotic index Rapid growth Infiltrative growth without capsule Invasion Metastases

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

Nasopharyngeal CA Cervical CA & Cancer of the penis Burkitt Lymphoma Multiple myeloma Chronic lymphocytic leukemia

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Individual predisposition to disease Individual response to environmental agents Individual response to drugs

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FACTORS WHICH MAY PLAY A ROLE IN THE INCIDENCE OF CANCER INCLUDE :

4!( "& astric CA High in Japan Skin CA High in New Zealand Hepatocellular CA High in Africa,China Breast CA High in USA Prostatic CA High in USA Colorectal CA High in USA Nasopharyngeal CA Far East Burkitt Lymphoma Africa

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CANCERS common in JORDAN include :

Lung CA ð Colorectal CA } MALES ð Prostate CA ð Breast CA ð Colorectal CA } FEMALES ð Lung CA ð Lymphomas are also common ð

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Diet Occupation Sunlight Personal habits

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In general , cancer incidence Ƽ AE However , certain cancers occur more in children Acute Leukemia Some Lymphoma Some CNS Tumors Bone &soft tissue Sarcomas

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Inherited Cancer Syndromes : Presence of defined genetic abnormality, usually AD, often specific phenotype e.g. ð

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APC gene : Familial Adenomatous Polyposis Coli MEN1 & RET genes : MEN syndrome NF1 & NF2 genes : Neurofibromatosis RB gene : Retinoblastoma

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Familial cancers : No specific phenotype & multifactorial Family have higher incidence to common cancers | ) )5

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Younger age groups, multiple or bilateral, two or more family are affected. Some linked to inheritance of mutant genes e.g. ) 2)

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Chromosomal & DNA instability Best example : XERODERMA PIMENTOSUM

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These are associated with increased risk for CA and most are related to rapid or abnormal cell proliferation .

1 Endometrial Hyperplasia & carcinoma 2 Cervical Dysplasia & Cervical CA Bronchial dysplasia & lung CA X Liver Cirrhosis & Hepatocellular

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4 Chronic healing process Ulcerative Colitis & Colorectal CA 6 ïillous Adenoma & Colorectal CA 7 Leukoplakia & Squamous cell CA

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roup of cells produced from a single ancestral cell by repeated cellular replication. Thus they can be said to form a single "clone". ||

Principles : ð

Tumors arise from clonal growth of cells that have developed mutations in four classes of genes : ð ð ð ð

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rowth promoting protooncogenes rowth inhibiting tumor suppressor genes enes regulating apoptosis enes involved in DNA repair

More than one mutations in above result in abnormal growth of cells

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Multistep Carcinogenesis :

Steps in Neoplastic Transformation : 1Non lethal damageu TRANSFORMATION 2Cell Proliferation : initially Polyclonal u MONOCLONAL CELLS Xenetic instability of malignant phenotype u cells with diverse features u progression of tumor u INïASION & METASTASES

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

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Chronic myeloid leukemia (CML): Philadelphia Chromosome (9:22 ) Multiple Myeloma u single immuno globulin specific for the tumor. T&B cell lymphomas : specific gene rearrangement

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Tumor Progression : This is the stepwise accumulation of mutations resulting in increasing features of malignancy.

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enes in Neoplastic Transformation:

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Protooncogenes ð

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Normal genes whose products (Oncoproteins) promote cell growth Oncogenes are mutant versions of proto oncogenes that function autonomously without normal signals

4!!$( ( 1& !$'#! ð Arise from mutant protooncogenes ð They are dominant genes. ð They include : ð rowth factors ð Cell surface receptors ð Signal transduction proteins ð Nuclear transcription factors ð Cell cycle proteins ð Inhibitors of apoptosis

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Normal Cell growth is stimulated by F Platelet derived growth factor (PDF) seen in glioblastomas Fibroblast growth factor(FF)stomach CA & melanomaƦƦetc Transforming rowth Factor (TFY)in sarcomas Products of other oncogens (e.g.RAS) may cause over expression of F

