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)
References: Archives 2006;130:1133, eMedicine
Primary myelofibrosis variant with rapid clinical course
See Acute panmyelosis with myelofibrosis in Leukemia-acute chapter
Chronic neutrophilic leukemia - chronic myeloid neoplasms chapter
Rare
Associated with splenomegaly (Orv Hetil 2006;147:827)
Usually chronic course with poor prognosis, often death from cerebral hemorrhage (J Clin Pathol 2002;55:862)
Laboratory: increased serum vitamin B12
Diagnosis (WHO 2008): ≥25 x 109/L WBC in peripheral blood, with >80% segmented neutrophils or bands, <10% immature granulocytes and <1% myeloblasts (<5% blasts in the bone marrow); no BCR-ABL, no dyserythropoiesis, no granulocyte dysplasia, no monocytosis (Ann Hematol 2008;87:1)
Case reports: 74 year old man with Sweet’s syndrome (Singapore Med J 2007;48:e74), transformation to AML (Jpn J Clin Oncol 2000;30:362)
Treatment: optimal treatment unknown
Micro description:
Bone marrow: hypercellular with granulocyte hyperplasia; variable erythroid and megakaryocyte hyperplasia; no/minimal dysplastic changes; no increased myeloblasts
Cytogenetics: 90% normal, also +8, 20q-
Molecular: monoclonal (J Clin Pathol 2003;56:292), occasionally has JAK2 V617F mutation (Blood 2005;106:1207), no BCR-ABL
DD: CML with p230 variant BCR-ABL fusion transcript and mature peripheral blood neutrophils (Cancer 2002;94:2416); myeloma or other neoplasms that secrete G-CSF or other cytokines (Am J Hematol 2005;80:243)
Chronic eosinophilic leukemia (CEL) not otherwise categorized - chronic myeloid neoplasms chapter
“Not otherwise categorized” because there are no rearrangements of PDGFRA, PDGFRB or FGFR1 genes
Much rarer than reactive eosinophilia
Note: published cases without molecular analysis may be chronic eosinophilic leukemia, hypereosinophilic syndrome, myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 or mast cell disease (with eosinophilia)
Usually multiorgan disease (heart, lungs, CNS, GI tract, skin) due to eosinophil infiltration and release of cytokines and other substances from eosinophil granules
Diagnosis: bone marrow examination with tryptase (to identify mast cells), T cell clonal studies, immunohistochemistry, cytogenetic studies and molecular studies to detect (and rule out) PDGFRA, PDGFRB or FGFR1 rearrangements
Diagnostic criteria: ≥ 1.5 x 109/L peripheral blood eosinophils (persistent); either peripheral blood blasts > 2%, bone marrow blasts > 5% or abnormal cytogenetics; exclusion of secondary eosinophilia; exclusion of other acute or chronic myeloid neoplasms; and no evidence of phenotypically abnormal or clonal T lymphocytes
Note: WHO 2001 included criterion of evidence of clonality (Blood 2004;104:3836), which is not explicitly indicated in WHO 2008
Diagnostic algorithm (WHO 2008)
Case reports: liver infiltration resembling Budd-Chiari syndrome (Rinsho Ketsueki 2007;48:505)
Treatment: possibly interferon for patients with JAK2 617F mutations (Haematologica 2007;92:e118)
Micro description:
peripheral blood: mostly mature eosinophils, occasionally immature forms; no/occasionally mildly dysplastic forms; may have increased neutrophil count
bone marrow: hypercellular marrow with marked increased in eosinophil precursors; normal erythroid, neutrophil and megakaryocyte maturation; normal or mildly increased myeloblasts; variable dysplastic changes
Cytogenetics: usually no abnormalities
DD: reactive eosinophilia, acute or chronic myeloid neoplasms, mast cell disease
Hypereosinophilic syndrome - chronic myeloid neoplasms chapter
Diagnosis of exclusion; also called idiopathic hypereosinophilic syndrome
See also discussions in these chapters: Gallbladder-eosinophilic cholecystitis, Lung-nontumor: eosinophilic pneumonia, Pancreas-eosinophilic pancreatitis
Much rarer than reactive eosinophilia
