Myeloproliferative neoplasm differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2] Zahir Ali Shaikh, MD[3] Mohamad Alkateb, MBBCh [4] Shyam Patel [5]

Overview

Myeloproliferative neoplasm must be differentiated from myelodysplastic syndrome, acute myelogenous leukemia, acute lymphoblastic leukemia, Waldenstrom's macroglobulinemia, and lymphoproliferative disorder. Each of these conditions has a unique set of causes, laboratory abnormalities, physical exam findings, and investigations.

Differentiating Myeloproliferative Neoplasm from other Diseases

ABBREVIATIONS

EPO: Erythropoietin, FISH: Fluorescence in situ hybridization, Hb: Hemoglobin, LAD: Leukocyte alkaline dehydrgenase, LAP: Leukocyte alkaline phosphatase, LDH: Lactate dehydrogenase, LFTs: Liver function tests, NL: Normal, PCR: Polymerase chain reaction, Plt: Platelet, PUD: Peptic ulcer disease, RFTs: Renal function tests, WBCs: White blood cells.

Disease Clinical manifestations Diagnosis Other features
Symptoms Signs CBC & Peripheral smear Bone marrow biopsy Other investigations
WBCs Hb Plt
WBC Blasts Left
shift
Baso-
phils
Eosino-
phils
Mono-
cytes
Chronic myeloid leukemia
(CML)[1][2]
<2% + NL
Polycythemia vera
(PV)[3][4][5][6]
  • Constitutional
NL or ↑ None - ↑ or ↓ NL or ↑ NL ↑↑ NL
  • Hypercellularity for age with tri-lineage growth
Primary myelofibrosis (PMF)[7][8][9][10] Erythroblasts - Absent NL NL
  • Variable with fibrosis or hypercellularity
Essential thrombocythemia (ET)[11][12][13]

NL or ↑

None

-

↓ or absent

NL

NL

↑↑

  • Normal/Hypercellular
Disease Symptoms Sign WBC Blasts Left
shift
Baso-
phils
Eosino-
phils
Mono-
cytes
Hb Plt Bone marrow biopsy Other investigations Other features
Myelodysplastic
/myeloproliferative
neoplasms
(MDS/MPN)
Chronic myelomonocytic leukemia (CMML)[14]
[15][16]
< 20% NL ↑↑
  • Overlapping of both, MDS and MPN
  • Absolute monocytosis > 1 × 109/L (defining feature)
  • MD-CMML:WBC ≤ 13 × 109/L (FAB)
  •  MP-CMML:WBC > 13 × 109/L (FAB)
Atypical chronic myeloid leukemia (aCML), BCR-ABL1-[17][18] <20% + <2% of WBCs N/A N/A
Juvenile myelomonocytic leukemia (JMML)[19][20] N/A N/A N/A
MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)[21][22][23]
  • Variable
NL or ↑ NL - NL N/A N/A
Disease Symptoms Sign WBC Blasts Left
shift
Baso-
phils
Eosino-
phils
Mono-
cytes
Hb Plt Bone marrow biopsy Other investigations Other features
Chronic neutrophilic leukemia (CNL)[24][25][26] Minimal + NL NL NL
Chronic eosinophilic leukemia,
not otherwise specified
(NOS)[27][28][29][30]
Present + ↑↑
MPN,
unclassifiable
Variable ± ↑ or ↓ ↑ or ↓ ↑ or ↓
Mastocytosis[31][32][33][34]
  • Constitutional
None - NL NL ↓ or ↑
Myeloid/lymphoid neoplasms
with eosinophilia and rearrangement
of PDGFRA, PDGFRB, or FGFR1,
or with PCM1-JAK2[35][36][37][38]
NL - NL NL
  • FISH shows t(8;13) and t(8;22)
Disease Symptoms Sign WBC Blasts Left
shift
Baso-
phils
Eosino-
phils
Mono-
cytes
Hb Plt Bone marrow biopsy Other investigations Other features
B-lymphoblastic leukemia/lymphoma[39][40] NL or ↑ >25% N/A ↑ or ↓ ↑ or ↓ ↑ or ↓
Myelodysplastic syndromes
(MDS)[41][42]
Variable -
  • Leukemia transformation
  • Acquired pseudo-Pelger-Huët anomaly
Acute myeloid leukemia (AML)
and related neoplasms[43][44]
NL or ↑ N/A ↑ or ↓ ↑ or ↓ ↑ or ↓

with dysplasia

Blastic plasmacytoid
dendritic cell neoplasm
[45][46][47][48]
NL NL NL NL
Disease Symptoms Sign WBC Blasts Left
shift
Baso-
phils
Eosino-
phils
Mono-
cytes
Hb Plt Bone marrow biopsy Other investigations Other features
T-lymphoblastic leukemia/
lymphoma
T-lymphoblastic leukemia/
lymphoma[49][50][51]
>25% blasts (Leukemia)

