Test Center

My Recent Searches

  • No Recent Search.

My Tests Viewed

  • No Test Viewed.

Myeloproliferative Neoplasms Laboratory Support of Diagnosis and Management

Myeloproliferative Neoplasms Laboratory Support of Diagnosis and Management

Clinical Focus

Myeloproliferative Neoplasms

Laboratory Support of Diagnosis and Management

  

Contents:

Clinical Background  - Table 1

Individuals Suitable for Testing

Test Availability - Table 2

Test Selection  - Table 3 - Table 4 - Table 5 - Table 6
Figure 1 - Figure 2 - Figure 3 - Figure 4

References
 

Clinical Background [return to contents]

Myeloproliferative neoplasms (MPNs), formerly classified as chronic myeloproliferative diseases, are clonal stem cell disorders characterized by proliferation of 1 or more of the myeloid lineages (granulocytic, erythroid, mast cell, or megakaryocytic). These neoplasms collectively have an incidence of 6 to 10 per 100,000 population annually.1 This Clinical Focus describes the various MPNs and the use of laboratory testing for diagnosis and management.

The classic, more common MPNs include chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), and unclassifiable MPN are rare. MPNs typically occur in adults 50 to 70 years old and are uncommon in individuals <20 years old. Frequently, the onset is insidious and the clinical course indolent. Patient complaints may include fatigue and lethargy, weight loss, abdominal discomfort, easy bruising, night sweats, and swollen, painful joints. Physical examination may reveal pallor, enlargement of the spleen or liver, and petechiae.

Distinguishing between the MPNs is often difficult because of the overlap of clinical and laboratory findings. For example, most MPNs result in increased numbers of granulocytes, RBCs, and/or platelets. Each MPN begins with effective hematopoiesis resulting in circulating mature blood cells, but may result in marrow failure due to myelofibrosis, ineffective hematopoiesis, or progression to acute myeloid leukemia (AML). Table 1 details hematologic characteristics of the various MPNs, including those considered diagnostic by the World Health Organization (WHO).

The tables in this Clinical Focus are provided for informational purposes only and are not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

Table 1. Hematologic Characteristics, Including 2008 WHO Diagnostic Criteria for Myeloproliferative Neoplasms (MPNs) (bolded)2-8

MPN Major Diagnostic Criteria Minor Diagnostic Criteria
Chronic myelogenous leukemia (CML) Positive for Ph and/or BCR/ABL1 Leukocytosis (median WBC count

~100 x 109/L in chronic phase)

Predominance of neutrophils in

different stages of maturation in both PB and BM with increase in myelocytes

Absolute basophilia; eosinophilia ±

Platelet count normal or

BM:

Hypercellular due to granulocytic

hyperplasia

Blasts <5%; eosinophils

Small megakaryocytes

Reticulin fibers in ≈30% of

patient

 

Essential thrombocythemia (ET)

Four criteria required:

Small to atypical large, giant

platelets

Normal WBC count and differential

P latelet count 450 x 109/L for

2 months

Predominantly megakaryocyte

proliferation with mostly mature, enlarged forms with hyperlobulated nuclei in BM

Positive for JAK2 V617F or other

clonal markers; or rule out reactive thrombocytosis

Rule out other myeloid

neoplasms including CML,

MDS, PMF, and PV

 

Polycythemia vera (PV) Two major and 1 minor criteria or first major plus 2 minor (bolded) criteria required:
 

Hemoglobin (>18.5 g/dL in men;

>16.5 g/dL in women) or RBC

mass

Positive for JAK2 V617F or

exon 12 mutation

BM cellularity with trilineage

hyperplasia

Serum erythropoietin

Endogenous erythroid colony

growth

WBC count >12 x 109/La

Platelet count >400 x 109/L

Stainable iron absent in BM

 

Primary myelofibrosis (PMF) Three major and 2 minor criteria (bolded) required:
 

Megakaryocyte proliferation with

abnormal forms in BM:

•  either with reticulin and/or

collagen fibrosis or

•  without reticulin fibrosis

and with cellularity,

granulocytic proliferation,

and often erythropoiesis

Leukoerythroblastosis

Serum lactate dehydrogenase

Anemia

Splenomegaly

WBC count and/or platelets

RBC poikilocytosis (teardrop

shapes)

Positive for JAK2 V617F or other

clonal markers (eg, MPL W515K/L) or if negative, rule out other secondary causes of BM fibrosis

Rule out other myeloid

neoplasms including CML,

MDS, and PV

 

Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) Persistent eosinophilia 1.5 x

109/L

Rule out other myeloid

neoplasms including CML, ET, PMF, PV, and MDS/MPN overlap syndrome

Negative for t(5;12)(q31-35;p13)

or other rearrangement of PDGFRB

Negative for FIP1L1/PDGFRA or

other rearrangement of PDGFRA

Negative for FGFR1

rearrangement

<20% blasts in PB and BM;

negative for cytogenetic and other features associated with AML

>2% blasts in PB or >5% in BM or

positive for a clonal cytogenetic or molecular genetic abnormality

 

 
Systemic mastocytosis (SM) The major and 1 minor criterion or 3 minor criteria required:
Dense multifocal clusters or

aggregates of mast cells (15 per aggregate) in BM and/or in an extracutaneous organ

>25% of mast cells are immature

or atypical

KIT mutation at codon 816 in PB,

BM, or an extracutaneous organ

Positive for CD2 and/or CD25 in

addition to normal mast cell markers

Serum tryptase levels persistently

>20 ng/mL in the absence of an associated clonal myeloid disorder

 

Chronic neutrophilic leukemia (CNL) PB:

WBC count 25 x 109/L

Segmented neutrophils and

bands >80%

Immature granulocytes <10%

Blasts <1%

BM:

Cellularity with % and

number of neutrophils

Myeloblasts <5% of nucleated

marrow cells

Normal neutrophilic maturation

pattern

Hepatosplenomegaly

No identifiable cause for

physiologic neutrophilia, or if present, also positive for myeloid clonality by cytogenetic or molecular studies

Negative for BCR/ABL1 and

rearrangements of PDGFRA, PDGFRB, or FGFR1

Rule out other myeloid

neoplasms including ET,

MDS, PMF, PV, and MDS/

MPN overlap syndrome

 

Ph, Philadelphia chromosome; PB, peripheral blood; BM, bone marrow; MDS, myelodysplastic syndrome.
a In the absence of fever or infection.