Note: published cases without molecular analysis may be chronic eosinophilic leukemia, hypereosinophilic syndrome, myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 or mast cell disease (with eosinophilia)
Diagnosis: bone marrow examination with tryptase (to detect mast cells), T cell clonal studies, immunohistochemistry, cytogenetic studies and molecular studies to detect (and rule out) PDGFRA, PDGFRB, or FGFR1
Diagnostic criteria: ≥ 1.5 x 109/L peripheral blood eosinophils (persistent), exclusion of secondary eosinophilia, exclusion of other acute or chronic myeloid neoplasms, no evidence for phenotypically abnormal or clonal T lymphocytes, no cytogenetic abnormality, < 2% peripheral blasts and < 5% bone marrow blasts
Note: some studies add criterion of no evidence of clonality, which may be difficult to determine if no cytogenetic abnormalities are present
Diagnostic algorithm (WHO 2008)
Case reports of organ/tissue involvement: cardiac (Pathol Int 2008;58:138, Am J Hematol 2007;82:920), CSF (Surg Neurol 2007;68 Suppl 1:S52), liver (Intern Med 2007;46:1095), oral mucosa (Oral Dis 2008 Jan 10 [Epub ahead of print]), venous disease (Arch Dermatol 2006;142:1606)
Treatment: immediate therapy may not be required if asymptomatic and no organ damage; cytoreductive therapy includes corticosteroids, interferon-alpha and hydroxyurea (Cancer J 2007;13:384)
Micro description:
bone marrow: hypercellular marrow, increased eosinophilic precursors
References: eMedicine #1, #2, Orphanet
Mast cell disease - chronic myeloid neoplasms chapter
See also discussions of mastocytosis in these chapters: Bone, Lymph Node, Skin-nontumor, Spleen
Rare, 0.3% of bone marrow biopsies
Variable symptoms of diarrhea, weight loss, weakness, fractures or osteoporosis in 25%, arthralgia, flushing, bronchospasm
Most commonly affected sites are skin (urticaria pigmentosa) and bone marrow
Serum tryptase may predict bone marrow involvement (Haematologica 2008;93:120)
Sometimes associated with clonally related second myeloid neoplasm (J Clin Pathol 2004;57:604), including primary myelofibrosis (J Mol Diagn 2008;10:58)
Diagnosis: examine bone marrow with tryptase stain to confirm presence of abnormal (spindle shaped) mast cells, use flow cytometry of bone marrow to look for CD25+ (phenotypically abnormal) mast cells, mutation screening to find KITD816V and to exclude other abnormalities (Haematologica 2008;93:6)
Diagnostic criteria: mast cell disease is working diagnosis if (a) bone marrow aggregates of morphologically abnormal mast cells are present, or (b) when histology is equivocal, if KITD816V or phenotypically abnormal (CD25+) mast cells are present; other requirements: no BCR–ABL, no dyserythropoiesis, no granulocyte dysplasia, no monocytosis, no rearrangements of PDGFRA, PDGFRB or FGFR1
Case reports: 63 year old man with pancytopenia
Treatment: may not be necessary if indolent; IFN-alpha and cladribine if systematic; usually resistant to imatinib
Micro: paratrabecular aggregates resembling microgranulomas of oval or spindled cells with clear cytoplasm and distinct cell outlines resembling hairy cell leukemia; associated with eosinophils and thickened bone; focal lesions may be perivascular and associated with medial or adventitial hypertrophy and collagen fibrosis
Positive stains: tryptase, CD25 (AJSP 2004;28:1319), CD68, CD117/kit; also Giemsa, toluidine blue, polychrome methylene blue, chloroacetate esterase (Leder)
Negative stains: myeloperoxidase, CD20
Molecular: KITD816V mutation (Proc Natl Acad Sci USA 1995;92:10560)
DD: mast cell hyperplasia (diffuse interstitial pattern in bone marrow, round CD25- mast cells, AJCP 2005;124:560)
References: eMedicine #1, #2, Archives 2007;131:784
Myeloproliferative neoplasms - unclassifiable - chronic myeloid neoplasms chapter
Has clinical phenotype of myeloproliferative neoplasms, but does not meet diagnostic criteria for any classic or non-classic myeloproliferative neoplasms
