The paraproteinaemias

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1 The paraproteinaemias MGUS (Monoclonal Gammopathy of Unknown Significance) Multiple Myeloma: - variant: plasmocytoma (without BM involvement) - smoldering, extramedullary Waldenström macroglobulinaemia Amyloidosis Heavy chain disease

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3 Myeloma pathogenesis B-sejt proliferáció Kialakulásában: celluláris oncogénaktiváció (c-myc,ras),cytokindereguláció(il-6/il-6r),suppresszor-gén mutáció(p53), virus infectio(hhv8) IL-6+IL-6R complex a membran gp130- hoz kötődve indukál tyrosin foszforilációt

4 Pathogenesis of MM

5 Multiple myeloma

6 Plasma cells in bone marrow

7 Disease characteristics Monoclonal protein production /serum and urine samples/, elevated ESR Lytic bony lesions( or diffuse osteoporosis) bone pain and fractures, hypercalcaemia Bone marrow involvement-cytopenia Renal involvement mostly of lambda light chain production

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10 MGUS

11 Rouloux formation in MM

12 Scalp lytic lesions in MM

13 MM in humerus

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15 MRI of MM involvement of vertebral columne

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18 Durie Salmon classification of MM

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20 13q- in Multiple myeloma

21 Therapeutic considerations Overall survival: 1-3 yrs 1960.Gold standard : Alkeran, Prednisolon Others:VAD,M2,VMCP+/-Alpha interferon From VEGF-INH /THALIDOMID,LENALINOMID (combination with Melplanae and predniolon (response 80% 3-yr survival:74%) (side effect: neuropathy, DVT!) BORTESOMIB /VELCADE in combination with cyclophosphamide, melphalane, dexamtehasone ( side effect : neuropathy) ARSENIC TRIOXIDE CY/weekly, dex/monthly, low dose Thal (CR: 17%, PR: 62%) (OS at 2 yrs : 66%) ASCT( for good performance status age<65): prolongation of life: +2-3 yrs, after that inevitable recurrence of the disease. Near future: anti CD38 Ab immunotherapy

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23 Supportive care Epo GM-CSF In hypercalcaemia: bisphosphonates, hydration, steroid Allopurinol Irradiation plasmapheresis

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25 Prognostic Indicators in Myeloma Beta 2-microglobulin (β2-microglobulin or β2-m)a protein normally found on the surface of cells; serum levels reflect the extent of disease n<3 µg/ml Albumin Level Serum levels often an indication of general health status; higher levels may indicate better prognosis n 3.5 g/dl Plasma cell labeling index (PCLI)The relative percentage of plasma cells actively growing; a low PCLI may indicate longer survival n< 1% C-reactive protein (CRP)Increased levels of this protein may indicate poorer prognosis n<6 µg/ml Lactate dehydrogenase (LDH)Measures tumor-cell burden Age 60 y: U/L Age >60 y: U/L Plasmablastic morphologythe general appearance of plasma cells; increased numbers of immature plasma cells (plasmablasts) indicates poor prognosis. Absence of plasmablastic morphology means better prognosis Chromosome analysis (cytogenetic testing)assesses the number and structure of chromosomes. It is evaluable only in proliferating cells. Hpyoploidity is of poor prognostic significance fluorescence in situ hybridization (FISH) is a test that detects abnormalities of specific chromosomes like 13 wich loss is a poor prognostic marker in MM. FISH is evaluable on interphase cells

26 AMWBC, DSS, SWOG összevetése

27 Oral manifestations in myeloma Jaw lesions (in the posterior portion of the mandibula)-causing pain,functional impairment or pathological fracture Lesions might involve oral soft tissues appearing as tumors of the gingiva Primary amyloidosis cause macroglossia, infiltrating salivary glands leading to their enlargement and xerostomia

28 Amyloidosis Definíció: Extracelluláris fibrózus proteindepozíció Hisztológiai: bucca, rectum, abdominalis subcutan zsírból eredő mintában kongó vörös festéssel zölden fluoreszkál polarizációs mikroszkóppal nézve Osztályozás: 1/könnyűlánc-Amyloidosis: a/primer-b/myelomához tásuló 2/szekunder v. reaktív: chr.infectióhoz:lepra,osteomyelitis,tbc, kötőszöveti megbetegedés: RA 3/ chr.dializáltakban, Alzheimer kórban

29 Amyloidosis Definíció: Extracelluláris fibrózus proteindepozíció Hisztológiai: bucca, rectum, abdominalis subcutan zsírból eredő mintában kongó vörös festéssel zölden fluoreszkál polarizációs mikroszkóppal nézve Osztályozás: 1/könnyűlánc-Amyloidosis: a/primer-b/myelomához tásuló 2/szekunder v. reaktív: chr.infectióhoz:lepra,osteomyelitis,tbc, kötőszöveti megbetegedés: RA 3/ chr.dializáltakban, Alzheimer kórban

30 Klinikai megjelenés A viszkózus anyag lerakódása a parenchymás szervekben vezet: Vesében: proteinuria,nephrosis Szívben: kongesztív cardiomyopathia jellemző ECHO kép, EKG eltérések: alacsony lengések, vezetési zavarok, arritmiák,card.decomp, digitalis érzékenység Bőr: hajlatokban papulák, black eye sy. Neuropathia: -autonom:székrekedés vagy diarrhoea, collapsus-hajlam, incontinentia, -perifériás idegek: rekedtség, carpal-tunnel sy.

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33 Accumulation of amyloid leads to formation of yellow nodules on the tounge, palate, buccal or labial mucosa Oral biopsy should be performed Dental management: elective dental procedures should be performed Problem: bleeding tendency, infective complications spontaneously or under chemotherapy Consultation with haematologist is needed before intervention

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35 amyloidosis

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37 Black-eye syndrome

38 Amyloid deposition in the skin

39 Nehézlánc-betegség (a szekretált nehéz láncnak megfelelő elnevezés) Gamma: lgl,h,s>, láz, anemia, a Waldeyer gyűrű involváltsága miatt palatum-oedema Alpha: un. Mediterrán lymphoma: a vékonybél lamina propriájának lymphoplasmocytoid infiltrációja miatt chr.diarrhoea, ts,mediastinalis lgl, kezdetben antibiotikus kezelés hat µ(mű): gyakori társulás CLL-hez, kappa könnyűlánc ürül, vacuolizált lymphocyták a kenetben

40 Haevy chain disease: called according to the secreted haevy chain Gamma: lgl,h,s>, fever, anemia, secondary to the involvement of the Waldeyer ring palatum-oedema Alpha: Mediterranean lymphoma: small intestine lamina propria lymphoplasmocytoid infiltration- secondary chr.diarrhoea, weight loss,mediastinal lgl, antibiotic therapy might be effective in the begining µ(mű): frequent association to CLL, κ (kappa) light chain in the urine, vacuolizated lymphocytes in the smear

41 Waldenström macroglobulinaemia IgM monoclonality: hyperviszkozity Hepato-splenomegaly, lymphadenopathy Fundus paraproteinaemicus: segmentated dilatation f the retinal veins Staging: bone marrow analysis, US, CT Terápy: plasmapheresis, myeloma-protocols anti-cd20 immunotherapy

42 Oral manifestations of Waldenstrom's macroglobulinaemia Gingival and mucosal bleeding (spontaneous or postextraction) Mucosal ulcers Infiltartion caused enlargement of the salivary glands