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F integrate with membrane receptors u tyrosine kinase activity u nucleus Mutant receptor u continuous signals even in the absence of FƦ..OR Normal but overexpressed u hypersensitive to F Epidermal F receptor family: ERBB1 in 80% of sq.CA lung ERBB2 ( HER 2 NEU) in 2X0% of breast & ovarian CA Increase = POOR PRONOSIS

X (!!( $ RAS & non receptor ABL RAS action:

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4uproliferation

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Mutations in APs(|6):|! ' Commonest oncogen mutation Point mutations in codon 12, 1X are present in GX0% of cancers, specially CA pancreas &Colon

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Normal ABL is located in nucleus where it promotes apoptosis Chronic myeloid leukemia : Mutation 9:22 translocation u BCR ABL gene This new gene is retained in cytoplasm where it has tyrosine kinase activity u cell proliferation New action is Proliferation +No Apoptosis

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o |! "6 DNA transcription regulated by genes e.g. MYC*, JUN, FOSƦ.etc. In normal :MYC protein + DNA u Activation of Cyclin Dependant Kinases ( CDKƞs) uinitiation of cell cycle u MYC MYC mutation u sustained activation Examples : ð

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Dysregulation of MYC present in Burkittƞs lymphoma (t8:14) Breast ,colon, lung CA & neuroblastoma

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

CELL CYCLE PHASES











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1" ( " Cyclin D family u CDK4 & CDK6 at 1 u S phase checkpoint Cyclin BCDK1 activate 2 uM transition

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Activity of CDK/ Cyclin regulated by CDK inhibitors ð

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Non selective wide inhibition : p21, p27 and p7 Selective effect on cyclinD/CDK4 & cyclinD/CDK6 : p1, p16, p18, and p19

Cyclin/CDK/RB function ð

Loss of normal cell cycle control is central to malignant transformation& at least one of the following is mutated in most human cancers : Cyclin D CDK 2, CDK 4, CDK 6 CDK inhibitors RB

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Mutations that disregulate activity of cyclins & CDKs cell proliferation Examples : ð Cyclin D is overexpressed in breast, liver, & esophageal cancers ð Amplification of CDK4 gene present in melanoma, sarcomas, glioblastoma

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rowth inhibitory pathway by: * Regulate cell cycle : Rb gene

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

Cancer suppressor genes are recessive genes which may be lost in familial or sporadic cases.

)(!! First studied in Retinoblastoma: ð Called RB gene ð Both copies of gene must be lost for neoplastic transformation to occur ð This is called loss of heterozygosity ð

Retinoblastoma : ð ð ð

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Autosomal dominant hereditary disease May be sporadic In familial, patients carry one mutation in their genome No tumor develops unless two alleles in 1Xq14 become mutant (two hit theory) $incidence of bilateral Retinoblastoma and $ osteosarcoma

Inheritance of Retinoblastoma

Mode of action of RB gene: ð

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RB exists in active nonphosphorylated & inactive phosphorylated forms. Active RB binds to transcription factors (E2F) u NO TRANSCRIPTION CyclinD/CDK4, and cyclinE/CDK2 phosphorylate RB. Inactive RB releases transcription factor E2F u TRANSCRIPTION (1 u S phase ) Many oncogenic DNA viruses may act similarly by inactivating RB

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X 70% of tumors show homozygous loss of pX pX is a negative regulator of cell cycle, present in low levels with short half life MDM2 protein which targets it for destruction Called Ɲuardian of the enomeƞ OR (Policeman) preventing genetically damaged cells from progressing through new cycle.

