Acute Leukemias of Ambiguous Origin
|
|
- Frederica Morrison
- 6 years ago
- Views:
Transcription
1 AJCP / Review Article Acute Leukemias of Ambiguous Origin Anna Porwit, MD, PhD, 1 and Marie C. Béné, PharmSciD, PhD 2 From the 1 Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Canada, and 2 Immunology Laboratory, University Hospital of Nancy-Brabois, Nancy, France. Key Words: Acute leukemia; Immunophenotype; Lineage; Myeloid; Lymphoid; Mixed phenotype acute leukemia; Undifferentiated acute leukemia Am J Clin Pathol September 215;144: ABSTRACT Objectives: This session of the Society for Hematopathology/ European Association for Haematopathology Workshop focused on acute leukemias of ambiguous origin. Methods: We provide an overview of mixed-phenotype acute leukemia (MPAL) as recognized in the current World Health Organization classification and summarize diagnostic criteria for major categories of MPAL: B/myeloid, T/myeloid, B/T, and B/T/myeloid. Results: Most MPAL cases submitted were B/myeloid and T/myeloid MPAL, the most frequent types, but three cases of B/T MPAL were also submitted, and examples of all categories are illustrated. We emphasize that a comprehensive approach to immunophenotyping is required to accurately establish the diagnosis of MPAL. Flow cytometry immunophenotyping using a large panel of antibodies is needed as well as confirmatory immunohistochemical analysis and cytochemistry studies for myeloperoxidase and nonspecific esterase. We discuss technical issues in determining blast lineage and possible pitfalls in MPAL diagnosis. In particular, rare cases of B-acute lymphoblastic leukemia (B-ALL) can express myeloperoxidase but are otherwise consistent with B-ALL and should be treated as such. Last, we review the differential diagnosis between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation. Conclusions: There was an agreement that diagnosis of MPAL can be challenging, especially if applied flow cytometry panels are not comprehensive enough. What Is the Definition of Acute Leukemia of Ambiguous Lineage? In the 28 World Health Organization (WHO) classification, 1 acute leukemias of ambiguous lineage were defined as leukemias that show no clear evidence of differentiation along a single lineage. The recognition of acute leukemia of ambiguous lineage requires extensive multiparametric flow cytometry (FCM) immunophenotyping disclosing the specific features of these diseases Figure 1. In extremely rare cases of acute undifferentiated leukemia (AUL), although markers of all lineages have been investigated, no significant expression is detected on blast cells except for CD34 and/or HLA-DR (present in most of these cases). A second, slightly more frequent occurrence is that of blast cells labeling with several monoclonal antibodies, recognizing antigens normally expressed on different lineages. Formerly called biphenotypic acute leukemias (BALs), these neoplasms have been renamed mixed-phenotype acute leukemia (MPAL). On the basis of associated cytogenetic anomalies, MPAL can be subdivided according to the presence of the Philadelphia chromosome into subgroups: t(9;22)/bcr- ABL1, t(v;11q23)/mll, or not otherwise specified. All other unusual immunophenotypes, including early natural killer (NK) leukemias, constitute the remainder of leukemias of ambiguous origin. Introduction to MPAL The morphologic features of the blasts in most cases of MPAL are mostly uninformative, and therefore the Am J Clin Pathol 215;144:
2 Porwit and Béné / Mixed-Phenotype Acute Leukemias Acute undifferentiated leukemia With t(9;22) Extensive immunophenotyping Mixed phenotype acute leukemia With t(n;11q23) Others, including natural killer Not otherwise specified Figure 1 Schematic for the classification of acute leukemias of ambiguous origin. diagnosis of MPAL relies exclusively on immunophenotypic features. MPAL cells appear most often as morphologically undifferentiated, but sometimes the neoplastic cells may display more lymphoblastic or myeloblastic cytology. In some cases, two types of blasts with a distinctive size and morphology point to the different, extremely rare occurrence of a bilineal or biclonal leukemia. These neoplasms can also be recognized by FCM analysis as two cell subsets with different immunophenotypes. MPAL can be identified using the recommended panel of the European LeukemiaNet 2 or other comprehensive combinations. 3 Importantly, several markers specific for the myelo/monocytic lineage as well as for the B- and T-lymphoid lineages must be tested, excluding a restrictive strategy of quick orientation followed by selected lineage-specific markers. Of note, as detailed below, at least two key cytoplasmic (c) markers must be investigated: myeloperoxidase (MPO) for myeloid lineage and ccd3 for T lineage. Recommendations were first published by the European Group for the Immunological Characterization of Leukemias (EGIL), 4 with a scoring system identifying BAL as cases with more than two immunophenotypic points in more than one lineage. This proposal relied on 26 antibodies to perform a proper score, yet published reports seldom applied such extensive panels. In the 28 WHO classification, 1 the name of these leukemias and their immunophenotypic definition (as above) were changed. MPO stands as the most robust marker that will identify myeloid engagement. Recent publications have redefined the threshold for MPO positivity, 5,6 and yet most MPAL cases with a myeloid component will express MPO broadly in most blasts. An alternative, for MPAL with a strong monocytic differentiation, is represented by (very rare) cases in which blasts will be positive for nonspecific esterase and/or express at least two of the following antigens: CD14, CD11c, CD36, CD64, or cytoplasmic lysozyme. Determination of the engagement of blast cells in the B-lymphoid lineage will rely on the expression of surface CD19. If the latter is bright, demonstration of expression of one other B-lineage associated marker (eg, ccd79a, surface or ccd22, or CD1) will be required. If CD19 expression is weak, however, at least two other B-lineage markers need to be expressed by the blasts. Assessment of T-lineage engagement relies on the demonstration of ccd3 expression as mentioned above. Of note, the fluorochrome used for this determination should yield strong fluorescence, for instance, phycoerythrin or allophycocyanin. The immunophenotypic strategy to explore these cells involves the use of two monoclonal antibodies directed to CD3 (usually anti-e chain) conjugated to different fluorochromes. Cells are first incubated without manipulation, ideally using whole bone marrow (BM). After incubation, permeabilizing reagents will allow both lysis of erythrocytes and intracytoplasmic labeling with the second anti-cd3 antibody. Analysis by FCM will then identify normal residual T lymphocytes as costained with both antibodies, while T-lineage blast cells lacking surface CD3 will be stained with the second anti-cd3 only. What Possible Combinations of MPAL Occur and What Are Their Frequencies? All possible combinations of MPAL can be observed, including B/myeloid, T/myeloid, B/T, or even rare B/T/ myeloid. In a series of 1 cases of MPAL published by the EGIL, 7 B/myeloid cases were most frequent, representing 59% of all MPAL cases. The frequencies of T/myeloid, B/T, or B/T/myeloid were 35%, 4%, and 2%, respectively. The blast cells in MPAL show a specific gene expression pattern, as illustrated by a microarray study of acute leukemias performed at St Jude Children s Research Hospital, where 35 childhood MPAL cases segregated in a specific cluster between B-acute lymphoblastic leukemia (B-ALL), T-acute lymphoblastic leukemia (T-ALL), and acute myeloid leukemia (AML). 8 How Are Patients With MPAL Managed Clinically? The clinical management of MPAL cases is problematic. Often, an initial course of corticosteroids is attempted, followed by an acute lymphoblastic leukemia (ALL) like approach. In the absence of response to corticosteroids, most clinicians will switch to an AML-like approach with alkylating agents. However, patients who fared well in the literature were clearly those who could benefit from allogeneic stem cell transplantation. It is important to identify MPAL cases and not misdiagnose these tumors as ALL or AML by using immunophenotypic panels that are not sufficiently comprehensive. Indeed, 362 Am J Clin Pathol 215;144:
