1. No category

MPN, myeloproliferativ neoplasi
WHO classification of tumours of haematopoietic and lymphoid tissues
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MPN, myeloproliferativ neoplasi anno 2008
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Kronisk myeloid leukæmi m. BCR-ABL1 (CML)
Kronisk neutrofil leukæmi (CNL)
Polycytæmia vera (PV)
Primær myelofibrose (PMF, tidl. CIMF)
Essentiel trombocytose (ET)
Kronisk eosinofil leukæmi, NOS (CEL NOS)
Mastocytose
Myeloproliferativ neoplasi, uklassificerbar (MPN,U)
WHO classification of tumours of haematopoietic and lymphoid tissues
Myeloproliferativ neoplasi – større ændringer:
•
Nyt navn; chronic myeloproliferative disease ændret til
myeloproliferative neoplasia
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Mastocytose inkluderet i MPN
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Ændret klassifikation af sgd. med eosinofili
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Ændrede diagnostiske kriterier for PV, ET og PMF; inkl. af
JAK2, større vægt på morfologiske kriterier
Generelle træk
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Initielt hypercellulær KM
Trombo-, leuko- og erythrocytose varierende
Bevaret opmodning af poieserne
Hepato- og splenomegali varierende
Progression til myelofibrose varierende
Transformation – accelereret fase 10-19% blaster
blastfase >20% blaster
Case 13a
53-årig tidligere rask mand indl. grundet svær leukocytose. Igennem
ca. 6 mdr. åndenød og tyngdefornemmelse under ve. kurvatur.
Vekslende nattesved. Vægttab på få kg. Ingen feber.
På mistanke om iskæmisk hjertesygdom henvises e.l. til arbejdstest,
og i forbindelse hermed tages i dag forblodprøver, der viser svær
leukocytose 370. Differentialtælling viser neutrofile 218,
metamyelocytter 28,7, myelocytter 24,6, promyelocytter 20,5,
blastceller 16,4. Desuden svær basofili, eosinofili og monocytose. Hb
6,2, trombocytter 200, nyre-, væsketal upåfaldende.
Objektivt
Fremtræder upåvirket. Klar, relevant og orienteret. Ikke forpint. Varm
og tør. Ej dyspnøisk. Ingen cyanose eller icterus. Lidt blege
conjunctivae.
RES: ingen palp. glandler på hals, periklavikulært, aksillært eller ingv.
Abd.: blødt og indolent. Splenomegali ca. 1 håndsbredde under
kurvaturen. Der er diskret ømhed ved palp. Ingen hepatomegali.
Hud: intet at bemærke.
IHC MPO
IHC CD61
IHC CD117
Sea blue histiocytes
Kronisk myeloid leukæmi m. BCR-ABL1 (CML)
Philadelphia kromosom
Translokation
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Kronisk fase:
<10% blaster i PB/KM
basofili, evt. eosinofili, fortykket myeloid cuff, mange små
megakar., fibrose, sea-blue histiocytes
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Accelereret fase:
mellem komosom 9 og 22
Fusionsgen abl;bcr
10-19% blaster i PB/KM
svær at definere efter RTKI beh. (>20% basofile)
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Blast fase: >20% blaster i PB/KM (70% myeloide 30% lymfoide NB!)
Hematologic Responses in Six Patients Receiving
500 mg of STI571 per day
Bone marrow changes:
Reduced granulocytic cellularity
Normalized megakaryocytes
Regression of fibrosis
Increased apoptosis
Reactive lymphocytic infiltrates
Druker, B. J. et al. N Engl J Med 2001;344:1031-1037
Myeloproliferativ neoplasi - MPD
Essentiel trombocytose
Polycytæmia vera
Primær myelofibrose
Philadelphia negative
PCV
90 %
ET
50 %
PMF
50 %
Kronisk myeloid leukæmi
Involvement of Janus Kinases in Cytokine Signal Transduction (Panel A)
and Structural Map of Janus Kinase 2 (Panel B)
Original Article
Mutation in TET2 in Myeloid Cancers
François Delhommeau, Pharm.D., Ph.D., Sabrina Dupont, Ph.D., Véronique Della
Valle, Ph.D., Chloé James, M.D., Ph.D., Severine Trannoy, B.S., Aline Massé, Ph.D.,
Olivier Kosmider, Pharm.D., Ph.D., Jean-Pierre Le Couedic, B.S., Fabienne Robert,
Ph.D., Antonio Alberdi, Ph.D., Yann Lécluse, B.S., Isabelle Plo, Ph.D., François J.
Dreyfus, M.D., Christophe Marzac, M.D., Nicole Casadevall, M.D., Catherine
Lacombe, M.D., Ph.D., Serge P. Romana, M.D., Ph.D., Philippe Dessen, M.D., Ph.D.,
Jean Soulier, M.D., Ph.D., Franck Viguié, M.D., Michaela Fontenay, M.D., Ph.D.,
William Vainchenker, M.D., Ph.D., and Olivier A. Bernard, Ph.D.
N Engl J Med
Volume 360(22):2289-2301
May 28, 2009
Goldman, J. M. N Engl J Med 2005;352:1744-1746
WHO classification of tumours of haematopoietic and lymphoid tissues
Study Overview
This article describes mutations or deletions in TET2 in patients with a spectrum of
myelodysplastic syndromes and myeloproliferative disorders
The defect was independent of the JAK2 V617F mutation in such patients
It occurs in primitive hematopoietic stem cells and is an early event in the course
of the disease
Since TET2 has features of a tumor-suppressor gene, it may have an initiating role
in some cases of myelodysplastic syndromes and myeloproliferative disorders
Myeloproliferativ neoplasi – større ændringer:
Men der er stadig en del patienter hvor den
• Nyt navn; chronic myeloproliferative disease ændret til
molekylære patogenese er ukendt:
myeloproliferative neoplasia
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Conclusion
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Somatic mutations in TET2 occur in about 15% of patients with various
myeloid cancers
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- Eninkluderet
del ET og
PMF
Mastocytose
i MPN
ptt.
