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

myeloma medicus előadás - III. SZ. BELGYÓGYÁSZATI · PDF filebone pain and fractures, ... (FISH) is a test that detects abnormalities of ... chr.infectióhoz:lepra,osteomyelitis,tbc,

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The paraproteinaemias

• MGUS (Monoclonal Gammopathy of Unknown Significance)

• Multiple Myeloma:- variant: plasmocytoma (without BM involvement)

- smoldering, extramedullary

• Waldenström macroglobulinaemia• Amyloidosis• Heavy chain disease

Myeloma pathogenesis

• B-sejt proliferáció• Kialakulásában: celluláris

oncogénaktiváció (c-myc,RAS),cytokin-dereguláció(IL-6/IL-6R),suppresszor-gén mutáció(p53), virus infectio(HHV8)

• IL-6+IL-6R complex a membran gp130-hoz kötődve indukál tyrosin foszforilációt

Pathogenesis of MM

Multiple myeloma

Plasma cells in bone marrow

Disease characteristics

• Monoclonal protein production /serum andurine 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

MGUS

Rouloux formation in MM

Scalp lytic lesions in MM

MM in humerus

MRI of MM involvement of vertebralcolumne

Durie Salmon classification of MM

13q- in Multiple myeloma

Therapeutic considerations• Overall survival: 1-3 yrs1960.Gold standard : Alkeran, Prednisolon• Others:VAD,M2,VMCP+/-Alpha interferonFrom 2006.• 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

Supportive care

• Epo• GM-CSF• In hypercalcaemia: bisphosphonates,

hydration, steroid• Allopurinol• Irradiation• plasmapheresis

Prognostic Indicators inMyeloma

• Beta 2-microglobulin (β2-microglobulin or β2-M)A protein normally found on thesurface 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 levelsmay indicate better prognosis n≥3.5 g/dL

• Plasma cell labeling index (PCLI)The relative percentage of plasma cells activelygrowing; a low PCLI may indicate longer survival n< 1%

• C-reactive protein (CRP)Increased levels of this protein may indicate poorerprognosis n<6 µg/mL

• Lactate dehydrogenase (LDH)Measures tumor-cell burden Age ≤60 y: 100-190 U/L Age >60 y: 110-210 U/L

• Plasmablastic morphologyThe general appearance of plasma cells; increasednumbers of immature plasma cells (plasmablasts) indicates poor prognosis. Absenceof plasmablastic morphology means better prognosis

• Chromosome analysis (cytogenetic testing)Assesses the number and structure ofchromosomes. It is evaluable only in proliferating cells. Hpyoploidity is of poorprognostic significance

• fluorescence in situ hybridization (FISH) is a test that detects abnormalities ofspecific chromosomes like 13 wich loss is a poor prognostic marker in MM. FISH is evaluable on interphase cells

AMWBC, DSS, SWOG összevetése

Oral manifestations in myeloma

• Jaw lesions (in the posterior portion of themandibula)-causing pain,functionalimpairment or pathological fracture

• Lesions might involve oral soft tissuesappearing as tumors of the gingiva

• Primary amyloidosis cause macroglossia, infiltrating salivary glands leading to theirenlargement and xerostomia

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 tásuló2/szekunder v. reaktív:

chr.infectióhoz:lepra,osteomyelitis,tbc,kötőszöveti megbetegedés: RA

3/ chr.dializáltakban, Alzheimer kórban

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 tásuló2/szekunder v. reaktív:

chr.infectióhoz:lepra,osteomyelitis,tbc,kötőszöveti megbetegedés: RA

3/ chr.dializáltakban, Alzheimer kórban

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.

• Accumulation of amyloid leads to formation of yellownodules 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

amyloidosis

Black-eye syndrome

Amyloid deposition in the skin

Nehézlánc-betegség(a szekretált nehéz láncnak megfelelő elnevezés)

• Gamma: lgl,H,S>, láz, anemia, a Waldeyer gyűrűinvolváltsága miatt palatum-oedema

• Alpha: un. Mediterrán lymphoma: a vékonybél laminapropriájának 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

Haevy chain disease: called according to thesecreted haevy chain

• Gamma: lgl,H,S>, fever, anemia, secondary to theinvolvement of the Waldeyer ring palatum-oedema

• Alpha: Mediterranean lymphoma: small intestine laminapropria lymphoplasmocytoid infiltration- secondarychr.diarrhoea, weight loss,mediastinal lgl↑, antibiotictherapy might be effective in the begining

• µ(mű): frequent association to CLL, κ (kappa) light chainin the urine, vacuolizated lymphocytes in the smear

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-protocolsanti-CD20 immunotherapy

Oral manifestations of Waldenstrom's macroglobulinaemia

• Gingival and mucosal bleeding(spontaneous or postextraction)

• Mucosal ulcers• Infiltartion caused enlargement of the

salivary glands