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Chronic Myeloid Neoplasms

Myeloproliferative neoplasms (MPN)

Chronic myelogenous leukemia (CML)


Reviewer: Nikhil Sangle, M.D., University of Utah & ARUP Laboratories (see Reviewers page)
Revised: 8 August 2011, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Clinical features
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● Most common chronic myeloproliferative neoplasm
● Incidence of 10-20 cases per million annually
● All ages affected; median age in 5th-6th decade
● Originates from pluripotent stem cell that gives rise to myeloid and lymphoid cells
● Marrow has neoplastic and normal granulocyte precursors; BCR-ABL identified in all myeloid lineages, and some lymphoid cells and endothelial cells, but clinically only affects granulocytes
● Insidious onset with anemia, fatigue, weight loss; may have dragging sensation due to splenomegaly; 2040% are asymptomatic and diagnosed incidentally by WBC count
● 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 <100K or >1000K, increasing splenomegaly or white blood cell count while on therapy, marked myelofibrosis, additional or clonal cytogenetic abnormalities with lack of response to treatment, then
blast transformation (phase) 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 (Am J Surg Pathol 2004;28:1240); blasts may accumulate as tumor mass in soft tissue or lymph nodes (extramedullary blast proliferation); presumptive diagnosis of blast phase is warranted if blasts occupy significant portions of bone marrow (e.g. an entire intertrabecular area, Arch Pathol Lab Med 2001;125:1385)

Poor prognostic factors
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● Evolution to myelofibrosis (loss of marrow volume to fibrosis, Hum Pathol 2003;34:391)
● Failure to achieve a cytogenetic response to treatment

Diagnosis
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● Chronic myeloproliferative neoplasm with Philadelphia chromosome or BCR-ABL
Algorithm - if no Philadelphia chromosome but dwarf megakaryocytes, consider performing FISH to detect cryptic translocation of BCR-ABL

Case reports
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● 22 year old woman with pelvic pain and weight loss (Case of the Week #27)
● Teenage boy with CML post-treatment for anaplastic large cell lymphoma (Hum Pathol 2007;38:1576)
● With plasmacytoid T cell lymphoma (Am J Surg Pathol 1985;9:380)
● With complex translocations (Arch Pathol Lab Med 2001;125:437)
● With T cell blast crisis (Arch Pathol Lab Med 2003;127:e249, Hum Pathol 2002;33:770)

Treatment
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Imatinib mesylate (Gleevec/STI571, J Clin Invest 2007;117:2036) an oral tyrosine kinase inhibitor, prevents phosphorylation of tyrosine residues by competing with ATP for binding to the BCR-ABL1 kinase domain
● 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, drug resistance can develop due to point mutations preventing the binding of the inhibitor to the kinase domain of BCR-ABL1
● Imatinib resistance can be circumvented by second generation protein kinase inhibitors (PTKI) such as nilotinib and dasatinib
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 the only curative approach
● Note: may progress to blast transformation despite hematologic response to treatment, suggesting bone marrow follow up is critical (Arch Pathol Lab Med 2004;128:980)

Micro description
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Peripheral blood: >100K white blood cells with neutrophilia, significant bulge in metamyelocytes and myelocytes, also basophilia and eosinophilia, monocytosis (but the monocyte fraction is <3%), low LAP score
● 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)

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 pseudo-Gaucher cells and 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
● CD34 and / or terminal deoxynucleotidyl transferase (TdT) immunohistochemical stains may be required to identify blasts in fibrotic marrows

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; splenic infarcts may appear

Micro images
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Chronic phase-peripheral blood:

Immature to mature myeloid cells


Dysgranulopoiesis


Patient in early chronic phase has WBC count of 10K and platelet count of 617K, with rare immature neutrophils


Later chronic phase has WBC count of 18K, platelet count of 736K and 8% basophils


44 year old woman with WBC count of 425K


Promyelocyte, myelocytes, neutrophils and 2 basophils


Two early promyelocytes and other stages of neutrophil maturation and 3 basophils (52 year old man with WBC count of 147K and platelet count of 740K)

   

Various images

Chronic phase-bone marrow biopsy:

Hypercellular marrow with panmyeloid hyperplasia and moderate adipocytes

       

Hypercellular marrow with increased megakaryocytes; myeloid cells are primarily neutrophils

   

PAS stain: left image shows perivascular and peritrabecular accentuation of promyelocytes and myelocytes (lighter staining compared to darker staining neutrophils); right image shows promyelocytes and myelocytes adjacent to vascular structure

Chronic phase-bone marrow smear:

Pseudo-Gaucher cells

Accelerated phase-peripheral blood:

Blast, immature basophil (high N/C ratio, moderate to intense basophilic cytoplasm, numerous granules) and mature basophil; mature neutrophils show prominent nuclear hyposegmentation


5 basophils and mature neutrophil with pseudo-Pelger-Huet nucleus


33 year old man with knee pain: peripheral blood shows 47% basophils, 10% blasts, t(9;22) present

Accelerated phase-bone marrow biopsy:
   
Moderately hypercellular bone marrow biopsy with numerous megakaryocytes; some megakaryocytes are micromegakaryocytes with hypolobulated nuclei


