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Le discrasie plasmacellulari

Le discrasie plasmacellulari. Discrasie plasmacellulari I: Gammopatia monoclonale di significato indeterminato (MGUS): primitiva secondaria Mieloma Multiplo Smoldering myeloma Plasma cell leukemia Mieloma micromolecolare Mieloma non-secernente

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Le discrasie plasmacellulari

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  1. Le discrasie plasmacellulari

  2. Discrasie plasmacellulari I: • Gammopatia monoclonale di significato indeterminato (MGUS): • primitiva • secondaria • Mieloma Multiplo • Smoldering myeloma • Plasma cell leukemia • Mieloma micromolecolare • Mieloma non-secernente • Mieloma osteosclerotico (POEMS: polineuropatia, organomegalia, • endocrinopatia, M protein, skin changes) • Plasmocitoma solitario • osseo • extraosseo

  3. Discrasie plasmacellulari II • Macroglobulinemia di Waldenström • Amiloidosi • primitiva (AL) • secondaria • Malattia da catene pesanti (HCD) •  HCD •  HCD •  HCD • Crioglobulinemie • Linfoma maligno

  4. Presenza di componente monoclonale (M protein)

  5. Immunoeletrophoresis Immunofixation SP        

  6. normale IgA MM BJ MM iper IgG MM IgM WD

  7. MGUS: < 3 gr% M-protein < 10% BM PC no end-organ damage no AL incidenza: 1.5% > 50 anni 3% > 70 anni 10% > 80 anni rischio di evoluzione: 1% anno SMM: > 3 gr% M-protein > 10% BM PC no end-organ damage no AL rischio di evoluzione: 25% anno (16% di tutti i MM all’esordio) MM: > 3 gr% M-protein > 10% BM PC end-organ damage

  8. Active myeloma: end-organ damage bone pain -often with loss of height constitutional - weakness, fatigue and weight loss anemia- responds to erythropoeitin renal disease-renal tubular dysfunction susceptibility to infections- neutropenia, hypogammaglobulinemia) hypercalcemia- myeloma cells secrete osteoclast activating factors hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia neurologic dysfunction- spinal cord or nerve root compression

  9. IRA/IRC

  10. Median Survival (months) Myeloma staging system cells x 1012 /sqm Stage I no anemia (Hb > 10gr%) >60 <0.6 no hypercalcemia no more than one bony lesion low M protein (IgG < 5gr/dl; IgA < 3 gr/dl; BJ < 4 gr/24 ore) Stage II between I and III 41 0.6-1.2 Stage III anemia (Hb < 8.5 gr%) 23 >1.2 hypercalcemia (Ca > 12 mg/dl) advanced lytic bone disease high M protein (IgG > 7gr/dl; IgA > 5 gr/dl; BJ > 12 gr/24 ore) A/BA: creatininemia < 2; B: creatininemia > 2

  11. Myeloma diagnostic work-up

  12. MIDOLLO OSSEO • cellule emopoietiche • vasi • cellule stromali • adipociti • fibroblasti • macrofagi • mastociti • matrice extracellulare • OSSO: • matrice ossea (trabecole) • osteoclasti • osteoblasti Il midollo osseo è un tessuto complesso

  13. instabilita’ genetica alterazioni genetiche microambiente interazione diretta interazione indiretta sistema immunitario B linfocita CG Long-lived PC symptomatic myeloma intramedullary symptomatic myeloma extramedullary smoldering myeloma MGUS • homing delle PC nel midollo • paracrinia • sopravvivenza • differenziazione • proliferazione • angiogenesi • osteoclastogenesi • inibizione osteogenesi Adapted from Nature Reviews - Cancer 2. 177-189, 2002

  14. ECM Mechanisms of disease progression: ROLE OF MICROENVIRONMENT

  15. stromal cell endothelial cell VEGF PTX3 IL-6 immune system T cells 2M MHC class I+ cells

  16. Causes of death in multiple myeloma • Progressive myeloma 45% • Sepsis 25% • Renal failure 10% • Other (old age) 20%

  17. Principles of treatment • no evidence that early treatment prolongs survival • wait for symptoms, or evidence of disease progression to start treatment • supportive measures are critically important • drink 3 liters of fluids daily • treat infections promptly • prophylactic bisphosphonates reduce skeletal cmplications • anemia responds to erythropoeitin

  18. Trattamenti utilizzati: chemioterapia convenzionale chemioterapia ad alte dosi con autotrapianto alte dosi di steroidi (DEX) interferone talidomide allotrapianto mieloablativo/non-mieloablativo inibitori del proteasoma (Velcade)

  19. Malattia di Waldenstrom • produzione di IgM da parte di B linfociti pre-switch • anomalie citogenetiche specifiche • familiarita’ • interessamento midollo osseo, linfonodi, milza • midollo compatibile con linfoma plasmocitico • IgM+, CD19+, CD20+, CD79+, • CD10-, CD23-, CD25+, CD27+ • IgM con caratteristiche particolari • iperviscosita’ • autoimmunita’ • neuropatia • amiloidosi • crioglobulinemia

  20. Malattia di Waldenstrom Asintomatico Sintomatico Hb < 10 gr% piastrine < 100,000/mmc iperviscosita’ neuropatia periferica sintomatica amiloidosi crioglobulinemia sintomatica TERAPIA

  21. viscosimetria TERAPIA Malattia di Waldenstrom iperviscosita’:non correlata ai livelli di IgM sanguinamento mucose (nasale, gengivale) cefalea disturbi visivi (alterazioni del fundus) disturbi neurologici (vertigini, acufeni, atassia)

  22. Amiloidosi: • disturbo della struttura secondaria delle proteine • le proteine son prodotti in forma solubile dalle cellule • diventano insolubili a livello extracellulare per • - difetto strutturale della proteina stessa • - effetto proteolitico a livello tessutale • formano depositi a livello tessutale (fibrille) • i depositi portano a disfunzione tessutale rene cuore

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