Molecular: may have JAK2 617F mutation (Mod Path 2007;20:929)
MDS/MPN - chronic myeloid neoplasms chapter
MDS/MPN-general - chronic myeloid neoplasms chapter
Disorders which bridge the myelodysplastic (MDS) and myeloproliferative neoplasm (MPN) categories at time of initial presentation
Have morphologic dysplasia and proliferative advantage of one or more of the myeloid differentiating cell lines
WHO classification of MDS/MPN
Diagnosis requires correlation of bone marrow and peripheral blood findings with clinical, genetic and other laboratory information (Semin Diagn Pathol 2003;20:154)
WHO 2008 classification
4.1 Chronic myelomonocytic leukemia
4.2 Juvenile myelomonocytic leukemia
4.3 Atypical chronic myeloid leukemia
4.4 MDS/MPN, unclassifiable
WHO 2001 classification
Atypical chronic myeloid leukemia
Chronic myelomonocytic leukemia
Juvenile myelomonocytic leukemia
Myelodysplastic / myeloproliferative disease, unclassifiable
References: Leukemia 2008;22:14 (WHO 2008), Blood 2002;100:2292 (WHO 2001)
Chronic myelomonocytic leukemia (CMML) - chronic myeloid neoplasms chapter
Mean age 70 years, 70% male (Leuk Res 2007 Sep 18 [Epub ahead of print])
Variable clinical and hematologic presentations:
(1) myelodysplastic features of blood cytopenias, ineffective hematopoiesis, dysplastic changes and increased blasts resembling refractory anemia, refractory cytopenia with multilineage dysplasia or refractory anemia with excess blasts; plus monocytosis (monocytes may have dysplastic features)
(2) marked leukocytosis with monocytosis, organomegaly, normal hematopoiesis, normal red blood cell and platelet counts, no/minimal dysplastic changes or excess blasts; previously called Philadelphia chromosome negative CML
80% of cases arises de novo; 20% arise from prior myelodysplasia, occasionally with monocytosis (AJCP 2006;126:789)
Splenomegaly in 30-50% with rare rupture (Am J Hematol 2007;82:405, AJSP 1983;7:197), hepatomegaly in 20%
May have tumor forming accumulations of CD123+ plasmacytoid monocytes in lymph nodes, bone marrow or skin (AJSP 2004;28:585)
More closely related to myelodysplasia than myeloproliferative neoplasms using loss of heterozygosity evaluation (Mod Path 2007;20:1166)
Type 1: <5% blasts in blood or <10% blasts in bone marrow
Type 2: 5-19% blasts in blood, 10-19% blasts in bone marrow or Auer rods present; also <20% blasts in blood or marrow; poorer prognosis
If blasts + promonocytes are 20% of more of bone marrow different count, classify as AML
Diagnosis: persistent peripheral blood monocytosis of more than 109/L, with monocytes >10% of WBCs; peripheral blood may have dysplastic changes typical of myelodysplasia, or dysplasia may be limited to monocytes; usually no marrow monocytosis (Mod Path 2006;19:1536)
Case reports: colonic involvement (Nat Clin Pract Gastroenterol Hepatol 2007;4:229), kidney involvement (Archives 2001;125:657), extramedullary tumors (Archives 1996;120:62), 73 year old man with abnormal complete blood count
Treatment: decitabine; median survival 19 months (Cancer 2007;109:713)
Chronic myelomonocytic leukemia (continued)
Micro description:
peripheral blood: monocytes may be normal appearing or have dysplastic features of increased basophilic cytoplasm, abnormal granulation, hyperlobulated nuclei; other lineage cells may have dysplastic changes
bone marrow: hypercellular marrow with mildly increased monocytes (but not diagnostic by itself) and increased granulocytes; may have increased reticulin fibers; variable dysplastic changes in erythroid cells and megakaryocytes
Positive stains: CD13, CD14 and CD33, CD123 (plasmacytoid monocytes), CD42b (abnormal megakaryocytes); nonspecific esterase (alpha naphtyl butyrate esterase or alpha naphtyl acetate esterase-stains monocytes and promonocytes), CD34 (stains blasts, useful for subtyping or differentiating from AML)
