Chronic myeloid neoplasms
Last revised 22 January 2008
Last major update January 2008
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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)
Micro images (general MDS findings):
erythroid: dysplastic erythroid precursor #1; #2 with intercytoplasmic bridge
granulocytes/monocytes: dysplastic granulocyte has hyperlobulated nucleus #1; #2; pseudo-Pelger-Huet cell #1; #2; #3; myeloid maturation arrest is demonstrated by hypolobulated cells; myeloid karyorrhexis
megakaryocytes: micromegakaryocyte; dwarf binuclear megakaryocyte
other: various images; hypercellular marrow; hypocellular MDS; various images
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
EM images: platelet has atypical, very 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
Images: Table of WHO classification (click to improve legibility)
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
Micro images:
peripheral blood: pseudo-Pelger-Huet cell
bone marrow biopsy: slightly hypercellular for a 53 year old man, marked erythroid hyperplasia, prominent megakaryocytes but no increase in their number
bone marrow smear: two post-mitotic erythroid precursors (upper left) with internuclear chromatin bridging; various images #1; #2
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
Micro images:
peripheral blood: red blood cells are dimorphic with normochromic and markedly hypochromic cells
bone marrow smear: Prussian blue stain shows most red blood cell precursors are encircled by small granules of iron #1; #2; #3; various images #1; #2; #3; RARS with thrombocythemia #1; #2; fig 1: peripheral blood shows dual population of microcytic and normocytic red cells with marked poikilocytosis, fig 2: bone marrow smear shows marked erythroid hyperplasia with many erythroid precursors having megaloblastoid maturation or nucleocytoplasmic asynchrony, fig 3: iron stain shows numerous ringed sideroblasts (perinuclear iron granules encircle more than 1/3 of nuclear circumference), fig 4: transmission EM shows nonspecific siderosomes (black arrow) and iron-laden mitochondria (white arrow)
EM: perinuclear iron present in mitochondrial cristae
EM images: erythroid precursor shows iron deposits 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
Micro images: various images
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)
Micro images:
peripheral blood: neutrophil has hypogranular cytoplasm; neutrophil has hypogranular cytoplasm and bilobed, pseudo-Pelger-Huet nucleus
bone marrow biopsy: moderately hypocellular marrow #1; #2-marrow had 11% myeloblasts, blood had 2% myeloblasts, biopsy shows promyelocytes and myelocytes; abnormal localization of immature precursors due to loosely structured focus of myeloblasts and promyelocytes; numerous megakaryocytes with variation in size #1; #2-some megakaryocytes are hypolobulated and have finely dispersed chromatin
bone marrow smear: blast in center with adjacent hypogranular neutrophils, erythroid precursor with multiple nuclear fragments in upper left; large neutrophil (upper right) is hypogranular with marked nuclear hyperlobulation, also single myeloblast with prominent nucleolus and two neutrophils with markedly hypogranular cytoplasm; promyelocytes and myelocytes, and two myeloblasts on right; various images #1; #2; #3
RAEB-1: various images
RAEB-2: blood, marrow and myocardial infiltration; blast and atypical lymphocytes; Auer rod present in blast, 6-8% myeloblasts, neutrophils show nuclear hypolobulation #1; #2; various images
RAEB-2: 47 year old woman with 12% myeloblasts and occasional Auer rods: normocellular biopsy #1; #2-normal erythroid precursors but shift to immature granulocytes; #3-same patient 4 years later has slightly more cellular marrow; #4-high power of #3 shows more immature granulocytes than 4 years prior
RAEB-2: 62 year old man with pancytopenia, and subsequent AML-M2: marked fibrosis with streaming effect plus mature megakaryocytes, some in clusters, no shift to immaturity identified; bone marrow aspirate produced only a few cells, including this blast with an Auer rod
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
Micro images:
peripheral blood: blast and numerous platelets (platelet count was 567K)
bone marrow biopsy: increased megakaryocytes with overall increased PAS+ cytoplasm, nuclear hypolobulation; various images #1; #2; case with JAK2 V617F mutation
bone marrow smear: two small megakaryocytes have granular cytoplasm and nonlobulated nuclei, otherwise classified as RAEB; numerous small megakaryocytes with hypolobulated nuclei
Molecular: interstitial deletions of 5q12 to 5q32
Cytogenetic images: karyotypes #1; #2
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)
Micro images:
peripheral blood: post radiochemotherapy and splenectomy for Hodgkin’s disease, has hypogranular neutrophil with pseudo-Pelger-Huet nucleus, marked poikilocytosis of erythrocytes
bone marrow smear: large erythroid precursors with lobulated nuclei and karyorrhexis
stains: PAS+ erythroid precursors in bone marrow smear
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
Micro images:
peripheral blood: post-chemotherapy for breast cancer, erythrocytes have anisopoikilocytosis with numerous macrocytes, large red cell precursor has marked nuclear lobulation
bone marrow smear: numerous red cell precursors with marked nuclear lobulation, no increased 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
Micro images:
child 2 years post etoposide for ALL with t(9;11)(p21;q23): peripheral blood shows increased monocytes #1; #2-marked increase in monocytes and 3% blasts; bone marrow smear shows slight shift to immaturity with 5% blasts
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
Micro images:
bone marrow smear: 59 year old woman with pancytopenia, abnormally bilobed nuclei in granulocytes, red cell (upper left) has lobulated nucleus, no increase in blasts, monocytes or ringed sideroblasts, could not classify; megakaryocyte clustering and hyperlobulated forms (figs 2/3)
37 year old man with monosomy 5 and 7, pancytopenia: marked increase in megakaryocytes, many with hyperlobulated nuclei; erythroid hyperplasia with marked dyserythropoiesis and megaloblastoid changes; large erythroid precursors with hyperlobulated nuclei, also ringed sideroblasts (<15%), occasional dysplastic neutrophils, no increase in myeloblasts
6 year old girl with trisomy 8, severe anemia and 1-2% blasts in peripheral blood: hypercellular marrow with marked fibrosis, increased megakaryocytes (singly and in clusters) and scattered erythroid islands; cluster of large megakaryocytes with abnormal nuclear lobulation, and adjacent erythroid precursors; bone marrow biopsy post allogeneic bone marrow transplant shows marked reduction in megakaryocytes, overall cellularity and connective tissue; bone marrow biopsy one month post transplant shows recurrence with increased marrow cellularity and prominent megakaryocytes
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)
Micro images:
peripheral blood images: erythroid precursor with slightly lobulated megaloblastoid nucleus
bone marrow smear: erythroid precursors have marked dysplastic changes including nuclear lobulation and karyorrhexis
EM: megaloblastic features of high N/C ratio and nuclear-cytoplasmic dyssynchrony (Blood 1979;53:820)
EM images: figure 2 shows abnormal erythroblasts
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)
Micro images:
peripheral blood: giant platelet #1; #2
bone marrow smear: emperipolesis #1; #2; dysplastic megakaryocyte #1; #2; #3; basophil
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