3 AJCP / Review Article some refractory cases of acute leukemia, with poor response to therapy, may represent undetected cases of MPAL that were incorrectly assigned to a single lineage. Using an FCM intracytoplasmic orientation panel combining MPO, ccd3, and CD19 (possibly with ccd79a, ccd22, or CD1) could be a good approach to detect such cases early in the process of immunophenotyping a neoplasm. It is important to point out that immunohistochemistry (IHC) on BM biopsy sections also can be useful to confirm B, T, or myeloid differentiation by using antibodies specific for PAX5, CD3, and MPO and/or lysozyme, respectively. Immunohistochemical analysis may be of great help in cases with two or more different populations with specific distributions in BM or other tissue biopsy specimens since it allows direct visualization of cell location. Discussion of Workshop Cases There were 32 cases included in this workshop session. Several cases submitted initially to this session did not completely meet the criteria for MPAL and were moved to other sessions, although the moving in some cases was debated by members of the review panel, revealing the need for more robust criteria and greater consensus on definitions. The workshop cases are discussed in the subtypes to which they were allocated. The summary of these cases (below) illustrates the heterogeneity of MPAL presentation. The following discussion also describes the characteristics of MPAL cases, technical issues involved in MPAL diagnosis, and groups of cases that can be linked by some common characteristics or diagnostic issues. Typical Examples of MPAL MPAL B/Myeloid Typical examples of MPAL with populations of blasts showing B lineage and myeloid differentiation are illustrated in Image 1 and Image 2. Immunophenotypes of all cases classified as B/myeloid MPAL are given in Table 1. Expression of the B-cell marker CD19 was moderate to strong in cases 1, 28, 285, 323, and 328 and weak/partial in all other cases. B-cell lineage was most often corroborated by expression of ccd79a (demonstrated by FCM, IHC, or both), ccd22 (by FCM), and/or PAX5 (by IHC), whereas CD1 was positive in three cases (cases 1, 28, and 214). MPO expression was variable: most blast cells were MPO positive in four cases (cases 1, 76, 285, and 323), but other cases showed only subpopulations of MPOpositive cells. Cases 28, 328, and 214 represented the most common cytogenetic variant of B/myeloid MPAL, associated with t(9;22)(q34;q11.2)/bcr-abl1. Three cases had highly hyperdiploid and/or a near-tetraploid karyotype, and one case showed hypodiploidy. Highly hyperdiploid and/or near-tetraploid karyotypes are rare in AML and ALL 9,1 and have been reported previously as common in MPAL and BAL classified according to the EGIL system. 4,7,11 In the case series collected for this workshop, the highly hyperdiploid and/or near-tetraploid karyotype was also common (five [16%] of 32 cases: three B/myeloid, one T/myeloid, and one B/T). One of the near-tetraploid cases (case 285) carried also the t(12;17)(p13;q11.2) involving the ZNF384/CIZ (chromosome 12p13) and TAF15 (chromosome 17q11.2) genes. The t(12;17)(p13;q11) has been described as a rare but recurrent abnormality, predominantly observed in B-ALL cases that usually have an early pre B immunophenotype and showing aberrant expression of the myeloid antigens CD13 and/ or CD33. The t(12;17) is less common in AML, and reported cases often showed aberrant expression of CD In a recent case report, a pro B/B-I ALL, which switched to an AML at relapse, was described. 17 Case 285 is the first case with this translocation in which the WHO criteria for MPAL are fulfilled. Another chromosomal abnormality hitherto not described in MPAL, inv(3)(q21q26.2), was detected in case 283. Inv(3)(q21q26.2) or t(3;3)(q21;q26.2) displays an inversion or homologous reciprocal translocation that leads to juxtaposition of the ecotropic viral integration site 1 (EVI1) gene with the ribophorin 1 (RPN1) gene. AML cases carrying this abnormality are classified as one of the categories of AML with recurrent cytogenetic abnormalities in the WHO classification and most commonly have a myeloid or myelomonocytic immunophenotype and poor prognosis. 18,19 An MPAL phenotype has not been reported previously in a leukemia with inv(3) or t(3;3). MPAL T/Myeloid The characteristics of MPAL cases with T and myeloid lineage markers are illustrated in Image 3, Image 4, and Table 2. Most T/myeloid MPALs were characterized by two populations of blasts: one with a T-precursor immunophenotype (usually coexpressing some myeloid markers but negative for MPO) and the other fulfilling MPAL criteria. In two cases (case 139 and 2), the myeloid lineage showed a monocytic differentiation pattern. In two patients (cases 2 and 42), different immunophenotypes were observed in a lymph node biopsy specimen and the BM. In case 2, BM showed an immunophenotype suggestive of AML with monocytic differentiation, but in the lymph node two aberrant populations were detected: one with ccd3 positivity and one with a myelomonocytic immunophenotype. Cytogenetic analysis also showed two different clonal populations, Am J Clin Pathol 215;144:
4 Porwit and Béné / Mixed-Phenotype Acute Leukemias A B C D Image 1 Example of B/myeloid mixed-phenotype acute leukemia, BCR-ABL1 positive, with a heterogeneous population of blasts with myeloperoxidase (MPO) positive larger myeloid blasts (arrows) and MPO-negative smaller lymphoid blasts (arrowheads) (A, May-Grünwald-Giemsa; B, MPO). Bone marrow biopsy specimen shows a mixed population of CD79+ smaller blasts (C) and MPO+ larger blasts (D). See Table 1 for details and Image 2 for flow cytometry findings. (Case 28, courtesy of E. Moore, MD, and colleagues.) one with 46,XY,der(12)t(11;12)(q21;p11.2) and the other with 45,XY,dic(12;18)(p11.2;p11.2). In case 42, a lymph node biopsy specimen showed a T-precursor immunophenotype, whereas in the BM, a population of blasts fulfilling the criteria of MPAL was detected. MPAL B/T MPAL cases that express both B- and T-lineage markers are rare (<5% of MPALs).7 Three examples (cases 312, 359, and 39) were submitted to the workshop Table 3 and Image 5. In two cases, a population of blasts was detected that coexpressed CD19 (strong) and ccd3. B-cell lineage was supported by CD22 expression in one case and CD79a 364 Am J Clin Pathol 215;144: in the other cases. CD7 was expressed in one of the cases, and no other T-cell associated markers were seen in the other. One of these cases had a normal karyotype, and one was hyperdiploid. The third MPAL B/T case had trisomy 11 and two populations of blasts: one with an immunophenotype of B-precursor ALL (EGIL B-II) and one of T-ALL with early T-cell precursor immunophenotype (EGIL T-I).2 MPAL B/T/Myeloid Case 268 was the only case of acute leukemia that expressed markers of all three lineages fulfilling criteria for B/T/myeloid MPAL. The patient was a 58-year-old man with two separate leukemic cell populations. One
5 AJCP / Review Article 1, 1, 1, SSC-W SSC-W CD2 SSC-W CD45 CD45 CD34 CD45 CD34 CD34 MPO CD79a CD CD1 CD3 CD3 Image 2 Flow cytometry immunophenotypic findings in case 28 (see Table 1 for details): Complicated case where it was difficult to differentiate CD45 low blasts from other leukocytes (upper row left plots). Granulocytes are intermingled with blasts, and there is also a continuum between lymphocytes and blasts. CD34 allows discriminating the myeloid blast population (upper row, right plots, CD34: dark blue dots, back-gated). CD34+ cells are CD19+ and express an unusual heterogeneous CD1 pattern (lower row, left plots). Myeloperoxidase expression is dim but definitively positive, and cytoplasmic CD79 is positive at a similar level as for normal B cells (lower row, right plots). SSC, side scatter. Red, neutrophils; green, monocytes; pink, lymphocytes; light blue, blasts. population corresponded to an AML and was positive for CD7, CD4 (dim), CD11b, CD13, CD33, CD34, CD117, MPO, and HLA-DR, and the other population corresponded to MPAL with a B/T immunophenotype positive for TdT, CD19, CD2, CD1, ccd79a, CD22, PAX5, CD33 (dim), ccd3, and CD5 (dim) and negative for MPO Image 6 and Image 7. Conventional cytogenetics showed a normal karyotype, and BCR-ABL1 was negative. Another case fulfilling criteria for T/myeloid MPAL and also showing weak CD19 expression was case 356 (Table 2). The patient was a 14-year-old girl in whom both a lymph node biopsy specimen and a BM showed blasts positive for ccd3 and MPO with weak expression of CD19 and ccd79a. However, other B-cell markers were not found and the criteria for B-lineage differentiation were not fulfilled. MLL Rearrangement and Immunophenotype Switch Cases 18, 256, 37, and 392 were examples of MPAL associated with MLL rearrangement Table 4. MPAL with MLL rearrangement is considered a separate entity in the WHO classification, 21 with a frequency of approximately 1% of adult and 12% to 18% of pediatric MPAL cases. 7 Most cases of MPAL with MLL rearrangement are B/ myeloid. Case 256 illustrated a rare occurrence of a T/ myeloid MPAL (Table 4). The other three cases demonstrated an immunophenotype switch, previously reported in MLL rearranged leukemias MLL rearrangement juxtaposes the amino-terminus of the histone methyltransferase MLL with a variety of different fusion partners. To date, more than 7 fusion partners of the MLL gene have been characterized. 28 Deregulation of HOX seems to be one of the most important factors in MLL-induced leukemogenesis. Since HOX expression is high in stem cells and early precursors and needs to be downregulated for maturation, a continuous ectopic HOX expression will create a basis for the development of abnormal preleukemic precursors that may progress to various forms of acute leukemia. 28,29 In cases 18 and 37 submitted to this session, the primary diagnosis was AML with t(9;11)(p22;q23), but the relapse presented as ALL/lymphoma with an EGIL B-I immunophenotype (CD1 negative). In the third patient (case 392), a therapyrelated myeloid neoplasm presented as a t(4;11)(q21;q23) B-ALL/lymphoma with an EGIL B-I immunophenotype, whereas AML with monocytic differentiation was seen at first relapse and B/myeloid MPAL at second relapse. The Am J Clin Pathol 215;144:
6 Porwit and Béné / Mixed-Phenotype Acute Leukemias Table 1 Summary of Cases of MPAL, B/Myeloid Case No. Patient Age, y/ Sex Immunophenotype Cytogenetics/Molecular Genetics 28 36, F Two populations of blasts (75% of BM cells in total): B lymphoblastic (39%) CD19+, CD1+, CD13+, CD34+, ccd79a+, HLA-DR+, TdT+ with variable expression of ccd22 IgM, negative for CD4, CD11b, CD14, CD15, CD64, MPO Myelo(mono)blastic (36%) with the following immunophenotype: CD4+, CD13+, CD15+, CD19+, CD33+, CD34+, CD64+, HLA-DR+, MPO+ with variable expression of CD1, CD11b, ccd79a, and TdT and negative for ccd22 and IgM , M FCM: 13% blasts CD34+, CD117s+, CD33+, CD13s+, CD15s+, CD19+, CD22s+, ccd79a dim+, CD25s+, TdT+, MPOs+, CD1, CD66c, CD2, CD5, CD7, CD56 IHC: PAX5+ (8%-9%), CD19+ (5%), TdT+ (9%), MPO+ (3%), CD117, CD , F Two populations of blasts (6% of BM cells in total): B-lymphoblastic: CD19+, CD1+, CD34+, CD33+, HLA-DR+, and CD38+, TdT+, PAX5+, CD45 dim Myelo(mono)blastic: HLA-DR, CD33, CD4, partial CD5, dim CD11B, CD14, CD64, partial CD15, CD38, CD45 bright, increased SSC, MPO, and lysozyme positive by IHC , F One population of blasts: CD19+, ccd79a+, MPO+, CD33+, CD34, HLA-DR+, CD38+, and with partial expression of CD13 and CD , M One blast population 4% CD2, surface CD3, ccd3, CD4, CD5, CD7+, CD8, CD1, CD11bs+, CD11cs+, CD13+, CD14, CD15s+, CD16, CD19s+, CD2, CD22s+, ccd22s+, CD33+, CD34+, CD36, CD38+, CD45+, CD56, CD64, CD79as+, CD117+, HLA-DR+, MPOs+ (6%-8%), TdTs , F One population of blasts: CD19 dim, CD14 dim, CD15+, CD45 dim, scd22 dim, CD56 dim, CD71 dim, CD79a+ and CD34+, lcd13, CD2 or CD33, ccd79a+, ccd3 By IHC: MPO+, PAX5+, TdT+, CD79a+/, and negative for lysozyme, CD1, and CD2 1 5, F One population of blasts: CD45 dim/, low SSC, CD1+, CD19+, CD22+, partial CD13+, partial CD33+, CD34+, ccd79a+, ntdt+, HLA-DR, MPO+, ccd3, CD15, and CD , M One population of blasts: BM FCM: CD34+, CD33+, HLA-DR+, CD7+, MPO+, ccd79a+, ccd22 dim+, ccd3 dim/, scd5+ and scd19+, TdT, CD2, CD4, CD8, and mcd3 Lymph node IHC: CD34+, CD33+, CD99+, CD5+, CD56+ weak, CD7+, MPO+, CD79+a, PAX5+; negative for ccd3, CD4, CD8, CD2, CD1, CD123, CD117, and TdT 26 51, F Two populations of blasts (9% of BM cells in total): main population: CD4s+, CD7 dim+, CD13s+, CD14+, CD15+, CD36+, CD38+, CD45 dim+, CD58+, CD117 / dim, HLA-DRs+, MPOs+, ccd3, CD5, CD8, CD19, CD2, CD22, CD34, CD56, CD61, ntdt, ccd79a t(9;22)(q34;q11.2); BCR-ABL1 (by FISH) e1a2 BCR-ABL1 by RT-PCR 46,XY,t(9;22)(q34;q11.2) [15] and 46,idem, del(2)(q11.2q13.3)[5] e1a2 BCR-ABL1 by RT-PCR 45,XX,del(7)(p15), t(9:22)(q34:q11.2), 16 [19]/46,XX[1] 82-84,XXXX, 1, 2, 3, 4, 7,+8, 9, 1, t(12;17)(p13;q11.2)x2, der(12)t(12;17) (p13;q11.2),+13, 15, 16, 17, 2, 21,+22[cp7]/46,XX[13] Negative for BCR-ABL1 by FISH Consensus WHO Diagnosis/ *Comments MPAL (B/ myeloid), with t(9;22) (q34;q11.2) MPAL (B/ myeloid), with t(9;22) (q34;q11.2) MPAL (B/ myeloid), with t(9;22) (q34;q11.2) MPAL, NOS (B/ myeloid) *Associated with t(12;17) (p13;q11.2) 46,XY,inv(3)(q21q26.2), inv(9) [2] MPAL, NOS, B/ myeloid 35,XX, 3, 4, 5, 7, 8, 9, 13, 15, 16, 17, 2[9] 46,XX,?t(5;6)(q23;q24)[1] 46,XX[1] FISH for t(9;22) and MLL: neg 63-64<3n>,XXX,add(1)(p13), 2, 3, 7,+1, 13, 14, 15, 16, 19, 2,+21,+21[cp6]/63 65<3n>,idem,?add(2)(p23), 1,+mar[cp2]/46,XX,[26] FISH for t(9;22) and MLL: neg 8-85<4n>,XXY, Y,add(1)(p36), 2,add(2) (q31)x1-2, 3,add(3)(q12-21)x2, 6, 7,der(7) t(7;8)(p15;q13), 8, 8, 9, 9,add(12)(p11.2) x2, 13, 13, 15, 15, 16, 16, 17, 17, 18,+3-9mar[cp9]/46,XY[16] 46,XX; negative for BCR-ABL1 gene fusion and MLL rearrangement by FISH *Associated with inv(3) (q21q26.2) MPAL, NOS, B/ myeloid *With hypodiploidy MPAL, NOS, B/ myeloid *Associated with hyperdiploidy MPAL, NOS, B/ myeloid *Associated with near tetraploidy MPAL, NOS, B/ myeloid 366 Am J Clin Pathol 215;144:
7 AJCP / Review Article Table 1 (cont) Summary of Cases of MPAL, B/Myeloid Case No. Patient Age, y/ Sex 26 51, F , M Immunophenotype Cytogenetics/Molecular Genetics Minor population (5%-7%): CD19+, CD22 s /bright, CD34+, CD38+, CD45 dim+, CD58+, ntdt+, ccd79a+, CD1, CD14, CD33, ccd3, MPO Blasts 42% of BM cells: CD34+, CD33 dim+, CD38s+, 45,XY, 7 [2] MPO dim+ (18%), CD7+, HLA-DR dim+, CD117+, CD64 dim+, CD11bs+, CD19s+ (3%), CD79a dim+, ntdt, ccd3, CD15, CD13, CD2, CD14 IHC: MPO+, lysozyme+, CD68+, PAX5s+ FISH tri8 2% Consensus WHO Diagnosis/ *Comments MPAL, NOS, B/ myeloid BM, bone marrow; c, cytoplasmic; FCM, flow cytometry; FISH, fluorescence in situ hybridization; IgM, immunoglobulin M; IHC, immunohistochemistry; MPAL, mixedphenotype acute leukemia; MPO, myeloperoxidase; neg, negative; NOS, not otherwise specified; RT-PCR, reverse transcriptase polymerase chain reaction; SSC, side scatter; WHO, World Health Organization. A B C D Image 3 Example of T/myeloid mixed-phenotype acute leukemia showing in both bone marrow smears (A, May-GrünwaldGiemsa) and biopsy sections (B, H&E) presence of small myeloperoxidase (MPO) negative blasts and approximately 25% larger MPO+ blasts. Positivity for both cytoplasmic CD3 (C) and MPO (D) is illustrated in the lymph node sections from the same patient. See Table 4 for details and Image 4 for flow cytometry findings. (Case 279, courtesy of R. E. Alexander, MD, and M. Czader, MD, PhD.) Am J Clin Pathol 215;144:
8 Porwit and Béné / Mixed-Phenotype Acute Leukemias 1, SS CYTO CD3-PC5 CD15-FITC CYTOMPO-F CD45-ECD CD45-ECD CD117-RD1 CD45-ECD CD2-FITC CD8-FITC CD71-FITC CD45-ECD CD7-PE CD4-PE CD33-PE CYTOTDT-FITC Image 4 Flow cytometry immunophenotypic findings in case 279: bilineal case with clearly different immunophenotypes on lymphoblasts (cyan dots, ccd3+, CD7+, CD2+, TdT+) and myeloblasts (dark blue dots, CD33+, CD15+, CD117+, MPO+). FITC, fluorescein isothiocyanate; MPO, myeloperoxidase. Red, neutrophils; green, monocytes; pink, lymphocytes; light blue, lymphoblasts; dark blue, myeloid blasts. MLL-AF4 fusion has been reported in therapy-related ALL, after treatment with either topoisomerase II inhibitors or alkylating agents, and seems to be associated with a worse clinical outcome. 3,31 What Are Some of the Important Technical and Interpretation Issues in the Diagnosis of MPAL? MPO The issue of MPO expression in the diagnosis of MPAL has been discussed in the literature Previous French- American-British group guidelines, based on cytochemistry, used 3% of MPO-positive blasts in BM smears as sufficient to call a leukemia MPO positive. 35,36 A threshold of 1% expression has been used by the EGIL group. 3 However, discordant cases are found when both methods are compared, 6,37 leading to the conclusion that the 1% threshold may be conservative but not very sensitive. It should be emphasized that MPO expression can be a difficult test to establish by FCM immunophenotypic analysis since differences in permeabilization reagents and various antibodies have been reported Thus, MPO expression in leukemic blasts has to be compared with internal negative and positive controls. In a study comparing MPO expression detected by FCM and cytochemistry in cases of AML and ALL, a 13% threshold was found to be relevant using an isotype control as a background reference (sensitivity, 95.1%; specificity, 91.7%). 5 If residual normal lymphocytes were used as reference, a threshold of 28% had to be applied, yielding an improved 97.4% sensitivity and 96.1% specificity in distinguishing between ALL and AML. The WHO criteria for MPAL do not indicate any lower limit for MPO expression in leukemic blasts, 1 but it seems reasonable to use published thresholds. 3,5 Since MPAL cases often show more than one population of blasts, MPO could be present in only a minor population, which has to be identified as the myeloid component. Another issue is that AML with minimal differentiation and no MPO expression could be involved in MPAL. Therefore, as stated in the WHO criteria, when there are two or more distinct populations of leukemic cells, one with coexpression of a number of myeloid markers, no MPO and no lymphoid markers also can be accepted to define the myeloid component of MPAL. 1 Rarely, cases of otherwise typical B-ALL/lymphoma can express MPO by FCM or IHC (case 259) or least often by cytochemistry ,41 These cases are best classified and treated as B-ALL/lymphoma. In contrast, most MPAL cases show expression of other myeloid-associated markers and also are characterized by the presence of two or more 368 Am J Clin Pathol 215;144:
9 AJCP / Review Article Table 2 Summary of Cases of MPAL, T/Myeloid Case No. Patient Age, y/sex Immunophenotype Cytogenetics/Molecular Genetics , M Two populations of blasts: T lymphoblasts: CD2+, CD7+, CD5+, ccd3+, ntdt+, CD38+ The myeloid/t-cell population: CD33+, CD15+, CD117+, CD64+, CD2+, CD7+, CD38+, MPO+, ccd3s , F Two populations of blasts: 9% ccd3+, ntdt+, CD34+, CD13+, CD % also cmpo+ (cytochemistry MPO+ 1%) 225 7, M Two populations: all CD34 and ccd3, subpopulation also CD117+ and MPO+ by FCM and IHC 33 67, M CD34+, partial CD117+, CD13+, CD33+, CD11b+, HLA-DR, TdT and MPO, ccd3+/dim, CD5+ and CD7+, ccd79a 139 8, M Two populations: 17% blast gate CD4+/7+/11b+/ 13+/33+/34+/56s+/64s+ and ccd3 (partial), 5% monocyte gate: CD4+/11b+/13+/14+/33+/64+ IHC: lysozyme+ 2 58, M BM: FCM CD33 dim, CD7 dim, CD4 dim, CD38+, HLA-DR+, CD11cs+, CD11bs+; AML was favored. IHC: CD68+, CD34-MPO, CD117, CD3, CD2, lysozyme Lymph node: FCM CD33dim, CD7+, CD4 dim, CD5s, dim CD11b dim, CD38+, HLA-DR+. IHC: two distinct blast populations, nodules CD3+, CD4+, CD5+, CD7+, CD99+, at the periphery of the nodules CD7+, lysozyme+, CD33+, TdT+, CD99+, MPO+, CD11c+ 42 1, F Lymph node FCM: 74%, CD7+, CD5 dim, CD2+, CD34+, CD117+, CD11b+, CD3+, CD71+, ntdt+, HLA-DRs+, ccd3+, CD1a, CD4, CD8, MPO BM FCM: 7%-8%, CD7+, CD34+, ccd3+, MPOs , F Lymph node: two populations: 53% T-lymphoblasts, CD45 dim, ccd3+,cd2+, CD5 dim, CD7+, CD13+, CD19 dim+, other T-cell and myeloid markers including MPO IHC showed also myeloid cell area: CD33+, CD15+, CD68 (KP1+), MPO+, CD34, CD117 BM, two populations: 36% lymphoid blasts CD2+, CD7+, ccd3, CD19 dim, ccd79a dim, CD13+, CD33 dim, CD45 dim+ Myeloid blasts with intermediate SSC (37%): CD33 bright, CD4+, MPO+, CD64+, HLA-DR+, CD11bs+, CD11Cs+, CD2+, CD7+, CD13+, CD19s dim, CD45 dim, ccd3 Consensus WHO Diagnosis/ *Comments 45-46,XY,add(1)(p22), der(3)dup(3) MPAL, NOS; T/ (q21q29)r(3)(p26q29), add(5)(q13),add(7) myeloid (q34),del(8)(22), t(9;14)(p22;q11.2), 11, 15,+add(19)(q13.3), +mar2[cp2]/ Nonclonal[1]/46,XY[4] 46,XX MPAL, NOS; T/ myeloid 46,XY 45,XY, 7,del(2)q11.2q13.1) [4]/47,idem,+2mar[2]/46,XY[3] High hyperdiploid karyotype: trisomies for chromosomes 8, 11, and 12 and an extra chromosome X. In addition, five of these abnormal cells had trisomies for chromosomes 1 and ,XY,der(12)t(11;12)(q21;p11.2) [6]/45,XY,dic(12;18)(p11.2;p11.2) [5]/46,XY[9] 45,XX,der(5)t(5;12)(q22;q13), 7, 12,der(13)t(7;13)(q11.2;q34),+der(?) t(?;7)(?;p?15)[9]/46,xx[11] BM aspirate: complex karyotype. 