Background
Acute myelogenous leukemia (AML) arises from myeloid precursor cells in the bone marrow. These immature cells or blasts give rise to myeloblasts, monoblasts, erythroblasts, and megakaryoblasts. The symptoms of AML are similar to other acute leukemias and may present with flu-like symptoms, bleeding, and occasionally hepatosplenomegaly and lymphadenopathy. The identification of several chromosomal abnormalities has led to tremendous advances in leukemia research. Some investigators have proposed new classification systems based upon any possible association with myelodysplasia and cytogenetic abnormalities.
OUTLINE
FAB CLASSIFICATION CHROMOSOME ABNORMALITY FREQUENCY (PERCENTAGE) M3 t(15;17)(q22;q11-12) 95-100 M4EO inv(16)(p13q22) or t(16;16)(p13;q22) 100 M2 t(8;21)(q22;q22) 18-20 M1-M2 t(9;22)(q34;q11) 8 M1, M2, M4, M5, M6 +8 9 M1, M4, M5 t(v;11)(v;q23)
v=vary chromosomes 9 and 199
HISTOLOGICAL TYPES CHARACTERIZATION BLASTS Type I myeloblast Fine nuclear chromatin with 2-4 distinct nucleoli
Moderate rim of pale to basophilic cytoplasm without azurophilic granulesType II myeloblast Similar to type 1 blast with addition of up to 20 delicate azurophilic granules in the cytoplasm
Promyelocyte is larger than type II blast and has numerous azurophilic granules
Type III myeloblast Numerous azurophilic granules but smaller than promyelocyte FRENCH-AMERICAN-BRITISH CLASSIFICATION (FAB) By definition, acute leukemia is diagnosed with 20%of type I and II blasts but some variants such as M3 rarely have 20% blasts
MPO is myeloperoxidase
SBB is Sudan Black B
NSE is non specific esteraseM0
Acute myeloblastic leukemia, minimally differentiated>/= 20% blasts
<3% blasts reactive for MPO, SBB, or NSE>/= 20% blasts express one or more myeloid antigens: CD13, CD14, CD33
May be TdT positive but blasts negative for lymphocyte antigens
Diagnostic Criteria for Minimally Differentiated Acute Myeloid Leukemia (AML-M0) Evaluation and a Proposal
Zahid Kaleem, MD, and Glenda White, MT(ASCP)
Am J Clin Pathol 2001;115:876-884 Abstract quote
We studied immunophenotypic features of 30 cases of minimally differentiated acute myeloid leukemia (AML-M0) using multiparameter flow cytometry and immunohistochemistry and evaluated the immunophenotypic features of previously reported cases to facilitate correct identification of myeloid lineage. All but 1 of our 30 cases expressed CD13 and/or CD33; 2 expressed CD19; 1 expressed CD10; none expressed both CD10 and CD19. Eleven of 30 cases expressed T-cell–associated antigens. All but 2 cases expressed CD34 and/or HLA-DR. Twelve of 27 cases expressed terminal deoxynucleotidyl transferase. Myeloperoxidase (MPO) expression was seen in 22 of 22 cases by immunohistochemistry and 1 of 4 by flow cytometry. None of 27 cases expressed cyCD3 and cyCD79a.
We propose following modified criteria for AML-M0: (1) standard criteria for acute leukemia; (2) undetectable or less than 3% MPO or Sudan black B staining in blasts; (3) lack of expression of lymphoid-specific antigens, cyCD3 for T lineage and cyCD79 and cyCD22 for B lineage; and (4) positivity for any of the myelomonocytic lineage antigens known not to be expressed on normal T or B lymphocytes or positivity for MPO as detected by ultrastructural cytochemistry, immunohistochemistry, or flow cytometry.
M1
Acute myeloblastic leukemia, without maturation>/= 20% blasts
>/= 3% blasts reactive for MPO or SBB
<10% or marrow nucleated cells are promyelocytes or more mature neutrophilsBlasts positive for CD13, CD14, CD33
M2
Acute myeloblastic leukemia, with maturation>/= 20% blasts
>/= 3% blasts reactive for MPO or SBB
>/= 10% of marrow nucleated cells are promyelocytes or more mature neutrophilsBlasts myeloid antigen positive
40-80% t(8;21) associated cases are CD19+
20% of t(8;21) associated cases are Tdt+M3
Acute promyelocytic leukemia>/= 20% blasts and abnormal promyelocytes
Intense MPO and SBB positivity
Promyelocytes and blasts with mulitiple Auer rods (faggot cells)
t(15;17) chromosomal abnormalityMyeloid antigens
Promyelocytes are HLA-DR negative in most cases Microgranular (hypogranular) M3 Morphologic, Cytogenetic, and Molecular Abnormalities in Therapy-Related Acute Promyelocytic Leukemia
C. Cameron Yin, MD, PhD, Armand B. Glassman, MD, Pei Lin, MD, Jose R. Valbuena, MD, Dan Jones, MD, PhD, Rajyalakshmi Luthra, PhD, and L. Jeffrey Medeiros, MD Am J Clin Pathol 2005;123:840-848 Abstract quote
We describe 17 cases of therapy-related acute promyelocytic leukemia (tAPL). Treatment for the initial neoplasms (mostly carcinomas and non-Hodgkin lymphomas) included radiation and chemotherapy in 11 patients, radiation in 3, and chemotherapy in 3. The interval between the initial neoplasm and tAPL ranged from 17 to 116 months (median, 40 months).