Chronic Myelogenous Leukemia

Patients may present with splenomegaly, but more commonly CML is detected with increased WBC count and percent neutrophils in asymptomatic patients. The hallmark of CML is the presence of the Philadelphia chromosome (Ph) and/or the BCR/ABL1 fusion gene.2 CML progresses through 2 or 3 sequential phases: 1) chronic phase in which most patients are diagnosed, 2) accelerated phase, and/or 3) blast phase. Each phase is progressively more resistant to therapy, and thus, early diagnosis and treatment is imperative.

Essential Thrombocythemia

Although some patients present with symptoms of vascular occlusion or hemorrhage, ET is asymptomatic in more than 50% of patients and is identified fortuitously with a routine CBC that reveals an elevated platelet count.3 Thrombocytosis due to secondary causes such as systemic infections, inflammatory conditions, bleeding, or malignancy must be ruled out before clonal ET can be diagnosed. Thrombosis and hemorrhage are the most frequent clinical complications in patients with ET. The use of cytoreductive therapy to reduce elevated platelet counts has been suggested for high-risk patients (ie, age 60 years or a history of thrombosis).9

Polycythemia Vera

The most serious complications of PV are thrombosis, hemorrhage, and hypertension. Approximately 20% of patients present with venous or arterial thrombosis, myocardial ischemia, or stroke.4 Major complaints at diagnosis include headache, dizziness, visual disturbances, and numbness/tingling. Erythromelalgia (vasodilation with burning), pruritus, and gout may also be present. About 70% of patients have plethora or splenomegaly and 40% have hepatomegaly.4 Low dose aspirin and phlebotomy targeting reduction in hematocrit are typically used to treat PV.

Primary Myelofibrosis

PMF, previously known as agnogenic myeloid metaplasia, is characterized by anemia, progressive splenomegaly and bone marrow fibrosis, and multi-organ extramedullary hematopoiesis (EMH). Up to 30% of patients with PMF are asymptomatic at diagnosis, and CBC findings or splenomegaly seen during a routine physical examination trigger the diagnostic workup.5 The remainder present with signs of EMH, which accounts for many of the peripheral blood findings in fibrotic PMF. Major causes of morbidity and mortality include AML, which develops in 5% to 30% of PMF patients; bone marrow failure due to hemorrhage or infection; thromboembolic events; portal hypertension; and cardiac failure.5

Chronic Eosinophilic Leukemia

In 2008, the WHO categorized neoplastic eosinophilia into 2 classes: 1) a MPN called CEL, NOS that is derived from a myeloid stem cell and 2) eosinophilia associated with abnormalities of PDGFRA, PDGFRB, or FGFR1, all of which are derived from a mutated lymphoid-myeloid stem cell. Clinical features are similar between the 2 classes. Sometimes hypereosinophilia is detected incidentally and no symptoms are apparent.6 Other patients may experience constitutional symptoms including fever, fatigue, cough, angioedema, muscle pains, pruritus, and diarrhea. Tissue infiltration by eosinophils, especially in the heart, skin, nervous system, and lungs, may lead to more serious symptoms. Organ involvement, especially in the heart, is the most severe complication.

Systemic Mastocytosis

Clinical symptoms of SM can be grouped into 1) constitutional symptoms; 2) skin conditions such as pruritus and urticaria; 3) mast cell mediator-related features including abdominal pain, flushing, headache, and respiratory symptoms; and 4) musculoskeletal complaints including arthralgia, myalgia, and bone pain and fractures.7 Symptoms range from mild to life-threatening depending on the degree of organ involvement. SM should be distinguished from cutaneous mastocytosis, a childhood disorder usually confined to the skin that frequently shows spontaneous regression.

Chronic Neutrophilic Leukemia

Splenomegaly, the most constant clinical feature, is caused by neutrophilic infiltration and may be symptomatic.8 Most patients have hepatomegaly, and 25% to 30% report a history of bleeding.

Individuals Suitable for Testing [return to contents]

  • Individuals with hematologic abnormalities, with or without clinical symptoms of MPNs (eg, organomegaly, vascular occlusion or hemorrhage)

  • Individuals being monitored following diagnosis of a MPN

Test Availability [return to contents]

Table 2 lists tests used for diagnosis and management of MPNs.

Table 2. Tests Available to Support the Diagnosis and Management of Myeloproliferative Neoplasms (MPNs)
Test Code Test Name Clinical Use

Morphology and Immunophenotyping Tests

17734(X)

Comprehensive Hematopathology Report

Includes hematopathologist interpretation of morphologic
and ancillary studies. Additional tests are performed, at an additional charge, when deemed medically necessary for the diagnosis. Such tests may include IHC and flow cytometric markers as well as chromosomal, FISH, or PCR genetic studies.

Diagnose hematologic disorders
3541(X)

Tissue, Consultation on Referred Slides or Blocks

Includes hematopathologist interpretation of morphologic
and IHC studies. Additional IHC tests are performed, at an additional charge, when deemed medically necessary for the diagnosis.

