Chronic myeloid neoplasms
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Table of Contents - Chronic myeloid neoplasms
Myelodysplastic syndromes (MDS): general, childhood, classification, refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, 5q- syndrome, therapy related, unclassified, arsenic toxicity
Myeloproliferative neoplasms (MPN): general, WHO classification, chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, mast cell disease, unclassifiable
MDS/MPN: general, WHO classification, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical CML, unclassifiable
Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1: PDGFRA, PDGFRB, FGFR1
Miscellaneous: transient myeloproliferative disorder of Down’s syndrome
American Journal of Clinical Pathology (AJCP) [free full text and no registration after 1 year]; January 1997 to January 2008
American Journal of Surgical Pathology (AJSP); August 1979 to January 2008
Archives of Pathology and Laboratory Medicine (Archives) [always free full text and no registration]; January 1997 to January 2008
Biomed Central [always free full text and no registration]; 16 August 1999 to 9 January 2008
Human Pathology (Hum Path); January 1997 to January 2008
Modern Pathology (Mod Path) [free full text and no registration after 1 year]; January 1988 to January 2008
Rosai, J: Ackerman’s Surgical Pathology (9th Ed), Mosby, 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Brunning: Tumors of the Bone Marrow (AFIP Atlas of Tumor Pathology, Series 3, Vol 9, 1994)
Websites (images): ASH image bank
Journal search terms: myelodysplasia, myeloproliferative and each topic below
Please refer to these primary references for more detailed discussions and photographs
Myelodysplastic syndrome - chronic myeloid neoplasms chapter
Myelodysplastic syndrome (MDS) - general
Clonal disorders of multipotent bone marrow stem cells with ineffective or disorderly hematopoiesis
Note: myelodysplasia also means abnormal development of spinal cord
“Ineffective hematopoiesis” means cytopenia (anemia most common) despite a cellular/hypercellular marrow with normal or increased precursors for one or more cell lines; cytopenias may be due to aberrant expression of various cytokines and accelerated apoptosis
15K new cases in US each year (Cancer 2008 Jan 10 [Epub ahead of print])
25-45% of patients develop acute myeloid leukemia (AML)
Must rule out MDS in any adult with unexplained cytopenias or monocytosis
Mean age 65 years; may affect any age, but less than 50 years is uncommon
Symptoms are related to cytopenias or defective platelet aggregation (Acta Haematol 2007;118:117), but 50% are initially asymptomatic
Primary MDS: etiology unknown (age 50+ years)
Secondary / therapy related MDS (t-MDS): due to radiation or alkylating agents (2-8 years after exposure), see below
Laboratory: usually macrocytic anemia with increased red cell distribution width (RDW) and low/normal reticulocyte count; variable neutropenia or thrombocytopenia
Mean survival: refractory anemia-10 years, refractory anemia with ringed sideroblasts - 7 years; RA with multilineage dysplasia (3 years, Leuk Res 2006;30:971); refractory anemia with excess blasts or chronic myelomonocytic leukemia - 1 year; therapy related MDS - 5 months; death often due to AML or bleeding / infection
Poor prognostic factors: multiple clonal chromosomal abnormalities, severe cytopenias (< 0.5 neutrophils or < 50K platelets), high %blasts in marrow or any blasts in blood, lack of ringed sideroblasts, abnormal localization of immature granulocyte precursors in bone marrow biopsy; patients with Auer rods and <5% blasts usually progress rapidly to AML or death (AJCP 2005;124:191); patients with RA, RARS, RCMD with peripheral blasts (even <1%) have similar prognosis as refractory anemia with excess blasts-type 1 (Leuk Res 2008;32:33)
Good prognostic factors: younger age, normal/moderate neutropenia and thrombocytopenia, low blast percentage in marrow with no blasts in blood, no Auer rods in blasts, ringed sideroblasts present, normal karyotype or -Y, 5q- or 20q- alone
Diagnosis: cellular marrow but peripheral blood cytopenias with dysplastic changes in hematopoietic cells; bone marrow biopsy / aspirate is necessary to confirm diagnosis and obtain material for additional studies; must correlate findings with complete clinical information; by definition, myeloblasts are < 20% (if 20% or more, classify as AML)
Treatment: bone marrow transplant (Hematology Am Soc Hematol Educ Program 2006;205), support (antibiotics, transfusions)
Myelodysplastic syndrome (MDS) - general (continued)
Micro description:
peripheral blood smear (general MDS findings):
- erythroid: dimorphic population of oval macrocytes and hypochromic microcytic RBCs, basophilic stippling, erythrocyte vacuoles, nucleated red blood cells, Howell-Jolly bodies
- granulocytes: neutropenia with immature, hypogranular forms, pseudo-Pelger-Huet neutrophils (2 lobes), monocytosis, myeloblasts
- platelets: thrombocytopenia, giant platelets, hypogranular platelets, micromegakaryocytes
bone marrow: (general MDS findings):
usually hypercellular or normocellular, 10% are hypocellular; iron stores often increased; disordered (dysplastic) differentiation affecting all 3 lineages; myelofibrosis in therapy related MDS