Flow cytometry: monocytosis with abnormal antigen expression of 2+ antigens plus 20% of marrow monocytes showing CD14+ expression is specific for CMML versus reactive monocytosis (AJCP 2005;124:799)
Cytogenetics: abnormalities in 20-40%, including trisomy 8, monosomy 7, 7q-, abnormalities of 12p; occasionally t(5;12)(q33;p13) (see below)
Molecular: RAS mutations in 1/3, JAK2 V617F mutations in 13% (Blood 2005;106:3370)
DD: CML and atypical CML (few monocytes identified by nonspecific esterase, no peripheral monocytosis, no CD123+ plasmacytoid monocytic nodules)
Chronic myelomonocytic leukemia with eosinophilia - chronic myeloid neoplasms chapter
Rare (<2% of cases); <50 cases reported to date
Associated with t(5;12)(q33;p13) - PDGFRbeta and TEL genes (Blood 1995;85:2848)
Peripheral eosinophil count > 1500 per microliter; occasionally has only bone marrow eosinophilia
Men, median age 55 years, range 18-68 years
Usually fatal, often due to blast crisis with additional cytogenetic aberrations (AJCP 2006;125:49)
Case reports: abnormal bone marrow eosinophils (Archives 2003;127:1214)
Treatment: imatinib may be useful (Blood 2002;100:1088)
Micro description:
peripheral blood: marked leukocytosis with eosinophilia (80%), monocytosis (60%) and basophilia (40%)
bone marrow: hypercellular
References: Acta Haematol 2002;107:113, Atlas of Genetics and Cytogenetics
Juvenile myelomonocytic leukemia (JMML) - chronic myeloid neoplasms chapter
Formerly called juvenile chronic myelogenous leukemia
Resembles CMML more than CML
60% are children less than 2 years old, range of 1 month to teenagers
10% associated with neurofibromatosis 1 and deletion of NF1 gene
Due to stem cell defect causing deranged hematopoiesis
Varied clinical presentation may include failure to thrive, malaise, fever, bleeding, pallor, lymphadenopathy and hepatosplenomegaly; less frequently skin, lung and GI involvement; rarely CNS involvement (J Pediatr Hematol Oncol 2007;29:770)
Most patients die of disease, although it may wax and wane
Definition: absolute monocyte count > 1 billion/L AND <20% blasts+promonocytes in marrow AND no Philadelphia chromosome AND no BCR-ABL AND
at least two of the following: HbF increased for age, myeloid precursors in blood smear, WBC > 10 x 109/L, clonal abnormality or GM-CSF hypersensitivity of myeloid progenitors (Leukemia 2003;17:277, Table)
Typically WBC is 20-30 million/L with granulocytes and monocytes, occasional dysplasia but not prominent
Case reports: related to EBV infection (Leuk Res 2008;32:181)
Treatment: bone marrow transplant (Blood 2005;105:410); cord blood may provide graft versus leukemia effect (Pediatr Blood Cancer 2008;50:665)
Micro description:
peripheral blood: leukocytosis, monocytosis, nucleated red blood cells
bone marrow: hypercellular with granulocytic hyperplasia, 5-30% monocytes, decreased megakaryocytes, dysplasia not prominent
Juvenile myelomonocytic leukemia (continued)
Cytogenetics: usually normal, occasionally monosomy 7; NO Philadelphia chromosome or BCR-ABL
Molecular: somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases; PTPN11 mutations also occur in Noonan syndrome (Blood 2005;106:2183) no FLT3 activation (Haematologica 2007;92:1557)
DD: Wiskott-Aldrich syndrome (atopic dermatitis-like eczema, no intracellular WASP expression, WASP gene mutation, J Pediatr Hematol Oncol 2007;29:836)
References: US National Cancer Institute, Wikipedia
Atypical chronic myeloid leukemia (aCML) - chronic myeloid neoplasms chapter
Resembles CML due to increased white blood cell count, primarily neutrophils, >10% neutrophilic precursors, <10% monocytes, splenomegaly common
Differs from CML due to lack of BCR-ABL by cytogenetics or RT-PCR, presence of marked granulocytic and multilineage dysplasia, anemia and thrombocytopenia are common, basophilia is uncommon
Median survival less than 2 years, may progress to bone marrow failure or AML