- CNL ptt.
Ændret -klassifikation
sgd. med eosinofili
eosinofili afptt.
Ændrede diagnostiske kriterier for PV, ET og PMF; inkl. af
JAK2, større vægt på morfologiske kriterier
Dynamics of the disease process in PV
Evolution
Manifestation
Transformation
Post-polycythemic
myeloid metaplasia
(spent phase)
~10%-15%
mimicking “ET”
~ 30 %
osis
Fibr
10 - 15 yrs.
Splenom
egaly
JAK2 +/JAK2 +/+
definite increase in red
cell mass
(t)
~ 10 - 15 %
Blastic crisis
EPO ↓↓
Initial stage
Polycythemic stage
Terminal stage
Issues to perform a bone marrow biopsy in MPN
1.
2.
Confirmation of diagnosis in the absence or failing data concerning
mutation status
Identification and quantification of blast population (accelerated
phase)
3.
Discrimination between PV and secondary polycythemia as well as
ET
4.
Recognition of early myelofibrosis (stage of disease)
Checkliste til diagnosticering af MPN (WHO)
Discrimination between PV and SP
SP
KM biopsi fra ubehandlet pt.
Incidence of BM
features (%)
Cellularitet ift. alder
Erythropoiesis
Kvantitet, venstreforskydning
Granulopoiesis
Kvantitet, venstreforskydning
Megakaryopoiesis
Fibre
Antal, størrelse, lejring: peritrabekulært, klynger
Kerne lobulering , atypi, nøgne kerner
Mængde (score 0,1,2,3)
reticulin/collagen
PV
SP
• pleomorphous aspect
(differences in size)
97
0
• increased nuclear lobulation
87
11
• loose clusters
63
15
2
0
• perivascular plasmocytosis
4
91
• iron-laden macrophages
12
87
• cellular debris
0
94
Megakaryocytes
• naked nuclei
Stroma
Discrimination between initial PV and ET
Staghorn
PV
Incidence of BM
features (%)
Increase in
PV
• cellularity
100 20
• erythropoiesis
98
9
• granulopoiesis
78
21
ET
Cloudlike
Megakaryocytes
• giant forms
25
98
• pleomorphous aspect
(differences in size)
97
5
Staghorn vs.
hypercellulær
Megakaryocyt
morfologi
Loose
Megakaryocyt
klynger
Tight
Staghorn +
cloudlike
Staghorn vs.
tight cluster
Semiquantitative grading of myelofibrosis
Impact of BM morphology on the differential diagnosis
of true ET and early stages of PMF
ET
Morphological features of distinctive impact in ET
and prodromal PMF (PMF-0/1)
ET
PMF-0/1
cellularity
normal
increased
granulopoiesis
normal
increased
erythropoiesis
normal
reduced
fibers (reticulin)
no increase
no significant
increase
Megakaryocyte features of ET and PMF-0/1
PMF-0
ET
PMF-0/1
Frequency (vs.
cellularity)
markedly increased
increased
histotopography
loose clusters or randomly loose to
distributed
dense clusters
size
large to giant
median to giant
staghorn-like,
bulbous lobulation,
deep lobulation
cloud-like features
no
+++
nuclear features
maturation
defects
ET
PMF-0
ET
ET
PMF-0
Quiz
44 år kvinde trombocytose, Mb Bechterew, MTX beh. 3683
Quiz
Quiz
CD61
Find tre fejl!
Quiz
Find tre fejl!
Quiz
ny pt.
CD138
PMF
PMF
Quiz
CD138
PMF - CD61
PMF - CD61 paratrabekulært
PMF - AVG
Myeloproliferative neoplasm, unclassifiable
Cases that
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have definite clinical, laboratory and morphologic features of MPD, but fail to
meet the criteria for any of the specific MPD entities.
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present with features that overlap two or more of the categories.
MPN differential diagnostics –
secondary polycythemia - reactive
Myeloproliferative neoplasm, unclassifiable
Cases that
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have definite clinical, laboratory and morphologic features of MPD, but fail to
meet the criteria for any of the specific MPD entities.
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present with features that overlap two or more of the categories.
Two categories
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initial stages of PV, CIMF or ET in which the characteristic features are not yet fully
developed at the time of first presentation, e.g. pre-fibrotic CIMF, polycythaemic PV
and ET.
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Late stage, advanced chronic CMPDs, in which pronounced myelofibrosis,
osteosclerosis, or transformation to a more aggressive stage obscures the
underlying disorder, e.g. PPMM and CIMF
reakt
MPN differential diagnostics –
MPN differential
diagnostics
–
MPD differential
diagnostics
– neupogen
secondary polycythemia iatrogen
secondary polycythemia iatrogen
neupog
MPN differential diagnostics – iatrogen – CD61
MPN differential diagnostics – iatrogen - MPO
MPN differential diagnostics – reticulin
MPN differential diagnostics – AVG
c.mam.
MPN differential diagnostics -
MPN differential diagnostics – carcinoma – CK7
MPN differential diagnostics – carcinoma - ER
ny pt.
CML med trombocytose
ny pt.
CML med trombocytose
ny pt.
CML med trombocytose