Morphologically, all 13 cases with available bone marrow aspirate smears showed tAPL. Dyserythropoiesis or dysmegakaryopoiesis was identified in 11 cases. In 2 cases, too few nonneoplastic cells and, in all cases, too few maturing granulocytes were present to assess for dysplasia. Conventional cytogenetics or fluorescence in situ hybridization (FISH) showed the t(15;17)(q22;q21) in all cases; 6 as a sole abnormality, 9 with additional abnormalities, and 2 assessed only by FISH. Reverse transcription–polymerase chain reaction (PCR) studies showed PML/RARa in 13 cases (8 short form, 5 long form). Mutations of the flt3 gene were detected by PCR in 5 (42%) of 12 cases.
We conclude that dysplastic features, secondary cytogenetic abnormalities, and flt3 mutations are common in tAPL.M4
Acute myelomonocytic leukemia>/= 20% myeloblasts, monoblasts, and promonocytes
>/= 80% monocytic cells in marrow
>/= 5x10*9/L monocytic cells in blood
>/= 20% neutrophils and precursors in marrow
Monocytic cells reactive for NSE
Abnormal eosinophils in M4 with associated inv(16) chromosome abnormalityVarying proportions of blasts and monocytic cells positive for CD13, CD14, CD15, CD33
Monocytes positive for CD36 M4EO
Acute myelomonocytic leukemia with increased marrow eosinophilsDysplasia and High Proliferation Rate Are Common in Acute Myeloid Leukemia With inv(16)(p13q22)
Xiaoping Sun, MD, PhD, L. Jeffrey Medeiros, MD, Di Lu, MD, PhD, George Z. Rassidakis, MD, and Carlos Bueso-Ramos, MD, PhDAm J Clin Pathol 2003;120:236-245 Abstract quote
Acute myeloid leukemia (AML) with inv(16)(p13q22), also known as M4Eo, is a distinct type of AML with a favorable prognosis associated with abnormal bone marrow eosinophils.
We reviewed the morphologic findings of archival bone marrow specimens with M4Eo, specifically assessing for dysplasia, and performed immunohistochemical studies to assess the growth fraction using the MIB-1 (Ki-67) antibody. We also assessed the apoptotic rate by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–nick end labeling. All assessable cases had more than 10% dysplastic forms in at least 1 lineage. Seventeen cases had 10% or more dysplastic forms, and 3 cases had more than 50% dysplastic forms in at least 2 lineages. Immunoreactivity for Ki-67 was higher in M4Eo than in other AML types (P = .000). The apoptotic rate in M4Eo was similar to other AML types (P = .724).
Our data show that dysplasia is a prominent feature, but not a prognostic indicator, in M4Eo. M4Eo is associated with a significantly higher proliferation rate than other AML types.M5A
Acute monoblastic leukemia, poorly differentiated>/= 80% monocytic cells
Monoblasts >/=80% of monocytic cells
Monoblasts and promonocytes NSE positive although 10-20% cases are negative
Monoblasts usually MPO and SBB negativeVarying proportions of CD13, CD14, CD15, and CD33 positive
Monoblasts CD36 and usually CD4+M5B
Acute monoblastic leukemia, differentiated>/=80 monocytic cells
Monoblasts<80% of monocytic cells
Promonocytes predominate
Monoblasts and promonocytes NSE positive
Promonocytes scattered MPO and SBB positive granulesVarying proportions of CD13, CD14, CD15, and CD33 positive
Monoblasts and promonocytes CD36+M6
Erythroleukemia>/= 50% erythroid precursors
>/= 20% of nonerythroid precursors are myeloblasts
Auer rods may be present in myeloblasts
Dyserythropoiesis
Erythroid precursors frequently PAS positiveMyeloid antigens in myeloblasts
Erythroid precursors express glycophorin A, hemoglobin A, and express CD36M7
Acute megakaryoblastic leukemia>/= 30% blasts
>/= 50% megakaryocytic cells by morphology, immunophenotype studies, or electron microscopyMegakaryocytes cells express myeloid antigen CD33
Platelet glycoproteins (CD41 and CD61)
CD36 proteinsADDITIONAL VARIANTS 3(q21;q26) t(6;9)(p23;q34) Acute Myeloid Leukemia With t(6;9)(p23;q34) Is Associated With Dysplasia and a High Frequency of flt3 Gene Mutations
Mauricio P. Oyarzo,MD , Pei LinMD, , Armand GlassmanMD, , Carlos E. Bueso-RamosMD, PhD, , Rajyalakshmi LuthraPhD, , and L. Jeffrey MedeirosMD, Am J Clin Pathol 2004;122:348-358 Abstract quote
We report 12 cases of t(6;9)(p23;q34)-positive acute myeloid leukemia (AML), all classified using the criteria of the World Health Organization classification.