Diagnose hematologic disorders
19771(X)

Hematopathology Morphologic Evaluation

Includes hematopathologist interpretation of bone marrow and/or peripheral blood smear morphology.

Diagnose hematologic disorders

10248(X)

Intracellular Markers by Flow Cytometrya

Specify 1 or more of the following markers: CD3, CD22,
IgM, MPO, TdT.

Differential diagnosis of leukemia
and lymphoma; detect relapse

35080(X)

Leukemia/Lymphoma Evaluationa

Includes flow cytometry analysis of CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD13, CD19, CD20, CD23, CD33, CD34, CD38, CD45, CD56, CD64, CD117, HLA-DR, kappa, and lambda, with pathologist interpretation. Additional markers are tested, at an additional charge, when deemed medically necessary for the diagnosis.

Differential diagnosis of leukemia
and lymphoma

16002

Leukemia/Lymphoma Evaluation, Histogram Only (No Interpretation)a

Includes flow cytometry analysis of CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD13, CD19, CD20, CD23, CD33, CD34, CD38, CD45, CD56, CD64, CD117, HLA-DR, kappa, and lambda.

Differential diagnosis of leukemia
and lymphoma

Molecular and Chromosome Tests

16029(X)

ABL Kinase Domain Mutation in CML, Cell-basedb

Predict imatinib drug resistance
prior to clinical relapse in patients
with CML

Identify individuals who may
benefit from alternative therapy

16031(X) ABL Kinase Domain Mutation in CML, Plasma-based, Leumeta® b
19783(X)

ABL T315I Mutation in CML, Cell-basedb

Predict a high degree of resistance to imatinib, dasatinib, and nilotinib
in patients with CML

Identify individuals who may
benefit from alternative therapy

19782(X) ABL T315I Mutation in CML, Plasma-based, Leumetab
16876 BCR-ABL1 Kinase Domain Mutation, 35-Nucleotide Insertionb Predict imatinib drug resistance
prior to clinical relapse in patients
with CML

Identify individuals who may
benefit from alternative therapy

91065 BCR-ABL1 Gene Rearrangement, Quantitative PCRb

Diagnose CML

Monitor CML patients for therapeutic response, MRD, and early relapse

11230(X) CD117 (c-KIT), IHC with Interpretation

Diagnose SM

Predict response to imatinib
therapy

19961

c-KIT Mutation Analysis, Cell-basedb

19960(X)

c-KIT Mutation Analysis, Plasma-based, Leumetab

14600(X) Chromosome Analysis, Hematological Malignancy

Diagnose, assess prognosis, and select treatment for MPNs

Detect clonal evolution

12070(X)

FISH, CML/ALL, BCR/ABL1 Translocation 9;22a

Diagnose or rule out CML

Assess prognosis and
effectiveness of therapy in
BCR/ABL1-positive patients

10055(X)

FISH, Chromosome 20q Deletiona

Assess prognosis in patients with PV, PMF, CNL, or CEL
16837 FISH, HES/Leukemia, 4q12 Rearrangement (FIP1L1/PDGFRA)a

Diagnose or rule out CEL with FIP1L1/PDGFRA rearrangement

Predict response to imatinib therapy

19799(X)

FISH, MDS/Myeloid Panel, -5/5q-, -7/7q-, +8, 20q-a

Diagnose myeloid malignancies

Monitor therapeutic response in myeloid marker-positive patients

Assess prognosis

16175 JAK2 Mutation (V617F) Analysis, Quantitative, Plasma-based, Leumetab,c

Diagnose or confirm the diagnosis of PV, ET, or PMF

Monitor patients for therapeutic response and relapse

16536(X) JAK2 Exons 12 and 13 Mutations, Qualitative, Leumetab,c Diagnose or confirm the diagnosis of PV
16539(X)

JAK2 V617F Mutation, Qualitative PCR, Leumeta
with Reflex to Exons 12,13b,c

Reflex testing is performed when initial mutation results
are negative.

Diagnose or confirm the diagnosis of PV, ET, or PMF
16538(X)

JAK2 V617F, Qualitative, Leumeta with Reflex to Exons 12,13 and Reflex to MPL W515, S505b,c

Reflex testing is performed when initial mutation results
are negative.

Diagnose or confirm the diagnosis of PV, ET, or PMF
16184(X) MPL W515 and MPL S505 Mutation Analysis, Qualitative, Leumetab Diagnose or confirm the
diagnosis of ET or PMF in
individuals without JAK2 mutation
91401 Myeloproliferative Neoplasm Mutations (without
BCR-ABL
, JAK2, and MPL)b
Diagnose MPN in individuals who tested negative for BCR-ABL, JAK2, and MPL mutations
15930(X) T-Cell Receptor (TCR) Gene Rearrangement, Qualitative PCR, Cell-basedb

Differentiate hypereosinophilia due to T-cell clonality from CEL due to eosinophilic clonality

Determine leukemia and lymphoma lineage

17862(X) T-Cell Receptor (TCR) Gene Rearrangement, Qualitative PCR, Leumetab

Other Tests

4420 C-Reactive Protein Rule out inflammatory conditions as a cause of reactive thrombocytosis, leukocytosis, or eosinophilia
427 Erythropoietin (EPO) Differentiate secondary from primary polycythemia
457 Ferritin

Rule out iron deficiency as cause of anemia

Differentiate PV from secondary erythrocytosis or from ET

34484

Tryptased

Differentiate systemic from cutaneous mastocytosis in the absence of other myeloid disease

Monitor effectiveness of SM therapy

CML, chronic myelogenous leukemia; MRD, minimal residual disease; ALL, acute lymphoblastic leukemia; SM, systemic mastocytosis; PV, polycythemia vera; PMF, primary myelofibrosis; CNL, chronic neutrophilic leukemia; CEL, chronic eosinophilic leukemia.
a This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.
b This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

c This test is performed pursuant to a license agreement with Roche Molecular Systems, Inc.
d This test was performed using a kit that has not been approved or cleared by the FDA. The analytical performance characteristics of this test have been determined by Quest Diagnostics Nichols Institute. This test should not be used for diagnosis without confirmation by other medically established means.