46,X,t(X;9)(q13;p24),del(3)(q12),t(4;12) (q12;p13),t(11;14)(p13;q11.2),del(13) (q13q31),del(16)(q22),del(18)(q21) [16]/46,XX[4] FISH: Homozygous deletion of CDKN2A(9p21) in 92% of 2 cells; loss of 3 ETV6 (12p13) in 87.5% of cells; loss of 3 TCR (14q11.2) in 9% of cells studies. No evidence of a BCR-ABL fusion gene or rearrangements involving the MLL, FGRR1, or IGH loci. MPAL, T/myeloid, NOS MPAL, T/myeloid, NOS *Relapse as AML MPAL, NOS T/myeloid (bilineal) *Monocytic differentiation and hyperdiploidy MPAL, NOS T/myeloid *Bilineal in the lymph node, monocytic differentiation MPAL, NOS T/myeloid *T-LBL in the lymph node, MPAL in BM MPAL, NOS T/myeloid *Bilineal; CD19 dim and CD79 dim do not fully corroborate B lineage AML, acute myeloid leukemia; BM, bone marrow; c, cytoplasmic; FCM, flow cytometry; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MPAL, mixedphenotype acute leukemia; MPO, myeloperoxidase; NOS, not otherwise specified; SSC, side scatter; T-LBL, T-lymphoblastic; WHO, World Health Organization. subpopulations of blasts with slightly different immunophenotypes. In some cases of MPAL, MPO may be expressed only in a small subset of blasts, with or without lymphoid markers (biphenotypic or bilineal presentation). Cytoplasmic CD3 Cytoplasmic CD3 (ccd3) is considered the most specific marker for the T-cell lineage and has been used to diagnose T-cell malignancies since the 198s. 42,43 FCM immunophenotyping methods to detect ccd3 were established in the 199s when permeabilization reagents became available. 39,4 As in the case of MPO, expression of ccd3 in leukemic blasts has to be determined in comparison with internal negative and positive controls (B cells, monocytes, granulocytes, and normal T lymphocytes, respectively). At least a fraction of blasts should express ccd3 at the level of Am J Clin Pathol 215;144:
10 Porwit and Béné / Mixed-Phenotype Acute Leukemias Table 3 Summary of Cases of MPAL, B/T Patient Age, Case No. y/sex Immunophenotype 39 82, M , M 312 Cytogenetics/Molecular Genetics One population of blasts: ccd3+, CD7+, CD19+, 46,XY, FISH negative for:5p15.2 CD22h, CD13+, CD117+, CD15s+, CD5, (D5S23), 5q31 (EGR1), 7cen (D7Z1), CD11b, CD14, CD33, CD56, CD61, CD79a, 7q31 (D7S486), 8cen (D8Z2), CD235a, MPO 11q23(MLL), 13q14 (D13S319), 13q34 (LAMP1), and 2q12 (D2S18) One population of blasts: CD34+, CD19+, CD33+, 5,XY,dup(1)(p22p36.1),+4,+1, CD56+, HLA-DRs+, CD49d+, ccd79a+, 15,+21,+22,+mar[12]5,idem, CD123s+, CD45 dim, CD38 bright, ccd3s+, del(11)(q12),add(19)(q13.1)[3]; CD1, CD2, mcd3, CD4, CD5, CD7, CD8, diploid male karyotype 46,XY[5] CD1, CD13, CD14, CD15, CD2, CD22, Negative for all recurrent CD25, CD36, CD41, CD64, CD66c, CD81, translocations, negative for CD117, TdT, sig, cigm, MPO mutations in IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, FLT3 (including ITD), and CEBPA Two blast populations: 1: CD45 dim+, CD19+, 47,XX,+11[19]/46,XX[1]. FISH negative CD2 /dim+, CD1+, TdT+, CD34 dim+, CD117, for monosomy 7, BCR-ABL1, ETV6MPO, CD13, CD33, CD38+, CD79a, PAX5 RUNX1, MLL rearrangement 2: ccd3+, mcd3, CD7+, CD34+, CD117+, HLA-DR+, CD38+, CD19, CD2, CD1, TdT, MPO, CD13+, CD33 11, F Consensus WHO Diagnosis/ *Comments MPAL, NOS, B/T MPAL, NOS, B/ *With hyperdiploidy MPAL, NOS, B/T *Bilineal c, cytoplasmic; FISH, fluorescence in situ hybridization; MPAL, mixed-phenotype acute leukemia; MPO, myeloperoxidase; NOS, not otherwise specified; WHO, World Health Organization. B A E1 D 13 E2 CD1 cy79a C 13 E3 E cycd E1 E2 E3 E4 1 Image 5 Example of rare B/T mixed-phenotype acute leukemia with medium- to large-sized blasts: (A, May-Grünwald-Giemsa) bone marrow smear and (B, H&E) bone marrow biopsy specimen. By flow cytometry, blasts were positive for ccd3 (T lineage, C) and CD19, CD1 and CD79a (B lineage, C and D). See Table 3 for details. (Case 39, courtesy of H. Ayyad, MD, and colleagues.) 1 2 CD Am J Clin Pathol 215;144:
11 AJCP / Review Article A B C D Image 6 Immunohistochemistry on bone marrow biopsy sections of case 268 shows CD117+ PAX5 area (A, 1) corresponding to acute myeloid leukemia and CD117 PAX5+ area (B, 1) corresponding to mixed-phenotype acute leukemia B/T (see Image 7 for flow cytometry findings corroborating B- and T-lineage characteristics). C and D, Higher magnification ( 4) of outlined area as shown in A and B, respectively. (Case 268, courtesy of S. A. Ely, MD, and colleagues.) normal T cells, and weak expression in a minor fraction of blasts is insufficient to diagnose MPAL. Many AML cases show aberrant expression of other T-cell associated markers, such as CD2, CD4, CD5, or CD7, or NK-cell associated markers, such as CD56.44,45 Thus, the correct interpretation of ccd3 staining is important for final diagnosis. If a BM biopsy specimen is available, the expression of ccd3 may be confirmed by IHC. In case 261, positive for CD2, CD4, and CD56, review of the FCM files revealed no sufficient ccd3 expression, and no confirmatory IHC could be performed. Thus, considering the presence of a complex karyotype, a consensus diagnosis of AML with myelodysplasia-related changes was rendered Table 5. Similarly, in case 349 (Table 5), expression of ccd3 was very weak and could not be confirmed by IHC. Also, in case 33 (Table 2), heterogeneous expression of ccd3 was not confirmed by IHC, although a fraction of blasts that showed adequately high expression to qualify as MPAL was observed by FCM, together with CD5 and CD7. No ccd3 expression was seen at relapse in this patient. CD19 and Other B-Cell Markers The WHO classification provides no definite threshold for the size of the population expressing CD19 that is Am J Clin Pathol 215;144:
12 Porwit and Béné / Mixed-Phenotype Acute Leukemias A 1, 1, 1, SSC-Height SSC-Height SSC-Height CD45 PerCP CD45 PerCP CD45 PerCP B 1, CD19 PE cytdt FITC SSC-Height cycd3 APC CD19 PE CD45 PerCP C 1, CD13 PE cympo FITC SSC-Height CD34 APC CD34 APC CD45 PerCP D 1, CD34 APC CD2 APC SSC-Height CD38 FITC CD38 FITC CD45 PerCP Image 7 Flow cytometry immunophenotypic findings in case 268: CD45 dim (blast) area contains complex populations of normal B-cell precursors, myeloid blasts, and an abnormal B/T population coexpressing cytoplasmic CD3 and surface CD19. A, Apparently homogeneous blast (Bermudes) cell population. B, B/T compartment. C, Myeloid M blasts. D, Hematogones. FITC, fluorescein isothiocyanate. Red, neutrophils; green, monocytes; pink, lymphocytes; light blue, blasts; dark blue, CD34+ cells; yellow, hematogones. (Case 268, courtesy of S. A. Ely, MD, and colleagues.) 372 Am J Clin Pathol 215;144:
13 AJCP / Review Article Table 4 Summary of Cases of MPAL With MLL Rearrangement Case No. Patient Age, y/sex Immunophenotype Cytogenetics/Molecular Genetics , F Lymph node: FCM: 37% blasts, CD3 dim, CD5 dim, CD7+, CD33+, CD34+, CD79a+, TdT+, CD11s+, MPOs+. IHC: CD3 (weak), CD34, TdT, MPO (weak), CD2, lysozyme, NOTCH1 negative, suggesting the absence of activating alterations in this pathway. BM 3% blasts not available for review , M Initial: CD34, cmpo, CD117, CD45+, HLA DR+, CD4+, CD11b+, CD15+, CD36+, CD64+, CD3, CD1, CD19 Relapse: CD34, cmpo, CD117, CD45+, HLA-DR+, CD4, CD11b, CD15, CD36, CD64, CD3, CD1, CD19+, ccd79a+, ntdt+, ccd22+/ 37 9, M 25 BM: FCM, 74% blasts CD33+, CD15+, CD4+, CD16+, CD56+, HLA-DR+, CD11b. The blasts were negative for CD13 and CD14, B and T markers. 26 BM: FCM, 91% blasts CD19+, CD22+, HLA-DR+. Myeloid, other B and T markers negative 212: Extradural vertebral mass, FCM: 65% blasts CD45 dim, CD19s+, CD11bs+, CD79as+, CD38+, HLA-DR, negative: m and ccd3, CD2, CD5, CD7, CD4, CD8, CD1, CD2, m and ccd22, sig, CD13, CD14, CD33, CD23, CD15, CD16, CD56, CD117, CD36, CD64, TdT and MPO. IHC: MPO+, CD68, lysozyme, CD19: weakly (7%), CD79a+(9%), PAX5+ (9%) , M Previous therapy for B-lymphoma. Diagnosis: FCM: CD45 dim, HLA-DR+, CD19 bright, CD22h+, CD38+, CD34s+, CD1. IHC: TdT+, PAX5+, and CD79as+, negative: CD1, CD34, CD117, CD22, CD68, lysozyme, and BCL6 Relapse 1: FCM CD45+, HLA-DR+, CD14+, CD11c+, CD11b+, CD13+, CD33+, CD34, CD117 expression B markers negative. IHC: CD68+, lysozyme+, CD163 weak, negative TdT, CD34, CD117, CD1, PAX5, CD45RA, CD123, MPO Relapse 2: FCM, two abnormal populations: B-LBL 5% CD45 dim, HLA-DR+, CD19+, CD22+, CD38+, CD34s+, CD5, CD1, CD11c, CD11b, CD13, CD33, CD2, CD23, SIg. Monocytic: 2%-3% CD45h+, CD14+, HLA-DR+, CD4h, CD11c+, CD11b+, CD13h+, CD33+, CD38+. IHC: TdT+, PAX5 5%+, CD68 4%+, lysozyme 8%+, negative CD79a, CD2, CD22, CD1, CD34, CD117, MPO FISH on the lymph node, break-apart probe MLL rearrangement+, BCR-ABL1 negative on blood t(9;11)(p22;q23) BM 25: 46,XY,add(12)(p11.2) [9]ish ins(9;11)(p22;q23q23) (5 MLL+,9cen+,WCP11 ; MLL+, WCP11+) /46,XX[15] nuc ish 11q23(MLLx2)(5 MLL spx1)[124]/11q23(mllx2)[76] BM 26: 46,XY,t(14;19) (q32;p13)ish t(14;19) (q32;p13)(3 IGH+,5 IGH con 3 IGH+)[7]/46,XY[23] nuc ish (5 MLLx3,3 MLLx2) (5 MLL con 3 MLL x2)[45]/ (MLLx2)[155]/12p13(TELx2), 21q22(AML1x2)[2] 212: Extradural vertebral mass 46,XY,inv(3)(p21q27),inv(12) (q13q24.3),t(14;19)(q32;p13) [8]/46,XY[1]ish ins(9;11) (p22;q23q23)(5 MLL+;MLL+) nuc ish(5 MLLx3,3 MLLx2) (5 MLL con 3 MLLx2) [134/2]/ (ETV6x2)[2]/ (5 IGHx2,3 IGHx3)(5 IGH con 3 IGHx2) [136/2] Diagnosis: 46,XY,t(4;11) (q21;q23)[16]/46,xy,t(4;11) (q21;q23),del(7)(q22q34)[4] Relapse 1: 46,XY,t(4;11)(q21;q23) [13]/46,XY[7] Relapse 2: MLL confirmed by FISH Consensus WHO Diagnosis/ *Comments MPAL, T/myeloid, with t(v;11q23); MLL rearranged Acute leukemia with recurrent cytogenetic abnormality, t(9;11) (p22;q23) *Presented with acute monocytic leukemia with lymph node involvement, relapse as B-acute lymphoblastic leukemia, CD1 negative Acute leukemia with MLL rearrangement with cryptic variant t(9;11)(p22;q23), MLTT3-MLL fusion with evolving new clone of IGH rearrangement presenting as (1) acute myeloid leukemia in 25, (2) first relapse as B-acute lymphoblastic leukemia in 26, and (3) second relapse as extramedullary (vertebral mass) involvement by B-acute lymphoblastic leukemia Therapy-related myeloid neoplasm, with t(4;11), MLL rearranged, presenting as B-lymphoblastic leukemia with relapse as acute myeloid leukemia (monocytic differentiation) and second relapse as MPAL B/myeloid with t(v;11q23); MLL rearranged (bilineal) B-LBL, B-lymphoblastic; BM, bone marrow; c, cytoplasmic; FCM, flow cytometry; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MLL, mixed-lineage leukemia; MPAL, mixed-phenotype acute leukemia; MPO, myeloperoxidase; WHO, World Health Organization. Am J Clin Pathol 215;144:
14 Porwit and Béné / Mixed-Phenotype Acute Leukemias Table 5 Summary of AUL and AML Cases Discussed in the Session Case No. Patient Age, y/ Sex Immunophenotype Cytogenetics/Molecular Genetics , F FCM, one blast population CD34+, CD117+/, CD13, CD33 dim, HLA-DR, TdT, CD11b dim, CD4, CD7s dim, and ccd22 dim, negative for CD3, CD19, CD2, CD1, CD2, CD5, and MPO. IHC: PAX5s and CD79as 25 47, F FCM, one blast population (86%): CD7+, CD33+, CD34+, CD38+, HLA-DR+ Negative: ccd3, scd3, CD1, CD11c, CD14, CD19, CD22, CD56, CD61, CD64, ccd79a, MPO , M FCM, one blast population (96%): CD34+, HLA-DR+, CD7+, CD33 dim, CD38s dim, CD9s dim, CD52, CD58, CD81, CD49b, CD184s dim Negative: CD19, CD2, CD22, ccd79a, CD1, sig, CD1, CD2, CD3, ccd3, CD4, CD8, CD5, CD25, CD56, TdT, CD13, CD14, CD15, CD41, CD64, CD117, and MPO mo, M FCM: one population (skull mass and BM) ccd3 dim, CD13 dim, CD33, CD34, CD56 bright, and CD117. Negative for CD1a, CD2, mcd3, CD5, CD4, CD7, CD8, CD11b, CD11c, CD14, CD16, CD41, CD61, CD64, glycophorin A, HLA-DR, MPO, and TdT , F FCM one population (82%) CD2+, CD4+, CD13+, CD33+, CD34+ dim, CD56+, CD6, and MPO 46,XX 92-97<4n>,XXXX,+4,+4,+6, 7,?t(1;11)(p12-13;q14-21) x2, 13,i(17) (q1),+2[cp4]/46,xx[16] FISH for BCR-ABL1 negative, four signals each for BCR and ABL1; FISH for PML-RARA negative, four signals each for PML and RARA Insufficient Molecular: Negative for b3a2, b2a2, and e1a2 transcripts of bcr-abl/ t(9;22)(q34;q11), the short and long forms of PML-RARA/t(15;17) (q22;q21), the A and D forms of CBFb-MYH11/inv(16), AML1-ETO/t(8;21)(q22;q22), E2A-PBX-1/t(1;19)(q23;p13), MLL-AF4/t(4;11)(q12;q23), and TEL-AML1/t(12;21)(p12;q22) 46,XY 46,XX,inv(21)(p13q22.1)[8]/45-46,sl,add(6)(p22),i(8)(q1)[2],der(11) t(11;11)(p15;q13),del(12)(p11.2) [2],add(16)(p13.1), 17[3],add(17) (p13)[3],del(17)(p13)[4],del(18) (q21.1)[2][cp1]/46xx[2] Consensus WHO Diagnosis/ *Comments AUL (consensus not reached) *Infiltrates of plasmacytoid dendritic cells AML with minimal differentiation, with t(1;11); PICALM/MLLT1 AML with minimal differentiation AML with minimal differentiation AML with myelodysplasia related changes (complex karyotype) AML, acute myeloid leukemia; AUL, acute unclassifiable leukemia; BM, bone marrow; c, cytoplasmic; FCM, flow cytometry; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MPO, myeloperoxidase; WHO, World Health Organization. necessary to define B-lineage involvement. In two cases of bilineal B/myeloid MPAL (cases 26 and 365), only minor CD19+ populations were detected (5%-7% and 12.5% in cases 26 and 365, respectively). Since B-cell lineage was confirmed by other markers (Table 1), criteria were met for the diagnosis of MPAL. The intensity of CD19 expression by blasts should be compared with that expected by normal B cells and, if comparable, considered bright. It has to be stressed that in cases in which the whole blast cell population strongly expresses CD19, with the immunophenotype otherwise being consistent with B-ALL/lymphoma, the presence of MPO expression as a sole aberrant marker should not dissuade therapy using a B-ALL regimen, and patient prognosis does not seem to differ from other patients with B-ALL. 32 What Criteria Are Helpful in the Differential Diagnosis of AUL vs AML With Minimal Differentiation? Five cases submitted to this session (cases 199, 25, 261, 349, and 396) illustrated classification difficulties between AUL and AML with minimal differentiation (Table 5). True AUL is very rare, and these neoplasms should not express markers of B, T, or myeloid lineage and should not fulfill criteria for B- or T-ALL, AML with minimal differentiation, or MPAL. Nevertheless, AUL cases can be positive for CD34, CD38, HLA-DR, and/or TdT. Importantly, there may be cases that cannot be adequately classified due to insufficient immunophenotyping data or discordant expression of various markers, rendering definitive classification impossible. The latter cases should be designated as acute 374 Am J Clin Pathol 215;144:
15 AJCP / Review Article unclassifiable leukemia, which is different from AUL. 46 The diagnosis of acute unclassifiable leukemia could be applied to case 199, for which the review panel could not reach a consensus. In three other cases (Table 5), the panel consensus diagnosis was AML with minimal differentiation due to the expression of CD33 with no expression of B- or T-lineage associated markers. Corresponding author: Anna Porwit, MD, PhD, Dept of Pathobiology and Laboratory Medicine, University of Toronto, University Health Network, Toronto, ON, Canada; anna.porwit@uhn.ca. Acknowledgments: The following were contributors or co-contributors of cases to this session: S. Acree, R. E. Alexander, S. Al-Quran, S. A. Alghamdi, D. Arber, H. Ayyad, A. Bagg, F. H. Barakat, A. Basen, A. R. Brothman, C. E. Bueso-Ramos, L. Cannizzaro, C. L. Cantu, C. Carter, W. Z. Chen, P. Cohen, A. M. B. Collie, C. V. Curry, M. Czader, G. Deeb, M. E. DeLelys, M. T. Elghetany, S. A. Ely, J. Emmons, S. Garg, J. T. Geyer, B. Gray, D. Grier, R. P. Hasserjian, F. Hernandez-Ilizaliturri, E. D. Hsi, J. W. Hussong, E. M. Hyjek, K. Inamdar, J. L. Jorgensen, K. H. Karner, P. Kaur, T. Kelley, A. Kumapeli, V. Leventaki, P. Lin, A. L. Lewis, M. R. Lewis, M. A. Linden, Y. Li, C. Manavi, S. Mathew, C. McMahon, E. Medina, M. Merzianu, E. Moore, R. Musani, T. Muzzafar, V. Neppalli, D. Ng, G. E. Nybakken, A. Orazi, Y. R. Orduz, J. L. Patel, K. P. Patel, S. Perkins, K. Qidwai, K. H. Ramesh, F. Rashid-Korvear, M. Roshal, D. Roy, S. Sait, M. Salama, A. M. Sands, B. Shackley, I. Siddiqi, M. Simmons, A. R. Sohani, C. M. Spier, A. Suarez, J. Y. Song, V. Sriganeshan, L. Taddesse-Heath, W. Tam, J. M. T. Urrego, J. van den Berghe, S. Wang, W. Wang, H. J. Weinstein, J. Yan, M. Zapata, and C. Zaremba. References 1. Borowitz M, Bene MC, Harris NL, et al. In: Swerdlow S, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC; 28: Béné MC, Nebe T, Bettelheim P, et al. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 1. Leukemia. 211;25: Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 28;111: Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9: Guy J, Antony-Debré I, Benayoun E, et al; GEIL (Groupe d Etude Immunologique des Leucémies). Flow cytometry thresholds of myeloperoxidase detection to discriminate between acute lymphoblastic or myeloblastic leukaemia. Br J Haematol. 213;161: van den Ancker W, Westers TM, de Leeuw DC, et al. A threshold of 1% for myeloperoxidase by flow cytometry is valid to classify acute leukemia of ambiguous and myeloid origin. Cytometry B Clin Cytom. 213;84: Matutes E, Pickl WF, Van t Veer M, et al. Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 1 patients defined according to the WHO 28 classification. Blood. 211;117: Rubnitz, JE, Onciu M, Pounds S, et al. Acute mixed lineage leukemia in children: the experience of St Jude Children s Research Hospital. Blood. 29;113: Bene MC, Castoldi G, Derolf A, et al. Near-tetraploid acute myeloid leukemias: an EGIL retrospective study of 25 cases. Leukemia. 26;2: Lemez P, Attarbaschi A, Bene MC, et al. Childhood neartetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases. Eur J Haematol. 21;85: Manola KN. Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview. Br J Haematol. 213;163: La SR, Aventin A, Crescenzi B, et al. CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients. Leukemia. 25;19: Martini A, La SR, Janssen H, et al. Recurrent rearrangement of the Ewing s sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res. 22;62: Nyquist KB, Thorsen J, Zeller B, et al. Identification of the TAF15-ZNF384 fusion gene in two new cases of acute lymphoblastic leukemia with a t(12;17)(p13;q12). Cancer Genet. 211;24: Asahara SI, Saigo K, Hasuike N, et al. Acute lymphoblastic leukemia accompanied by chromosomal abnormality of translocation (12;17). Haematologia. 21;31: Krance RA, Raimondi SC, Dubowy R, et al. t(12;17) (p13;q21) in early pre B acute lymphoid leukemia. Leukemia. 1992;6: Grammatico S, Vitale A, La SR, et al. Lineage switch from pro B acute lymphoid leukemia to acute myeloid leukemia in a case with t(12;17)(p13;q11)/taf15-znf384 rearrangement. Leuk Lymphoma. 213;54: Haferlach C, Bacher U, Haferlach T, et al. The inv(3) (q21q26)/t(3;3)(q21;q26) is frequently accompanied by alterations of the RUNX1, KRAS and NRAS and NF1 genes and mediates adverse prognosis both in MDS and in AML: a study in 39 cases of MDS or AML. Leukemia. 211;25: Sun J, Konoplev SN, Wang X, et al. De novo acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2): a clinicopathologic and cytogenetic study of an entity recently added to the WHO classification. Mod Pathol. 211;24: Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 29;1: Bene MC, Porwit A. Acute leukemias of ambiguous lineage. Semin Diagn Pathol. 212;29: Carulli G, Marini A, Ferreri MI, et al. B-cell acute lymphoblastic leukemia with t(4;11)(q21;q23) in a young woman: evolution into mixed phenotype acute leukemia with additional chromosomal aberrations in the course of therapy. Hematol Rep. 212;4:e Shimizu H, Culbert SJ, Cork A, et al. A lineage switch in acute monocytic leukemia: a case report. Am J Pediatr Hematol Oncol. 1989;11: Krawczuk-Rybak M, Zak J, Jaworowska B. A lineage switch from AML to ALL with persistent translocation t(4;11) in congenital leukemia. Med Pediatr Oncol. 23;41: Stasik C, Ganguly S, Cunningham MT, et al. Infant acute lymphoblastic leukemia with t(11;16)(q23;p13.3) and lineage switch into acute monoblastic leukemia. Cancer Genet Cytogenet. 26;168: Am J Clin Pathol 215;144:
Mixed Phenotype Acute Leukemias
Mixed Phenotype Acute Leukemias CHEN GAO; AMY M. SANDS; JIANLAN SUN NORTH AMERICAN JOURNAL OF MEDICINE AND SCIENCE APR 2012 VOL 5 NO.2 INTRODUCTION Most cases of acute leukemia can be classified based
More informationCME/SAM. Mixed Phenotype Acute Leukemia
AJCP / Original Article Mixed Phenotype Acute Leukemia A Study of 61 Cases Using World Health Organization and European Group for the Immunological Classification of Leukaemias Criteria Olga K. Weinberg,
More informationCase 1. Sa A.Wang, MD UT MD Anderson Cancer Center Houston, TX
Case 1 Sa A.Wang, MD UT MD Anderson Cancer Center Houston, TX Disclosure of Relevant Financial Relationships The USCAP requires that anyone in a position to influence or control the content of all CME
More informationAML: WHO classification, biology and prognosis. Dimitri Breems, MD, PhD Internist-Hematoloog Ziekenhuis Netwerk Antwerpen
AML: WHO classification, biology and prognosis Dimitri Breems, MD, PhD Internist-Hematoloog Ziekenhuis Netwerk Antwerpen Acute myeloid leukemia Clonal expansion of undifferentiated myeloid precursors Impaired
More informationReporting cytogenetics Can it make sense? Daniel Weisdorf MD University of Minnesota
Reporting cytogenetics Can it make sense? Daniel Weisdorf MD University of Minnesota Reporting cytogenetics What is it? Terminology Clinical value What details are important Diagnostic Tools for Leukemia
More informationTest Name Results Units Bio. Ref. Interval. Positive
LL - LL-ROHINI (NATIONAL REFERENCE 135091533 Age 28 Years Gender Male 1/9/2017 120000AM 1/9/2017 105415AM 4/9/2017 23858M Ref By Final LEUKEMIA DIAGNOSTIC COMREHENSIVE ROFILE, ANY 6 MARKERS t (1;19) (q23
More informationThe spectrum of flow cytometry of the bone marrow
The spectrum of flow cytometry of the bone marrow Anna Porwit Lund University Faculty of Medicine Dept. of Clinical Sciences Div. Oncology and Pathology anna.porwit@med.lu.se Disclosure of speaker s interests
More informationDiagnostic challenge: Acute leukemia with biphenotypic blasts and BCR-ABL1 translocation
Case Study Diagnostic challenge: Acute leukemia with biphenotypic blasts and BCR-ABL1 translocation Ling Wang 1 and Xiangdong Xu 1,2,* 1 Department of Pathology, University of California, San Diego; 2
More informationChapter. Both authors contributed equally to this paper. Department of Hematology, CCA-V-ICI, VU University Medical Center, Amsterdam, The Netherlands
Chapter CHALLENGING DIAGNOSIS IN A PATIENT WITH CLEAR LYMPHOID IMMUNOHISTOCHEMICAL FEATURES AND MYELOID MORPHOLOGY: MIXED PHENOTYPE ACUTE LEUKEMIA WITH ERYTHROPHAGOCYTOSIS 2 David C. de Leeuw a, *, Willemijn
More informationUpdate on the WHO Classification of Acute Myeloid Leukemia. Kaaren K. Reichard, MD Mayo Clinic Rochester
Update on the WHO Classification of Acute Myeloid Leukemia Kaaren K. Reichard, MD Mayo Clinic Rochester reichard.kaaren@mayo.edu Nothing to disclose Conflict of Interest Objectives Present a practical
More informationDifferential diagnosis of hematolymphoid tumors composed of medium-sized cells. Brian Skinnider B.C. Cancer Agency, Vancouver General Hospital
Differential diagnosis of hematolymphoid tumors composed of medium-sized cells Brian Skinnider B.C. Cancer Agency, Vancouver General Hospital Lymphoma classification Lymphoma diagnosis starts with morphologic
More informationHEMATOPATHOLOGY SUMMARY REPORT RL;MMR;
HEMATOPATHOLOGY SUMMARY REPORT RL;MMR; Page 1 of 1 05/15/20XX HP000000-20XX 05/21/20XX (212) 123-457 (51) 32-3455 (51) 123-457 Age: 78 DOB: 0/05/19XX SS#: 45-45-45 Clinical Information: 78 y/o female with
More informationNUP214-ABL1 Fusion: A Novel Discovery in Acute Myelomonocytic Leukemia
Case 0094 NUP214-ABL1 Fusion: A Novel Discovery in Acute Myelomonocytic Leukemia Jessica Snider, MD Medical University of South Carolina Case Report - 64 year old Caucasian Male Past Medical History Osteoarthritis
More informationAcute myeloid leukemia. M. Kaźmierczak 2016
Acute myeloid leukemia M. Kaźmierczak 2016 Acute myeloid leukemia Malignant clonal disorder of immature hematopoietic cells characterized by clonal proliferation of abnormal blast cells and impaired production
More informationTest Name Results Units Bio. Ref. Interval. Positive
Lab No 135091548 Age 35 Years Gender Female 1/9/2017 120000AM 1/9/2017 103420AM 4/9/2017 23753M Ref By Dr UNKNWON Final Test Results Units Bio Ref Interval LEUKEMIA DIAGNOSTIC COMREHENSIVE ROFILE 3 t (1;19)
More informationBlastic Plasmacytoid Dendritic Cell Neoplasm with DNMT3A and TET2 mutations (SH )
Blastic Plasmacytoid Dendritic Cell Neoplasm with DNMT3A and TET2 mutations (SH2017-0314) Habibe Kurt, Joseph D. Khoury, Carlos E. Bueso-Ramos, Jeffrey L. Jorgensen, Guilin Tang, L. Jeffrey Medeiros, and
More informationRisk Stratification in Childhood Leukemia
Risk Stratification in Childhood Leukemia Why is risk stratification important? Toxicities Deepa Bhojwani, MD May 11, 2018 To determine intensity of therapy - When to intensify therapy - When to de-intensify
More informationTest Name Results Units Bio. Ref. Interval. Positive
LL - LL-ROHINI (NATIONAL REFERENCE 135091534 Age 36 Years Gender Female 1/9/2017 120000AM 1/9/2017 105316AM 2/9/2017 104147AM Ref By Final LEUKEMIA GENETIC ROFILE ANY SIX MARKERS, CR QUALITATIVE AML ETO
More informationAcute Myeloid Leukemia with Recurrent Cytogenetic Abnormalities
Acute Myeloid Leukemia with Recurrent Cytogenetic Abnormalities Acute Myeloid Leukemia with recurrent cytogenetic Abnormalities -t(8;21)(q22;q22)(aml/eto) -inv(16) or t(16;16) -t(15;17) -11q23 Acute Myeloid
More informationCase Report Mixed phenotype acute leukemia, B/myeloid, NOS with near-tetraploidy: a case report
Int J Clin Exp Pathol 2017;10(11):11206-11210 www.ijcep.com /ISSN:1936-2625/IJCEP0054881 Case Report Mixed phenotype acute leukemia, B/myeloid, NOS with near-tetraploidy: a case report Kimberley M Nix
More informationExtramedullary precursor T-lymphoblastic transformation of CML at presentation
Extramedullary precursor T-lymphoblastic transformation of CML at presentation Neerja Vajpayee, Constance Stein, Bernard Poeisz & Robert E. Hutchison Clinical History 30 year old man presented to the emergency
More informationObjectives. Morphology and IHC. Flow and Cyto FISH. Testing for Heme Malignancies 3/20/2013
Molecular Markers in Hematologic Malignancy: Ways to locate the needle in the haystack. Objectives Review the types of testing for hematologic malignancies Understand rationale for molecular testing Marcie
More informationRole of FISH in Hematological Cancers
Role of FISH in Hematological Cancers Thomas S.K. Wan PhD,FRCPath,FFSc(RCPA) Honorary Professor, Department of Pathology & Clinical Biochemistry, Queen Mary Hospital, University of Hong Kong. e-mail: wantsk@hku.hk
More informationPRECURSOR LYMHPOID NEOPLASMS. B lymphoblastic leukaemia/lymphoma T lymphoblastic leukaemia/lymphoma
PRECURSOR LYMHPOID NEOPLASMS B lymphoblastic leukaemia/lymphoma T lymphoblastic leukaemia/lymphoma B lymphoblastic leukaemia/lymphoma Definition: B lymphoblastic leukaemia/lymphoma is a neoplasm of precursor
More informationInitial Diagnostic Workup of Acute Leukemia
Initial Diagnostic Workup of Acute Leukemia Guideline from the College of American Pathologists (CAP) and the American Society of Hematology (ASH) Publication: Archives of Pathology and Laboratory Medicine
More informationMixed-Phenotype Acute Leukemia
Special Section 2016 New Frontiers in Pathology, Part II Mixed-Phenotype Acute Leukemia Mixed-phenotype acute leukemia (MPAL) is a heterogeneous category in the World Health Organization classification
More informationJordi Esteve Hospital Clínic (Barcelona) Acute Leukemia Working Party. The European Group for Blood and Marrow Transplantation
36th EBMT & 9th Data Management Group Annual Meeting Vienna, 23 March 2010 Jordi Esteve Hospital Clínic (Barcelona) Acute Leukemia Working Party The European Group for Blood and Marrow Transplantation
More informationThe Revised 2016 WHO Classification of Acute Leukemias
The Revised 2016 WHO Classification of Acute Leukemias Robert P Hasserjian, MD Associate Professor Massachusetts General Hospital and Harvard Medical School Acute leukemias Aggressive hematopoietic neoplasms
More informationClassification of Hematologic Malignancies. Patricia Aoun MD MPH
Classification of Hematologic Malignancies Patricia Aoun MD MPH Objectives Know the basic principles of the current classification system for hematopoietic and lymphoid malignancies Understand the differences
More informationCCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma
AJCP /CASE REPORT CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma Yuan Miao, MD, 1,2 Pei Lin, MD, 1 Wei Wang, MD, 1 L. Jeffrey Medeiros, MD,
More informationMast Cell Disease Case 054 Session 7
Mast Cell Disease Case 054 Session 7 Rodney R. Miles, M.D., Ph.D. Lauren B. Smith, M.D. Cem Akin, M.D. Diane Roulston,, Ph.D. Charles W. Ross, M.D. Departments of Pathology and Internal Medicine University
