9. HESの分類 (Hypereosinophilic Diseases Working Group 2005)
9
Hypereosinophilic syndromes (HES) classification
FIP1L1-PDGFRA FIP1L1-PDGFRA
positive
Myeloproliferative HES Lymphocytic HES
Undefined
HES
Associated
HES
With a defined
diagnosis
Churg-
Strauss,
mastocytosis,
inflammatory
bowel disease,
sarcoidosis,
HIV and other
diseases
Overlap
HES
Associated
with organ-
restricted
eosinophilic
disorders (may
not meet all 3
criteria),
eosinophil-
associated
gastrointestinal
disorders,
eosinophilic
pneumonia,
eosinophilia
myalgia
syndrome
Familial
HES
Family
history of
documented
persistent
eosinophilia
of unknown
cause
Benign
No
organ
involve-
ment
negative
Episodic
Cyclical
angioedema
and
eosinophilia
Complex
Organ dysfunction
but not
myeloproliferative
or lymphocytic
variant
Aetiology unknown
Clonal eosinophils* or 4
or more of:
Dysplastic eosinophils,
High serum B12,
High serum tryptase,
Anaemia,
Thrombocytopenia,
Hepatosplenomegaly,
Marrow hypercellularity,
Spindle-shaped mast cells
and/or myelofibrosis
Monitor for T-cell clonality or other cytogenetic abnormalities
Chronic
eosinophilic
leukaemia
(CEL)
Cytogenic
abnormalities
and/or blasts
Eosinophils ≥ 1.5 × 109/l
Persistent eosinophilia and/or end organ damage/dysfunction
Exclusion of secondary causes of eosinophilia
Clonal T cells
*Clonality analysis based on the digestion of genomic
DNA with methylation-sensitive restriction enzymes
followed by PCR amplification of the CAG repeat at the
human androgen receptor gene (AR) locus on the X
chromosome
Review
10. 骨髄増殖性のHES
Chronic Eosinophilic Leukemia, SM with Eosinophiliaが代表的
圧倒的に男性例が多い.
FIP1L1-PDGFRA陽性例は極 かな例外を除いて全て男性例.
iHESと同じように心血管障害も多い. Loefflar endocarditisを呈する.
CELはCMLの1 typeでありImatinibが有効.
特にFIP1L1-PDGFRA陽性例は著効し, 投与量も100mg/dの低用量でOK
HESのうち, FIP1L1-PDGFRA陽性例は4-12.5%と母集団により様々.
10
British Journal of Haematology, 2009;145:271–285
12. 骨髄 刺所見による鑑別.Review
British Journal of Haematology, 2009;145:271–285
PDGFRβ (+): PDGFRB-rearranged eosinophilic leukemia/
Chronoic Myelomonocytic leukemia
FGFR1 (+): FGFR1-rearranged (stem cell leukemia and
lymphoma syndrome with 8p11 translocations)
Cancer J 2007;13: 384–391
13. CEL vs SM with Eoの鑑別.
Score >0ではFIP1L1/PDGFRA陽性 CELを示唆,
Score <0ではKIT D816V陽性 SM with Eoを示唆する.
他にEo上昇をしめす骨髄増殖性疾患は,
Acute leukemia associated with eosinophilia
MDS associated with eosinophilia
他のMPD associated with eosinophilia
Table II. Risk factor scores to distinguish eosinophilia due to separate mutations.
Score Risk factor for FIP1L1/PDGFRA eosinophilia Score Risk factor for KIT D816V eosinophilia
+3 Absolute eosinophil count/tryptase > 100 )3 Absolute eosinophil count/tryptase £100
+3 Dense mast cell aggregates in bone marrow absent )3 Dense mast cell aggregates in bone marrow present
+3 Peak absolute eosinophil count > 10,000
+2 Serum B12 increased
)2 Gastrointestinal symptoms
)2 Urticaria pigmentosa
+1 Pulmonary symptoms
)1 Female gender
+1 Cardiac symptoms
)1 Thrombocytosis
Positive total score denotes FIL1L1/PDGFRA-associated hypereosinophilic syndrome or chronic eosinophilic leukaemia. Negative total score denotes
KIT D816V-associated systemic mastocytosis with eosinophilia.