There were 10 women and 2 men with a median age of 51 years (range, 20-76 years). Dysplasia was present in all cases (9 previously untreated), and basophilia was present in 6 (50%). Immunophenotypic studies showed that the blasts were positive for CD9, CD13, CD33, CD38, CD117, and HLA-DR in all cases assessed. CD34 was positive in 11 (92%) of 12, and terminal deoxynucleotidyl transferase was positive in 7 (64%) of 11 cases. The t(6;9) was the only cytogenetic abnormality detected in 7 cases (58%), and 5 cases had additional chromosomal abnormalities. Of 8 cases assessed, 7 (88%) had flt3 gene mutations.
We conclude that t(6;9)-positive AML cases have distinctive morphologic features, an immunophenotype suggesting origin from an early hematopoietic progenitor cell, and a high frequency of flt3 gene mutations.t(8;21)
- Correlation between karyotype and quantitative immunophenotype in acute myelogenous leukemia with t(8;21).
Khoury H, Dalal BI, Nantel SH, Horsman DE, Lavoie JC, Shepherd JD, Hogge DE, Toze CL, Song KW, Forrest DL, Sutherland HJ, Nevill TJ.
1Department of Cellular and Molecular Biology, Princess Margaret Hospital, Toronto, Ontario, Canada.
Mod Pathol. 2004 Oct;17(10):1211-6 Abstract quote.
Acute myelogenous leukemia with t(8;21) is a distinct clinicopathologic entity in which the malignant myeloblasts display a characteristic pattern of surface antigen expression. Quantitative analysis of surface marker expression in patients with this chromosomal abnormality compared to acute myelogenous leukemia patients with a different karyotype has not been reported.
From 305 consecutive newly diagnosed acute myelogenous leukemia patients underwent immunophenotyping and cytogenetic analysis at our center; 16 patients (5.2%) had a t(8;21). Fluorescence intensity values were obtained, using a set of reference microbeads, by conversion of mean channel fluorescence to molecular equivalent of soluble fluorochrome. Patients with t(8;21) displayed higher levels of CD34, HLA-DR and MPO expression (P<0.001 for each) and lower levels of CD13 (P=0.03) and CD33 (P=0.02) expression. In order to study the sensitivity, specificity and predictive value of these markers, molecular equivalent of soluble fluorochrome thresholds were statistically determined. The statistically established threshold for each of the individual markers (CD34>60.5 x 10(3), HLA-DR>176.1 x 10(3), MPO>735.1 x 10(3), CD13<24.3 x 10(3) and CD33<17.3 x 10(3)) had a sensitivity of 100%, a specificity of 62-92% and a positive predictive value of 7-45%.
In multivariate analysis, two quantitative patterns (CD34>60.5 x 10(3) and MPO>176.1 x 10(3); CD33<17.3 x 10(3) and MPO>176.1 x 10(3)) had a sensitivity, specificity and positive predictive value of 100%. These aberrant phenotypic patterns might help identify patients with t(8;21) at diagnosis and could be useful in minimal residual disease monitoring.Acute basophilic leukemia >/= 20% blasts
Evidence of differentiation to basophils by light or EM
Usually + for metachromatic stainsHYPOCELLULAR AML Acute myeloid leukemia and transient myeloproliferative disorder of Down syndrome ACUTE MYELOFIBROSIS BIPHASIC
Biphasic acute myeloid leukemia with near-tetraploidy and immunophenotypic transformation.
Imkie M, Davis MK, Persons DL, Cunningham MT.
Department of Pathology, University of Kansas Medical Center, Kansas City, Kan 66223, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):448-51. Abstract quote
This report describes a case of acute myeloid leukemia (subtype M1) with biphasic morphology. The bone marrow biopsy showed 2 distinct regions of blasts, one containing large cells and the other small cells. Morphometric and DNA ploidy analysis showed that the mean nuclear area and mean DNA index for the large cell region were 2-fold higher than those for the small cell region. Cytogenetic analysis showed an abnormal near-tetraploid clone. The tumor relapsed following aggressive therapy. The cells from the relapse specimen were similar to the original small cell region with respect to nuclear area and DNA index; however, there was immunophenotypic transformation with gain of CD7 and gain of CD56.