<25% blasts (Lymphoma)

± ↑ or ↓ ↑ or ↓ ↑ or ↓
  • Hypercelluarity with increased T cells precursors
Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymph[52] ± ↑ or ↓ ↑ or ↓ ↑ or ↓
  • N/A
Provisional entity: Early T-cell precursor lymphoblastic leukemia[53][54] ± ↑ or ↓ ↑ or ↓ ↑ or ↓
  • Hypercelluarity with increased T cells precursors

Differentiating Myeloproliferative neoplasm from other Diseases

Characteristic Causes Physical examination Laboratory abnormalities Therapy Other associations
Myeloproliferative neoplasm
  • JAK2 mutation
  • CALR mutation
  • MPL mutation
  • BCR-ABL translocation
  • CSF3R mutation
  • SETBP1 mutation
  • PDGFRA or PDGFRB rearrangement
  • Splenomegaly
  • Hepatomegaly
  • Evidence of infection
  • Pallor
  • Ruxolitinib
  • Hydroxyurea
  • Anagrelide
  • Imatinib
  • Midostaurin
  • Stem cell transplant
  • Variable features based on the subtype of myeloproliferative neoplasm
Myelodysplastic syndrome
  • Prior exposure to alkylating agents
  • Prior exposure to topoisomerase II inhibitors
  • Age-related changes in hematopoietic stem cells
  • Deletion of chromosome 5q or 7
  • Gain of chromosome 8
  • Lenalidomide
  • Decitabine
  • Azacitidine
  • Erythropoiesis-stimulating agents (ESAs)
  • Granulocyte colony-stimulating factor (G-CSF)
  • Transfusion support
  • Stem cell transplant for high-risk myelodysplastic syndrome
  • Age-related changes in the bone marrow contribute to myelodysplastic syndrome
Acute myeloid leukemia
  • Chromosomal instability
  • Sporadic mutations
  • Prior exposure to benzene
  • Prior exposure to alkylating agents
  • Prior exposure to topoisomerase II inhibitors
  • Germline RUNX1 mutation
  • Pyrexia
  • Evidence of infection
  • Pallor
  • Mucosal bleeding
  • Bruising
  • Cytarabine
  • Anthracycline
  • Enasidenib
  • Liposomal daunorubicin plus cytarabine
  • Gemtuzumab ozogamycin
  • Midostaurin
  • Stem cell transplant
  • Variable prognosis based on cytogenetic and molecular profile
  • Four new FDA-approved therapies became available in 2017
Acute lymphoblastic leukemia
  • Chromosomal instability
  • Sporadic mutations
  • Neurologic deficits
  • Pallor
  • Lymphadenopathy
  • Anemia
  • Thrombocytopenia
  • Neutropenia
  • Elevated LDH
  • Elevated uric acid
  • Elevated phosphorus
  • Elevated potassium
  • Low calcium
  • Greater than 20% lymphoblasts on bone marrow aspirate
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)[56]
  • R-HyperCVAD (inclusion of rituximab)
  • Peg-asparaginase
  • Intrathecal methotrexate
  • Intrathecal cytarabine
  • Blinatumomab (bispecific T cell engager)
  • Inotuzumab ozogamycin (anti-CD22 antibody)
  • Tisagenlecleucel (chimeric antigen receptor T (CAR-T) cell therapy)
  • Stem cell transplant
  • Sanctuary sites include the central nervous system (CNS) and testes[57]
Waldenstrom's macroglobulinemia
  • MYD88 mutation
  • Lymphoplasmacytic cell proliferation
  • Hepatomegaly
  • Splenomegaly
  • Retinal vascular dilation and thrombosis
  • Decreased visual acuity
  • Headache
  • Elevated immunoglobulin M (IgM) paraprotein
  • Presence of M-spike on protein electrophoresis
  • Elevated serum free light chains (kappa and lambda)
  • Increased serum viscosity
  • MYD88 mutation testing is standard-of-care
  • Plasmapheresis should be initiated if symptoms of hyperviscosity are present
  • Typically does not require stem cell transplant
Lymphoproliferative disorder[58]
  • Elevated lymphocyte count with presence of clonality
  • Anemia
  • Thrombocytopenia
  • Neutropenia
  • Variable based on the etiology
  • Cytotoxic chemotherapy
  • Antiviral agents
  • Biologic therapy with anti-CD20 monoclonal antibodies
  • Tapering immunosuppressive medications (for post-transplant lymphoproliferative disorder)
  • Can be due to a variety of causes
  • Variable prognosis

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