Modified from J Allergy Clin Immunol, 120, Maric, I., Robyn, J., Metcalfe, D.D., Fay, M.P., Carter, M., Wilson, T., Fu, W., Stoddard, J., Scott, L.,
Hartsell, M., Kirshenbaum, A., Akin, C., Nutman, T.B., Noel, P. & Klion, A.D. KIT D816V-associated systemic mastocytosis with eosinophilia and
FIP1L1/PDGFRA-associated chronic eosinophilic leukaemia are distinct entities, 680-687. Copyright 2007, with permission from Elsevier. The absolute
eosinophil count is given as eosinophils/mm3
and the tryptase level is given as ng/ml to maintain the correct ratios presented in the original article.
ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 271–285 275
British Journal of Haematology, 2009;145:271–285
Cancer J 2007;13: 384–391
14. Systemic
Mastcytosis
WHOではSMを7つに分類.
WHOのSM診断Criteria
Major 1つ+ Minor 1つ
もしくはMinor 3つで診断.
14
Cancer J 2007;13: 384–391
TABLE 3. “B” Findings: Indication of High Mast Cell Burden
1. Infiltration grade (mast cells) in Ͼ30% in bone marrow on histologic examination and serum total tryptase levels Ͼ200 ng/mL
2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for
syndrome or myeloproliferative disorder
3. Organomegaly: palpable hepatomegaly, splenomegaly, or lymphadenopathy (on computed tomography scan or ultrasound) Ͼ2 cm
function
Data from Ref. 65.
TABLE 4. “C” findings: Indication of Impaired Organ Function Attributable to Mast Cell Infiltration66
1. Cytopenia(s): absolute neutrophil count Ͻ1,000/L, or hemoglobin Ͻ10g/dL, or platelets Ͻ100,000/L
2. Hepatomegaly with ascites and impaired liver function
3. Palpable splenomegaly with hypersplenism
4. Malabsorption with hypoalbuminemia and weight loss
5. Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures
6. Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast c
Data from Ref. 66.
TABLE 5. WHO Criteria for Diagnosis of SM*
Major
Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ sections (Ͼ15 mast cells aggregating)
Minor
a. Ն25% mast cells in tissue sections or bone marrow aspirate smear are spindle shaped or have atypical morphology
b. c-kit point mutation at codon 816V
c. Expression of CD2 and/or CD25 by mast cells
d. Baseline serum tryptase persistently Ͼ20 ng/mL (not valid in presence of another non–mast cell clonal disorder)
al residual disease after imatinib therapy can be as-
by quantitative molecular analysis.44
PDGFRB rearrangement was first characterized in the
of a fusion tyrosine kinase encoding regions of
RB and the ets-like gene, ETV6 [ETV6-PDGFRB,
(q33;p13)].46 At present, several other PDGFRB fu-
anscripts are known to exist and are associated with
nt myeloproliferative neoplasm (MPN) phenotypes
ted with eosinophilia.47–55 As has been seen in indi-
with PDGFRA-rearranged MPNs, imatinib therapy
es complete hematologic remission in PDGFRB-rear-
clonal eosinophilia.48,49,51,55–57
FGFR1 translocations are usually associated with a clin-
enotype with features of both an aggressive, eosinophilia-
ted MPN and T cell lymphoblastic lymphoma.58 The
site syndrome is known as either the 8p11 myeloprolif-
syndrome or stem cell leukemia lymphoma syndrome
molecularly characterized by fusion of various 5Ј partner
o the 3Ј part of FGFR1, making it constitutively active.
utation is present in both myeloid and lymphoid lineage
–63 Clinically, 8p11 myeloproliferative syndrome/stem
kemia lymphoma syndrome has an aggressive clinical
with a rapid transformation into acute leukemia. At
, drug therapy is ineffective and allogeneic stem cell
antation should be considered as soon as the particular
sis is established.
ation and Management of
hoproliferative Variant Idiopathic
ophilia
The lymphoproliferative variant of HES is a poorly
number and/or function (Table 2).65 Accordingly, 7 disease
variants are considered, including cutaneous mastocytosis, indo
lent systemic mastocytosis (ISM), SM with an associated clona
hematologic non–mast cell disorder (SM-AHNMD), aggressive
systemic mastocytosis (ASM), mast cell leukemia, mast cel
sarcoma, and extracutaneous mastocytoma.