Test Selection [return to contents]

Bone Marrow Histology

WHO diagnostic guidelines include bone marrow findings as criteria for identifying and distinguishing between the MPNs (Table 1). The WHO recommends that bone marrow biopsy and peripheral blood specimens be evaluated together to reach a diagnosis.1 Quest Diagnostics uses various stains and immunohistochemical markers to evaluate bone marrow. Cellularity, collagen and reticulin fibrosis, and proliferation of granulocytes, megakaryocytes, mast cells, and erythrocytes are routinely evaluated to aid in the diagnosis of a MPN.

MPN progression is associated with increased bone marrow fibrosis and transformation to AML.
Thus, once a MPN has been diagnosed, disease progression may be monitored with periodic evaluation of bone marrow cellularity, degree of fibrosis, and cytogenetic changes. A more aggressive clinical course is predicted by 20 myeloblasts; morphologic evidence of dysplasia; and/or increased reticulin fibrosis, followed by collagen fibrosis, which may result in marrow failure.

Genetic Abnormalities

Because of the clonal nature of the MPNs, detecting chromosomal abnormalities and somatic mutations is important for diagnosis, treatment selection, and monitoring. In the case of CML, a specific chromosomal abnormality (ie, Ph+) is considered diagnostic (Table 1). No other single chromosomal abnormality or molecular marker is solely diagnostic for the other MPNs. However, recurring abnormalities that are not disease-specific have been associated with the non-CML disorders (Table 3). Detection of these abnormalities meets the WHO requirement for establishing clonality and thus supports the diagnosis of a MPN.1 Additionally, identification of a chromosomal abnormality rules out a non-malignant reactive disorder.

Comparing baseline bone marrow karyotyping with subsequent karyotyping is used to identify clonal evolution, which is the appearance of a genetic abnormality not present previously. Clonal evolution is associated with a poor prognosis and, in CML, is indicative of passing from the chronic to the accelerated or blast phase (Table 3).

Table 3. Recurring Chromosomal Abnormalities Associated with MPNs2-8,10,11
Disease Abnormalities
CML – chronic, accelerated, and blast phase t(9;22)(q34:q11) (BCR/ABL1)
CML – accelerated or blast phase +8, +19, +17, +21, -7, -17, -Y, inv(17q), t(3;21)(q26;q22)(EVI1/AML1)
ET +8, del(11q21), del(13q), del(20q), inv(3), t(2;3),
t(13;14)
PMF +8, +9, 5q-, -7/del(7q), del(3q), del(11q), del(12p),
del(13q), del(20q), der(1q9p), t(1;7), der(6)t(1;6)
(q21-23;p21.3), t(1;20), t(4;13), t(5;17)
PV +8, +9, +19, del(9p), del(13q), del(20q), t(3;17), t(Y;1)
CEL, NOS and MPN with eosinophilia and gene rearrangements +8, i(17q), 4q12 rearrangements, 8p11 rearrangements (FGFR1), t(5;12)(q31 33;p12)(ETV6/PDGFRB)
SM +8, +9
CNL +8, +9, +21, del(11q14), del(12p), del(20q), t(2;2)(q32;p24)

CML, chronic myelogenous leukemia; ET, essential thrombocythemia; PMF, primary myelofibrosis; PV, polycythemia vera; CEL, NOS, chronic eosinophilic leukemia not otherwise specified; SM, systemic mastocytosis; CNL, chronic neutrophilic leukemia.

Identification of MPN-associated somatic mutations (Table 4) also meets the WHO diagnostic criterion for establishing clonality and rules out reactive causes of erythrocytosis, myelofibrosis, or thrombocytosis. These mutations are associated with the constitutive (unregulated) activation of a protein-tyrosine kinase (PTK) that is implicated in the pathogenesis of each of the MPNs. Thus, drugs targeting PTK activity, such as imatinib, have been successfully used to treat patients with a MPN.16

Table 4. Somatic Gene Mutations and Their Frequencies in MPNs2,4,12-15
Disease Genetic Mutation Frequency (%)
CML BCR/ABL

100

ET JAK2 V617F
MPL
W515

ASXL1

IDH1/2

TET2

50
1

<7
<1
4-11

PMF

JAK2 V617F
MPL
W515

ASXL1
EZH2
IDH1/2
TET2

50
5-7

19-40
13
4
19

PV

JAK2 V617F
JAK2 exon 12
ASXL1
EZH2
IDH1/2
TET2

>95
2-4
<7
3
2
15

SM KIT D816V

95

SM with eosinophilia FIP1L1/PDGFRA 15

CML, chronic myelogenous leukemia; ET, essential thrombocythemia; PMF, primary myelofibrosis;
PV, polycythemia vera; SM, systemic mastocytosis.

