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Acute myeloid leukemias

o General
Aquired onogenic mutation
Replaces BM w/ blasts leading to anemia, thrombocytopenia, and
neutropenia
Occurs at all ages; MC 39-60; 13,000 cases each year in US
o Classifications
Particular genetic aberrations
AML after a MDS disorder or w/ MDS-like features
Therapy-related AML
AMLs lacking any of these features
o Pathogenesis
Gene aberrations disrupt transcription factors
T(8;21) and inversion(16) disrupt RUNX1 and CBFB
Blocks maturation of myeloid cells
Activation of growth factor signaling pathways
T(15;17) fusion gene w/ RAR to form PML
Interfers w/ terminal differentiation of granulocytes
o Treated w/ all-trans retinoic acid or arsenic trioxide
Frequently RTK (FLT3)
Mutations affecting factors that impact state of epigenome
Suggests epigenetic alterations have central role
o Morphology
Diagnosis based on >20% of myeloid blasts
Delicate nuclear chromatin, 2-4 nucleoli, voluminous cytoplasm
Auer rods- distinctive needle like azurophilic granules
Monoblasts have folded/lobulated nuclei and lack Auer rods
Aleukemic leukemia
Blasts entirely absent from blood; reason BM examination is
essential
o Cytogenetics
Karyotype abberations in 50-70% (standard) and 90% (high resolution)
Balanced chromosomal translocations in AMLs in younger adults
T(8;21), inv(16), and t(15;17)
AMLs following myelodysplastic syndromes or chemo often have
deletions
Chromosomes 5 and 7; usually lack translocations
AMLs in older adults associated with bad aberrations (d 5q, 7q)
o Clinical features
Anemia, neutropenia, and thrombocytopenia
Fatigue, fever, and spontaneous mucosal and cutaneous bleeding
Cutaneous petechial/ecchymoses
Serosal hemorrhages (body cavities/viscera); mucosal (gingivae and
urinary tract)
Frequent infects: Pseudomonas and opportunistic pathogens
Tumors w/ monocytic diff. often infiltrate the skin (leukemia cutis)/
gingiva

Occasionally presents as myeloblastoma, granulocytic sarcoma, or


chloroma
Localized soft-tissue mass
o Prognosis
60% achieve complete remission w/ chemo; only 15-30 remain free
after 5 years
AMLs w/ t(15;17) have best prognosis (80%)
AMLs following MDS/genotoxic therapy or adults has worst prognosis
High risk and relapse forms treated w hematopoietic stem cell
transplantation
DNA sequencing important in selecting therapy
Myelodysplastic syndromes
o General
Maturation defects w/ ineffective hematopoiesis; high risk for AML
Peripheral blood cytopenias
Primary (idiopathic) or secondary to therapy (t-MDS)- appears 2-8
years after
o Pathogenesis
Epigenetic factors, RNA splicing factors, and Transcription factors
10% have loss of function mutations of TP53= poor outcome
Monosomies 5, 7; deletions of 5q, 7q, 20q, and trisomy 8
Trisomy 8 increases oncoprotein MYC
o Morphology
Bone marrow hypercellular at diagnosis but can be normal or
hypocellular
Disordered/dysplastic differentiation is most characteristic finding
Ring sideroblsts, magaloblstoid maturation, nuclear budding
abnormalities
Pseudo-Pelger-Huet cells: neutrophils w/ only 2 lobes
Pawn ball megakaryocytes
o Megakaryocytes w/ 1 nuclear lobe or multiple separate
nuclei
Myeloid blasts may be increased but are less than 20%; usually less
than 10%
o Clinical features
Primary MDS: older adults; mean age of 70
Discovered incidentally in half of the cases
Weakness, infections, and hemorrhages all due to pancytopenia
8 categories based on morph and cytogenetic features; 5 major
prognostic groups
Median survival is 9-29 months; progression to AML in 10-40%
Thrombocytopenia (bleeding) and neutropenia (infections)
Outlook is worst in t-MDS; 4-8 months
Treatment limited
Thalidomide-like drugs, DNA methylation inhibitors improve
hematopoiesis
o Presence of isolated 5q is correlated w/ thalidomide like
drugs

Myeloproliferative disorder
o General
Mutated, constitutively activated tyrosine kinase
No impairment to differentiation
Most commonly increases production of one or more mature blood
elements
Most originate in multipotent myeloid progenitors
4 common features
Increased proliferative drive in bone marrow
Extramedullary hematopoiesis
Variable transformation to marrow fibrosis and peripheral blood
cytopenia
Variable transformation to acute leukemia
o CML
General
Presence of a chimeric BCR-ABL gene derived from BCR (22) and
ABL (9)
90% of cases have reciprocal (9;22)(q34;q11) translocation
o Philadelphia chromosome
Pathogenesis
RTKs normally regulated by ligand-mediated
dimerization/autophos
ABL kinase phosphorylates=induces pro-growth/survival
o RAS and JAK/STAT pathways
Preferentially drives prolif of granulocytic/megakaryocytic
precursor
Morphology
Hypercellular due to massively increased numbers of
granulocytic precursors- elevated proportion of eosinophils and
basophils
o Megakaryocytes are increased and usually small/dysplastic
Sea-blue histocytes- scattered macrophages w/ green-blue
cytoplasm
Leukocytosis often greater than 100,000; blasts increased but
less than 10%
Platelets usually increased, spleen is often greatly enlarged
Clinical features
Primarily in adults; peak is 5th-6th decade of life; 4,500 new
cases/year
Insidious onset; dragging sensation in abdomen
Median survival is 3 years w/o treatment
50% enter accelerated phase
o Increasing anemia and thrombocytopenia
o Trisomy 8, iso 17q, or duplication of Ph chromosome
o Phase terminates in 6-12 mons- acute leukemia; resembles
blast crisis
50% blast crises ends abruptly w/o accelerated phase