The WHO classification of mastocytosis mandates a
TABLE 2. WHO Variants of Mastocytosis65
1. Cutaneous mastocytosis (CM)
a. Maculopapular CM
b. Diffuse CM
c. Mastocytoma of skin
2. Indolent systemic mastocytosis (ISM)
a. Smoldering systemic mastocytosis (SSM)
b. Isolated bone marrow mastocytosis
3. Systemic mastocytosis with an associated clonal hematological non–
mast cell lineage disease (SM-AHNMD)
a. SM-myelodysplastic syndrome
b. SM-myeloproliferative disorder
c. SM-chronic eosinophilic leukemia
d. SM-chronic myelomonocytic leukemia
e. SM-non-Hodgkin lymphoma
4. Aggressive systemic mastocytosis (ASM)
With eosinophilia (SM-eo)
5. Mast cell leukemia (MCL)
Aleukemic MCL
6. Mast cell sarcoma
7. Extracutaneous mastocytoma
15. 肥満細胞の活性化の評価には “B”症状の評価,
肥満細胞浸潤による臓器障害は “C”症状で評価する.
SMによるEosinophiliaでは皮膚症状が多い.
肥満細胞クローンはCD25+ and/or CD2+最も多い.
また, 血中Tryptase<20ng/mLはSMを除外し得る.
KITD816V mutaionが代表的な遺伝子異常. 15
TABLE 3. “B” Findings: Indication of High Mast Cell Burden
1. Infiltration grade (mast cells) in Ͼ30% in bone marrow on histologic examination and serum total tryptase levels Ͼ200 ng/mL
2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for myelodysplastic
syndrome or myeloproliferative disorder
3. Organomegaly: palpable hepatomegaly, splenomegaly, or lymphadenopathy (on computed tomography scan or ultrasound) Ͼ2 cm without impaired organ
function
Data from Ref. 65.
TABLE 4. “C” findings: Indication of Impaired Organ Function Attributable to Mast Cell Infiltration66
1. Cytopenia(s): absolute neutrophil count Ͻ1,000/L, or hemoglobin Ͻ10g/dL, or platelets Ͻ100,000/L
2. Hepatomegaly with ascites and impaired liver function
3. Palpable splenomegaly with hypersplenism
4. Malabsorption with hypoalbuminemia and weight loss
5. Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures
6. Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast cells
Data from Ref. 66.
TABLE 5. WHO Criteria for Diagnosis of SM*
Major
Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ sections (Ͼ15 mast cells aggregating)
Minor
a. Ն25% mast cells in tissue sections or bone marrow aspirate smear are spindle shaped or have atypical morphology
b. c-kit point mutation at codon 816V
c. Expression of CD2 and/or CD25 by mast cells
d. Baseline serum tryptase persistently Ͼ20 ng/mL (not valid in presence of another non–mast cell clonal disorder)
*Major plus one minor or three minor criteria.
The Cancer Journal • Volume 13, Number 6, November/December 2007 HES, CEL, and MCD
Cancer J 2007;13: 384–391
17. 骨髄, リンパ増殖性のHES vs iHESの鑑別OSINOPHILIC SYNDROME AND CLONAL EOSINOPHILIA
Peripheral blood screening
for FIP1L1-PDGFRA
using FISH or RT-PCR
Bone marrow biopsy
with cytogenetics
Peripheral blood lymphocyte
phenotyping and TCR
gene rearrangement studies
First step
Second step
Third step
Mutation
present
Idiopathic eosinophilia
including HES
“Lymphocytic” variant
hypereosinophilia
5q33 translocation
present
8p11 translocation
present
Other abnormalities
or excess blasts present
All the above negative
FIP1L1-PDGFRA–
associated
clonal eosinoplilia
PDGFRB-rearranged
clonal eosinophilia
FGFR1-rearranged
clonal eosinophilia
CEL-NOS or
other WHO-defined
myeloid neoplasm
Abnormal or clonal
lymphocytes present
Mayo Clin Proc. 2010;85(2):158-164
18. HESの分類 (Hypereosinophilic Diseases Working Group 2005)
18
Hypereosinophilic syndromes (HES) classification
FIP1L1-PDGFRA FIP1L1-PDGFRA
positive
Myeloproliferative HES Lymphocytic HES
Undefined
HES
Associated
HES
With a defined
diagnosis
Churg-