JAK2 Mutations

JAK2 V617F is the first acquired gain-of-function mutation found to be associated with PV, PMF, and ET; its detection supports the diagnosis of these MPNs but does not distinguish between them. A negative result does not rule out the diagnosis, however, because the mutation is not always present (Table 4). In JAK2 V617F-negative patients suspected of PV, JAK2 exon 12 mutations should be sought, especially when erythrocytosis is present.12 Several clinical studies have indicated that the JAK2 V617F mutation is not present in patients with CML, secondary erythrocytosis, SM, or normal control subjects,17,18 but is present in up to 2% of de novo AML cases.19 Rarely, JAK2 V617F mutations are found in patients with CNL.8

Although mutation analysis testing frequently uses bone marrow or peripheral blood cells, the Leumeta® tests employed by Quest Diagnostics are performed using plasma samples (Table 2). For JAK2 mutation testing, plasma was shown to provide a higher mutation detection rate,20 to distinguish hemizygous/homozygous from heterozygous mutations,21 and to detect mutations in RNA that might be missed with DNA cell-based testing.22 Furthermore, quantitation of JAK2 V617F allele burden in plasma permits true quantitation of leukemic burden, reporting in pg/μL plasma.

MPL Mutations

The myeloproliferative leukemia gene (MPL), found at chromosome 1p34, encodes the thrombopoietin receptor that works in concert with thrombopoietin for platelet production. Acquired MPL mutations (eg, W515L and W515K) are associated with severe anemia and have been detected in patients with ET or PMF but not in patients with PV (Table 4).14,23 Typically, mutations in MPL are investigated after the JAK2 V617F mutation has been ruled out. An inherited MPL mutation (S505N; exon 10) has also been found in a Japanese pedigree with familial ET.24

KIT Mutations

SM is associated with somatic activating point mutations within the KIT gene.7 The most common is mutation of the PTK domain at codon 816 (D816V). Detection of the D816V mutation satisfies a minor criterion for diagnosis of SM and predicts resistance to imatinib.25

FIP1L1/PDGFRA Fusion Gene

The presence of the FIP1L1/PDGFRA somatic mutation confirms the diagnosis of FIP1L1/PDGFRA- associated CEL and predicts a favorable response to imatinib treatment.10 Favorable responses are also seen in a subset of patients with SM who are positive for FIP1L1/PDGFRA and eosinophilia (Table 4).

ASXL1, EZH2, IDH1, IDH2, KRAS, NRAS, TET2 Mutations

These mutations may be of assistance in MPN diagnosis when BCR-ABL1, JAK2, and MPL mutations have been ruled out, which happens in a significant number of cases. Their presence is consistent with a clonal hematopoietic neoplasm, eg, MPN, myelodysplastic syndrome, and AML. Thus, they cannot be used to differentiate among the various neoplasms.

Immunophenotyping

Flow cytometric analysis for cell surface and cytoplasmic markers (immunophenotyping) is used to determine lineage for the differential diagnosis of leukemia and lymphoma and to distinguish benign from malignant processes. Such testing can be especially useful when transformation to AML is suspected. When a MPN progresses as reflected by increased aberrant cells, immunophenotyping helps guide therapeutic decisions. Decreases in abnormal marker-positive cells are associated with therapeutic success.

Chronic Myelogenous Leukemia Testing

Diagnosis of CML begins with testing for BCR/ABL1 in symptomatic patients or in those who have MPN-related abnormalities in their CBC (Figure 1). Fluorescence in situ hybridization (FISH) testing provides qualitative results for BCR/ABL1, whereas reverse transcription-PCR (RT-PCR) results are quantitative. Positive results are diagnostic of CML, while negative results eliminate CML. Other MPNs (BCR/ABL1-negative) should then be considered.

Figure 1. Differential diagnosis of the more common MPNs.

Approximately 95% of patients with CML are Ph+, whereas all are positive for BCR/ABL1 by FISH and RT-PCR. This seeming discrepancy can be explained by the presence of a masked Ph, which is not observed by conventional karyotyping but is detected by the molecular tests.2

Imatinib is the first-line therapy recommended for patients with chronic phase CML,26 because it results in the lowest rate (~7%) of disease progression after 6 years of follow-up.27 Bone marrow cytogenetics and quantitation of BCR/ABL1 transcripts are recommended prior to treatment (baseline assessment) and to assess therapeutic response (Table 5).26 The goal of CML therapy is to achieve complete cytogenetic response (CCyR) (ie, the absence of Ph+ metaphase cells) within 18 months of start of therapy.26 For molecular testing, RT-PCR is favored over FISH because BCR/ABL1  mRNA correlates with CCyR, and can be used to monitor the kinetics of leukemia disease burden. Most studies have found a good correlation between blood and marrow PCR values, thus avoiding bone marrow sampling.

As shown in Table 5, the testing performed and the frequency of testing depends on the clinical response to PTK inhibitor therapy. Monitoring begins with testing for the Ph chromosome and quantitating BCR/ABL1 transcripts. Decreasing levels indicate therapeutic success, while increasing levels may require more frequent monitoring and may be associated with an increased risk of therapeutic failure.

Table 5. NCCN Recommendations for Monitoring CML Patients Receiving PTK Inhibitor Therapy26
Clinical Stage BCR/ABL1,
Quantitative PCR
Bone Marrow Karyotype ABL Kinase Domain Mutation Analysis
Initial diagnosis X X Consider if accelerated or blast phase
Patient responding to treatment Every 3 months

6 months

12 months if CCyR not achieved at 6 months

18 months if CCyR not achieved at 12 months

 
Patient achieves CCyR Every 3 to 6 months As needed
Patient not responding to treatmenta
 
    Consider testing to select alternative therapy
Patient has 1 log increase
of BCR/ABL1 transcripts
     

With MMRb

Without MMR

Repeat in 1 - 3 months

 

X

 

Consider testing to select alternative therapy

NCCN, National Comprehensive Cancer Network; CCyR, complete cytogenetic response; CHR, complete hematologic response; MMR, major molecular response.

a CHR not achieved at 3 mos; no or minimal cytogenic response at 6 mos; or no or minor cytogenic response at 12 mos.

b MMR is defined as 3-log reduction of BCR/ABL1 transcript.