- erythroid: erythroid hyperplasia, ringed sideroblasts (iron-laden mitochondria visible as perinuclear granules with Prussian iron stain), megaloblastoid nuclear maturation, nuclear budding abnormalities (polypoid outlines, internuclear bridging, nuclear fragments), PAS positive erythroblasts
- leukocytes: myeloblasts may be increased but < 20% of nonerythroid cells (or is defined as AML); abnormally localized immature precursors (ALIP), neutrophils with decreased secondary granules or 2 lobes (pseudo Pelger-Huet cells), toxic granulations, Dohle bodies, increased basophils or monocytes; rarely monocytic nodules (AJCP 2003;120:874); myeloid cells are myeloperoxidase negative
Note: in ALIP, aggregates (3-5) or clusters (6+) of immature precursors are remote from trabeculae (normal maturing granulocytes extend from trabeculae or blood vessels towards central areas)
- megakaryocytes: megakaryocytes occur in clusters; single nuclear lobe, hypolobulation or multiple separate nuclei; micro-megakaryocytes present
Spleen: splenomegaly uncommon; erythrophagocytosis, red pulp plasmacytosis, extramedullary hematopoiesis or marked red pulp expansion due to monocytic proliferation; splenomegaly usually due to dyspoiesis, not proliferation (AJSP 1998;22:1255)
Myelodysplastic syndrome (MDS) - general (continued)
Stains: often aberrant antigen expression
EM: same findings as AML; erythroid cells show unusual shapes, redundant cell membranes, large vacuoles, duplication of nuclear membrane and nuclear blebs; maturing neutrophils show decreased primary and secondary granules of abnormal size and shape; monocytes show increased cytoplasmic microfilaments and abnormal granules; megakaryocytes and micromegakaryocytes show decreased granules and demarcation membranes, platelets are hypogranular or have large granules
Cytogenetics/molecular: recommended to use karyotyping or FISH in all suspected patients; MDS has no specific cytogenetic abnormalities, but abnormalities are present in 30% of de novo MDS and 80% of therapy related MDS; usually chromosomal losses not gains; common findings are complete or partial loss of #5 or #7, +8, 20q- or complex chromosomal abnormalities; t(3;5) cases are due to NPM-MLF1 fusion, usually young males with good prognosis (Hum Path 2003;34:809)
DD: copper deficiency (Am J Hematol 2007;82:625), arsenic toxicity (see below), AML (20% or more blasts, t(8;21), inv(16) or t(15;17) with any percentage of blasts), parvovirus B19 infection, storage of bone marrow aspirates in EDTA at room temperature (AJCP 2002;117:57), aplastic anemia (lower PCNA and CD34 expression, AJCP 1997; 107:268), Behçet's disease (J Clin Immunol 2007;27:145)
References: Archives 2005;129:1299, eMedicine #1; #2, Wikipedia
Childhood MDS - chronic myeloid neoplasms chapter
3-9% of pediatric hematologic malignancies
Estimated annual incidence in US is 0.5 to 4 cases per million for children compared to 20-40 cases for adults
Usually diagnosed at ages 6-8 years, although juvenile myelomonocytic leukemia is usually diagnosed at age 2 years
Difficult to diagnosis because (a) less dysplasia at younger ages, (b) dysplasia may be confused with treatment effects of G-CSF, (c) often hypocellular, resembling aplastic anemia, (d) resembles HHV6 (Pediatr Blood Cancer 2006;47:543) or parvovirus (Rinsho Ketsueki 2001;42:1096, Pediatr Hematol Oncol 2000;17:475) infections
Causes: 69% idiopathic, 24% associated with constitutional/inherited disorders (Down’s syndrome, neurofibromatosis, Bloom’s syndrome, Fanconi’s anemia, Atlas of Genetics and Cytogenetics), 7% therapy related (Archives 2007;131:1110)
Similar prognosis as AML M6 and M7, with poor induction success rate (Pediatr Blood Cancer 2007;49:17)
Modified WHO classification for childhood MDS: diagnosis requires: (a) sustained and unexplained cytopenia, (b) at least bilineage dysplasia, (c) a clonal cytogenetic abnormality, and (d) at least 5% blasts (Leukemia 2003;17:277); may be most successful system for classification (Archives 2007;131:1110)
Molecular: monosomy 7 in 30%
MDS - classification - chronic myeloid neoplasms chapter
WHO classification system for myelodysplasia (2001):
Reduced blast requirement for AML from 30% to 20%, eliminated RAEB-T category (but see Acta Haematol 2007;117:221), added multilineage dysplasia and 5q- syndrome, shifted CMML to new group of MDS/MPN (Blood 2002;100:2292); better than FAB in predicting outcome (Br J Haematol 2007;137:193, Blood 2004;103:3265)
Refractory anemia (RA): <5% blasts, <15% ringed sideroblasts; variable marrow cellularity
RA with Ringed Sideroblasts (RARS): 15% or more sideroblasts, less than 20% erythroblasts
Refractory cytopenia with multilineage dysplasia (RCMD)
RA with Excess Blasts (RAEB): type 1 has 5-9% blasts in blood/marrow, type 2 has 10-19% blasts in blood/marrow
5q- syndrome
Therapy related MDS
MDS, unclassified
French American British (FAB) classification system for myelodysplasia (used prior to WHO):
Refractory anemia (RA): <5% blasts, <15% ringed sideroblasts; variable marrow cellularity
RA with Ringed Sideroblasts (RARS): 15% or more sideroblasts, less than 30% erythroblasts
RA with Excess Blasts (RAEB): 5-30% blasts in marrow, < 5% in peripheral blood
RA with Excess Blasts in Transformation (RAEB-T): 20-30% blasts in marrow, >5% in peripheral blood (now AML in WHO classification)