Mode of activation & action : ð

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PX senses DNA damage through various sensors e.g. ATM protein PX is activated by anoxia, or DNA damage and accumulates in cell with long half life after release of MDM2 Activated pX ð

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Transcription of CDKI(p21) cell cycle arrest at 1 Transcription of ADD4 ( repair gene) pX is a regulator of apoptosis

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More time for repair u Normal Failed repairu Apoptosis or Senescence (permanent cell cycle arrest) ð

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Action of pX

PX may show the following : ð

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

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Antiproliferative activity: regulation of RB pathway at 1 by action on some cyclins & CDKs blocks F signals Mutational inactivation of TF ˜ components seen in 100% of pancreatic carcinoma & the majority of colonic CA

o (!! Cytoplasmic protein , acts as an adhesion molecule by regulating level of ˜ ! in cytoplasm * ˜ ! $&! Result u intercellular adhesion · ˜ ! u nucleus Result u stimulates proliferation

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Individuals with inherited one mutant allele of APC develop 100s to 1000s of adenomatous polyps in their 2nd. Xrd.decade of life Additional mutations u colonic carcinoma 100% risk in familial polyposis coli 7080% of sporadic colonic carcinoma show mutant APC

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X %"" : Mutations in genes involved in programmed cell death which regulate mitochondrial permeability promoting or suppressing apoptosis. *;>" !"! !'# ; *&'"! !'# 0X #" ! !(!&!'!

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BCL2 prevents apoptosis, prolonging life. Activated by translocation (18:14) Follicular B cell Lymphoma

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These are specialized structures at the end of chromosomes which are shortened after each division and may play a role in determining the life of individual cells. Shortening is prevented by TELOMERASE Active in stem cells, not in somatic cells Majority of cancers telomerase

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Repair mutations in other genes Persons with inherited mutations in these genes are at $ risk for cancer

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These include :

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1 Nucleotide excision repair genes ð

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Damage by Uï light . Defective in Xeroderma igmentosum Damage by ionizing radiation Drugs e.g. nitrogen mustard

)!" (!!!$ 2Mismatch repair genes : These repair errors in pairing of nucleotides during cell division

e.g. +T instead of A+T 0| ? (0ereditary |on"olyposis olonic a.)

)!" (!!!$ X BRCA 1 & BRCA2 80% familial breast cancer & ovarian CA BRCA ƛ2 in breast CA in both sexes, e.g: prostate,ovary, pancreas, stomach CA ð

Rarely inactivated in sporadic cases.

: +!%!"!!$((!! Tumors remain small or in situ ( <12mm.diameter) without angiogenesis Angiogenesis Ƽ Antiangiogenesis Angiogenic Switch ð Controlled by hypoxia which induces angiogenic factors by tumor cells ð HypoxiaInduced Factor(HIF1Y) u ïEF ð RAS mutation u ïEF ð Proteases from tumor or stroma ïEF ð

Anti Angiogenesis : ïHL protein can destroy HIF1 Y u No ïEF so ïHL acts as tumor suppressor ð erm line mutation of ïHL u hereditary renal CA , hemangiomas in CNSƦƦetc ð Antiangiogenic factors : e.g. PX u antiangiogenic thrombospondin ð Inactivation of PX u angiogenesis vascular density = Poor prognosis ð

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Tumors may generate clones with different phenotypic features, accumulate mutations, leading to a more aggressive nature e.g.

Non antigenic growth , Increase rate of growth, Invasion, Metastases Ʀetc ð

Rate of generation of these clones differs in individual tumors e.g. Osteosarcoma versus Basal Cell Carcinoma

Metastatic Pathway:

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Loosening of intercellular junctions Attachment Degradation of ECM Migration $!

!&% +!&! ! Inactivation of ECadherin OR activation of ˜ cateninu detachment of tumor cells Loss of function ECadherin in many CAs +!( $ '#" !! :e.g. Matrix Metalloproteinase (MMPs) Cathepsin D Type Iï collagenase

Result of digestion of ECM u Cleavage products

of matrix have chemotactic activity for more tumor cells

X &! ! to matrix components by laminin & integrin receptors to basement membrane & ECM o ( ! Tumor derived cytokines e.g. Autocrine motility factor

$! : %&! Adhesion to endotheliumu retraction of endothelium u vessel <'#|>!, some escape by formation of a thrombus X "! Adhesion to endotheliumu retraction of endothelium u escape to tissue