Cytogenetically, the relapse specimen showed no evidence of the near-tetraploid clone, but instead had a previously unidentified abnormal clone containing 46 chromosomes and structural abnormalities of 2q and 7q. Biphasic morphology in acute myeloid leukemia may be predictive of a near-tetraploid subclone and immunophenotypic transformation.GRANULOCYTIC SARCOMA (LEUKEMIA CUTIS) Concurrent Chronic Lymphocytic Leukemia Cutis and Acute Myelogenous Leukemia Cutis in a Patient with Untreated CLL
Michael K. Miller, M.D.; James A. Strauchen, M.D.; Khanh T. Nichols, M.D.; Robert G. Phelps, M.D.
From the Departments of Dermatopathology, Dermatology, and Pathology, Mount Sinai School of Medicine, New York, New York.
Am J Dermatopathology 2001;23:334-340 Abstract quote
Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare.
In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies.
Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient.
The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.PSEUDO-CHEDIAK-HIGASHI ANOMALY Acute Myeloid Leukemia With Pseudo–Chédiak-Higashi Anomaly Exhibits a Specific Immunophenotype With CD2 Expression
Hong Chang, PhD, MD, FRCPC, and Qi Long Yi, PhD
Am J Clin Pathol 2006;125:791-794Abstract quote
Acute myeloid leukemia (AML) with pseudo–Chédiak-Higashi (PCH) anomaly is a rare morphologic entity.
We characterized 5 cases by multiparameter flow cytometry and found that in all cases, the blasts aberrantly expressed CD2, a pan–T cell–associated marker, in addition to their myeloid-associated markers.
In contrast, CD2 was expressed in only 25 (17.9%) of 140 cases of newly diagnosed AML without PCH anomaly. CD2 expression correlated strongly with AML with PCH anomaly (P < .01), suggesting a link between a specific immunophenotypic marker, CD2, and AML with PCH anomaly.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION Sudan Black B (SBB) Positive in cells of neturophili, eosinophil, and monocyte lineage Nonspecific esterase (NSE) Positive in monocytes Myeloperoxidase (MPO) Positive in cells of neturophili, eosinophil, and monocyte lineage Evaluation of Bone Marrow Specimens With Acute Myelogenous Leukemia for CD34, CD15, CD117, and Myeloperoxidase Comparison of Flow Cytometric and Enzyme Cytochemical Versus Immunohistochemical Techniques
Cherie H. Dunphy, MD, Jacek M. Polski, MD, H. Lance Evans, MD, and Laura J. Gardner, MD
From the Division of Hematopathology, Department of Pathology, St Louis University Health Sciences Center, St Louis, Mo (Drs Dunphy, Evans, and Gardner); and the Department of Pathology, University of South Alabama, Mobile, Ala (Dr Polski).
Arch Pathol Lab Med 2001;125:1063–1069. Abstract quote
Context. —Immunophenotyping of bone marrow (BM) specimens with acute myelogenous leukemia (AML) may be performed by flow cytometric (FC) or immunohistochemical (IH) techniques. Some markers (CD34, CD15, and CD117) are available for both techniques. Myeloperoxidase (MPO) analysis may be performed by enzyme cytochemical (EC) or IH techniques.
Objective. —To determine the reliability of these markers and MPO by these techniques, we designed a study to compare the results of analyses of these markers and MPO by FC (CD34, CD15, and CD117), EC (MPO), and IH (CD34, CD15, CD117, and MPO) techniques.
Materials and Methods. —Twenty-nine AMLs formed the basis of the study. These AMLs all had been immunophenotyped previously by FC analysis; 27 also had had EC analysis performed. Of the AMLs, 29 had BM core biopsies and 26 had BM clots that could be evaluated. The paraffin blocks of the 29 BM core biopsies and 26 BM clots were stained for CD34, CD117, MPO, and CD15. These results were compared with results by FC analysis (CD34, CD15, and CD117) and EC analysis (MPO).
Results. —Immunodetection of CD34 expression in AML had a similar sensitivity by FC and IH techniques. Immunodetection of CD15 and CD117 had a higher sensitivity by FC analysis than by IH analysis. Detection of MPO by IH analysis was more sensitive than by EC analysis. There was no correlation of French-American-British (FAB) subtype of AML with CD34 or CD117 expression. Expression of CD15 was associated with AMLs with a monocytic component. Myeloperoxidase reactivity by IH analysis was observed in AMLs originally FAB subtyped as M0.
