NEOPLASIA

NEOPLASIADr G R Wright

School of PathologyDivision of Anatomical PathologyUniversity of the Witwatersrand

NeoplasiaEpithelial lesionsConnective tissue lesionsTumours of childhoodEffects of tumours / Paraneoplastic syndromesPathology of Chemotherapy / Irradiation

Effects of TumoursEffects of TumoursDepends on the SITE, NATURE and SIZE of the individual tumour

LOCAL and GENERALISED effects

PARANEOPLASTIC SYNDROMESLocal effectsBENIGN TUMOURS:

Pressure / ObstructionFunctional ActivityLocal Anatomical ComplicationsTorsion, infection, haemorrhage, ulcerationMalignant TransformationAcoustic neurilemmoma deafness, RICPBle duct papilloma obstructive jaundice5Local EffectsMALIGNANT TUMOUS:

Pressure / ObstructionDestruction of TissueLocal Anatomical ComplicationsUlceration, haemorrhage, infectionPain

Ca Colon bowel obstruction6Generalised EffectsStarvation Cachexia Fever Haematological ChangesImmunological EffectsHormone production

More pronounced with malignant tumoursParaneoplastic SyndromesParaneoplastic SyndromesCollection of symptoms that can not be explained by the growth of the tumour

Clinical importance:First manifestation of malignancySignificant morbidityMimic metastatic diseaseParaneoplastic SyndromesDivided into:

EndocrinopathiesNerve and muscle syndromesDermatological disordersOsseous, articular and soft tissue changesVascular and haematological changesEndocrinopathiesHormone / Hormone-like substance produced by cells that are not of endocrine origin

Cushing syndromeHypercalcaemiaCarcinoid syndromePolycythaemiaHypoglycaemiaCushing SyndromeACTH or ACTH-like substance

Small cell carcinoma of lungPancreatic carcinomaNeural tumours

Carcinoid SyndromeExcessive serotonin productionNeuroendocrine tumours

Clinical features:Vasomotor disturbances (flushing)Intestinal hypermotility (cramps, diarrhoea)BronchoconstrictionSystemic fibrosis

Myasthenia? ImmunologicalBronchogenic carcinomas

Weakness, autonomic dysfunction

Acanthosis Nigricans? Epidermal growth factors from tumoursGastric, lung & uterine carcinomas

Middle aged-elderly adultsFlexuresAcanthosis NigricansVelvety hyperpigmentedAcanthosisDermatomyositisImmunologicalBronchogenic and breast carcinoma

Rashes & muscle weaknessHypertrophic osteoarthropathyCause unknownBronchogenic carcinoma

Features: Periosteal new bone formationArthritis of adjacent jointsClubbingHypertrophic osteoarthropathyClubbingVenous ThrombosisTrousseau phenomenon

Pro-coagulatory products of tumoursPancreatic & bronchogenic carcinoma

Nonbacterial Thrombotic EndocarditisHypercoagulabilityAdvanced mucin secreting adenocarcinoma

Bland small fibrinous vegetations on valves (L>R)PATHOLOGY OF IRRADIATIONRadiationElectromagnetic waves and particles80% from natural sources UV light, cosmic radiation, radioisotopes20% manufactured instruments, nuclear power plantsEffects dependant on dose and timing of exposureCauses acute and chronic effectsRadiationNON-IONISING RADIATIONLong wavelength, low frequencyElectricity, radio waves, microwaves, infrared, UVIONISING RADIATIONShort wavelength, high frequencyXrays, gamma rays, cosmic radiationPARTICULATE alpha and beta particles, protone, mesons,deutronsRadiation EffectsDependant on:Dose rateWhole body vs focal & fractionatedRapidly dividing cells are more radiosensitive than quiescent cellsCells in G2 or Mitoses are most sensitiveDifferent cells have different repairative responses

Mechanisms of Cellular DamageIonizationProduction of free radicalsDNA DamageStrand breaks multiple double strandBase alterations mutationsCross-linking replication preventedTissue SensitivityDirectly proportional to rate of cell division:HIGHHaemopoietic tissueLymphoid tissueGonadsIntestinal mucosaMEDIUMLiverPancreasEndocrine glandsConnective tissuesLOWHeart muscleSkeletal muscleNerve cellsBrainMature boneMature cartilageEffects on CellsImmediate deathPrevention of further division apoptosisChange in genotype mutation RepairBlood vesselsEndothelial damage and lossExposure of collagenThrombosis and necrosisEndothelial and intimal proliferationTelangiectasisEndarteritis obliteransBone MarrowSuspends renewal of all 3 cell lines Time to decrease in blood counts dependant on physiological survival of cellsWhole body marrow failureLocalised marrow fibrosisGastro-intestinal MucosaNausea, vomiting, diarrhoea dehydration, electrolyte abnormalitiesUlcerationHaemorrhageSecondary infectionStricture, obstruction