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Anatomical Location Complimentary adhesion molecule between tumor cells & target organs Chemoatractants liberated by target organs Protease inhibitors present in certain tissues

-"! "0( Prostatic Carcinoma u Bone ð Lung Carcinoma u Adrenals & Brain ð Neuroblastoma u Liver & Bone Less common sites of metastases include skin,muscle thyroid,breastƦ.etc. Spleen , Cartilage , Heart are almost never involved by metastatic tumours. ð

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Each cancer must result from accumulation of multiple mutations, in many genes including those in apoptosis & senescence EXAMPLE :

Different ene Lesions : ð ð

mainly in RAS !$ mainly in hematopoietic tumors: 9;22 , 8;14 , 14;18 & rare in solid tumors :Ewing Sarcoma

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4!!" : Neuroblastoma : NMYC Breast carcinoma : HER2/NEU

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& $!!: More in nonhematopoietic & solid tumors e.g. Retinoblastoma 1Xq band14 also several in colorectal CA & ! ( : ( Aneuploidy)

Result : Change in structure or quantity of gene product

ene Amplification :

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Direct Carcinogens Directly produce damage without prior metabolic conversion Indirect Carcinogens (Procarcinogen) Metabolic conversion in liver by cytochrome P40 dependent mono oxygenasesu ultimate carcinogen

Action of chemical carcinogens : ð

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Initiator Chemical inducing irreversible DNA damage Promoter Augment effect of initiator by promoting cell growth e.g. phorbol ester (PTA) activate signal transduction or F secretion , hormones, saccharine Ʀ..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 u CA Lung X Aromatic Amines & Azo dyes : Rubber & Food Industry e.g. ˜ naphthylamineu Bladder CA

Chemical carcinogens ( Continued) 4 Nitrosamines : Endogenous or food preservatives e.g.astric & Colon CAƦetc. Aflatoxin B1 : Naturally occurring carcinogen present in fungus. Aspergillus flavus u Hepatocellular CA

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Chemical carcinogens contain highly reactive electrophil groups that combine to DNA, RNA, or proteins producing mutations enes commonly affected are RAS & PX May be very specificƝ Signature Mutationƞ Some strong chemicals act as Initiator & Promoter e.g. polycyclic hydrocarbon

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Uï light : Effect depends on intensity of exposure & quantity of melanin Production of pyrimidine dimers in DNA u MUTATION in RAS , P X Failed repair u Skin CA Skin cancer includes : Squamous Cell CA Basal Cell CA Melanoma

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Ionizing Radiation: Explosions Leukemia after 7 yrs. Latent period u Breast,colon, thyroid, lung CA Therapeutic exposure u Thyroid CA, Leukemia Mechanism:Free radical injury u Mutations in RAS, RB. PX Asbestos fiber inhalation : Mesothelioma & Lung CA

X ))|4 | +| ! : 0 0" Benign squamous papilloma (wart) groups 1,2,4 & 7 * Low risk groups (6, 11) u enital Squamous Cell Papilloma * High risk group ( 16, 18 ) u Squamous Cell CA in cervix, vulva, perianal & oropharyngeal regions

Mode of Action : ð

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HPï have transforming early genes (E6,E7) inactivate suppressor genes E6 acts on pXuno apoptosis E7 ubinds to E2F ublocks Rb action & activates cyclins, & inhibit CDKI High risk groups have a stronger affinity of early genes to E2F Result uCell proliferation

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BURKITTƞS LYMPHOMA **

B CELL LYMPHOMA HODKINƞS LYMPHOMA subset NASOPHARYNEAL CA ð Post transplant lymphoma ð CNS Lymphoma in AIDS patients

Mode of action in Burkittƞs Lymphoma : ð

EBï has LMP1 gene receptor for B lymphocytes ð ð

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Induce B cell proliferation Prevents apoptosis by activating BCL2

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

In Nasopharyngeal Carcinoma : LMP 1 is expressed on epithelial cells activating cell proliferation ======================== ð LMP 1 also activates pro angiogenic factors ð Both in Burkitt Lymphoma & Nasopharyngeal Carcinoma other environmental factors play a role ð