More informationCost-Effective Strategies in the Workup of Hematologic Neoplasm. Karl S. Theil, Claudiu V. Cotta Cleveland Clinic
Cost-Effective Strategies in the Workup of Hematologic Neoplasm Karl S. Theil, Claudiu V. Cotta Cleveland Clinic In the past 12 months, we have not had a significant financial interest or other relationship
More informationWHO Classification of Myeloid Neoplasms with Defined Molecular Abnormalities
WHO Classification of Myeloid Neoplasms with Defined Molecular Abnormalities Robert W. McKenna, M.D. 1/2009 WHO Classification of Myeloid Neoplasms (4th Edition)--2008 Incorporates new information that
More informationCase #1. 65 yo man with no prior history presented with leukocytosis and circulating blasts: Bone marrow biopsy was performed
Case #1 65 yo man with no prior history presented with leukocytosis and circulating blasts: WBC 187.4K/uL ; Hgb 10.0gm/dL; Platelet 68K/uL Neutrophil % 25.0% Lymphocyte % 38.0% Monocyte % 12.0% Metamyelocyte
More informationFluorescence in-situ Hybridization (FISH) ETO(RUNX1T1)/AML1(RUNX1) or t(8;21)(q21.3;q22)
PML/RARA t(15;17) Translocation Assay Result : nuc ish(pml 2)(RARA 2)[200] : 200/200(100%) interphase nuclei show normal 2O 2G signals for PML/RARA : is Negative for t(15;17)(q22;q21.1) 2 Orange 2 Green
More informationHEMATOLOGIC MALIGNANCIES BIOLOGY
HEMATOLOGIC MALIGNANCIES BIOLOGY Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic stem cell FAILURE OF TERMINAL DIFFERENTIATION
More informationMolecular Markers in Acute Leukemia. Dr Muhd Zanapiah Zakaria Hospital Ampang
Molecular Markers in Acute Leukemia Dr Muhd Zanapiah Zakaria Hospital Ampang Molecular Markers Useful at diagnosis Classify groups and prognosis Development of more specific therapies Application of risk-adjusted
More informationSWOG ONCOLOGY RESEARCH PROFESSIONAL (ORP) MANUAL LEUKEMIA FORMS CHAPTER 16A REVISED: DECEMBER 2017
LEUKEMIA FORMS The guidelines and figures below are specific to Leukemia studies. The information in this manual does NOT represent a complete set of required forms for any leukemia study. Please refer
More informationADx Bone Marrow Report. Patient Information Referring Physician Specimen Information
ADx Bone Marrow Report Patient Information Referring Physician Specimen Information Patient Name: Specimen: Bone Marrow Site: Left iliac Physician: Accession #: ID#: Reported: 08/19/2014 - CHRONIC MYELOGENOUS
More informationCombinations of morphology codes of haematological malignancies (HM) referring to the same tumour or to a potential transformation
Major subgroups according to the World Health Organisation (WHO) Classification Myeloproliferative neoplasms (MPN) Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or
More informationA pediatric patient with acute leukemia of ambiguous lineage with a NUP98-NSD1 rearrangement SH
A pediatric patient with acute leukemia of ambiguous lineage with a NUP98NSD1 rearrangement SH20170203 Rebecca LeemanNeill, Ronald Rice, Anita Malek, Patricia Raciti, Susan Hsiao, Mahesh Mansukhani, Bachir
More informationKrishna Reddy CH and Ashwin Dalal. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad
Clinical Cytogenetics in the Diagnosis and Prognosis of Leukemias Krishna Reddy CH and Ashwin Dalal Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad Email: krishnareddy.chr@gmail.com
More informationTherapy-related MDS/AML with KMT2A (MLL) Rearrangement Following Therapy for APL Case 0328
Therapy-related MDS/AML with KMT2A (MLL) Rearrangement Following Therapy for APL Case 0328 Kenneth N. Holder, Leslie J. Greebon, Gopalrao Velagaleti, Hongxin Fan, Russell A. Higgins Initial Case: Clinical
More informationVUmc Basispresentatie
Clinical diagnostic cytometry Gerrit J Schuurhuis Dept of Hematology VU University Medical Center Amsterdam, Netherlands Use of immunophenotyping at diagnosis to trace residual disease after therapy 1.
More informationMeeting VAKB 8 februari 2011 Nancy Boeckx, MD, PhD
Meeting VAKB 8 februari 2011 Nancy Boeckx, MD, PhD What is it? clonal expansion of myeloid precursor cells with reduced capacity to differentiate as opposed to ALL/CLL, it is limited to the myeloid cell
More informationBCR-ABL1 positive Myeloid Sarcoma Nicola Austin
BCR-ABL1 positive Myeloid Sarcoma Nicola Austin Cytocell UK & Ireland User Group Meeting Jesus College, Cambridge 4 th - 5 th April 2017 Myeloid Sarcoma WHO Classification Tumours of Haematopoietic and
More informationCase #16: Diagnosis. T-Lymphoblastic lymphoma. But wait, there s more... A few weeks later the cytogenetics came back...
Case #16: Diagnosis T-Lymphoblastic lymphoma But wait, there s more... A few weeks later the cytogenetics came back... 46,XY t(8;13)(p12;q12)[12] Image courtesy of Dr. Xinyan Lu Further Studies RT-PCR
More informationHematology Measure #1: Myelodysplastic Syndrome (MDS) and Acute Leukemias: Baseline Cytogenetic Testing Performed on Bone Marrow
Hematology Measure #1: Myelodysplastic Syndrome (MDS) and Acute Leukemias: Baseline Cytogenetic Testing Performed on Bone Marrow This measure may be used as an Accountability measure Clinical Performance
More informationElisabeth Koller 3rd Medical Dept., Center for Hematology and Oncology, Hanusch Hospital, Vienna, Austria
Elisabeth Koller 3rd Medical Dept., Center for Hematology and Oncology, Hanusch Hospital, Vienna, Austria Incidence Diagnosis Prognostic factors Treatment Induction therapy - HSCT Indications for HSCT
More informationCASE REPORT. Abstract. Introduction. Case Reports
CASE REPORT Two Elderly Patients with Philadelphia Chromosome Positive Mixed Phenotype Acute Leukemia Who Were Successfully Treated with Dasatinib and Prednisolone Hiroyuki Takata 1, Taichi Ikebe 1, Hitohiro
More informationCase Workshop of Society for Hematopathology and European Association for Haematopathology
Case 24 2007 Workshop of Society for Hematopathology and European Association for Haematopathology Aliyah Rahemtullah 1, Martin K Selig 1, Paola Dal Cin 2 and Robert P Hasserjian 1 Departments of Pathology,
More informationV. Acute leukemia. Flow cytometry in evaluation of hematopoietic neoplasms: A case-based approach
V. Acute leukemia Evaluating a sample for an acute leukemia Acute leukemia is a neoplasm of immature myeloid or lymphoid cells characterized by a block in maturation, usually at the stage of an early progenitor
More informationLymphoblastic Leukemia / Lymphoma
1 5014 - Topics in Pediatric Hematopathology: Acute Lymphoblastic Leukemia, Including Changes in the Revised WHO Classification, and Unusual Pediatric Myeloid Neoplasms Robert W. McKenna, MD MASCP * Elizabeth
More informationSuccessful flow cytometric immunophenotyping of body fluid specimens
Successful flow cytometric immunophenotyping of body fluid specimens Fiona E. Craig, MD Division of Hematopathology Mayo Clinic Arizona 2017 MFMER slide-1 Financial disclosure No conflicts 2017 MFMER slide-2
More informationStandard immunophenotyping of leukemia cells in acute myeloid leukemia (AML)
Clinical immunology Standard immunophenotyping of leukemia cells in acute myeloid leukemia (AML) ` JOLANTA WOZNIAK, JOANNA KOPEÆ-SZLÊZAK Department of Haematological Cytobiology, Institut of Haematology
More informationHandout for lecture on lymphoblastic neoplasms presented by Rob McKenna
Handout for lecture on lymphoblastic neoplasms presented by Rob McKenna The following slides represent a near final version of the presentation that will be given in Maui, January 23,2018. Minor changes
More informationAcute Myeloid Leukemia with RUNX1 and Several Co-mutations
Case SH2017-0281 Acute Myeloid Leukemia with RUNX1 and Several Co-mutations James Bauer, MD, PhD David Yang, MD Erik Ranheim, MD, PhD Catherine Leith, MB, Bchir Clinical History Chief Complaint: 72 year
More information2013 AAIM Pathology Workshop
2013 AAIM Pathology Workshop John Schmieg, M.D., Ph.D. None Disclosures 1 Pathology Workshop Objectives Define the general philosophy of reviewing pathology reports Review the various components of Bone
More informationBumps on the Neck and Groin of a 2-Year-Old Male. Laboratory Findings: Table 1, Table 2; Figure 1; Image 1, Image 2, Image 3
Bumps on the Neck and Groin of a 2-Year-Old Male 1 Erikakelly Strand, BS* Clinical History Patient: 2-year-old white male. Chief Complaint: Bumps on neck and groin. History of Present Illness: A 2-year-old
More information2010 Hematopoietic and Lymphoid ICD-O Codes - Alphabetical List THIS TABLE REPLACES ALL ICD-O-3 Codes
Acute basophilic leukemia 9870/3 Acute biphenotypic leukemia [OBS] 9805/3 Acute erythroid leukemia 9840/3 Acute megakaryoblastic leukemia 9910/3 Acute monoblastic and monocytic leukemia 9891/3 Acute myeloid
More information2012 Hematopoietic and Lymphoid ICD-O Codes - Numerical List THIS TABLE REPLACES ALL ICD-O-3 Codes
Malignant lymphoma, NOS 9590/3 Non-Hodgkin lymphoma, NOS 9591/3 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma 9596/3 Primary
More informationBeyond the CBC Report: Extended Laboratory Testing in the Evaluation for Hematologic Neoplasia Disclosure
Beyond the CBC Report: Extended Laboratory Testing in the Evaluation for Hematologic Neoplasia Disclosure I am receiving an honorarium from Sysmex for today s presentation. 1 Determining the Etiology for
More informationIntegrated Diagnostic Approach to the Classification of Myeloid Neoplasms. Daniel A. Arber, MD Stanford University
Integrated Diagnostic Approach to the Classification of Myeloid Neoplasms Daniel A. Arber, MD Stanford University What is an integrated approach? What is an integrated approach? Incorporating all diagnostic
More informationHematology Unit Lab 2 Review Material
Objectives Hematology Unit Lab 2 Review Material - 2018 Laboratory Instructors: 1. Assist students during lab session Students: 1. Review the introductory material 2. Study the case histories provided