Imatinib therapy can result in acquired resistance, resulting from point mutation(s) in the kinase domain (KD) domain of BCR/ABL1 or insertion of a 35-nucleotide segment from intron 8 into the ABL1 KD.28,29 Point mutations in particular may precede or accompany progression to a more aggressive disease.30 ABL1 KD mutation testing is appropriate for patients presenting with advanced disease and for chronic-phase patients with inadequate initial response (Table 5). In addition, mutation testing is indicated when loss of response is apparent (eg, patient shows hematologic relapse, return of Ph+, or an increase in BCR/ABL1 transcripts).26

Depending on the mutation, imatinib resistance can be overcome by increasing the dosage or by changing to second-generation PTK inhibitors, such as dasatinib and nilotinib. KD point mutations such as F311L, F359V, and L387M may be addressed by increasing the dosage, whereas M244V, G250E, and M351T may require switching to a second-generation drug.28 However, the T315I KD mutation is associated with resistance to all 3 of these PTK inhibitors. Molecular modeling suggests that the BCR/ABL135INS mutation will cause resistance similar to the T315I mutation.29 However, the degree of resistance may depend on the relative proportion of mutated vs wild-type BCR/ABL1 expression.29

Both dasatinib and nilotinib have been successfully used in patients with CML who develop acquired resistance to imatinib.31 However, resistance may develop with this second-line treatment, and, if so is usually associated with the emergence of new KD mutations.31

Table 6 summarizes testing used in selecting and monitoring therapy and assessing prognosis for CML and other MPNs.

Table 6. Tests Used in the Management of Patients with MPNs
Assay Select
Therapy
Monitor
Therapy
Assess
Prognosis
CML      

ABL Kinase Domain Mutation in CML

X X X

ABL T315I Mutation in CML

X X X

BCR/ABL1 Kinase Domain Mutation, 35-Nucleotide Insertion

X X X

BCR/ABL1 Gene Rearrangement, Quantitative PCR

  X X

Bone Marrow Histology

  X X

Bone Marrow Chromosome Analysis

X X X

% Blast Cells

X X X
ET      

Bone Marrow Histology

  X X

Bone Marrow Chromosome Analysis

  X  

JAK2 Mutation (V617F) Analysis, Quantitative

    X

Platelet and WBC count

X X X
PV      

Bone Marrow Histology

  X X

Bone Marrow Chromosome Analysis

  X X

Hematocrit and WBC count

X X X

JAK2 Mutation (V617F) Analysis, Quantitative

  X X
PMF      

Bone Marrow Histology

  X X

Bone Marrow Chromosome Analysis

  X X

WBC count, hemoglobin, and % blast cells

  X X
CEL/HES      

Bone Marrow Histology

  X X

Bone Marrow Chromosome Analysis

  X  

Eosinophil Count

  X  

FISH, HES/Leukemia, 4q12 Rearrangement (FIP1L1/PDGFRA)

X   X

% blast cells

    X
SM      

Bone Marrow Histology

  X  

FISH, HES/Leukemia, 4q12 Rearrangement (FIP1L1/PDGFRA)

X   X

KIT Mutation Analysis

X X  

Tryptase

  X  
CNL      

Bone Marrow Histology

  X  

Bone Marrow Chromosome Analysis

  X  

Neutrophil and platelet count, hemoglobin, and % blast cells

  X X

CML, chronic myelogenous leukemia; ET, essential thrombocythemia; PV, polycythemia vera; PMF, primary myelofibrosis; CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; SM, systemic mastocytosis; CNL, chronic neutrophilic leukemia

Essential Thrombocythemia

Although ET is diagnosed mainly by exclusion, a sustained platelet count of 450 x 109/L, increased megakaryocyte proliferation in bone marrow studies, and presence of a JAK2 V617F mutation are consistent with the diagnosis (Table 1). Presence of the JAK2 V617F mutation can also serve to rule out CML, myelodysplastic syndrome (V617F is negative in up to 95% of patients), and non-hematologic cancer but not refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) (V617F positive in ~70%).32-34 On the other hand, absence of a JAK2 mutation should be followed up with chromosome testing to rule out neoplasms such as CML and MDS associated with del(5q) (Figure 1).3

Normal C-reactive protein levels rule out reactive causes of thrombocytosis, which are more common than clonal ET, while PV is ruled out with normal hemoglobin and hematocrit. Fibrotic stage PMF is ruled out by the absence of reticulin and/or collagen fibrosis in bone marrow.

Thrombosis is the most common complication in patients with ET and can lead to death. JAK2 V617F mutation is associated with a ~2-fold increased risk of thrombosis.35 In addition, the frequency of thrombosis and the risk of recurrence of a thrombotic event progressively increase with JAK2 V617F allele burden.35,36

Disease progression to PMF or AML is unusual but can be detected by increased fibrosis in bone marrow or by increases in chromosomal abnormalities, respectively. Laboratory tests used to select and monitor therapy and to assess prognosis for ET are presented in Table 6.

Polycythemia Vera

Increased hemoglobin (>18.5 g/dL in men or >16.5 g/dL in women) is the hallmark of PV diagnosis.

The WHO recommendations for diagnosing PV include ruling out the more common inherited and secondary, acquired erythrocytosis.4 Acquired erythrocytosis can be due to chronic hypoxia, treatment with erythropoietin (EPO) or androgens, or EPO-secreting tumors. Once elevated hemoglobin levels are observed, a positive JAK2 mutation (either V617F or in exon 12) and a subnormal serum EPO level excludes secondary erythrocytosis and inherited polycythemia (see Figure 1). An elevated EPO level rules out PV, while a normal level is inconclusive. Negative JAK2 mutation makes the diagnosis of PV very unlikely but does not rule it out.