X 00!" Multifactorial oncogenic effect but mainly Immunologically mediated chronic liver diseaseÈu Cirrhosis uHepatocellular CA in 70 8% Action :* Cell proliferation Èu mutation * HBï encodes Hbxprot. u growth promoting genes *Hbx binds to p X u Inactivates suppressor function (HCï is similar but HCï core Protein)

(!)| ! HTLï1 induces Leukemia /Lymphoma ð Transmitted sexually,blood or milk $! : ïirus * gene attaches to T cells: ð Produce cytokines +receptor u autocrine stimulation u proliferation ð Suppresses action of TPX &CDKI ð

POLYCLONALu MONOCLONAL u LEUKEMIA

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First described as a cause for peptic ulcer Multifactorial etiology in gastric CA & gastric lymphoma ( MALT lymphoma ) Immune mediated gastric damage with FR Occurs in only X% after a long latent period H.pylori contains (Cag A)genes uF u Cell proliferation

Mode of action : LYMPHOMA : Chronic gastritis umucosal lymphoid follicles u reactive polyclonal B cells u monoclonal B cells u Malt lymphoma ð CARCINOMA : Chronic gastritis u atrophy u intestinal metaplasia u dysplasia u astric Carcinoma ð

CANCERS ASSOCIATED CARCINOEN

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

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Normal immunity present to protect against development of tumors Evidence å ð When there is no immunity More Cancers ð Patients with congenital immune deficiency have 200 times risk of cancer & immunosuppressed patients have increased rates of cancers (Lymphoma)

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This may be lost during tumor progression There may be acquired immunosuppression produced by oncogenic agents

0!& 1 Sensitized Cytotoxic T lymphocytes 2 Natural Killer cells may kill tumor cells without previous sensitization. X Macrophages activated by IFN> may destroy tumor cells 4 Humoral AB mechanisms

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Tumors share MHC with normal cells Tumor specific & Tumor Associated As may be helpful in diagnosis & follow up of some tumors Therefore, they may act as tumor markers

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1 Products of mutant oncogenes & tumor suppressor genes e.g. RAS protein 2 Mutant proteins induced by chemical and radiation induced tumors X Overexpressed normal cellular proteins or aberrantly expressed e.g. : ð ð ð

Tyrosinase in melanoma Cancer Testes enes : MAE1(melanoma..) HER2 in CA breast

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4 Tumor A produced by oncogenic viruses in HPï & EBï infection Oncofetal A: Carcinoembryonic A (CEA) in colon and Y fetoprotein in liver CA 6 Several mucins: MUC1 in breast CA and CA12, CA199 in ovarian CA 7 Cell Type specific differentiation A in B lymphomas (CD10&CD20)

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! '$# Location of tumor is of importance 1 Mass effect by pressing on vital areas e.g.airway, intestine , Bï, brain,nerve u obstruction, infarction , paralysisƦetc 2 Local destruction of epithelial surface or Bï u ulceration , bleeding , infection X Hormonal activity

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Cancer Cachexia : ð

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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

Paraneoplastic Syndrome : ð

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Systemic symptoms that canƞt be explained by effects of local or distant spread of tumor or hormones appropriate to tumor tissue. Due to ectopic production of hormones or other factors They may precede the tumor or mimic metastases They occur in about 10%1% of malignant tumors.