Chronic myelomonocytic leukemia (CMML): elevated WBC, monocytosis > 1 billion/liter; trilinear dysplasia; 5-20% blasts in marrow, < 5% in peripheral blood
MDS, unclassified
Refractory anemia - chronic myeloid neoplasms chapter
Ineffective erythropoiesis with erythroid hyperplasia of marrow but low reticulocyte count and anemia
Initially termed “refractory” because refractory to iron, folate and vitamin B12 supplements
Diagnosis of exclusion; must eliminate other possible causes of anemia (folate/B12 deficiency, drugs, toxins, arsenic, congenital dyserythropoietic anemia)
Occasionally evolves to more aggressive MDS or AML
Laboratory: anemia, usually no other cytopenias
Treatment: none or transfusion support; combination of all-trans retinoic acid, calcitriol, and androgens may be effective (Leuk Res 2006;30:935)
Micro description:
peripheral blood: anisocytosis (variation in size), poikilocytosis (variation in shape), normochromic oval macrocytes; usually no neutrophilic or platelet dysplasia; no/rare myeloblasts, monocytes are less than 1 billion/L
bone marrow: hypercellular or normocellular
- erythroid: erythroid hyperplasia, may have mild to moderate dysplasia with megaloblastoid features; <15% ringed sideroblasts
- myeloid: myeloblasts <5% (or call RAEB), no/slight dysplasia
- megakaryocytes: no/slight dysplasia
Cytogenetics: no specific abnormality, 70% have normal karyotype (Atlas of Genetics and Cytogenetics)
Refractory anemia with ringed sideroblasts - chronic myeloid neoplasms chapter
Also called idiopathic acquired sideroblastic anemia
Laboratory: anemia (hemoglobin usually is 9-12 g/dL), usually no other cytopenias but may have thrombocytosis
Diagnosis: ringed sideroblasts (detect with iron stain) represent at least 15% of bone marrow erythroblasts
Case reports: 70 year old man with chronic anemia, 16 year old girl (Archives 2005;129:e199)
Micro description:
peripheral blood: two RBC populations-normal and microcytic hypochromic; occasional coarse basophilic stippling and Pappenheimer bodies; no dysplastic changes, minimal neutropenia, no myeloblasts, no monocytosis, no thrombocytopenia
bone marrow: hypercellular or normocellular marrow with erythroid hyperplasia
- erythroid: erythroid hyperplasia, may be mild to moderate
dysplasia; markedly increased iron stores, ringed sideroblasts ≥15% of
marrow erythroblasts, identify with iron stain on marrow smear, has nucleus
completely or partially encircled by iron granules
- myeloid: myeloblasts <5% (or call RAEB), no dysplasia
- megakaryocytes: no dysplasia
EM: perinuclear iron present in mitochondrial cristae
Molecular: no specific cytogenetic abnormality (Atlas of Genetics and Cytogenetics); JAK2-V617F mutation present in 48-67% with RARS and marked thrombocytosis (RARS-T), a provisional MDS/MPN disorder (Haematologica 2008;93:34, Blood 2006;108:2173)
DD: refractory cytopenia with multilineage dysplasia (may have 15%+ ringed sideroblasts, but also dysplastic changes in 2 or 3 lineages), congenital sideroblastic anemia, chloramphenicol or TB drug exposure, alcohol or chronic lead poisoning
Refractory Cytopenia with Multilineage Dysplasia (RCMD) - chronic myeloid neoplasms chapter
Cytopenia of 2-3 lineages and dysplastic changes in 10% of cells of 2-3 lineages, <5% myeloblasts in bone marrow and peripheral blood
More aggressive than refractory anemia, more likely to progress to AML
Some consider it an intermediate disorder between refractory anemia and refractory anemia with excess blasts
Poor prognosis if even 1% blasts in peripheral blood (Leuk Res 2008;32:33)
Proposed modified criteria are refractory anemia, >10% pseudo-Pelger-Huet anomalies, dysmegakaryopoiesis in ≥40% or micromegakaryocytes in ≥10%, and no 5q- syndrome (Leukemia 2007;21:678)
Termed RCMD with ringed sideroblasts if ≥15% ringed sideroblasts
Case reports: 65 year old man with fatigue and shortness of breath, associated with chloramphenicol and responsive to cyclosporine (Eur J Haematol 2006;76:255)
Treatment: possibly splenectomy (Rom J Intern Med 2007;45:89)
Micro description:
peripheral blood: cytopenia of 2-3 lineages, no/rare blasts, no Auer rods, < 1 billion/L monocytes
bone marrow: dysplastic changes in 10% of cells of 2-3 lineages, <5% myeloblasts in bone marrow, no Auer rods
DD: refractory anemia (no dysplastic changes in granulocytes, platelets or megakaryocytes), refractory anemia with excess blasts (myeloblasts >5%)
Refractory Anemia with Excess Blasts (RAEB) - chronic myeloid neoplasms chapter
Myeloblasts are 5-19% of bone marrow differential
Usually cytopenias in 2 or 3 lineages
Considered high risk MDS
Type 1: 5-9% blasts in bone marrow, no Auer rods, < 1 billion/L monocytes
Type 2: 10-19% blasts in bone marrow OR Auer rods in any MDS (AJCP 2005;124:191), < 1 billion/L monocytes; more aggressive, greater tendency to progress to AML
Refractory anemia with excess blasts in transformation (RAEB-T): classified as AML under WHO classification
Median survival of 16 months for RAEB-1 and 9 months for RAEB-2 (Br J Haematol 2006;132:162)
Laboratory: anemia (normochromic, normocytic or macrocytic), usually neutropenia and thrombocytopenia
Case reports: RAEB-2 - extensive myocardial infiltration (BMC Blood Disord 2006;6:4), cutaneous involvement (Cutis 2007;80:223)
Micro description:
