le discrasie plasmacellulari. discrasie plasmacellulari i: gammopatia monoclonale di significato...
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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• Mieloma osteosclerotico (POEMS: polineuropatia, organomegalia,
endocrinopatia, M protein, skin changes)
• Plasmocitoma solitario• osseo• extraosseo
Discrasie plasmacellulari II
• Macroglobulinemia di Waldenström
• Amiloidosi• primitiva (AL)• secondaria
• Malattia da catene pesanti (HCD)• HCD• HCD• HCD
• Crioglobulinemie
• Linfoma maligno
Presenza di componente monoclonale (M protein)
SP
Immunofixation
Immunoeletrophoresis
IgA MM
IgG MM
BJ MM
IgM WD
iper
normale
MGUS:
< 3 gr% M-protein< 10% BM PCno end-organ damageno AL
incidenza:1.5% > 50 anni3% > 70 anni10% > 80 anni
rischio di evoluzione:1% anno
SMM:
> 3 gr% M-protein> 10% BM PCno end-organ damageno AL
rischio di evoluzione:25% anno
(16% di tutti i MM all’esordio)
MM:
> 3 gr% M-protein> 10% BM PCend-organ damage
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
IRA/IRC
Myeloma staging systemcells x 1012 /sqm
MedianSurvival(months)
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/B A: creatininemia < 2; B: creatininemia > 2
Myeloma diagnostic work-up
MIDOLLO OSSEO• cellule emopoietiche• vasi• cellule stromali
adipocitifibroblastimacrofagimastociti
• matrice extracellulare
Il midollo osseo è un tessuto complesso
OSSO:• matrice ossea (trabecole)• osteoclasti• osteoblasti
B linfocitaCG
MGUSsmolderingmyeloma
symptomatic myelomaintramedullary
symptomatic myelomaextramedullary
Long-lived PC
Adapted from Nature Reviews - Cancer 2. 177-189, 2002
alterazioni geneticheinstabilita’ genetica
microambiente
• homing delle PC nel midollo
• paracrinia
sopravvivenza
differenziazione
proliferazione
• angiogenesi
• osteoclastogenesi
• inibizione osteogenesi
sistema immunitariointerazione direttainterazione indiretta
Mechanisms of disease progression:
ROLE OF MICROENVIRONMENT
ECM
T cells
VEGF
IL-6
2M
stromal cell
MHC class I+ cells
endothelial cell
PTX3
immune system
Causes of death in multiple myeloma
• Progressive myeloma 45%• Sepsis 25%• Renal failure 10%• Other (old age) 20%
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
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)
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
Malattia di Waldenstrom
Asintomatico Sintomatico
Hb < 10 gr%piastrine < 100,000/mmciperviscosita’neuropatia periferica sintomaticaamiloidosicrioglobulinemia sintomatica
TERAPIA
Malattia di Waldenstrom
iperviscosita’: non correlata ai livelli di IgM
sanguinamento mucose (nasale, gengivale)cefaleadisturbi visivi (alterazioni del fundus)disturbi neurologici (vertigini, acufeni, atassia)
viscosimetria
TERAPIA
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
Amyloid Protein Protein Precursor Clinical
AA SAA Reactive (secondary).Familial Mediterranean fever.Familial amyloid nephropathy with urticaria and deafness(Muckle-Wells' syndrome).
AL Immunoglobulin light chains Idiopathic (primary), myeloma or macroglobulinaemiassociated.
ATTR transthyretin (prealbumin) Familial amyloid polyneuropathy, Portuguese type;.familial amyloid cardiomyopathy, Danish type
AApoA1 apoA1 Familial amyloid polyneuropathy, Iowa type;Hereditary non-neuro pathic systemic amyloidosis
Agel Gelsolin Familial amyloidosis, Finnish type.
Acys Cystatin C Hereditary cerebral haemorrhage with amyloidosis,.Icelandic
Alys Lysozyme Hereditary non-neuropathic systemic amyloidosis (Ostertag-type).
Afib Fibrinogen Hereditary renal amyloidosis.Aß ß protein precursor Alzheimer's disease.
Down's syndrome.. Hereditary cerebral haemorrhage with amyloidosis, Dutch
Aß2M ß2-microglobulin Associated with chronic dialysis.
Ascr Scrapie protein precursor Creutzfeldt-Jakob disease, etc.Gerstmann-Straüssler-Scheinker syndrome.
Acal (Pro)calcitonin In medullary carcinomas of the thyroid
AANF Atrial natri-uretic factor solated atrial amyloid.
AAPP Islet amyloid polypeptide In islets of Langerhans, Diabetes type II, insulinoma.
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