Conclusions. —CD34 can be equally detected by FC and IH techniques. CD15 and CD117 are better detected by FC analysis and MPO is better detected by IH analysis.
CD99
- Immunoreactivity of MIC2 (CD99) and terminal deoxynucleotidyl transferase in bone marrow clot and core specimens of acute myeloid leukemias and myelodysplastic syndromes.
Kang LC, Dunphy CH.
Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Arch Pathol Lab Med. 2006 Feb;130(2):153-7. Abstract quote
CONTEXT: MIC2 ("thymus leukemia") antigen has been shown to be expressed by T cells and monocytes, as well as B cells and granulocyte-lineage cells. It is most intensely expressed by the most immature thymus T-lineage cells and is more intensely expressed by CD34-positive/CD33-positive myeloid cells (compared to more mature myeloid cells) and the earliest CD34-positive/CD10-positive B-cell precursor cells (compared to cells of later B-cell precursor stages). CD99 (MIC2) is characteristically expressed in precursor B- and T-cell lymphoblastic lymphomas/leukemias, as well as in Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET). It has also been shown to be expressed in a few terminal deoxynucleotidyl transferase (TdT)-positive myeloid processes, but has been uniformly negative in TdT-negative myeloid processes. A more recent study showed that 43% of acute myeloid leukemias (AMLs) and 55% of chloromas express CD99, concluding that CD99 is commonly expressed in AML and rarely seen in myeloproliferative disorders, myelodysplastic syndromes, or normal bone marrow. Although this study speculated that MIC2 expression was probably not limited to TdT-positive AML, there was no comparison with TdT reactivity in this study.
OBJECTIVE: Since AML and high-grade myelodysplastic syndrome may occasionally be difficult to distinguish morphologically from acute lymphoblastic leukemia and ES/ PNET, we undertook a study to analyze MIC2 expression in conjunction with TdT reactivity in distinguishing AML or high-grade myelodysplastic syndrome from acute lymphoblastic leukemia and ES/PNET.
DESIGN: We studied bone marrow core and clot paraffin specimens from AML (classified according to criteria of the World Health Organization; n = 49), myelodysplastic syndromes (n = 4), precursor B-cell acute lymphoblastic leukemia (n = 4), ES/PNET (n = 1), and normal bone marrow (n = 3) with MIC2 (CD99) and TdT immunohistochemistry.
RESULTS: Overall, CD99 was expressed in 24 (49%) of 49 AML cases, including all (11/11) TdT-positive cases. CD99 was expressed in all subtypes of AML except M5. Myelodysplastic syndromes and normal bone marrow specimens were uniformly CD99 negative. Expression of TdT was limited to a subset of AML-M0, -M1, -M2, and -M4, and AML with multilineage dysplasia.
CONCLUSIONS: In contrast to a previous study, CD99 expression was not restricted to TdT-positive hematologic proliferations. In particular, the CD99-positive M3 and M7 AMLs were TdT negative. An M5 AML may likely be excluded based on a uniform TdT-negative/CD99-negative immunophenotype. In addition, in our experience, CD99 should be routinely evaluated on bone marrow clots, owing to decreased reactivity or loss of reactivity in rapid decalcifying (RDO) solution-decalcified specimens.CD117 Usefulness of Anti-CD117 in the Flow Cytometric Analysis of Acute Leukemia
Christine P. Hans, MD, William G. Finn, MD, Timothy P. Singleton, MD,* Bertram Schnitzer, MD, and Charles W. Ross, MD
Am J Clin Pathol 2002;117:301-305 Abstract quote
We assessed the diagnostic usefulness of adding anti-CD117 to our existing flow cytometric profile in the analysis of 150 consecutive cases of acute leukemia (de novo or relapsed acute myelogenous leukemia [AML], AML arising in myelodysplastic syndrome, blast crisis of chronic myelogenous leukemia [CML], acute lymphoblastic leukemia, acute unclassifiable leukemia, and biphenotypic leukemia).
CD117 was expressed on more than 10% of blasts in 64% of de novo AMLs (42/66), 95% of relapsed AMLs (19/20), 75% of AMLs arising from a myelodysplastic syndrome (6/8), and 25% of myeloid blast crisis in CMLs (1/4). CD117 was not expressed in acute lymphoblastic, acute biphenotypic, or unclassified leukemia or lymphoid blast crisis of CML. The specificity, positive predictive value, sensitivity, and negative predictive value of CD117 for AML were 100%, 100%, 69%, and 62%, respectively. CD117 is a specific marker for myeloblastic leukemias. Sensitivity is greatest in French-American-British M2 and relapsed AML. Intensity of CD117 expression is dim.