peripheral blood: nucleated red blood cells, immature granulocytes, neutrophilic hyposegmentation, pseudo-Pelger-Huet cells and hypogranulation, myeloblasts (<19%), occasional micromegakaryocytes
bone marrow: normocellular or hypercellular; hyperplasia of granulocytes or erythrocytes; myeloblasts comprise 5-19% of white blood cells; Auer rods often seen; severe dysplastic changes in all 3 lineages, more severe than other MDS; abnormal localization of immature precursors; may have increased reticulin fibers
Refractory Anemia with Excess Blasts (continued)
Cytogenetics: no specific abnormality (Atlas of Genetics and Cytogenetics)
DD: copper deficiency (Leuk Res 2007 Aug 10 [Epub ahead of print])
5q- syndrome - chronic myeloid neoplasms chapter
Subtype of refractory anemia with good prognosis
Stable clinical course but often transfusion dependent causing frequent hemochromatosis
Usually elderly women
10% progress to AML
Laboratory: moderate to severe macrocytic anemia, thrombocytosis in 50%
Case reports: 46 year old woman with chronic anemia, 70 year old woman with macrocytic anemia and thrombocytosis
Treatment: lenalidomide, a thalidomide analogue and immunomodulating drug, has high response rate (N Engl J Med 2006;355:1456)
Micro description:
bone marrow biopsy: variable cellularity, erythroid hypoplasia, increased clusters of megakaryocytes with abundant cytoplasm but hypolobulated nuclei
bone marrow smear: reduced erythroblasts, megakaryocyte hyperplasia with nuclear hypolobulation; either granulocyte or megakaryocyte dysplasia but not both, <5% blasts, no Auer rods
Molecular: interstitial deletions of 5q12 to 5q32
References: Cancer Genet Cytogenet 1985;17:189, Hematology Am Soc Hematol Educ Program 2006:192, OMIM 153550, Atlas of Genetics and Cytogenetics, Hematology 2004;9:271
Therapy related myelodysplastic syndrome - chronic myeloid neoplasms chapter
May occur post-chemotherapy or post-radiation therapy
Rarely occurs after therapy for de novo AML (Leuk Res 2007 Dec 17 [Epub ahead of print))
Similar genetic abnormalities as de novo myelodysplasia and AML and therapy related AML, but different frequencies (Hematology Am Soc Hematol Educ Program 2007;392)
t(8;21) cases resemble de novo cases, but with additional dysplastic changes (AJCP 2002;117:306)
Poor outcome regardless of morphologic classification, and minimal survival difference between therapy related MDS and therapy related AML (AJCP 2007;127:197)
Survival varies by cytogenetic risk group (Hematology Am Soc Hematol Educ Program 2007;453)
Molecular: at least 8 alternative genetic pathways; either Class I mutations (activating mutations of genes in tyrosine kinase-RAS/BRAF pathway, leading to increased cell proliferation), Class II mutations (inactivating mutations of genes encoding hematopoietic transcription factors, causing disturbed cell proliferation), or inactivating mutations of p53 gene (Hematology Am Soc Hematol Educ Program 2007;392)
References: Haematologica 2007;92:1389
Alkylating agents causing therapy related myelodysplastic syndrome - chronic myeloid neoplasms chapter
Occurs median 5 years after initiation of therapy
Risk is associated with patient age and cumulative dose of alkylating agent
Typically presents with myelodysplastic syndrome and bone marrow failure
Poor prognosis; median survival is 7-8 months; may progress to AML or die without progression
Micro: hypocellular marrow; often severely dysplastic changes in blood and marrow; myelofibrosis and ringed sideroblasts common; <5% myeloblasts
Molecular: abnormalities of chromosomes 5 or 7 or complex cytogenetic abnormalities; also AML1 mutations (Blood 2004;104:1474)
Topoisomerase II inhibitors causing therapy related myelodysplastic syndrome - chronic myeloid neoplasms chapter
Occurs mean 2-3 years after initiation of etoposide or teniposide with doxorubicin
Poor prognosis
Molecular: balanced translocations of 11q23 and 21q22
MDS, unclassified - chronic myeloid neoplasms chapter
Often Auer rods but less than 5% blasts, isolated neutropenia without anemia, isolated thrombocytopenia without anemia, significant thrombocytosis, significant leukocytosis, hypocellular bone marrow (<30% in younger individuals, <20% if age 60 or more) or myelofibrosis
Some cases associated with prior aplastic anemia and monosomy 7 (AJCP 2006;126:925)
Myelofibrosis: when present, often is difficult to obtain bone marrow aspirate; patients often have pancytopenia with dysplasia in 3 lineages
Case reports: 82 year old man with moderate thrombocytopenia
DD: acute panmyelosis with myelofibrosis (20% or more blasts), AML-M7 (20% or more blasts), chronic idiopathic myelofibrosis (usually marked splenomegaly, no dysplasia)
Arsenic toxicity - chronic myeloid neoplasms chapter
May cause myelodysplastic changes in erythroblasts and neutrophils
Patients present with pancytopenia and dysplastic marrow elements
Note: arsenic trioxide is also a treatment for myelodysplasia (Curr Hematol Rep 2005;4:59)
Case reports: Am J Hematol 1991;36:291
Micro description:
peripheral blood: erythrocytes show coarse basophilic stippling and karyorrhexis (AJCP 1984;81:533)
bone marrow: erythroblasts show megaloblastic changes and karyorrhexis (Blood 1975;45:241)
EM: megaloblastic features of high N/C ratio and nuclear-cytoplasmic dyssynchrony (Blood 1979;53:820)
Myeloproliferative neoplasms (MPN) - chronic myeloid neoplasms chapter