Strauss,
mastocytosis,
inflammatory
bowel disease,
sarcoidosis,
HIV and other
diseases
Overlap
HES
Associated
with organ-
restricted
eosinophilic
disorders (may
not meet all 3
criteria),
eosinophil-
associated
gastrointestinal
disorders,
eosinophilic
pneumonia,
eosinophilia
myalgia
syndrome
Familial
HES
Family
history of
documented
persistent
eosinophilia
of unknown
cause
Benign
No
organ
involve-
ment
negative
Episodic
Cyclical
angioedema
and
eosinophilia
Complex
Organ dysfunction
but not
myeloproliferative
or lymphocytic
variant
Aetiology unknown
Clonal eosinophils* or 4
or more of:
Dysplastic eosinophils,
High serum B12,
High serum tryptase,
Anaemia,
Thrombocytopenia,
Hepatosplenomegaly,
Marrow hypercellularity,
Spindle-shaped mast cells
and/or myelofibrosis
Monitor for T-cell clonality or other cytogenetic abnormalities
Chronic
eosinophilic
leukaemia
(CEL)
Cytogenic
abnormalities
and/or blasts
Eosinophils ≥ 1.5 × 109/l
Persistent eosinophilia and/or end organ damage/dysfunction
Exclusion of secondary causes of eosinophilia
Clonal T cells
*Clonality analysis based on the digestion of genomic
DNA with methylation-sensitive restriction enzymes
followed by PCR amplification of the CAG repeat at the
human androgen receptor gene (AR) locus on the X
chromosome
Review
26. HESの分類 (Hypereosinophilic Diseases Working Group 2005)
26
Hypereosinophilic syndromes (HES) classification
FIP1L1-PDGFRA FIP1L1-PDGFRA
positive
Myeloproliferative HES Lymphocytic HES
Undefined
HES
Associated
HES
With a defined
diagnosis
Churg-
Strauss,
mastocytosis,
inflammatory
bowel disease,
sarcoidosis,
HIV and other
diseases
Overlap
HES
Associated
with organ-
restricted
eosinophilic
disorders (may
not meet all 3
criteria),
eosinophil-
associated
gastrointestinal
disorders,
eosinophilic
pneumonia,
eosinophilia
myalgia
syndrome
Familial
HES
Family
history of
documented
persistent
eosinophilia
of unknown
cause
Benign
No
organ
involve-
ment
negative
Episodic
Cyclical
angioedema
and
eosinophilia
Complex
Organ dysfunction
but not
myeloproliferative
or lymphocytic
variant
Aetiology unknown
Clonal eosinophils* or 4
or more of:
Dysplastic eosinophils,
High serum B12,
High serum tryptase,
Anaemia,
Thrombocytopenia,
Hepatosplenomegaly,
Marrow hypercellularity,
Spindle-shaped mast cells
and/or myelofibrosis
Monitor for T-cell clonality or other cytogenetic abnormalities
Chronic
eosinophilic
leukaemia
(CEL)
Cytogenic
abnormalities
and/or blasts
Eosinophils ≥ 1.5 × 109/l
Persistent eosinophilia and/or end organ damage/dysfunction
Exclusion of secondary causes of eosinophilia
Clonal T cells
*Clonality analysis based on the digestion of genomic
DNA with methylation-sensitive restriction enzymes
followed by PCR amplification of the CAG repeat at the
human androgen receptor gene (AR) locus on the X
chromosome
Review
33. Evaluate for secondary causes
Drug history
Travel history
Stool for ova and parasites
Other tests if indicated
Clonal eosinophilia
with a molecular
target for imatinib
Clonal eosinophilia
without a molecular
target for imatinib
Hypereosinophilic
syndrome
Hydroxyurea
Vincristine
Cladribine
Allogeneic transplant
Imatinib, 100 mg / d Consider treatment
option that is optimal
to the underlying
clonal disorder
Interferon alfa with or
without prednisone
No response
No response Imatinib, 400 mg / d
Evaluate for clonal eosinophilia
Bone marrow examination with tryptase stains
Cytogenetic studies
FISH or RT-PCR to detect FIP1L1-PDGFRA mutation
Mayo Clin Proc. 2005;80(1):75-83