Myelodysplastic syndrome 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] Nawal Muazam M.D.[4] Amandeep Singh M.D.[5]

Overview

Myelodysplastic syndrome must be differentiated from other diseases that cause anemia, neutropenia, and thrombocytopenia, such as: aplastic anemia, fanconi anemia, pure red cell aplasia, Shwachman-Diamond syndrome, paroxysmal nocturnal hemoglobinuria, parovirus B19 infection, and vitamin B12 defeciency

Differentiating Myelodysplastic Syndrome 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
Myelodysplastic syndromes
(MDS)[1][2]
Variable -
  • Leukemia transformation
  • Acquired pseudo-Pelger-Huët anomaly
Chronic myeloid leukemia
(CML)[3][4]
<2% + NL
Polycythemia vera
(PV)[5][6][7][8]
  • Constitutional
NL or ↑ None - ↑ or ↓ NL or ↑ NL ↑↑ NL
  • Hypercellularity for age with tri-lineage growth
Primary myelofibrosis (PMF)[9][10][11][12] Erythroblasts - Absent NL NL
  • Variable with fibrosis or hypercellularity
Disease Symptoms Sign WBC Blasts Left
shift
Baso-
phils
Eosino-
phils
Mono-
cytes
Hb Plt Bone marrow biopsy Other investigations Other features
Essential thrombocythemia (ET)[13][14][15]

NL or ↑

None

-

↓ or absent

NL

NL

↑↑

  • Normal/Hypercellular
Myelodysplastic
/myeloproliferative
neoplasms
(MDS/MPN)
Chronic myelomonocytic leukemia (CMML)[16]
[17][18]
< 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-[19][20] <20% + <2% of WBCs N/A N/A
Juvenile myelomonocytic leukemia (JMML)[21][22] N/A N/A N/A
MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)[23][24][25]
  • 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)[26][27][28] Minimal + NL NL NL
Chronic eosinophilic leukemia,
not otherwise specified
(NOS)[29][30][31][32]
Present + ↑↑
MPN,
unclassifiable
Variable ± ↑ or ↓ ↑ or ↓ ↑ or ↓
Mastocytosis[33][34][35][36]
  • Constitutional
None - NL NL ↓ or ↑
Myeloid/lymphoid neoplasms
with eosinophilia and rearrangement
of PDGFRA, PDGFRB, or FGFR1,
or with PCM1-JAK2[37][38][39][40]
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[41][42] NL or ↑ >25% N/A ↑ or ↓ ↑ or ↓ ↑ or ↓
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 myelodysplastic syndrome from other causes of macrocytic anemia

Disease Genetics Clinical manifestation Lab findings
History Symptoms Signs Hemolysis Intrinsic/Extrinsic Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Iron studies Specific finding on blood smear
Serum iron Serum Tfr level Transferrin or TIBC Ferritin Transferrin saturation
Folate deficiency[55]
  • Impaired DNA synthesis
Anisochromic Macrocytic Nl Nl
Vitamin B12 deficiency[56] Anisochromic Macrocytic Nl Nl
Orotic aciduria[57]
  • Neurological manifestation
Anisochromic Macrocytic Nl Nl NA
Fanconi anemia[58]
  • Significant for bilateral short thumbs
Anisochromic Macrocytic Nl Nl
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/Extrinsic Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Diamond-Blackfan anemia[59] Mutations in:
  • RPL5
  • RPL11
  • RPL35A
  • RPS7
  • RPS10
  • RPS17
  • RPS19
  • RPS24
  • RPS26
Anisochromic Macrocytic Nl Nl Nl NA
Liver disease[60]
  • Hepatitis
  • Binge drinking
  • Gall bladder disease
Anisochromic Macrocytic Nl Nl
Alcoholism[61] Anisochromic Macrocytic Nl Nl
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/Extrinsic Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear

Differentiating myelodysplastic syndrome from other causes of thrombocytopenia

Condition Etiology Mechanism Inherited Acquried Clinical manifestations Para−clinical findings Gold standard Associated findings
Demography History Symptoms Signs
Lab Findings
Fever Rash Bleeding BP Splenomegaly Jaundice Other CBC PBS Bone marrow exam Other
Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Plt HB WBC
Bone marrow disorders Myelodysplastic syndromes[62]
  • Unknown
  • Mutation
+ ± + Elderly Exposure to + Petechiae, purpura, diffuse erythematous rash + Nl + + Nl Bone marrow examination + clinical manifestation
Aplastic anemia[63] + ± ± Biphasic (the young and the elderly) + Nl
  • Elevated PT/PTT
Bone marrow examination +

laboratory findings

Acute leukemia[64][65] + + ± ± AML in adults
  • Exposure to chemicals
  • Radiation
  • Pre-existent blood disorders
± Petechiae + Nl ±
  • Blast cells
Bone marrow examination
Paroxysmal nocturnal hemoglobinuria (PNH)[66]
  • Mutations
+ + + Any age

(usually younger adults)

Nl ↓/Nl ↓/Nl
  • Hypocellular marrow in certain stages of the disease
Flow cytometry
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings
Thrombotic microangiopathy (TMA) Thrombotic thrombocytopenic purpura (TTP)[67]
  • Deficiency of, or antibodies to, the metalloprotease ADAMTS13
+ ± + Any age
  • Neurologic manifestations
  • Fatigue due to anemia
+ Petechiae Not common Nl or ↑ + Nl

or ↑

  • Fragmented RBCs
NA Laboratory findings
Hemolytic uremic syndrome (HUS)[68] + ± + Children
  • Exposure to contaminated water or milk
  • Consuming undercooked ground beef
+ Petechiae + Nl

or ↑

  • Fragmented RBCs
NA Laboratory findings
DIC[69][70]
  • Overstimulation of the coagulation system
+ + + Any age + + + + ↓↓ Clinical manifestation + laboratory findings
Nutrient deficiencies Folate, vitamin B12, copper deficiencies[71][72]
  • Decreased platelet production
+ + Any age
  • Malnutrition
  • Alcohol use
Nl Nl Nl Laboratory findings
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings
Congenital platelet disorders[73][74][75] MYH9-related disorders[76] + + Any age, very rare
  • Positive family history
+ Nl Nl
  • Döhle body-like inclusions in peripheral blood neutrophils
NA Nl Genetic study
Bernard-Soulier syndrome[77]
  • Absence of Gp Ib-IX-V
+ + Children, rare
  • Positive family history
+ Nl Nl Nl Nl Flow cytometry
Gray platelet syndrome[78] + + Rare
  • Positive family history
+

Mucocutaneous

Nl + Nl Nl Nl Genetic study
Wiskott-Aldrich syndrome[79] + + Rare
  • Positive family history
+ Nl Bloody diarrhea Nl Nl Nl Genetic study
Thrombocytopenia with absent radius (TAR) syndrome[80] + + Children
  • Positive family history
+ + Nl Nl Nl or ↑ Nl Evidence of absent radius

+

Laboratory findings

  • Cow's milk allergy
  • Various other anomalies
Fechtner syndrome[81]
  • Mutation of chromosome 22q11-13
+ + Children
  • Positive family history

petechia

+ Mucocutaneous Nl
  • Hearing loss
  • Eye abnormalities
Nl Nl or ↑ NA Clinical manifestation + genetic study
Von Willebrand disease[82]
  • VWF deficiency/dysfunction
+ + Rarely More common with O blood type
  • Positive family history
+ Nl/ ↓ Nl/↓ Nl NA Laboratory findings
  • Lifelong bleeding disorder
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings
ITP[83] + + + Any age

petechia

+ Mucocutaneous Nl ↓↓↓ Nl Nl Nl Nl Diagnosis of exclusion
  • Spontaneous remission
Systemic lupus erythematosus[84] + + Young women, more prevalent in Africans and Asians + Malar rash, generalized maculopapular rash, discoid rash +