Myeloproliferative neoplasms - general - chronic myeloid neoplasms chapter
First described by William Dameshek in 1951 (Blood 1951;6:372)
WHO 2001 called chronic myeloproliferative diseases
WHO 2008 calls them “myeloproliferative neoplasms”
All have effective clonal myeloproliferation with no dyserythropoiesis, no granulocyte dysplasia and no monocytosis; their phenotypic diversity is due to different mutations affecting tyrosine kinases or related molecules, causing different patterns of abnormal signal transduction
Initially hypercellular marrow with increased hematopoiesis, increased peripheral blood counts (often marked increase in all cell lines but with normal morphology) and extramedullary hematopoiesis in spleen with splenomegaly; then spent phase with marrow fibrosis and cytopenia
CML frequently progresses to acute myelogenous leukemia (AML), but other myeloproliferative neoplasms only rarely progress to AML
There is considerable morphologic overlap among subtypes and with benign hyperplastic marrow conditions
4 color flow cytometry is helpful in diagnosis (Archives 2003;127:1140)
Extramedullary hematopoiesis appears to be a clonal process (Hum Path 2007;38:1760) with JAK2 V617F mutation frequently present in splenic EMH cells (Mod Path 2007;20:929)
Occasionally has coexisting monoclonal B cell infiltrate in bone marrow detectable by IgH PCR, but not by morphology (Mod Path 2004;17:1521)
May have nodal or extranodal tumor-forming accumulations of plasmacytoid monocytes / interferon-producing cells, which are clonal, and related to underlying myeloid tumor (AJSP 2004;28:585)
Associated with chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension (Respiration 2007 Dec 21 [Epub ahead of print])
Usually prolonged survival
Micro: may have emperipolesis (ingestion of blood cells by megakaryocytes or other cells); rarely monocytic nodules similar to plasmacytoid monocyte nodules above (AJCP 2003;120:874)
Myeloproliferative neoplasms - general (continued)
Molecular: JAK2 V617F mutation (Janus kinase 2 gene) present in most nonCML chronic myeloproliferative diseases (85% of polycythemia vera, 65% of essential thrombocythemia, 65% of chronic idiopathic myelofibrosis, AJSP 2007;31:233), causes constitutive tyrosine kinase activity; c-Mpl mutation (thrombopoietin receptor) occurs in essential thrombocythemia and idiopathic myelofibrosis (J Transl Med 2006;4:41); occasionally are FLT3 mutations (AJCP 2006;126:530)
References: Ann Hematol 2008;87:1, Blood 2007;110:1092
WHO classification of myeloproliferative neoplasms - chronic myeloid neoplasms chapter
WHO 2008
Myeloproliferative neoplasms (MPN)
3.1 Chronic myelogenous leukemia
3.2 Polycythemia vera
3.3 Essential thrombocythemia
3.4 Primary myelofibrosis
3.5 Chronic neutrophilic leukemia
3.6 Chronic eosinophilic leukemia, not otherwise categorized
3.7 Hypereosinophilic syndrome
3.8 Mast cell disease
3.9 MPNs, unclassifiable
WHO 2001
Chronic myeloproliferative diseases
Chronic myelogenous leukemia (Philadelphia chromosome, t(9;22)(q34;q11), BCR-ABL positive)
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia (and the hypereosinophilic syndrome)
Polycythemia vera
Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
Essential thrombocythemia
Chronic myeloproliferative disease, unclassifiable
References: Leukemia 2008;22:14 (WHO 2008), Blood 2007;110:4030, Blood 2002;100:2292 (WHO 2001)
Chronic myelogenous leukemia (CML) - chronic myeloid neoplasms chapter
Most common chronic myeloproliferative neoplasm
Incidence of 10-20 cases per million annually
Due to pluripotent stem cell that gives rise to myeloid and lymphoid cells
Marrow has neoplastic and normal granulocyte precursors; BCR-ABL also in other myeloid lineages, B cells, possibly T cells, but clinically only affects granulocytes
Insidious onset with anemia, fatigue, weight loss; may have dragging sensation due to splenomegaly
Extramedullary hematopoiesis may cause hepatosplenomegaly and lymphadenopathy; may have splenic infarcts
Disease course (without treatment): usually chronic phase for 3-4 years; 50% have accelerated phase (10-19% blasts in blood or marrow, >20% basophils in blood, persistent platelet count of < 100K or > 1000K, increasing splenomegaly or white blood cell count while on therapy, marked dysplasia, marked myelofibrosis, additional cytogenetic abnormalities, Table) with lack of response to treatment, then blast transformation at mean 3 years after diagnosis (20% or more blasts in marrow or blood), often death shortly afterwards (median survival 3 years without treatment); 70% have myeloid blasts, 30% have lymphoid blasts resembling pre-B cells (TdT+, CD19/CD20+); rarely erythroid blasts (AJSP 2004;28:1240); blasts may accumulate as tumor mass in soft tissue or lymph nodes (Archives 2001;125:1385)
Laboratory >100K white blood cells with neutrophils, metamyelocytes and myelocytes, also basophilia and eosinophilia, low LAP score (below); 50% have thrombocytosis