Case reports: with leukemic pleural effusion (J Korean Med Sci 2006;21:936), 2 year old with t(5;12) successfully treated with imatinib (Leuk Res 2004;28 Suppl 1:S65)
Micro description:
peripheral blood: usually <5% blasts
bone marrow: hypercellular marrow with increased M/E ratio, marked granulocytic hyperplasia and dysplasia (convoluted lobulation of nuclei, pseudo-Pelger-Huet forms), <20% blasts; variable dyserythropoiesis and dysmegakaryopoiesis; no/minimal basophilia
Molecular: may have t(8;9) (Cancer Res 2005;65:2662; no BCR-ABL rearrangement; must use RT-PCR because (a) fusion gene may be present with normal karyotype (Hematol Oncol. 2006;24:86) and (b) karyotype may normalize after imatinib treatment (Leukemia 2004;18:1340)
DD: CML (BCR-ABL present, prominent basophils, usually no anemia, no thrombocytopenia, no dysplastic granulocytes)
References: Ann Oncol 2000;11:441, National Cancer Institute
MDS/MPN - unclassifiable - chronic myeloid neoplasms chapter
Includes RARS with dyserythropoiesis and marked thrombocytosis (RARS-T) with megakaryocytes similar to those in ET, PV or primary myelofibrosis; this is a provisional myelodysplasia/myeloproliferative disorder (Haematologica 2008;93:34, Blood 2006;108:2173), with JAK2-V617F mutation present in 48-67%
Case reports: essential thrombocythemia with ringed sideroblasts (Archives 2004;128:815), prominent erythroid dysplasia and t(8;9) progressing to acute erythroid leukemia (Hum Path 2005;36:1148), unclassified disorder with thrombocytosis and splenomegaly (Ann Hematol 2002;81:308)
Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
Myeloid neoplasm associated with PDGFRA rearrangement - chronic myeloid neoplasms chapter
Also called F/P-positive chronic eosinophilic leukemia
First discovered in 2003 (N Engl J Med 2003;348:1201, Proc Natl Acad Sci USA 2003;100:7830)
Expression of FIP1L1-PDFGRA in hematopoietic progenitors may induce a myeloproliferative phenotype by activating multiple signaling molecules including STAT5 (Cancer Res 2007;67:3759)
Fusion gene also associated with AML (Leukemia 2007;21:1183)
Diagnosis: bone marrow examination with tryptase stain, T cell clonal studies; use of immunostains, cytogenetics and molecular studies to detect PDFGRA rearrangement and absence of BCR-ABL
Case reports: with Budd-Chiari syndrome (hepatic vein outflow obstruction, Intern Med 2007;46:1095)
Treatment: very sensitive to imatinib (Blood 2007;109:4635); molecular monitoring appears to be useful (Blood 2007;110:3552)
Micro description: marked bone marrow hypercellularity due to eosinophils and myeloid precursors; also increased CD25+ mast cells and atypical spindle shaped mast cells but no mast cell aggregates; reticulin fibrosis
Molecular: FIP1L1-PDGFRA fusion gene results from cryptic 4q12 interstitial deletion; rare FIP1L1 breakpoint (J Mol Diagn 2007;9:414); other genes may partner with PDGFRA (Br J Haematol 2007;138:77); no KIT mutation
DD: systemic mastocytosis with eosinophilia (mast cell aggregates [highlighted by tryptase stain], no elevated serum tryptase, different mutations, J Allergy Clin Immunol 2007;120:680), chronic eosinophilic leukemia-not otherwise categorized or hypereosinophilic syndrome (no PDFGRA rearrangement)
References: Orphanet J Rare Dis 2007;2:37, Atlas of Genetics and Cytogenetics
Myeloid neoplasm associated with PDGFRB rearrangement - chronic myeloid neoplasms chapter
Very rare
Also called F/P-positive chronic eosinophilic leukemia
PDGFRB is at 5q31-33
Laboratory: leukocytosis and eosinophilia
Diagnosis: bone marrow examination with tryptase stain, T cell clonal studies; use of immunostains, cytogenetics and molecular studies to detect PDFGRB rearrangement and absence of BCR-ABL
Treatment: very sensitive to imatinib (N Engl J Med 2002;347:481, Blood 2007;109:61)
Molecular: PDGFRB gene rearrangements, most common is t(5;12)(q33;p13) involving ETV6/TEL (Acta Haematol 2002;107:113)