Other tissuesSkinErythema, desquamation, ulceration dermal fibrosisGonadsSterilityGerm cell mutation foetal abnormalitiesFollicular cell damage in ovary artificial menopauseLungRich blood supplyARDS / DAD alveolar fibrosisKidneyLoss of parenchyma decreased renal function hypertension

Whole Body IrradiationEffects depend on doseCerebral syndromeDrowsiness, convulsions, comaHours post exposureGastro-intestinal syndromeVomiting, diarrhoea Ulceration, haemorrhage, infectionDays post exposureHaemopoietic syndrome Leucocytopaenia, thrombocytopaenia infection , haemorrhage Weeks post exposureUltraviolet RadiationAssociated with squamous cell carcinoma, basal cell carcinoma, melanoma, etcThree typesUVAInhibits DNA repairUVBNon-ionising DNA strand linkageUVCFiltered out by ozone layerVery toxicRadiotherapySome tumours more sensitive than othersLocalised tumour cureDisseminated disease palliative relief of symptoms eg pain and pressure effectsUsed in combination with surgery / chemotherapyFractionation Normal tissue - attempt repair between doses More of tumour cells to enter cell cyclePATHOLOGY OF CHEMOTHERAPEUTICSChemotherapyPathology depends on class of drugClassesDNA damaging free radicals, cross linkingDNA repair inhibitors AntimetabolitesAntitubulinChemotherapySide effects:Nausea, vomitingHair lossMyelosuppressionMyositisOrgan specific toxicity (lung, heart, liver)SterilitySecondary malignanciesAdult Respiratory Distress Syndrome / Diffuse Alveolar Damage

Diffuse alveolar infiltrate on CXRARDS = Clinical dxDAD = Histological dxAdult Respiratory Distress Syndrome / Diffuse Alveolar DamageCauses:Infections eg. sepsis, TBPhysical / Injury eg trauma, drowningInhaled irritants eg smokeChemical injury eg chemotherapy - BleomycinHaematological conditions eg DICPancreatitisUreamiaHypersensitivity reactionsAdult Respiratory Distress Syndrome / Diffuse Alveolar DamageBleomycin:AntibioticGlycopeptidePulmonary toxicity dependant onAgeDoseDurationAdult Respiratory Distress Syndrome / Diffuse Alveolar Damage

ACUTE:HeavyFirmRed / CongestedBoggy

Normal LungAirway

Vein

Alveoli

Inter-alveolar septum

ArteryAdult Respiratory Distress Syndrome / Diffuse Alveolar Damage

Acute PhaseCongestion

Interstitial oedema

Intra-alveolar oedema, inflammation and fibrin depositionAdult Respiratory Distress Syndrome / Diffuse Alveolar Damage

Hyaline membranes

Pneumocyte type II proliferation and atypiaAdult Respiratory Distress Syndrome / Diffuse Alveolar Damage

Chronic PhaseOrganisation Fibrosis Thickening of inter- alveolar septaeAdult Respiratory Distress Syndrome / Diffuse Alveolar DamagePathogenesis:End result of alveolar injury due to different mechanismsDamage to alveolar capillary endothelium or alveolar epithelium Inflammatory processCardiotoxicityNB Adriamycin (Doxorubicin)Dilated cardiomyopathy - Progressive cardiac dilation and contractile dysfunctionRisk factors:AgeMediastinal DXTCombination therapyPre-existing cardiac pathologyDose intervals & total dose

Normal CXRDilated cardiomyopathy CXRDilated Cardiomyopathy

Thin wallDilated Cardiomyopathy

Histology = Non-specific Fibrosis

Vacuolar degeneration

Interstitial oedemaHepatotoxicityMany drugs and toxinsHistology depends on agent responsible:Centrilobular necrosis eg. paracetamolFatty change eg salicylatesMassive necrosis eg. halothaneFibrosis-cirrhosis eg. ethanolGranulomas Cholestasis eg. oral contraceptivesParacetamol toxicityHigh dose 10-20g (ie. 20-40 tablets) in adults2-3 days after overdoseNausea, vomiting, jaundiceLiver and kidney failureNormal Liver

Paracetamol toxicity

Normal liver

Portal tract

Central vein

NecrosisParacetamol toxicity

Central vein

Necrosis

Normal liverReferencesGeneral Pathology; JJ Ripey; Witwatersrand University Press, 2001General and Systemic Pathology; JCE Underwood; Churchill Livingstone, 2000Pathologic Basis of Disease; Robbins and Cotran; Elsevier Saunders, 2005www.pathologyoutlines.comhttp://atlases.muni.czClinical Medicine; Kumar & Clark, Elsevier Science Ltd, London, 2002