Leukocyte (neutrophil) alkaline phosphatase (LAP) score: LAP is marker of terminally differentiated neutrophils (Br J Haematol 1999;105:163); blood film is stained and 100 neutrophils are scored from 0 to 4+ on the basis of the intensity of the precipitated blue dye in their cytoplasm; values of the 100 cells are added and total score reported; scoring: 0: no staining, 1+: weak cytoplasmic staining; 2+: blue staining but clear areas of cytoplasm and pink staining of nuclear lobes still present, 3+: intense cytoplasmic staining but nuclear lobes still visible, 4+: intense cytoplasmic staining obscures the nucleus; low score indicates abnormal neutrophil development, associated with CML, PNH (Blood 1989;73:1113)
Poor prognostic factors: evolution to myelofibrosis (loss of marrow volume to fibrosis, Hum Path 2003;34:391), failure to achieve a cytogenetic response
Chronic myelogenous leukemia (continued)
Diagnosis: chronic myeloproliferative neoplasm with Philadelphia chromosome or BCR-ABL; algorithm - if no Philadelphia chromosome but dwarf megakaryocytes, consider performing FISH to detect BCR-ABL
Case reports: Case of the Week #27, teenage boy with CML post-treatment for anaplastic large cell lymphoma (Hum Path 2007;38:1576), with plasmacytoid T cell lymphoma (AJSP 1985;9:380), with complex translocations (Archives 2001;125:437), T cell blast crisis (Archives 2003;127:e249, Hum Path 2002;33:770)
Treatment: imatinib mesylate (Gleevec/STI571, J Clin Invest 2007;117:2036), an oral tyrosine kinase inhibitor, may reverse marrow fibrosis; 87% complete cytogenetic response rate with 96% estimated 3 year survival (Blood 2006;108:1835), peripheral blood normalizes before marrow, although BCR-ABL fusion gene may persist; interferon produces a complete hematologic response in 80%, effective even in accelerated phase, but complete cytogenetic response rate of only 28% and estimated 3 year survival of only 81%; hydroxyurea causes reduction in cellularity; hematopoietic stem cell transplant remains only curative approach
Note: may progress to blast transformation despite hematologic response to treatment, suggesting bone marrow follow up is critical (Archives 2004;128:980)
Micro description:
peripheral blood: >100K white blood cells with neutrophils, metamyelocytes and myelocytes, usually < 5% myeloblasts in blood and marrow; also eosinophilia, basophilia; 50% have thrombocytosis
bone marrow: up to 100% cellular with increased granulocyte precursors, basophils, eosinophils and occasionally monocytes; normal erythroid compartment, normal or increased megakaryocytes in clusters which are often smaller than usual; variable sea-blue histiocytes (storage histiocytes with wrinkled, sea-blue cytoplasm, usually singly and more prominent near vessels); increased reticulin fibers, but marrow fibrosis is rare at presentation; marrow fibrosis is associated with the number of CD61+ megakaryocytes
spleen: diffuse infiltration of red pulp cords and sinuses by myeloid cells in all stages of differentiation; obliteration of white pulp; no grossly visible nodules
Chronic myelogenous leukemia (continued)
Post-treatment changes
Positive stains: myeloperoxidase, specific esterase (naphthol-AS-D-chloracetate esterase), BB1 (basogranulin) stains basophils (AJCP 2006;125:273)
Molecular: t(9;22)(q34;q11)-Philadelphia chromosome (discovered in 1960-J Natl Cancer Inst 1960;25:85) or ABL gene (#9q34) and BCR gene (#22q11) fusion transcript (Cell 1984;36:93) is requirement for diagnosis; use FISH or PCR to detect fusion gene, which produces 210 kd protein with tyrosine kinase activity that affects cell motility, including the capacity to adhere to endothelial cells (BMC Cancer 2006;6:262); no FLT3 mutations (AJCP 2006;126:530)
DD: leukemoid reaction, other chronic myeloproliferative neoplasms (increased LAP, negative for BCR-ABL), paroxysmal nocturnal hemoglobinuria (LAP negative/low, negative for BCR-ABL)
References: Wikipedia, eMedicine
Polycythemia vera - chronic myeloid neoplasms chapter
Also called polycythemia rubra vera
Clonal, neoplastic proliferation of multipotent myeloid stem cells
Prevalence of 2-3 per million (Am J Hematol 2008 Jan 7 [Epub ahead of print])
Median age 60 years, uncommon in children
Most symptoms are due to polycythemia (increased hematocrit) with associated increased total blood volume, vascular distention and stasis; mild hepatosplenomegaly due to extramedullary hematopoiesis
Patients are plethoric, cyanotic and hypertensive with headache, dizziness, gastrointestinal symptoms, pruritis or ulcers, possibly from basophilic histamine; may have hyperuricemia or gout due to increased cell turnover
25% have thrombotic episodes (stroke, deep venous thrombosis, myocardial infarction) due to abnormal blood flow and possibly abnormal platelet function; also Budd-Chiari syndrome (hepatic vein thrombosis), bowel infarction, hemorrhagic strokes due to thrombosis of venous sinuses of brain, life threatening hemorrhage in 10%
May have iron deficiency due to bleeding, which corrects the hematocrit to normal
Prognosis: spent phase with marrow fibrosis and marked cytopenias in 15% after 10 years, death in months if no treatment
Acute myeloid leukemia in 2% with phlebotomy but 15% with alkylating agents or radioactive phosphorus (no longer used); acute lymphocytic lymphoma is rare
Case reports: 77 year old man who also developed variant hairy cell leukemia (Archives 2003;127:e209), transformation to AML-M7 (Archives 2000;124:1389), transformation to CML (Archives 2007;131:1719)
Laboratory: elevated red cell mass, white blood cell count and platelet count; marked increase in hemoglobin and hematocrit; abnormal aggregation of platelets, normal or increased LAP score, no CML translocation