Despite the high specificity and positive predictive value, the addition of anti-CD117 to our panel did not prove essential for the assignment of blast lineage.
PODOCALYXIN PodocalyxinA Marker of Blasts in Acute Leukemia
Todd W. Kelley, MD, etal. Am J Clin Pathol 2005;124:134-142 Abstract quote
Podocalyxin is a CD34 family member expressed by podocytes, vascular endothelium, mesothelium, and a subset of hematopoietic progenitors. Podocalyxin expression was not observed in the hematopoietic cells of normal adult bone marrow samples. However, podocalyxin was expressed by blasts in 30 (77%) of 39 cases of acute myeloid leukemia (AML), 22 (81%) of 27 cases of acute lymphoblastic leukemia (ALL), and 13 (87%) of 15 cases of cutaneous myeloid sarcoma.
No correlation with CD34 expression by immunohistochemical analysis was seen. Wilms tumor 1 (WT1) expression was detected in blasts in 17 AML cases (44%) and 21 ALL cases (78%). There was no correlation between WT1 and podocalyxin expression. We conclude that podocalyxin is expressed commonly by blasts in ALL and AML. Analysis of the expression of CD34 and podocalyxin increases sensitivity for the immunophenotypic detection of leukemic blasts compared with the analysis of CD34 alone.
Therefore, podocalyxin seems to complement CD34 as a useful hematopoietic blast marker. The physiologic role of podocalyxin in leukemic blasts remains unknown.VGEF Immunohistochemical Detection of VEGF in the Bone Marrow of Patients With Acute Myeloid Leukemia
Correlation Between VEGF Expression and the FAB Category
Minoo Ghannadan, PhD,1 Friedrich Wimazal, MD,1 Ingrid Simonitsch, MD,2 Wolfgang R. Sperr, MD,1 Matthias Mayerhofer, MD,1 Christian Sillaber, MD,1 Alexander W. Hauswirth, MD,1 Helmut Gadner, MD,3 Andreas Chott, MD,2 Hans-Peter Horny, MD,4 Klaus Lechner, MD,1 and Peter Valent, MDAm J Clin Pathol 2003;119:663-671 Abstract quote We studied vascular endothelial growth factor (VEGF) expression in bone marrow sections obtained from 3 healthy donors and 41 patients with acute myeloid leukemia (AML) of various French-American-British (FAB) subtypes by immunohistochemical analysis using an anti-VEGF antibody. In normal bone marrow, the anti-VEGF antibody reacted with myeloid progenitor cells and megakaryocytes but not with erythroid cells or mature granulocytic cells.
High levels of VEGF were found in the bone marrow in patients with AML-M1, -M2, -M3, -M4, -M4Eo, and -M5. In these leukemias, the vast majority of myeloblasts (>90%) expressed VEGF. By contrast, in AML-M0, the percentage of VEGF-positive blasts was lower in most cases (median, 42%), and if at all detectable, these blast cells contained only trace amounts of VEGF. In AML-M3 and -M4Eo, maturing granulocytes failed to express VEGF similar to granulocytes in normal bone marrow.
In AML-M6, myeloblasts exhibited VEGF, whereas erythroid cells did not. In AML-M7, blast cells and megakaryocytes were identified as major sources of VEGF. In summary, VEGF expression in the bone marrow is restricted to certain stages of differentiation and maturation of myeloid cells and correlates with the FAB category.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Poor prognostic factors:
Age>60 years
Marked leukocytosis
DICGENERAL
Value of combined morphologic, cytochemical, and immunophenotypic features in predicting recurrent cytogenetic abnormalities in acute myeloid leukemia.Arber DA, Carter NH, Ikle D, Slovak ML.
Hum Pathol. 2003 May;34(5):479-83. Abstract quote To evaluate the reliability of previously described morphologic, cytochemical and immunophenotypic criteria for the identification of acute myeloid leukemias (AMLs) with t(8;21), inv(16)/t(16;16) and t(15;17), 300 cases were reviewed retrospectively. Eighteen AMLs with features of t(8;21), 31 with features of inv(16)/t(16;16), and 22 with features of t(15;17) were identified.
Cytogenetic studies were available for 228 cases and identified 15 cases of t(8;21), 30 cases of inv(16)/t(16;16), 18 cases of t(15;17) and 11 cases 11q23 AML. The true positive rate for pre-cytogenetic evaluation was 95% for t(15;17), 88% for inv(16)/t(16;16) and 87.5% for t(8;21). No difference in 5-year survival was identified in the precytogenetic and corresponding cytogenetic disease groups. No specific features to predict 11q23 abnormalities were identified.