Hemoptysis

Nl or ↑ + + Clinical manifestation + serology
Antiphospholipid syndrome[85]
  • Autoantibody-mediated syndrome
+ + + Middle aged women, more in African American and Hispanic population Nl Nl Clinical manifestation + repeated positive tests of aPL
Felty's syndrome[86] + + ± + Rare, young women Nl +
  • Lymphadenopathy
Nl Nl Clinical manifestation
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings
Bacterial infections Sepsis[87] + + + Any + ± Nl to ↓ ± ↓/↑ Nl ↑↑ NA
  • Elevated PT/PTT
Clinical manifestation + culture
  • Associated with ↑ mortality
Helicobacter pylori[88]
  • Immune thrombocytopenia
+ + Any Nl Nl Nl NA Nl Clinical manifestation + culture
Tick-borne infection[89]
  • Immune thrombocytopenia
+ + Endemic area like China, Japan, and Korea
  • Being bitten by a tick
+ ± Nl to ↓ ± ± Nl NA PCR
Viral infections HIV[90]
  • Immune thrombocytopenia
+ + + + Any
  • High risk behaviors
  • Close contact
+ ± Nl to ↓ ± ± Isolation of HIV
Other viruses such as rubella, mumps, varicella, parvovirus, hepatitis C, & Epstein-Barr virus[91]
  • Immune thrombocytopenia
+ + Any
  • High risk behaviors
  • Close contact
+ Nl ± ± Clinical manifestation + lab tests
Parasitic infections Malaria[92]
  • Unknown
  • Immune thrombocytopenia
+ + Endemic area
  • Being bitten by a mosquito
+ ± Nl to ↓ ± ± Clinical manifestation + microscopic examination of blood smear
Babesiosis[93]
  • Unknown
  • Immune thrombocytopenia
+ + Rare + ± Nl to ↓ ± ± Clinical manifestation + microscopic examination of blood smear
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings
Antibiotics/

Antiepileptic[94]

  • Occurrence of drug-dependent, platelet-reactive antibodies
+ + + Any
  • Drug ingestion or injection
Nl ↓↓ Nl NA Nl Clinical manifestation + exclusion of the other causes NA
Heparin-induced thrombocytopenia[95]
  • Anti-heparin/PF4 antibody
+ + Any
  • Heparin injection
  • Necrotic skin lesions
Nl Nl Nl NA Nl ELISA
Cytotoxic chemotherapy[96] + + Patients with malignancy
  • Drug ingestion or injection
  • Cancer
Nl
  • Megakaryocytic hypoplasia or aplasia
Clinical manifestation + exclusion of the other causes
Radiation therapy[97] + + Patients with malignancy + Nl
  • Megakaryocytic hypoplasia or aplasia
Clinical manifestation + exclusion of the other causes
Chronic liver disease[98] + + Any + + + Nl NA Biopsy
Portal hypertension[99] + + Any + + + Nl NA
  • Elevated PT/PTT
Clinical manifestation
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings
Giant capillary hemangioma (Kasabach-Merritt syndrome)[100][101] + + Infants Intralesional bleeding Nl Visceral hemangiomas ↓↓ ↓↓ Nl Normocytic normochromic erythrocytes and markedly reduced platelets Normal erythropoiesis, myelopoiesis, and megakaryocytic hyperplasia Biopsy
  • Kaposiform hemangioendothelioma
  • Tufted angioma
Cardiopulmonary bypass[102] + + Elderly + Nl or ↑ Nl Normocytic normochromic erythrocytes and markedly reduced platelets NA Clinical manifestation
Alcohol[103] + + + Any Nl + + Cytopenia, macrocytosis Cytopenia, macrocytosis
  • Elevated PT/PTT
Clinical manifestation
Post-transfusion purpura[104][105] + + Women + ↓↓↓ Nl Nl NA Nl Positive circulating alloantibody to a common platelet antigen
  • Severe but rare reaction
Gestational thrombocytopenia[106]
  • Might be physiologic adaptation of pregnancy
+ Pregnant women
  • Positive history of mild thrombocytopenia
Nl Nl Nl Nl NA Nl Diagnosis of exclusion
  • Self-limited condition
HELLP syndrome[107][108]
  • Unknown
+ + Pregnant > 25 years + + Nl Schistocytes NA Proteinuria Lab abnormalities
Idiopathic cyclic thrombocytopenia[109] + + + Females with the median age of onset 35 years
  • Misdiagnosed as ITP with uniformly poor responses
Minor mucocutaneous bleeding Nl Nl Nl Reduced platelets and megakaryocytes Megakaryocytic hypoplasia or aplasia Nl Diagnosis of exclusion
Pseudothrombocytopenia[110] + Rare Collected sample in EDTA anticoagulant Nl Nl Nl Low platelet count and platelet clumps Low platelet count and platelet clumps Nl Repeat collecting sample in a heparin tube Nl
Condition Etiology Decreased platelet production Platelet destruction in blood Platelet destruction in spleen Inherited Acquried Demography History Fever Rash Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam UA Gold standard Associated findings

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