HHaemopoeaemopoetticic neopneopllasmsasms andand spspllenenicic disdisrroorrdedersrs ooff DDogsogs andand CCaatsts Peter Vajdovich Szent István University, Faculty of Veterinary Science, Department of Internal Medicine and Clinics Tumorgenesis Oncogene 1910. Rous–filtrableagent–avianleukosisvirus(retrovirus) „viraloncogen” (v-onc). Inthecells-„cellularoncogens” (c-onc). Theseare„proto-oncogens”-theyarechangablegenomsandcan be transformedtobe oncogenic. Protooncogen Oncogen The tumorgenesis is passive accumulation of genetic impairments. Normal gene dysregulation – proto-oncogenes (signal transduction /cell signaling/, proliferation, differentiation) The proto-oncogenes key genoms, they control the cellular proliferation, differentiation and apoptosis. The major funcfunctions are: Growth factors Growth factor receptors Protein kinases Signal transducers NuNucclear proteins and transcription factors Life of the cells Birth Proliferation Arrest in growing Differentiation Death (apoptosis) M Mitosis and cytokinesis Prophase Metaphase Anaphase Telophase Rb Cell cycle G1 willstart, when phosph. M thechromosomas mitosis and cytokinesis areseparatedto the Meta- mitoticspindle Pro- Ana- Telo- phase phase phasepahes M-delaying factors disappear, DNA-replik. block, G1 Chromos. condens. G0 Intermediate phase G2 Resting Biosynth.: prot, RNS Premitotic phase phase Restriction point 8 h-1 year Rb dephosph . S DNA-synth. Apoptosis (double starnd DNA-production, two identic chromatid) www2.nano.physik.uni-muenchen.de/research/rep03/ Cyklin/CDK INK, KIP HHaemaemopoopoeetticic ttuummoorsrs ooff ddogsogs CaCaninninee llyymmphophomama Causes: in humans herbicide (2,4 diclorphenoxyacetate) lawn defence Ebstein-Barr virus (EBV) Immundeficiency Familiar pre dysposition Forms: Ø Multicentric Ø Cranial mediastinal Ø Alimentary (gastrointestinal) Ø Skin Ø Other (kidney, spleen, CNS etc.) Multicentric form Lymphoblastic infiltration most common Nodular (N) and Extranodular (EN) forms N: nodes – submandibular, retropharingeal, prescapular etc. EN: eye, nervous system, bone, testicules, nasal cavity etc. Clinical signs: in20-40% badgen. cond., bw¯, appet. ¯, fever, pu/pd in27% diff. pulm. infiltr. in50% spleen•, liver• in60% chestx-ray+ (enlargedsternal, mediast. ln., orthymus) in20% cran. mediast. lnswell.® oftenT-lyorigin in10-40% totCa• (fromitin43% mediastln•) oftenT-lyorig. Alimentary form amongalllymphomasin5-7% thickerintest. walls(enlargedmesenterialln., spleen, liver) canbe mixed upwithLymphocyticPlasmacyticEnteritis Clinicalsigns: bw¯, appet. ¯, TP ¯ (malabs.), pu/pd Mesenteriallnswelling Hepatomegaly Mediastinal form in5% amonglymphomas Cranialmediastinalln •, (swellingof thymus) Clinicalsigns: bw¯, appet. ¯ respiratorydistress (tachypn., dyspnoe, oed. pulm.) precavalsyndrome (v. cavaconstriction– edemaonthehead, forelimbs, fluid inthechest) Sternallnswelling Skin form rare solitarytumors(evenmouthormucousmembr.), generallyB-cells generalized: mycosisfungoides (epitheliotropicform) ® T-cell Clinicalsigns: I. peeling, alopecia, pruritus!, erythema, II. thickeningof skin, III. placks, nodules, exudation, ulceration Other form i.e. ocularform