A high JAK2 V617F allele burden is associated with increased risk of cardiovascular events in patients with PV. Comparing the highest quartile allele burden with the lowest quartile revealed a 3.6-fold increase in risk of thrombosis.37 The frequency of thrombosis progressively increased with amount of JAK2 V617F allele burden both at diagnosis and during follow-up.37 After 5 years of follow-up post diagnosis, another study indicated that standard risk factors (eg, 60 years of age and previous thrombosis) lost their prognostic value and only JAK2 V617F allele burden predicted subsequent thrombosis.35

Disease progression may manifest with post-polycythemic myelofibrosis or transformation to AML and/or MDS. Assessment of bone marrow fibrosis and chromosome analysis is used to identify these transformations. Additional laboratory tests to select and monitor therapy and to assess prognosis for PV are presented in Table 6.

Primary Myelofibrosis

The classical presentation of PMF is the appearance of a leukoerythroblastic blood smear with teardrop poikilocytosis, anemia, splenomegaly and possibly hepatomegaly due to EMH, and bone marrow fibrosis.5 This picture is characteristic of the fibrotic, advanced stage of the disease. Diagnosis is more complicated in the 20% to 30% of patients who are at the prefibrotic stage, which can resemble PV or ET. Observation of marked atypical forms of megakaryocytes, increased number of neutrophils, and decreased numbers of erythroid precursors in bone marrow confirm a diagnosis of prefibrotic PMF.5

Detection of the JAK2 V617F mutation supports the diagnosis of PMF but does not distinguish between PV, ET, or PMF. Absence of the mutation does not rule out the diagnosis. Detection of a clonal abnormality, which is relatively common in PMF (≈35%), or a MPL mutation also supports the diagnosis. A testing algorithm for the differential diagnosis of PMF is presented in Figure 1.

Table 6 summarizes tests used to monitor therapy and assess prognosis of PMF. A combination of age >65 years, hemoglobin levels <10 g/dL, WBC count >25 x 109/L, 1% circulating blast cells, and the presence of constitutional symptoms predict shortened median survival.38 Although del(20q) or del(13q) confer a survival advantage, typically the presence of an abnormal karyotype is associated with a poor prognosis.38,39

Chronic Eosinophilic Leukemia

Hypereosinophilia (1.5 x 109/L) may be due to reactive eosinophilia, idiopathic hypereosinophilic syndrome (HES), or CEL. The differential diagnosis of CEL and HES begins with the exclusion of all causes of reactive eosinophilia, including parasitic infection, infectious disease, allergic reaction, pulmonary diseases such as hypersensitivity pneumonitis, collagen vascular diseases, and underlying neoplastic disease.6,9 Neoplastic diseases to be excluded include T-cell lymphomas, Hodgkin lymphoma, acute lymphoblastic leukemia/lymphoma, other MPNs, AML, and myelodysplastic syndromes. Once these diagnoses have been excluded, CEL is diagnosed if there is evidence of a clonal myeloid abnormality (eg, the presence of the FIP1L1/PDGFRA fusion gene) or increased number of blast cells (>2% in peripheral blood or >5% in the bone marrow). Figure 2 provides a testing algorithm for the differential diagnosis of hypereosinophilia.

Figure 2. Differential diagnosis of hypereosinophilia.

Table 6 summarizes tests used to select and monitor therapy and assess prognosis in patients with CEL or HES. Patients with idiopathic HES may be pre-leukemic; thus, monitoring is recommended.6

Systemic Mastocytosis

The major diagnostic criterion for SM is the presence of dense multifocal clusters or aggregates of mast cells (15 per aggregate) in a bone marrow biopsy specimen.7 Minor criteria include: 1) abnormal morphology in >25% of mast cells; 2) KIT mutation at codon 816; 3) mast cells coexpressing CD117 and CD2 and/or CD25; and 4) serum tryptase levels persistently >20 ng/mL in the absence of an associated hematologic clonal non-mast cell lineage disease. SM is diagnosed if at least the major criterion plus 1 minor criterion, or at least 3 minor criteria, are met (Table 1). A testing algorithm for SM diagnosis is presented in Figure 3. Diagnostic criteria for variants of SM are described in reference 7.

Figure 3. Differential diagnosis of systemic mastocytosis.

An elevated tryptase level is an important marker of SM but may also be seen in acute and chronic myeloid leukemias, other MPNs, myelodysplastic syndromes, and myelomastocytic leukemia.25

In addition to being a criterion for diagnosis, the KIT D816V mutation confers resistance to imatinib by interfering with the binding of the drug to the catalytic site of the KIT PTK. Conversely, the presence of wild-type KIT, KIT F522C, or the FIP1L1/PDGFRA fusion gene is associated with sensitivity to imatinib.14

Table 6 summarizes tests used to select and monitor therapy and assess prognosis in patients with SM.

Chronic Neutrophilic Leukemia

CNL is diagnosed when the hematologic criteria are met (Table 1), hepatosplenomegaly is present, no evidence of a physiologic neutrophilia is found, and other MPNs and myelodysplastic disorders are ruled out.8 A normal C-reactive protein level rules out inflammation and infection that could produce neutrophilia; however, an elevated level does not necessarily rule out CNL. Negative results for Ph or BCR/ABL1 rule out CML, which also presents with neutrophilia. Other MPNs are ruled out by the absence of their usual hematologic characteristics (Table 1). Furthermore, myelodysplastic disorders are ruled out by the absence of granulocytic dysplasia and myelodysplastic changes in other myeloid lineages. A testing algorithm for CNL diagnosis is presented in Figure 4.

