Myeloproliferative neoplasm differential diagnosis

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)		Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<2%	+	↑	↑	↑	↓	NL	Hypercellurarity with ↑ granuloscytosis and ↓ erythrocytosis Fibrosis	FISH for t(9;22)(q34;q11.2) Reverse transcriptase quantitative PCR (RQ-PCR) for BCR-ABL	Granulocytic dysplasia is minimal/absent May present with blast crisis Absolute leukocytosis (median of 100,000/µL) Classic myelocyte bulge thrombocytopenia indicates advanced stage
Polycythemia vera (PV)		Constitutional Thromboembolism and bleeding Pruritus after a warm bath PUD related	Facial ruddiness Related to underlying cause Splenomegaly Renal bruit	NL or ↑	None	-	↑ or ↓	NL or ↑	NL	↑↑	NL	Hypercellularity for age with tri-lineage growth Myelofibrosis (in up to 20% of patients)	Radioisotope studies Serum EPO levels LFTs RFTs Imaging studies ↓ Serum ferritin ↓ Folate levels ↑↑ B12 levels	May transform into myelofibrosis or leukemia
Primary myelofibrosis (PMF)		Constitutional Anemia related Bleeding Infection Abdominal Pain	Hepatosplenomegaly Petechiae & ecchymoses Abdominal distension Lymphadenopathy	↓	Erythroblasts	-	Absent	NL	NL	↓	↓	Variable with fibrosis or hypercellularity	JAK2 mutation CALR mutation MPL mutation ↑ LAP ↑ LAD ↑ Uric acid ↑ B12 levels	Bone marrow aspiration shows a dry tap Variable with leukocytosis or leukopenia
Essential thrombocythemia (ET)		Headache Dizziness Visual disturbances Priapism Acute chest pain	Splenomegaly Skin bruises	NL or ↑	None	-	↓ or absent	NL	NL	↓	↑↑	Normal/Hypercellular	JAK2 mutation CALR mutation MPL mutation	Thrombosis Hemorrhage Pregnancy loss
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)	Constitutional Anemia related Bleeding Infections Bone pain Leukemia Cutis	Organomegaly Bruising	↑	< 20%		NL	↑	↑↑	↓	↓	Myelodysplastic and myeloproliferative feature	Cytogenetic analysis Flow cytometry ↑ LDH	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-	Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<20%	+	<2% of WBCs	N/A	N/A	↓	↓	Granulocytic hyperplasia with prominent dysplasia	Cytogenetic analysis Flow cytometry	Granulocytic dysplasia is prominent Absence of BCR-ABL or PDGFRA, PDGFRB, or FGFR1 rearrangements WBC > 13 × 109/L
	Juvenile myelomonocytic leukemia (JMML)	Infections Anemia related	Hepatosplenomegaly Lymphadenopathy Rash	↑	↑	N/A	N/A	N/A	↑	↓	↓	Hypercelluar with ↑ myeloid cells in stages of maturation	Cytogenetic analysis Flow cytometry ↓ Serum Iron ↑ B12 levels	Polyclonal hypergammaglobulinemia
	MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)	Constitutional Anemia related Thrombosis	Variable	NL or ↑	NL	-	NL	N/A	N/A	↓	↑	Hypercellularity with dyserythropoiesis and increased megakaryocytes	Cytogenetic analysis Flow cytometry ↑ Serum Iron	Large atypical megakaryocytes Ringed sideroblasts SF3B1 mutation
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)		Asymptomatic Constitutional symptoms Bleeding Infection	Splenomegaly Heptomegaly Purpura Anemia related	↑	Minimal	+	NL	NL	NL	↓	↓	Uniforme and intense hypercellularity with minimal to none fibrosis Neutrophil toxic granulations and Dohle bodies	FISH Imaging for hepatosplenomegaly ↑ LDH ↑ B12 levels	Associationed with polycythemia vera and plasma cell disorders Leukocytosis with chronic neutrophilia
Chronic eosinophilic leukemia, not otherwise specified (NOS)		Constitutional Rash Rhinitis Gastritis Thromboembolism related	Hypertension Eczema, mucosal ulcers, erythema Angioedema Ataxia Anemia Lymphadenopathy Hepatosplenomegaly	↑	Present	+	↑	↑↑	↑	↓	↓	Hypercelluar with ↑ eosinophilic precursors, ↑ eosinophils, and atypical mononuclear cells	FISH Cytogenetic analysis of purified eosinophils and X-chromosome inactivation analysis ↑ B12 levels ↑ LDH	Heart failure Lung fibrosis Encephalopathy Erythema annulare centrifugam
MPN, unclassifiable		Similar to other myeloproliferative neoplasms	Similar to other myeloproliferative neoplasms	↑	Variable	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↑	↑ megakaryocyte proliferation with variable hypercellularity in granulocytic or erythrocytic cell lines	May resemble other myeloproliferative neoplasms	Similar to other myeloprolifeartive neoplasms but do not fulfil the criteria to be classified to a specific type
Mastocytosis		Constitutional Pruritus & Flushing Urticaria & Blisters Hypotension & PUD Bleeding Bronchoconstriction	Mastocytosis exanthema Blistering Swelling Lymphadenopathy Bleeding Fibrosis	↑	None	-	NL	↑	NL	↓	↓ or ↑	Multifocal dense infiltrates of mast cells with atypical morphology in >25 %	Cytogenetic analysis for c-KIT receptor mutations Serum tryptase levels 24-hour urine test for N-methyl histamine and 11-beta-prostaglandine ↑ Alkaline phosphatase ↑ LDH	Skin most commonly involved Susceptibility to anaphylaxix Osteoporosis
