Thomas V Widiyatno

sinonymsTumorGeschwlst (Deutsch)BlastomaTumbuh ganda (bahasa indonesia)

DefinitionWillysTumor (swelling)Crab/ cancerDevelopment of tumor : a stepwise process potencially preneoplastic changes : * hyperplasia * hypertrophy * metaplasia * dysplasia

Sir Ruppert A Willys (1967)A tumor is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change .

NomenclatureHistogenesis the tumor must be named by the specific tissue or cell type from which it arose and of which it is composed eg : Sertoli cell tumor, Leydig cell tumor

Nomenclature (contd.)Behaviour is an assessment of whether the tumor is relatively harmless or a dangerous, life-threatening lesion. Tumors that are confined, slow-growing and non invasive are called benign and carry the suffix -oma. Tumors that are invasive, rapidly growing, and dangerous are called malignant and carry the suffix sarcoma if derived from mesenchymal tissues, or the suffix carcinoma if derived from epithelial tissues.

Characteristics of benign and malignant tumors

benignmalignant1. StructureWell differentiated, typicalImperfectly differentiated and atypical2. Mode of growthExpansive and circumscribedInfiltrative, expansive and not circumscribed3. Rate of growthSlow, scanty mitotic figuresRapid, many mitotic figures4. End of growth+Rarely ceases growing5. MetastasisabsentFrequently present6. Clinical resultDangerous because of :Position accidental complicationProduction of excess hormoneDangerous also because of progressive infiltrative growth and metastasis

Cell CycleCell cycle consists of :

StatePhaseAbbreviationQuiescent/senescentGap 0G0InterphaseGap 1G1SynthesisSGap 2G2Cell DivisionMitosisM

Cell-cycle landmarks. The figure shows the cell-cycle phases (G0, G1,G2, S, and M), the location of the G1 restriction point, and the G1/S and G2/M cell-cycle checkpoints. Cells from labile tissues such as the epidermis and the gastrointestinal tract may cycle continuously; stable cells such as hepatocytes are quiescent but can enter the cell cycle; permanent cells such as neurons and cardiac myocytes have lost the capacity to proliferate. (Modified from Pollard TD and Earnshaw WC: Cell Biology. Philadelphia, Saunders, 2002.)Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 17 January 2007 02:57 AM) 2007 Elsevier

ProliferationCell proliferation controlled by signals (soluble or contact-dependent) from the microenvironment - stimulate - inhibitAccelerated growth can be accomplished by : - excess stimulator - deficiency inhibitor - shortening cell cycle * - conversion of resting or quiescent cells into proliferating cells by making the cells enter the cell cycle **) require stimulating signals to overcome normal physiologic blocs to cell proliferation

Cell proliferation can be stimulated under both physiologic and pathologic conditions

DifferentiationDifferentiation also impacts the size of cell population and its proliferative potential

Terminally differentiated cells : cardiac myocytes, neurons, bone marrow, skin, gutQuiescent differentiated cells : hepatocytes, kidney cells

ApoptosisPhysiologic or pathologicDeath factors ( FasL and TNF )P53 CTL and NKcellsCytochrom cThe final effector : Caspases

Tumor GrowthLatent period : clinically undetectableSmallest detectable mass : 1 gm or 109cells

10 doublings

1012 cells ( 1 kg)

Biology of Tumor Growth

Mitotic indexThe number of cells in microscopic field that contain condensed chromosome and lack of nuclear membranes

Proliferative potentialThe growth of tumor is not completely exponential. A proportion of tumor cells is lost from replicative pool because of irreversible cell cycle arrest, differentiation or death

*Schematic of tumor growth as cell pop. expands, progressively higher percentage of tumor cells leaves the replicative pool by reversion G0 , diff & death

telomeraseMany neoplastic cells regain the ability to produce telomerase and thus to replicate their telomeres tumor cell immortality (end of part 1 )

Thomas V Widiyatno

TUMOR EVOLUTIONNeoplasms develop as the result of multiple genetic and epigenetic changes that occur over a relatively long time course.

E.g : * Squamous cell carcinoma : - epidermal hyperplasia - carcinoma in situ - invasive carcinoma

initiationIntroduction of irreversible genetic change.Initiators are chemical or physical carcinogens that damage DNAInitiated cells appear morphologically normal and may remain quiescent for many years and may respond more vigorously to mitogenic signals or be more resistant to apoptosis-inducing stimuli

promotionThe second stage of tumor developmentPromotion refers to the outgrowth of initiated cells in response to selective stimuli. These selective stimuli termed promoting agents or promoters, drive proliferationPromoter is not mutagenic reversibleE.g : croton oilThe end of promotion phase : a benign tumor

progressionThe final stageMalignant conversion : an irreversible changeProgression is a complex and poorly understood process involving both genetic and epigenetic changes

TUMOR SPREADMetastasis is the single most reliable hallmark of malignancyCancer may metastasize by seeding of the body cavities and surfaces (transcoelomic), by lymphatic or by hematogenous spread

trancoelomicWhen cancers arise on the surface of an abdominal or thoracic cavities, they encounter a few anatomic barriers to spread.Mesotheliomas may be confined to the abdominal or pleural cavities, but the tumor cells readily to cover all visceral and parietal surfaces.Another example of transcoelomic spread : ovarian adenocarcinoma

lymphaticThe lymph nodes closest to the tumor are usually colonized earliest and the largest metastatic tumor masses.Regional lymph nodes actually represented a mechanical barrier to the spread of cancer.Mostly carcinomas

hematogenousTumors generally invade veins rather than do arteries because arterial walls are much thicker and more difficult to penetrateTumors that enter veins ultimately enter the vena cava and lodge in the lungs or enter the portal system and lodge in the liverSarcomas more frequently than carcinomas use the hematogenous route

MECHANISM OF METASTASISA complex process of metastasis :Invasion of extracellular matrix (ECM)Entry into blood vascular or lymphatic vesselsExtravasation of tumor cellsColonization of the metastatic site

Detachment from the main tumor massLoss of cadherin or catenin function tumor cells separate from each otherContact with ECM components such as : fibronectin, laminin, collagen through their receptors

Invasion and migrationIn malignant tumor the neoplastic epithelial cells penetrate the basement membrane to invade surrounding tissue. Degradation of basement membrane and ECMcomponents by secreting proteolytic enzymes (proteases)Tumor cell migration is stimulated by autocrine growth factor

Metastasis suppressionMetastatic potential is probably the cummulative effect of many differen genetic alteration.On the other hand, a small number of genes have been identified that seem to function to suppress metastasis effectivelyEg : gene encoding E-cadherin (metastasis suppressor gene)

The role of p53-gene

papilloma

papilloma

squamous cell carcinoma

sqaumous cell carcinoma

papilloma

papilloma

squamous cell carcinoma

basal cell tumor

heavily pigmented multiplebasal cell tumor

basal cell tumor with medussa head

solid basal cell tumor

baso-squamous tumor

trichoepihelioma

sebaceous adenoma

sebaceous adenoma

sebaceous adenoma with closely packed reserve cells with squamous metaplasia

Hepatoid adenoma

hepatoid /perianal adenoma

hepatoid adenocarcinoma

sweat gland cyst adenoma

sweat gland adenoma

sweat gland adenocarcinoma

multiple malignant melanoma

malignant melanoma

fibroma vulva

fibrosarcoma

equine sarcoid

equin sarcoid

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