Types of Paraneoplastic Syndromes : ð

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Endocrinopathies e.g hyperglycemia, hypoglycemia, Cushingƞs SƦ..etc Nerve & Muscle Syndromes e.g myasthenia gravis Dermatologic disorders Osseous & Articular changes ïascular & hematological changes Nephrotic syndrome

Well Known Examples of Paraneoplastic Syndromes ð

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Small Cell CA lung uÈ ACTH , ADH, Bone changes,nervous system disorders Squamous Cell CA lung & Breast CA u Parathormone related &othersuHypercalcemia Pancreatic & lung CA uclotting factors uDeep vein thrombosis ð

N.B. Hypercalcemia is commonly produced by lytic bone metastases

examples (continued)

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Hepatic & Renal CA u Polycythemia Pancreatic, astric CA u Carcinoid S. Advanced Cancers u Nonbacterial thrombotic endocarditis. Colonic Adenocarcinoma u Acanthosis nigricans

4 $(2(( Must be documented for all malignant tumours : ð To quantify the aggressiveness of tumor ð To outline mode of therapy ð To compare different modes of therapy ð To give an approximate prognosis

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This indicates the final outcome of the disease in of #! #! %%. This is influenced by : #"! e.g. Lung CA versus Lip CA 4 $!2(! 0 !

4 $! : Based on level of differention : This indicates the degree of resemblance of tumor cells to cell of origin and is 1# '!$ " ! ? ð rade I : Well differentiated tumor ð rade II :Moderately differentiated tumor ð rade III : Poorly differentiated tumor ð rade Iï : Anaplastic tumor

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

|((#! T : Size and extent of primary tumor(14) ð N : Presence and extent of lymph node involvement ( 0X) ð M : Presence or absence of distant metastasis ( X01) e.g.T1,N1, M0 ð

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

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History & clinical examination Radiographic techniques i X ray ii CT scan iii MRI iv Ultrasound Laboratory tests : general & specialized

Ô 1 Cytological methods : ð Study of cells : Smear FNA, Brush, Fluid tappingƦetc Papanicolaou stain (PAP) often used. False(+), False () A negative report does not exclude malignancy, repeat Advise biopsy, even if (+ )

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2 Histological methods : ð

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

X Immunocytochemistry ð

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

Undifferentiated Tumor

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Undifferentiated Malignant tumor

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4Electron microscopy : ð

For recognition of desmosomes , or neurosecretory granulesƦ.etc.

Flow Cytometry : ð For measuring DNA content , detecting diploid versus aneuploid tumorsƦ.etc. ð Correlates with rate of growth & prognosis ð Useful in the diagnosis & classification of Lymphoma & Leukemia

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Used to identify tumor associated enzymes, hormones , antigens Ʀ etc These are useful as markers for diagnosis of a tumor OR for assessing the progress of a known tumor

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

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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.

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Ectopic hormones in paraneoplastic S.not used

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Carcinoembryonic Antigen ( CEA ) : in fetal tissue & some malignancies ƛ Colorectal CA & Pancreatic CA Alpha Fetoprotein (AFP) : Cirrhosis : Elevated Hepatocellular carcinoma : Extremely high

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Prostatic Acid Phosphatase ( PAP ) levels seen in Metastatic prostatic CA Useful in : * Staging prostatic CA * Assessment of prognosis * Response to therapy.

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

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MUC1 in breast CA CA12 in ovarian CA CA199 in pancreatic & hepatobiliary CA

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Methods used include : ð ð

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PCR (Polymerase Chain Reaction) FISH (Fluorescent In Situ Hybridization)

Used to detect gene rearrangement, translocations, amplificationsƦetc ð ð ð

BCRABL Chronic Myeloid Leukemia Monoclonal proliferation of B or T cells 1Xq 14 deletion in RetinoblastomaƦ.

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For prognosis : gene amplification ð ð

HER 2 NEU in breast carcinoma NMYC in neuroblastoma

Detection of residual disease in chronic myeloid leukemia (BCRABL) ð Detection of genes of hereditary cancer e.g BRCA1 in breast cancer ð

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)5+4|| ) This is very important as many cancers are curable if they are diagnosed early. ð Specific symptoms should be followed up e.g. Abnormal bleeding Change of voice Change in a nevus Abnormal lump in breast An ulcer that does not healƦƦetc.

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Specific procedures : Self examination of the breast Mammography Serial PAP smears for the cervix Serial sputum cytology in smokers Serial urine cytology in some cases, e.g. bilharziasis, workers in rubber Screening for genetic mutations in familial cancers.

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