Diagnosis (WHO 2008):
Requires major criteria #1 and #2 plus one minor criterion, OR the major criterion #1 plus 2 minor criteria:
major criterion #1: Hgb > 18.5 g/dl for men or 16.5 g/dl for women OR Hgb or Hct > 99th percentile of reference range for age, sex or altitude of residence, OR Hgb > 17 g/dl men or 15 g/dl women if associated with a sustained increased of 2 g/dl or more from baseline that cannot be attributed to correction of iron deficiency OR Elevated red cell mass > 25% above mean normal predicted value
major criterion #2: Presence of JAK2 V617F or similar mutation
minor criterion #1: bone marrow trilineage myeloproliferation
minor criterion #2: subnormal serum erythropoietin level
minor criterion #3: endogenous erythroid colony growth
Table, WHO 2008 diagnostic algorithm
Polycythemia vera (continued)
Diagnosis (WHO 2001): polycythemia (increased red blood cell mass) with nonelevated erythropoietin levels; Table
Treatment: median survival of 10 years with phlebotomy; high risk patients (for thrombosis) get cytoreductive therapy (hydroxyurea) and low dose aspirin (N Engl J Med 2004;350:114); possibly interferon (Cancer 2006;107:451
Micro description:
peripheral blood: increased erythrocytes, leukocytes, platelets, basophils; large platelets
bone marrow: mean 80% cellularity (range 37-100%), usually marked erythroid hyperplasia although may be subtle; increased megakaryocytes, often larger and more polymorphic than normal; increased vascularity, modestly increased reticulin (particularly near megakaryocytes), reduced storage iron; late changes are fibrotic marrow
Positive stains: not used for diagnosis; VEGF (high expression, AJCP 2007;128:966)
Negative stains: not used for diagnosis; c-Mpl (thrombopoietin receptor) on megakaryocytes (usually moderate/strong)
Molecular: JAK2 V617F mutation in up to 97% (Blood 2006;108:1865, Hum Path 2006;37:1458), also JAK2 exon 12 mutations (N Engl J Med 2007;356:459)
DD: polycythemia due to dehydration, Gaisock syndrome (associated with hypertension, obesity, anxiety) or other causes (normal megakaryocytes, less cellular marrow, no increase in reticulin, more normal iron stores, normal or high erythropoietin levels), CML (no erythroid hyperplasia)
References: Archives 2006;130:1126, eMedicine #1, #2, American Family Physician, Wikipedia
Essential thrombocythemia - chronic myeloid neoplasms chapter
See MDS/MDN-unclassifiable for refractory anemia with ringed sideroblasts plus essential thrombocythemia
Prevalence of 2-3 per million (Am J Hematol 2008 Jan 7 [Epub ahead of print])
Median age of 65-75 years at diagnosis, but may occur at any age; 2/3 female
Closely related to polycythemia vera, but no increased red blood cell mass
Increased proliferation usually confined to megakaryocytes with platelet count > 450 x 109 / L
Thrombosis and hemorrhage common, due to qualitative and quantitative abnormalities in platelets
Indolent, long asymptomatic periods alternating with thrombotic or hemorrhagic crises
Life expectancy is almost normal (Orphanet J Rare Dis 2007;2:3)
Bone marrow examination necessary to exclude other myeloproliferative neoplasms (Archives 1991;115:475)
Diagnostic criteria (WHO 2008): must meet all 4 major criteria
criterion #1: platelet count of 450 x 109 / L or more
criterion #2: megakaryocyte proliferation with large and mature morphology, no or little granulocyte or erythroid proliferation
criterion #3: does not meet WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm
criterion #4: demonstration of JAK2 V617F or other clonal marker OR no evidence of reactive thrombocytosis
Table, WHO 2008 diagnostic algorithm
Diagnostic criteria (WHO 2001): sustained platelet count >600K, marrow shows proliferation mainly of megakaryocytes with enlarged mature forms, no other causes of thrombocytosis (thus, is a diagnosis of exclusion), Table
Treatment: high risk patients (for thrombosis) get cytoreductive therapy (hydroxyurea) and low dose aspirin
Essential thrombocythemia (continued)
Micro description:
peripheral blood: abnormally large platelets and increased platelets
bone marrow: mildly hypercellular, increased number and large forms of megakaryocytes with hyperlobulated nuclei, delicate reticulin fibers, but no overt fibrosis; increased angiogenesis (CD34+); usually no dyserythropoiesis, dysgranulopoiesis, macrocytosis or monocytosis; no increased trilineage proliferation; no highly bizarre megakaryocytes, no predominance of small megakaryocytes with monolobulated nuclei
Molecular: adults - JAK2 V617F mutation in up to 75% (Blood 2006;108:1865); JAK2 mutant allele burden contributes to clinical phenotype (Haematologica 2008;93:41); also W515L and W515K mutations in thrombopoietin receptor c-Mpl (J Transl Med 2006;4:41); may have del(20q) and unbalanced translocations between 1q and 7p
children - usually no JAK2 mutation (Blood 2006;108:3600)
DD: other myeloproliferative neoplasms (erythroid hyperplasia is present in polycythemia vera), reactive thrombocythemia (inflammatory disorders, asplenism, iron deficiency; no JAK2 or c-Mpl mutations)
References: Archives 2006;130:1144, eMedicine
Primary myelofibrosis - chronic myeloid neoplasms chapter
Previously called agnogenic (idiopathic) myeloid metaplasia, chronic idiopathic myelofibrosis with myeloid metaplasia