This study confirms the reliability of a combined morphologic, cytochemical and immunophenotypic approach to the initial classification of AML. Cytogenetic studies are still needed on all cases to identify the small proportion of cases that will be missed by these methods and to identify other significant cytogenetic abnormalities in AML.
BODY MASS INDEX
- Mortality in overweight and underweight children with acute myeloid leukemia.
Lange BJ, Gerbing RB, Feusner J, Skolnik J, Sacks N, Smith FO, Alonzo TA.
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pa 19104, USA.
JAMA. 2005 Jan 12;293(2):203-11 Abstract quote.
CONTEXT: Current treatment for acute myeloid leukemia (AML) in children cures about half the patients. Of the other half, most succumb to leukemia, but 5% to 15% die of treatment-related complications. Overweight children with AML seem to experience excess life-threatening and fatal toxicity. Nothing is known about how weight affects outcomes in pediatric AML.
OBJECTIVE: To compare survival rates in children with AML who at diagnosis are underweight (body mass index [BMI] < or =10th percentile), overweight (BMI > or =95th percentile), or middleweight (BMI = 11th-94th percentiles).
DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of BMI and survival in 768 children and young adults aged 1 to 20 years enrolled in Children's Cancer Group-2961, an international cooperative group phase 3 trial for previously untreated AML conducted August 30, 1996, through December 4, 2002. Data were collected through January 9, 2004, with a median follow-up of 31 months (range, 0-78 months).
MAIN OUTCOME MEASURES: Hazard ratios (HRs) for survival and treatment-related mortality.
RESULTS: Eighty-four of 768 patients (10.9%) were underweight and 114 (14.8%) were overweight. After adjustment for potentially confounding variables of age, race, leukocyte count, cytogenetics, and bone marrow transplantation, compared with middleweight patients, underweight patients were less likely to survive (HR, 1.85; 95% confidence interval [CI], 1.19-2.87; P = .006) and more likely to experience treatment-related mortality (HR, 2.66; 95% CI, 1.38-5.11; P = .003). Similarly, overweight patients were less likely to survive (HR, 1.88; 95% CI, 1.25-2.83; P = .002) and more likely to have treatment-related mortality (HR, 3.49; 95% CI, 1.99-6.10; P<.001) than middleweight patients. Infections incurred during the first 2 courses of chemotherapy caused most treatment-related deaths.
CONCLUSION: Treatment-related complications significantly reduce survival in overweight and underweight children with AML.CD2 Expression of CD2 in Acute Promyelocytic Leukemia Correlates With Short Form of PML-RARa Transcripts and Poorer Prognosis
Pei Lin, MD, Suyang Hao, MD, L. Jeffrey Medeiros, MD, Elihu H. Estey, MD, Sherry A. Pierce, Xuemei Wang, MS, Armand B. Glassman, MD, Carlos Bueso-Ramos, MD, PhD, and Yang O. Huh, MDAm J Clin Pathol 2004;121:402-407 Abstract quote
We studied the immunophenotype of 100 cases of acute promyelocytic leukemia (APL) with cytogenetic evidence of t(15;17)(q22;q21), 72 hypergranular (M3) and 28 microgranular (M3v), and correlated the results with molecular and clinical features. Most neoplasms (75/100 [75%]) had a typical immunophenotype: CD13+CD33+CD34–HLA-DR–. CD64, CD2, CD34, and HLA-DR were expressed in 27% (24/88), 23% (22/94), 21% (21/100), and 9% (9/98), respectively. CD34 expression was restricted to M3v; HLA-DR and CD2 were expressed more often in M3v than in M3 ( P < .001). PML-RAR a fusion transcripts were detected by reverse transcriptase–polymerase chain reaction in all 70 patients assessed.
The short form of PML-RAR a transcripts was found more frequently in M3v ( P < .002) and CD2+ APL ( P < .0001) than in M3 and CD2– APL, respectively. The median follow-up was 128 weeks. CD2+ APL was associated significantly with leukocytosis ( P = .004), shorter complete remission duration ( P = .03), and a trend toward shorter overall survival ( P = .07) than CD2– APL.
Overall survival for M3v vs M3 ( P = .68) and short vs long transcripts ( P = .21) was not significantly different. Immunophenotyping is useful for predicting the biologic and clinical behavior of APL.CHROMOSOMAL CHANGES Prognostic Implications inv(16) or t(16;16)Favorable +8,
t(15;17)
t(6;9)
t(8;21)
t(9;11)
t(9;22)Intermediate -7 or del(7q), complex defectsUnfavorable Normal chromosomes
inv(3)
del(5q)
Two to three miscellaneous defectsUndetermined Prognostic Impact of Acute Myeloid Leukemia Classification
Importance of Detection of Recurring Cytogenetic Abnormalities and Multilineage Dysplasia on Survival
Daniel A. ArberMD
Anthony S. SteinMD
Nora H. CarterMS
David IklePhD
Stephen J. FormanMD
Marilyn L. SlovakPhDAm J Clin Pathol 2003; 119:672-680 Abstract quote To evaluate the prognostic impact of acute myeloid leukemia (AML) classifications, specimens from 300 patients with 20% or more bone marrow myeloblast cells were studied. Specimens were classified according to the French-American-British Cooperative Group (FAB), the World Health Organization (WHO), the Realistic Pathologic Classification, and a cytogenetic risk group scheme.