Moderate increase in reticulin fibers which are focally accentuated (reticulin stain)


Marked hypercellularity with perivascular promyelocytes and myelocytes on right


Perivascular associated increase in reticulin fibers (reticulin stain)

Accelerated phase (general):

Various images

Myeloblastic transformation-bone marrow biopsy:

Increase in stromal and vascular structures


Marked increase in fibroblasts and scattered hematopoietic cells


Numerous blasts with dispersed chromatin and nucleoli


Marked increase in coarse reticulin fibers (reticulin stain)


Post-imatinib therapy

Myeloblastic transformation-bone marrow smear:

Four blasts and two basophils


50% of WBCs are blasts


One poorly differentiated blast and 3 erythroid precursors


Several myeloblasts and basophils, with immature basophil at upper left


Myeloblasts with Auer rod and pseudo-Pelger-Huet nucleus


Transformation to AML with inv(16), t(9;22) and M4 morphology shows increase in marrow eosinophils with abnormal basophil staining granules, increased blasts and slight monocytosis

Megakaryoblastic transformation-peripheral blood:
       

Left: EM showed platelet peroxidase in blasts; middle: high WBC count and high percentage of micromegakaryocytes; right: different patient; EM showed megakaryocyte differentiation

Lymphoblastic transformation-peripheral blood:

Differential showed 41% lymphoblasts, which are small cells with high N/C ratio, condensed chromatin and no/indistinct nucleoli


WBC count of 142K, 55% blasts, 34% neutrophils, blasts had preB phenotype, TdT+, also promyelocytes, myelocytes and neutrophils, may resemble AML-M2 due to large percentage of neutrophils and precursors

Lymphoblastic transformation-bone marrow biopsy:

Complete replacement by blasts, which were preB phenotype and TdT+, occasional mitotic figures present


Post-hydroxyurea and post-imatinib

Lymphoblastic transformation-bone marrow smear:

Blasts (TdT+, myeloperoxidase-)


Imprints from cervical node biopsy show uniform population of blasts, some with coarse azurophilic granules and slightly indented nuclei


Different patient-lymphoblasts resemble ALL-L3 (CD19+, CD20+, Oil Red O+ vacuoles that are PAS- but were TdT+ and surface Ig negative )

Lymphoblastic transformation-lymph node biopsy:

Diffuse replacement by lymphoblasts (preB phenotype, TdT+)


Uniform lymphoblasts, some with clefted nuclei

Lymphoblastic transformation-EM:

Blasts were pre-B phenotype and TdT+, have several large basophil granules and a theta granule

Erythroblastic transformation-bone marrow biopsy:

<6% blasts overall, several well circumscribed foci


Blasts have variable cytoplasm, fine chromatin, prominent nucleoli


Blasts are Hemoglobin A+

Focal blastic transformation:

Patient had 22% blasts in marrow; peripheral blood shows shows 3 blasts at lower left, platelets moderately reduced


Bone marrow biopsy shows foci of blasts with mitotic figures


Bone marrow smear with 12% blasts (not shown here), neutrophils at all stages of maturation

Osteomyosclerosis (26 year old woman with 3 year history of CML) - bone marrow biopsies:

Widened trabeculae and densely fibrotic medullary spaces


Marked increase in coarse reticulin fibers (reticulin stain)


Post-transplant biopsy shows regression of fibrosis with return of fat cells, but still widened bony trabeculae

   

5 months post-transplant biopsy; left image shows markedly hypocellular marrow with almost no fibrosis; right images shows erythroid cells and megakaryocytes, but reduced granulocytes

Spleen:

H&E and stains

Post-treatment changes
   
Post hydroxyurea: bone marrow biopsy shows slightly hypercellular marrow with numerous megakaryocytes; megakaryocytes are often small with hypolobulated nuclei


Post-interferon: peripheral blood smear shows slightly decreased WBCs with no evidence of CML


Post-interferon: bone marrow biopsy is slightly hypercellular with normal megakaryocytes and slight erythroid hyperplasia


Post-interferon: high power shows reduced granulocytes and slight erythroid hyperplasia, interstitium shows cellular depletion with loosely arranged cells

Positive stains
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● Myeloperoxidase, specific esterase (naphthol-ASD-chloracetate esterase)
● BB1 (basogranulin) stains basophils (Am J Clin Pathol 2006;125:273)

Molecular description
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● 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, RT-PCR or Southern-blot techniques to detect cryptic translocations
● Fusion gene produces 210 kd protein with tyrosine kinase activity that affects cell motility, deregulates the cell proliferation, reduces the capacity to adhere to bone marrow stroma or endothelial cells (BMC Cancer 2006;6:262)
● No FLT3 mutations (Am J Clin Pathol 2006;126:530)

Molecular images
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Karyotypes


Diagram of fusion proteins


Differential diagnosis
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● Leukemoid reaction, other chronic myeloproliferative neoplasms (increased LAP, negative for BCR-ABL), paroxysmal nocturnal hemoglobinuria (LAP negative/low, negative for BCR-ABL)

Additional references
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eMedicine

End of Chronic Myeloid Neoplasms > Myeloproliferative neoplasms (MPN) > Chronic myelogenous leukemia (CML)


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