Figure 4. Differential diagnosis of chronic neutrophilic leukemia.

Disease progression may be reflected by transformation to AML, which can be detected by chromosome analysis. A summary of tests used to monitor therapy and assess prognosis of CNL is presented in Table 6.

MPN, Unclassifiable

In 10% to 15% of MPN cases, clinical and laboratory features characteristic of a myeloproliferative disease are present but fail to meet the diagnostic criteria of any one MPN.40 Such patients are either in the early stages of the disease and characteristic features of a particular MPN will develop with time or are in the advanced stages of the disease with marked marrow fibrosis or blastic infiltration. In the former case, reevaluation at intervals of 4 to 6 months is recommended.40

References [return to contents]

  1. Vardiman JW, Brunning RD, Arber DA, et al. Introduction and overview of the classification of the myeloid neoplasms. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:18-30.

  2. Vardiman JW, Melo JV, Baccarani M, et al, Chronic myelogenous leukaemia, BCR/ABL1 positive. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:32-37.

  3. Thiele J, Kvasnicka HM, Orazi A, et al. Essential thrombocythaemia. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:48-50.

  4. Thiele J, Kvasnicka HM, Orazi A, et al. Polycythaemia vera. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:40-43.

  5. Thiele J, Kvasnicka HM, Tefferi A, et al. Primary myelofibrosis. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:44-47.

  6. Bain BJ, Gilliland DG, Vardiman JW, et al. Chronic eosinophilic leukaemia, not otherwise specified. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:51-53.

  7. Horny H-P, Metcalfe DD, Bennett JM, et al. Mastocytosis. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:54-63.

  8. Bain BJ, Brunning RD, Vardiman JW, et al. Chronic neutrophilic leukaemia. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:38-39.

  9. Tefferi A, Barbui T. bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment. Mayo Clin Proc. 2005;80:1220-1232.

  10. Bain BJ, Gilliland DG, Horny H-P, et al. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:68-73.

  11. Albitar M. Myeloproliferative diseases: molecular genetics. In: Encyclopedia of Life Sciences. New York, NY: John Wiley & Sons, Ltd; 2005:1-6.

  12. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459-468.

  13. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007;21:1960-1963.

  14. Pancrazzi A, Guglielmelli P, Ponziani V, et al. A sensitive detection method for MPLW515L or MPLW515K mutation in chronic myeloproliferative disorders with locked nucleic acid-modified probes and real-time polymerase chain reaction. J Mol Diagn. 2008;10:435-441.

  15. Vainchenker W, Delhommeau F, Constantinescu SN, et al. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;118:1723-1735.

  16. Cortes J, Kantarjian H. Beyond chronic myelogenous leukemia: potential role for imatinib in Philadelphia-negative myeloproliferative disorders. Cancer. 2004;100:2064-2078.

  17. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.

  18. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162-2168.

  19. Lee JW, Kim YG, Soung JH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene. 2006;25:1434-1436.

  20. Ma W, Kantarjian H, Zhang X, et al. Higher detection rate of JAK2 mutation using plasma. Blood. 2008;111:3906-3907.

  21. Ma W, Kantarjian H, Verstovsek S, et al. Hemizygous/homozygous and heterozygous JAK2 mutation detected in plasma of patients with myeloproliferative diseases: correlation with clinical behavior. Br J Haematol. 2006;134:341-350.

  22. Ma W, Kantarjian H, Zhang X, et al. Mutation profile of JAK2 transcripts in patients with chronic myeloproliferative neoplasias. J Mol Diagn. 2009;11:49-53.

  23. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:1140-1151.

  24. Ding J, Komatsu H, Wakita A, et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood. 2004;103:4198-4200.

  25. Patnaik MM, Rindos M, Kouides, et al. Systemic mastocytosis: a concise clinical and laboratory review. Arch Pathol Lab Med. 2007;131:784-791.

  26. National Comprehensive Cancer Network clinical practice guidelines in oncology � v.2.2010: chronic myelogenous leukemia. Available at: http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf.
    Accessed December 30, 2009.

  27. Hochhaus A, O�Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054-1061.

  28. Jabbour E, Soverini S. Understanding the role of mutations in therapeutic decision making for chronic myeloid leukemia. Semin Hematol. 2009;s22-s26.

  29. Lee T-S, Ma W, Zhang X, et al. BCR/ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations. Mol Cancer Ther. 2008;7:3834-3841.

  30. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23:4100-4109.

  31. Jabbour E, Jones D, Kantarjian HM, et al. Long-term outcome of patients with chronic myeloid leukemia treated with second generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood. 2009;114:2037-2043.

  32. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.

  33. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162-2168.

  34. Szpurka H, Tiu R, Murugesan G, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood. 2006;108:2173-2181.

  35. Carobbio A, Finazzi G, Antonioli E, et al. JAK2 V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol. 2009;37:1016-1021.

  36. DeStefano V, Za T, Rossi E, et al. Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation. Ann Hematol. 2009; prepublished online July 7, 2009.

  37. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2 V617F allele burden. Leukemia. 2007;21:1952-1959.

  38. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.

  39. Tefferi A. Prognostic relevance of cytogenetic abnormalities in primary myelofibrosis: comparison of recent reports from Japan, the Mayo Clinic, and MD Anderson Cancer Center. Eur J Haematol. 2009; 83:290-291.

  40. Kvasnicka HM, Bain BJ, Thiele J, et al. Myeloproliferative neoplasm, unclassifiable. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:64-65.


 

 Content reviewed 07/2013

top of page

* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.