irisswelling, anterioruveitis(frequentinstageV), hypopyon, posterior synechia, glaucoma Differential diagnosis Generalized lymphadenopathia Disseminated infections: · Bacteria–streptococcosis, Lyme-disease, mycoplasma, mycobact. · Viruses–adenovirus, distemperetc., · Rickettsias–bartonellosis,leishmaniasis, ehrlichiosis · Parasites–toxoplasmosis, demodicosis, · Fungi–aspergylosis, candidiasis,histoplasmosis, blastomyc. (can be hypercalcaemia) Immunmediated disorders Other haemopoietic neoplasms: · leukemias, · myeloma, · systemichistiocytosis, Tumor metastases Benign ln hyperpasia in cats Alimentary Intestines: · Infiltrativeenteritis -lymphcytic, plasmacytic, eosinophilicforms · Intestinal neoplasms, · Granulomatousenteritis, · Gastrointestinal mastocytoma(cat) Liver: · Hyperaemia, · Lipoticinfiltration(starv., hyperadrenocorticism, DM etc.) · Inflamm.-bacterial(cholangiohepatitis), viral(Rubarth-disease), parasitic(toxocariosis–larvaemigration, incatsflukesi.e.: Opistorchisfelineus), · Extramedullaryhaematopoiesis, · Cirrhosis, · Metastasesof otherneoplasmsinliver Spleen · Hyperemia, · Hematoma, · Chronicinflammation–hyperplasia, · Extramedullary haematopoiesis, · Haemolyticdiseases, · Sepsis, · Haemangiosarcoma, · Metastasesof otherneoplasmsinspleen Skin · Pyoderma · Immunemediateddermatitis (i.e.pemphigus), · Skintumors Mediastinum · Thymoma, · Heartbasetumor(chemodectoma), · Ectopicthyroidtumor, · Lymphomatoidgranulomatosisinlungs, · Granulomatosis(i.e.blastomycosis) Paraneoplastic syndromes non regenerativeanemia, maybehaemolyticanemia Ne•, Ly • (20%), Tcyt ¯ (30-50%), monoclongammopath, Ca • (PTHrp) and duetoit ® appet. ¯, pu/pd, kidneyfailure. Staging (TNM Classificationof TumorsinDomesticAnimals, Geneva, 1980) I.: onelninvolvement, II.: manyln-sbelongingtooneregion, III.: generalizedlnenlargement, IV.: splenicand/orliverinvolvement(stageIII. yes, orno), V.: bonemarrowinvolvement, appearanceof neoplasticcellsinblood, and/orinvolvementof a byln. Substae: „a”-no badcond.:bw ¯, appet ¯, dyspnoe, anemiaetc. „b”-ifthesesignsarevsible 80% in stage III.-IV ! Major diagnosticpointsof view inhaemopoieticneoplasms Frequent common signs: • decreased body weight, anorexia, matted fur, anemia • ln enlargement, abd cavity: hepato- és splenomegaly • paraneoplastic disorders (hypercalcaemia, fever) • metastases in other organs (lung, heart muscle, brain) Diagnosis of lymphoma •bloodtests •x-rayexamination(CT) •ultrasonography(abdomenand heart–doxorubicincaused cardiotoxicity) •ultrasoundguidedsplenic, liver, intestinalaspirationcytol. •bonemarrowaspiration, orbiopsy(corebiopsy) (from53 only28% had beenleukemic, butin57% therewere lymphoblastsingreaternumber) •cerebrospinalfluid (iftherewereCNS signs) Forfirmdiagnosis totallnexcisionis needed!! Histopathology follicular center diffuse large B-cell cell lymphoma lymphoma Immunfenotype B-cell marker: CD 79a T-cell marker: CD3 Proliferation markers Ki-67 % nuclear antigen (in all cell in cycle) PCNA % (prolifeartive cell nuclear antigen) AgNOR frequency and square (silver colloid method to stain nucleolar organizing regions) cytology follicular center histology cell lymphoma Basic principlesinthetherapyof haemopoietictumors