More informationABERRANT EXPRESSION OF CD19 AND CD43
ABERRANT EXPRESSION OF CD19 AND CD43 IN A PATIENT WITH THERAPY-RELATED ACUTE MYELOID LEUKEMIA AND A HISTORY OF MANTLE CELL LYMPHOMA Yen-Chuan Hsieh, 1 Chien-Liang Lin, 2 Chao-Jung Tsao, 2 Pin-Pen Hsieh,
More informationCase 0148 Acute myeloid leukemia with myelodysplasia-related changes and cryptic t(8;16)(p11;p13); KAT6A/CREBBP
Case 0148 Acute myeloid leukemia with myelodysplasia-related changes and cryptic t(8;16)(p11;p13); KAT6A/CREBBP Madhu M. Ouseph, M.D., Ph.D., Zakaria Grada, M.D., Karen A. Ferreira, Mark P. LeGolvan, D.O.,
More informationFLOW CYTOMETRY PRINCIPLES AND PRACTICE. Toby Eyre Consultant Haematologist Oxford University Hospitals NHS Foundation Trust June 2018
FLOW CYTOMETRY PRINCIPLES AND PRACTICE Toby Eyre Consultant Haematologist Oxford University Hospitals NHS Foundation Trust June 2018 Aims and Objectives Principles of flow cytometry Preparation Steps involved
More informationHematology Case Studies: MPAL & JMML. Nicholas Brehl, M.Ed., MLS (ASCP) CM
Hematology Case Studies: MPAL & JMML Nicholas Brehl, M.Ed., MLS (ASCP) CM 36 year old female Case 1 Symptoms: non-productive cough, fatigue, fever, chills, night sweats Physical Exam: Painful cervical
More informationDr. Anjali Kelkar (DNB Path, IFCAP)
Acute Leukemias : Morphology and Beyond Dr. Anjali Kelkar (DNB Path, IFCAP) Consultant - Diagnostic Haematology NABL Assessor Senior Associate Professor, Incharge Haematology Labs Bharati Vidyapeeth Deemed
More informationHematolymphoid lesions of the skin Part II Myeloid neoplastic proliferations Houston Society of Clinical Pathologists Symposium April 14, 2018
Hematolymphoid lesions of the skin Part II Myeloid neoplastic proliferations Houston Society of Clinical Pathologists Symposium April 14, 2018 Carlos A. Torres-Cabala, MD Associate Professor Chief, Dermatopathology
More informationDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 2
384 & 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00 De novo acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2): a clinicopathologic and cytogenetic study of an entity recently
More informationCLINICAL USE OF CELLULAR SUBPOPULATION ANALYSIS IN BM
CLINICAL USE OF CELLULAR SUBPOPULATION ANALYSIS IN BM CANCER RESEARCH CENTRE, UNIVERSITY AND UNIVERSITY HOSPITAL OF SALAMANCA (SPAIN)( Sao Paulo, 18th of April, 2009 IDENTIFICATION OF HPC (I) 1.- In vivo
More informationCase Presentation No. 075
Case Presentation No. 075 Session 4. Myelodysplastic Syndrome Cristina Montalvo, MD Baylor College of Medicine Houston, Texas 2007 Workshop of Society for Hematopathology and European Association for Haematopathology
More informationCase Report. Introduction. Mastocytosis associated with CML Hematopathology - March K. David Li 1,*, Xinjie Xu 1, and Anna P.
Mastocytosis associated with CML Hematopathology - March 2016 Case Report Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) involving chronic myelogenous
More informationTreatments and Current Research in Leukemia. Richard A. Larson, MD University of Chicago
Treatments and Current Research in Leukemia Richard A. Larson, MD University of Chicago 2 Acute (rapid progression) Myeloid Acute myeloid leukemia (AML) Acute promyelocytic leukemia (APL) Lymphoid Acute
More informationSH/EAHP WORKSHOP 2017 CASE 210 PRESENTATION
SH/EAHP WORKSHOP 2017 CASE 210 PRESENTATION Jonathon H Gralewski DO, MS, Ginell R Post MD, PhD, Youzhong Yuan MD September 9, 2017 Clinical History 60 year old male with history of c-maf high-risk IgG
More informationMixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification
MYELOID NEOPLASIA Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification Estella Matutes, 1 Winfried F. Pickl, 2 Mars
More informationMyelodysplastic Syndrome Case 158
Myelodysplastic Syndrome Case 158 Dong Chen MD PhD Division of Hematopathology Mayo Clinic Clinical History 86 year old man Persistent borderline anemia and thrombocytopenia. His past medical history was
More informationGENETICS OF HEMATOLOGICAL MALIGNANCIES
de DUVE INSTITUTE GENETICS OF HEMATOLOGICAL MALIGNANCIES INTERUNIVERSITY CERTIFICATE IN HUMAN GENETICS Université catholique de Louvain Brussels,19/02/2016 Professor Hélène Antoine-Poirel, MD, PhD Center
More informationSESSION 1 Reactive cytopenia and dysplasia
SESSION 1 Reactive cytopenia and dysplasia Falko Fend, Tübingen & Alexandar Tzankov, Basel 1 Disclosure of speaker s interests (Potential) conflict of interest none Potentially relevant company relationships
More information23/10/2017. Analysis of bone marrow for MDSrelated. Approach used at Hematopathology, Lund
Approach used at Hematopathology, Lund Analysis of bone marrow for MDSrelated aberrancies According to International/ELN Flow Cytometry Working Group (IMDSFlow) Anna Porwit Lund, Sweden 1. new patients
More informationCase 3. Ann T. Moriarty,MD
Case 3 Ann T. Moriarty,MD Case 3 59 year old male with asymptomatic cervical lymphadenopathy. These images are from a fine needle biopsy of a left cervical lymph node. Image 1 Papanicolaou Stained smear,100x.
More informationCase year old male with abdominal lymphadenopathy Treated with 8 cycles of R-CHOP One year later B-symptoms and progressive disease
Codirectors Tsieh Sun, M.D., FASCP Francisco Vega, M.D., Ph.D. Department of Hematopathology UT MD Anderson Cancer Center Houston Texas There is no conflict of interest involved in the content and presentation
More informationImmunophenotypic Profile of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia
Hematopathology / IMMUNOPHENOTYPE OF LPL/WM Immunophenotypic Profile of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia Sergej Konoplev, MD, PhD, L. Jeffrey Medeiros, MD, Carlos E. Bueso-Ramos,
More informationImmunophenotypic study of acute leukemia by flow cytometry at BPKMCH.
Nepal Medical Association Building Exhibition Road, Kathmandu Journal of Pathology of Nepal (2013) Vol. 3, 345-350 Association of Clinical Pathologist of Nepal-2010 Journal of PATHOLOGY of Nepal www.acpnepal.com
More informationMolecular Advances in Hematopathology
Molecular Advances in Hematopathology HOW MOLECULAR METHODS HAVE CHANGED MY PRACTICE Objectives Understand the importance of cytogenetic/molecular studies in hematolymphoid diseases Know some of the important
More informationHematopathology Case Study
www.medfusionservices.com Hematopathology Case Study CV3515-14 JUNE Clinical Presentation: Clinical Information: A 42 year old male with history of chronic myelogenous leukemia (CML) presents with an elevated
More informationDone By : WESSEN ADNAN BUTHAINAH AL-MASAEED
Done By : WESSEN ADNAN BUTHAINAH AL-MASAEED Acute Myeloid Leukemia Firstly we ll start with this introduction then enter the title of the lecture, so be ready and let s begin by the name of Allah : We
More informationSupplemental Material. The new provisional WHO entity RUNX1 mutated AML shows specific genetics without prognostic influence of dysplasia
Supplemental Material The new provisional WHO entity RUNX1 mutated AML shows specific genetics without prognostic influence of dysplasia Torsten Haferlach, 1 Anna Stengel, 1 Sandra Eckstein, 1 Karolína
More informationTemplate for Reporting Results of Biomarker Testing for Myeloproliferative Neoplasms
Template for Reporting Results of Biomarker Testing for Myeloproliferative Neoplasms Version: MPNBiomarkers 1.0.0.2 Protocol Posting Date: June 2017 This biomarker template is NOT required for accreditation
More informationProtocol for the Examination of Specimens From Patients With Hematopoietic Neoplasms Involving the Bone Marrow*
Protocol for the Examination of Specimens From Patients With Hematopoietic Neoplasms Involving the Bone Marrow* Version: Protocol Posting Date: January 2018 This protocol is NOT required for accreditation
More informationHaematology Probes for Multiple Myeloma
Haematology Probes for Multiple Myeloma MULTIPLE MYELOMA Multiple myeloma (MM) is a plasma cell neoplasm, characterised by the accumulation of clonal plasma cells in the bone marrow and by very complex
More informationIntroduction: The Revised (4 th Edition) World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues
Society for Hematopathology Scientific Symposium USCAP Companion Meeting, Boston, MA March 8, 2009 Boston, MA Steven H. Swerdlow and James Vardiman, Moderators Introduction: The Revised (4 th Edition)
More informationChanges to the Hematopoietic and Lymphoid Neoplasm Coding Manual
Changes to the Hematopoietic and Lymphoid Neoplasm Coding Manual KCR 2018 SPRING TRAINING 2018 Hematopoietic Database Updates Updates were done to the Hematopoietic Database based on the WHO Hematopoietic
More informationCytogenetic and molecular abnormalities in AML. Dr Elizabeth Tegg Director of haematology Pathology West
Cytogenetic and molecular abnormalities in AML Dr Elizabeth Tegg Director of haematology Pathology West Outline Classification of AML Types of genetic changes Next generation sequencing in HM Outline Classification
More informationLeukemia (2007) 21, Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas
Leukemia (2007) 21, 1566-1570 Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas Clinical presentation Mean age: 55.8 years (range: 16-87).
More information2007 Workshop of SH/EAHP. Session 5 Therapy-related myeloid neoplasms
2007 Workshop of SH/EAHP Session 5 Therapy-related myeloid neoplasms Classification: Key issues MDS vs. AML-M6 MDS vs. MDS/MPD Genetically defined entities Relevance of morphologic classification Clinical
More informationWHO Classification 7/2/2009
Least Malignant Myeloproliferative Disorders Myelodysplastic Syndromes Most Malignant Acute Leukemia Classifying Hematopoietic Disorders French-American-British (FAB) World Health Organization (WHO) Thanks
More information