70% of crises, the blasts are of myeloid origin; 30% pre B cell
(lymphoid)
Treatment w/ BCR-ABL inhibitors= sustained hematologic
remissions greater than 90% of patients with tolerable side
effects
o Does not extinguish the CML stem cell
o Decreases rate of mutations that leads to disease
progression
Hematopoietic stem cell transplantation is curable in 75% of
cases
o Young patients and in stable phase
o Polycythemia vera
General
Strong association w/ point mutations in RTK JAX2
Pathogenesis
JAK2 is part of JAK/STAT pathway, which lies downstream of
multiple hematopoietic growth factor receptors, including
erythropoietin
Serum EPO is low in PCV; high in secondary forms of
polycythemia
Patients prone to thrombosis and bleeding
Elevated hematocrit leads to blood viscosity/sludging
97% associated w/ JAK2 valine-phenylalanine substitution at 617
25-30% of cases contain 2 mutated copies
o Higher WBC, splenomegaly, symptomatic pruritus, and a
greater rate of progression to the spent phase
Proliferative drive in PCV is less than CML
Morphology
Increase in red cell progenitors is subtle and accompanied by
increase in granulocytic precursors and megakaryocytes as well
May have increase in reticulate fibers
Peripheral blood contains increased numbers of basophils and
abnormally large platelets
Transformation to AML in 1%
Clinical features
Uncommon but most common in middle aged adults
Increase in total blood volume
Headache, dizziness, hypertension, and GI symptoms are
common
Intense pruritus and peptic ulceration may occur, both due to
histamine release from basophils; hyperuricemia
Symptomatic gout in 5-10%
Abnormal blood flow and platelet function increases risk of major
bleeding and thrombotic episodes
Minor hemorrhages (epistaxis, bleeding gums) are common
Life threatening hemorrhages in 5-10%
Hemoglobin ranges from 14-28; hematocrit 60%; platelet
>500,000

Simply maintaining the red cell mass near normal by phlebotomy


extends median survival to 10 years
15-20% of people undergo spent phase transition after 10 years
where they exhibit myelofibrosis features
o Essential thrombocytosis
Associated w/ activating point mutations in JAK2 (50%) or MPL (5-10%)
Elevated platelet count but no polycythemia or marrow fibrosis
Bone marrow cellularity is only mildly increased
Megakaryocytes are often markedly increased in number+ abnormally
large
Dysfunctions of platelets derived from the neoplastic clone can lead to
thrombosis and hemorrhage- major clinical manifestations
Erythromelagia, a throbbing and burning of hands and feet caused by
occlusion of small arterioles by platelet aggregates- may also be seen
in PCV
Median survival time is 12-15 years; thrombotic complications most
likely (JAK2)
o Primary myelofibrosis
Hallmark is development of obliterative marrow fibrosis
Leads to cytopenia; extensive extramedullary hematopoiesis
JAK2 mutations in 50-60%
Chief pathologic feature is the extensive deposition of collagen in the
marrow by non-neoplastic fibroblasts
Caused by neoplastic megakaryocytes inappropriate release of:
o Platelet-derived growth factor fibroblast mitogen
o TGF-B- fibroblast mitogen; stims. collagen deposition;
angiogenesis
Both observed in myelofibrosis
Unclear if truly distinct from PCV and ET or an unusually rapid
progression in spent phase
Morphology
Marrow becomes more hypocellular and diffusely fibrotic
Clusters of atypical megakaryocytes
Extramedullary hematopoiesis- enlarged spleen (up to 4000gm)
o Firm and diffusely red to gray
Leukoerythroblastosis- premature release of nucleated erythroid
and early granulocyte progenitors
Teardrop-shaped red cells (dacryocytes)
Abnormally large platelets and basophilia (nonspecific though)
Clinical features
LC than PCV and ET; usually over 60 years old
Moderate to severe normochromic normocytic anemia
o Accompainied by leukoerythroblastosis
WBC normal or mildly reduced; platelets normal or mildly raised
Bone marrow biopsy essential for diagnosis
Harder to treat than PCV or ET
Median survival is 3-5 years

Threats to life include infections, thrombotic episodes, bleeding


related to platelet abnormalities, and transformation to AML (520% of cases)
JAK2 inhibitors recently approved and are effective at decreasing
splenomegaly and constitutional symptoms
Langerhans Cell Histiocytosis
o General
Histocytosis is umbrella term for proliferative disorders of dendritic
cells or macrophages
Some are malignant; some are benign
Langerhans cell falls between malignant and benign
Majority have oncogenic mutations
MC is activating valine-glutamate sub at res 600 in BRAF
o Found in 55-60% of hairy cell leukemia too
P53, RAS, and MET also sites of mutations
Presence of Birbeck granules in cytoplasm is characteristic
Pentalaminar tubules w/ dilated terminal end
Tennis racket-like appearance with langerin
Some tumor cells typically express CD1a and HLA-DR, S-100
o Multifocal (Letterer-Stwe disease)
MC before 2years of age
Development of cutaneous lesions resembling seborrheic eruption
Hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and
eventually destructive osteolytic bone lesions
Untreated is rapidly failure; intensive chemo 50% live 5 years
o Unifocal and multifocal (eosinophilic granuloma)
o Unifocal lesions
DiGeorge syndrome
Thymic hyperplasia