Cytostatic therapy (and prognosis) according to the tumor type! •different combinations of pharmacons (doses are calculated in square meters2 or bw) •danger of side effects •human health •prize of drugs •multidrug resistance (MDR) •Glucocorticoid-therapy?! •Symptomatic therapy: vitamins, alternative drugs Therapy of lymphoma Points: prize, period, combination, effect, toxicity, experience Monotherapy: doxorubicin: 50-70% completeremission(CR), life span(L): 6-8 month Combination: 1, COP (cyclo, vincr., pred.): 60-70% CR L: 6-7 m, 10-19%>1 year 2, CHOP: 80-90% CR L: 11,5 m, 27%>1 year, 13%>2 year(H=doxo) 3, L-VCA (UW-Madison): 94% CR L: 13,2 m, 50%>1year, 24%>2year (L=asparag) Surgery –stageI. (and spleniclymphoma) Radiotherapy –stageI. and palliative (submand., rectal, bone, mediast.) Beforetreatment After induction Beforetreatment After induction PPrrognoognossisis:: bad: Ø stageIV. b, V. Ø histology(high, lowgrade) Ø mediastlnenlargement Ø highgrade(ki67 pos. high%) Ø highAgNORfrequency, square Ø T-cellorigin Ø totCa• Ø previoussteroidtreatment Ø P-glycoprotein Notallhavebad prognosis! CCaaninenine lleeuukemkemicic didiseasesseases There are neoplastic white cells present in bone marrow. Ifthereis no increased(neopl.) whitecellcountinblood, itis not an exclusion! Acuteleukemicdisorders: Poorlydiffereniatedblast-cells willbe presentinperiphericblood. Sometimesneoplasticcellsarenotpresentinblood, onlyanemia, leukopenia, thrombocytopenia is detected. Bone marrow aspirationorhistologyis needed. •Acutelymphoblasticleukemia(ALL) •Acutemyeloidleukemia(AML) Chronicleukemicdisorders: Maturedifferentiatedcells arepresentinblood. •Chronicsmalllymphocyticleukemia(CLL) •Chronicmyeloid(neutrophilgranulocytic, eosinophilic, basophilic, monocyticleukemia, polycytaemiaabsolutavera (overgrowthof matureRBCs),essentialthrombocytosis(overgrowth of maturethrombocytes). Lymphoid leukemia Acute lymphoblastic leukemia (ALL) lybl-sinbm, spleen, liver, intest., mesent. ln-s, CNS lyblinfilt. from9: 4 null cell, 3 T-ly, 2 B-ly, (1 typeB-cell, 1 typeT-cell) Clinicalsigns: appet.¯, bw¯, pu/pd, spleen•, liver•, peteches,bleeding non reg. an., Ne ¯, Tcyt ¯, WBC > 14x109/l (v. WBC ¯) Diagnosis: Ly>15x109/l generally., lybl-sinbm(itis difficultto differentiatefromotherblastcellsof bm-cyto-, histochemistry) Stage: I. Ly • + ln • II. Ly • + spleen •, liver • III. Ly • + anemiaHb<7g% IV.Ly • + Tcyt ¯ (Tcyt<100 x 109/l) Therapy: adequatefeeding, maybewholebloodtransfusionis needed, broadspectr. ab-s, fluid therapy Prenisolone Vincristine L-asparaginase Doxorubicin Prognosis: average.: 120 day(in1 case: 19 month) Chronic small lymphocytic leukemia (CLL) differenciatedmatureLy-sinthebm, too from12, 8 T-ly (2 typesB-cell, 4 typesT -cell) Before treatment After 2 monthof treatment Clinicalsigns: Ly •, spleen •, ln • , Ht<35, Tcyt: 110-190 x 109/l glob • (60%), monoclonalgammopathy(68%) Therapy: Chlorambucil Prenisolone Vincristine splenectomyis recommended(especially, ifNe¯, Tcyt¯) Prognosis: L: 12 month >2 year(30%) MMyeyeloploprroliolifferaerattiiveve lleeuukkememiiasas (M(ML)L) 1/10 of thecaninelymphoproliferativedisorders ALL>CLL >ML Acute myeloid leukemia – myeloblastic (10 types!)