Cases with fewer than 30% blast cells did not have a 5-year survival significantly different from cases with 30% or more blast cells, and survival was similar for the low blast cell count group and cases with multilineage dysplasia and 30% or more blasts.
Categories of AML with recurrent cytogenetic abnormalities of t(15;17), t(8;21), inv(16)/t(16;16), and 11q23 showed significant differences in 5-year survival. No significant difference was identified between AMLs arising from myelodysplasia and de novo AMLs with multilineage dysplasia, but all cases with multilineage dysplasia had a worse survival than all other AMLs and other AMLs without favorable cytogenetics. FAB types M0, M3, and M4Eo showed differences in survival compared with all other FAB types, with M0 showing a significant association with high-risk cytogenetics and 11q23 abnormalities. Other FAB groups and WHO AML, not otherwise categorized subgroups did not show survival differences.
These findings suggest that the detection of recurring cytogenetic abnormalities and multilineage dysplasia are the most significant features of current AML classification.
TREATMENT Combination chemotherapy with maintenance chemotherapy
Bone marrow transplantation for relapse
CHEMOTHERAPY
Long-term follow-up of patients >or=60 yr old with acute myeloid leukaemia treated with intensive chemotherapy.Oberg G, Killander A, Bjoreman M, Gahrton G, Grimfors G, Gruber A, Hast R, Lerner R, Liliemark J, Mattson S, Paul C, Simonsson B, Stalfelt AM, Stenke L, Tidefelt U, Uden AM, Bjorkholm M; LGMS.
Department of Medicine, University Hospital, Uppsala, Sweden. Gunnar.
Eur J Haematol 2002 Jun;68(6):376-81 Abstract quote It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens.
We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients <or=70 yr of age was 30/42 (71%) and in patients >70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients <or=70 yr of age, 40% and 12%, respectively (P<0.005). The median cause-specific survival time was 178 d in the total patient group, and the 2-, 5-, and 10-yr survivals were 22%, 11%, and 8%, respectively.
The cause-specific survival was not significantly different between the two treatment arms. At long-term follow-up >or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission.
Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.
Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies.
Socie G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ, Remberger M, Deeg HJ, Ruutu T, Michallet M, Sullivan KM, Chevret S.
Service d'Hematologie Greffe de Moelle and Departement de Bio-Informatique, Hopital Saint Louis, Paris, France.
Blood 2001 Dec 15;98(13):3569-74 Abstract quote
In the early 1990s, 4 randomized studies compared conditioning regimens before transplantation for leukemia with either cyclophosphamide (CY) and total-body irradiation (TBI), or busulfan (Bu) and CY.
This study analyzed the long-term outcomes for 316 patients with chronic myeloid leukemia (CML) and 172 patients with acute myeloid leukemia (AML) who participated in these 4 trials, now with a mean follow-up of more than 7 years. Among patients with CML, no statistically significant difference in survival or disease-free survival emerged from testing the 2 regimens.
The projected 10-year survival estimates were 65% and 63% with Bu-CY versus CY-TBI, respectively. Among patients with AML, the projected 10-year survival estimates were 51% and 63% (95% CI, 52%-74%) with Bu-CY versus CY-TBI, respectively. At last follow-up, most surviving patients had unimpaired health and had returned to work, regardless of the conditioning regimen. Late complications were analyzed after adjustment for patient age and for acute and chronic graft-versus-host disease (GVHD). CML patients who received CY-TBI had an increased risk of cataract formation, and patients treated with Bu-CY had an increased risk of irreversible alopecia. Chronic GVHD was the primary risk factor for late pulmonary disease and avascular osteonecrosis. Thus, Bu-CY and CY-TBI provided similar probabilities of cure for patients with CML.
In patients with AML, a nonsignificant 10% lower survival rate was observed after Bu-CY. Late complications occurred equally after both conditioning regimens (except for increased risk of cataract after CY-TBI and of alopecia with Bu-CY).
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Auer rod-Azurophilic linear structure found in the cytoplasm of 60-70% cases of AML. Caused by an alignment of the azurophilic granules. If there is a blast proliferation of 30% or more, one Auer rod in one or more blasts is considered definitive evidence of AML.
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