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2		Asymptomatic Constitutional Rash Cough & breathlessness Peripheral neuropathy/ encephalopathy	Fever Lymphadenopathy	↑	NL	-	NL	↑	↑	NL	↓	Myeloid expansion with eosinophilia	FISH shows t(8;13) and t(8;22)	May present or evolve into acute myeloid or lymphoblastic leukemia Leukocytosis (30 - 59 × 109/L
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		Constitutional Anemia related Bleeding Infection Bone pain	Pallor Petechiae Organomegaly Lymphadenopathy	NL or ↑	>25%	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Hypercellular with blast infilterationwith or without myelodysplasia	Cytogenetic analysis Flow cytometry FISH Auer bodies	May present as extramedullary disease (Myeloid sarcoma)
Myelodysplastic syndromes (MDS)		Constitutional Anemia related Bleeding Infection	Pallor Petechiae Organomegaly	↓	Variable	-	↓	↓	↓	↓	↓	Hypercellular/ normocellular bone marrow with dysplastic changes	Cytogenetic analysis Flow cytometry Macro-ovalocytes Basophilic stippling Howell-Jolly body	Leukemia transformation Acquired pseudo-Pelger-Huët anomaly
Acute myeloid leukemia (AML) and related neoplasms		Constitutional Anemia related Bleeding Bone pain Joint pain Infections	Infection related Pallor Leukemia cutis Bruising & petechiae Lymphadenopathy Hepatosplenomegaly	NL or ↑	↑	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Increased immaturemyeloid cells with dysplasia	Cytogenetic analysis Flow cytometry FISH ↑ Potassium ↑ Uric acid ↑ Phosphorus ↓ Calcium ↑ LDH	Common in Down syndrome
Blastic plasmacytoid dendritic cell neoplasm		Cutaneous symptoms (brown/purple nodular lesions) on face, scalp, lower limb & trunk	Brown/violaceous bruise like lesions Lymphadenopathy Splenomegaly	NL	↑		NL	NL	NL	↓	↓	Malignant cells	Immunohistochemistry or flow cytometry for CD4 & CD56 Neutropenia	TdT expression positive May develop chronic myelomonocytic leukemia (CMML)
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	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	>25% blasts (Leukemia) <25% blasts (Lymphoma)	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysisFlow cytometry FISH ↑ LDH Positive for TdT	May involve brain, skin, and testes.
	Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymph	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	N/A	Cytogenetic analysis FISH Flow cytometry ↑ LDH	Similar to T-cell lymphoblastic leukemia but may have more aggressive clinical course. Diagnosis is usually based on presence of CD56 expression, and T-cell-associated markers such as CD2 and CD7. B-cell markers are absent.
	Provisional entity: Early T-cell precursor lymphoblastic leukemia	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysis FISH Flow cytometry ↑ LDH	Similar to T-cell lymphoblastic leukemia but is more aggressive clinically and cell are characterized by cytometry as CD1a−, CD8−, CD5− (dim), and positivity for 1 or more stem cell or myeloid antigens. Gene expression indicates more immature cells as compared to other subtypes of T-cell neoplasms.

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	Elevated hemoglobin Elevated white blood cell count Elevated platelet count Elevated eosinophil and/or neutrophil count Bone marrow fibrosis	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	Mucosal bleeding Petechiae Ecchymoses Evidence of infection Pallor	Dysplasia in at least 10% of cells of at least 1 cell line Low white blood cell count Anemia Neutropenia Thrombocytopenia	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	Anemia Thrombocytopenia Neutropenia Elevated LDH Elevated uric acid Elevated phosphorus Elevated potassium Low calcium Greater than 20% myeloblasts on bone marrow aspirate	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) 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
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	Rituximab Ibrutinib Plasmapheresis	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	Epstein-Barr virus (EBV) Human immunodeficiency virus (HIV) Human T cell lymphotrophic virus-1 (HTLV-1) Post-transplant status (post-transplant lymphoproliferative disorder (PTLD)) Chromosomal instability Sporadic mutations Rheumatologic disease	Lymph node enlargement Splenomegaly Hepatomegaly	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