Mean age 60 years, rarely occurs in children (eMedicine)
Incidence of 3 to 15 per 1 million annually
Clonal stem cell defect characterized by panmyelopathy with intact maturation, progressive marrow fibrosis (from inception), extramedullary hematopoiesis in spleen, liver and lymph nodes, and marked splenomegaly up to 4 kg
Also anemia, other cytopenias, “B” symptoms (fever, weight loss > 10%, night sweats), gout, infections, thrombotic episodes, bleeding
Rarely, extramedullary hematopoiesis forms masses in breast (AJSP 1980;4:281), lung (Archives 2008;132:99), prostate (AJSP 1991;15:486), retroperitoneum (AJSP 2000;24:51), spinal cord (J Korean Med Sci 2007;22:1090) or stomach (Archives 2004;128:568)
Fibrosis is due to neoplastic megakaryocytes releasing platelet derived growth factor, basic fibroblast growth factor, transforming growth factor beta or other cytokines, which causes nonneoplastic fibroblasts in marrow to deposit collagen
5% transform to AML
May coexist with systemic mastocytosis (J Mol Diagn 2008;10:58)
Survival 3.5 to 5.5 years
Atypical presentation: CD34+ cells in peripheral blood, circulating endothelial progenitor cells
Prognostic scoring systems (PSS): poor prognostic factors include Hb <10 g/dL, WBC <4 or >30 x 109/L, constitutional symptoms (fever, night sweats, weight loss), circulating blasts ≥ 1%, platelet count <100 x 109/L or absolute monocyte count ≥ 1 x 109/L
Dupriez PSS: uses Hb and WBC count (Blood 1996;88:1013)
Cervantes PSS: uses Hb, constitutional symptoms and circulating blasts (Br J Haematol 1998;102:684)
Mayo Clinic PSS: uses hemoglobin, platelet, leukocyte, and monocyte counts (Cancer 2007;109:2083)
Case reports: amyloidosis (Archives 1987;111:525), portal vein thrombosis (Archives 2003;127:e385), subsequent histiocytic sarcoma (Archives 2004;128:1167), subsequent granulocytic sarcoma (Hum Path 1996;27:417)
Laboratory: initially normal or increased blood counts with immature granulocytes and atypical platelets; later cytopenias develop, more dysplastic cells, teardrop elliptocytes; leukocyte (neutrophil) alkaline phosphatase (LAP) score is increased
Primary myelofibrosis (continued)
Diagnostic criteria (WHO 2008): must meet all 3 major criteria plus at least two minor criteria
major criterion #1: megakaryocyte proliferation and atypia (small to large megakaryocytes with dense clustering, an aberrant N/C ratio and hyperchromatic and irregularly folded nuclei) accompanied by either reticulum or collagen fibrosis OR in the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF)
major criterion #2: not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm
major criterion #3: demonstration of JAK2 V617F or other clonal marker or no evidence of reactive marrow fibrosis
minor criterion #1: leukoerythroblastosis
minor criterion #2: increased serum LDH
minor criterion #3: anemia
minor criterion #4: palpable splenomegaly
Table, WHO 2008 diagnostic algorithm
Diagnostic criteria (WHO 2001): prefibrotic myelofibrosis; fibrotic myelofibrosis
European Clinical and Pathological criteria: important for prefibrotic disease with WHO 2001 - see Table 3
Treatment: reduced intensity allogeneic stem cell transplant if intermediate to high risk, or palliation of extramedullary hematopoiesis and treatment of cytopenias (Leukemia 2008 Jan 10 [Epub ahead of print], Cancer J 2007;13:377)
Micro description:
peripheral blood: leukoerythroblastosis (immature granulocytes and normoblasts in peripheral blood) is common in later phases;
also dacrocytes (teardrop erythrocytes)
bone marrow: initially hypercellular with large, dysplastic, clustered (loose or tight) megakaryocytes and excess granulocytes; increased reticulin is present around clusters of megakaryocytes; megakaryocytes have aberrant N/C ratios and hyperchromatic, bulbous or irregularly folded nuclei; often bare megakaryocytic nuclei; intermediate phase has alternating areas of hematopoiesis and fibrosis; terminal phase is hypocellular and diffusely fibrotic with atypical megakaryocytes; marrow may be converted to bone (osteosclerosis); associated with dry bone marrow taps
spleen: red pulp sinuses contains megakaryocytes, granulocyte precursors, nucleated red cells; may be nodules of extramedullary hematopoiesis
Primary myelofibrosis (continued)
Positive stains: not diagnostic; VEGF (high expression, AJCP 2007;128:966), CD105 (to assess microvascular density, may have prognostic value-Mod Path 2004;17:1513),
Cytogenetics: abnormalities present in 56% (using FISH), but main recurrent chromosomal aberrations do not correlate with clinical features or prognosis (Cancer 2006;107:2801); no BCR-ABL fusion gene (or classify as CML)
Molecular: JAK2 V617F mutation present in 35-95% (AJCP 2006;125:625); mutational status predicts progression to large splenomegaly and leukemic transformation (Blood 2007;110:4030); 8% have mutations in thrombopoietin receptor c-Mpl/CD110 (J Transl Med 2006;4:41, Br J Haematol 2007;137:244)
DD: other causes of leukoerythroblastosis or dry taps are granulomatous marrow disease, metastases to marrow (desmoplasia but no increased reticulin) or lymphoma; polycythemia vera (25%) and essential thrombocythemia (2%) may have marrow fibrosis; primary hyperparathyroidism rarely causes myelofibrosis and pancytopenia (Int J Lab Hematol 2007;29:464