DD: chronic eosinophilic leukemia-not otherwise categorized or hypereosinophilic syndrome (no PDFGRB rearrangement)
References: Atlas of Genetics and Cytogenetics
Myeloid neoplasm associated with FGFR1 rearrangement - chronic myeloid neoplasms chapter
First described in 1995 as 8p11 myeloproliferative syndrome (Leukemia 1995;9:1628); previously called stem cell leukemia-lymphoma syndrome
Aggressive hematologic malignancy characterized by myeloid hyperplasia, eosinophilia and precursor lymphoblastic lymphoma, usually T cell type (Acta Haematol 2002;107:101, AJSP 2008;32:14)
Case reports: 19 year old woman with axillary nodule
Diagnosis: bone marrow examination with tryptase stain, T cell clonal studies; use of immunostains, cytogenetics and molecular studies to detect FGFR1 rearrangement and absence of BCR-ABL
Micro description:
bone marrow: hypercellular with myeloid hyperplasia and eosinophilia, no increased blasts, no dysplastic features
Molecular: balanced translocations with 8p11, most commonly t(8;13)(p11;q12) - FGFR1 and ZNF198 (Blood 1998;92:1735); 8p11 may also involve MOZ gene, a putative histone acetyltransferase, associated with AML-M4/M5 (Blood 1997;90:3130); t(5;12)(q33;p13) creating PDGFRB and ETV6 is associated with chronic myelomonocytic leukemia with eosinophilia (Acta Haematol 2002;107:113) - unclear if this should be classified as chronic eosinophilic leukemia with FGFR1 rearrangement or CMML
Molecular figures: Table of FGFR1 gene partners; FISH assay of FIM (also called ZNF198) and FGFR1
DD: chronic eosinophilic leukemia-not otherwise categorized or hypereosinophilic syndrome (no FGFR1 rearrangement)
Miscellaneous myelodysplastic / myeloproliferative type neoplasms
Transient myeloproliferative disorder (TMD) of Down’s syndrome - chronic myeloid neoplasms chapter
Not part of WHO classification system
Also called transient abnormal myelopoiesis, transient leukemia
Affects 10% of newborns with Down’s syndrome
Resembles congenital acute leukemia; occurs within first days of life with numerous blasts in peripheral blood, more than in marrow
Usually resolves in 2-14 weeks in neonates, but 20-30% progress to AML-M7 (AMKL) within 3 years
Early death in 17%, is associated with high WBC at diagnosis, increased bilirubin and liver enzymes, failure to normalize WBC (Blood 2006;107:4606)
Rarely occurs with trisomy 21 but without Down’s syndrome (Arch Dis Child Fetal Neonatal Ed 1998;79:F215)
Associated with hepatic fibrosis (J Clin Pathol 1995;48:973)
Laboratory: WBC up to 100K with 30-50% blasts, nucleated red blood cells, micromegakaryocytes
Case reports: neonate whose blasts exhibited erythroid differentiation (Archives 2002;126:474); nonimmune hydrops in a newborn with Down’s syndrome (Archives 2001;125:1609); placental chorangiosis and aggregates of immature cells with early vascular invasion, but full recovery (Hum Path 2000;31:396)
Micro description:
bone marrow: blasts have moderate basophilic cytoplasm with coarse azurophilic granules resembling those in basophils, round to slightly irregular nuclei; also promegakaryocytes, micromegakaryocytes, dyserythropoiesis
Positive stains: platelet antigens CD41 (100%), CD42b (75%), CD61 (75%); also CD7 (93%), CD13 (47%), CD14 (27%) CD34 (89%), CD33 (83%), CD45 (100%), HLA-DR (80%) (AJCP 2001;116:204, Blood 2006;107:4606)
Negative stains: CD10, myeloperoxidase, Sudan Black B, PAS
Molecular: mutations in GATA1 gene in almost all cases (compared to 4% of all Down’s syndrome infants, Blood 2007;110:2128), specific mutations may differ in TMD and subsequent AML-M7/AMKL (Int J Hematol 2007;86:250); loss of GATA1 impairs maturation of megakaryocyte erythroid progenitors (Blood 2006;107:87), JAK3 mutations found in 50% (Br J Haematol 2007;137:337)
DD: congenital leukemia (clinically aggressive)
End of Chronic myeloid neoplasms chapter