You are here

Article Text

Article menu

Download PDFPDF

PostScript
Correspondence
Erythrophagocytosis in T-cell type acute lymphoblastic leukaemia with near-tetraploidy
  1. Atsushi Watanabe1,
  2. Koshi Akahane1,
  3. Shinpei Somazu1,
  4. Hiroko Oshiro1,
  5. Kumiko Goi1,
  6. Hayato Miyachi2,
  7. Nobutaka Kiyokawa3,
  8. Takeshi Inukai1,
  9. Kanji Sugita1
  1. 1Department of Pediatrics, University of Yamanashi, Chuo-city, Yamanashi, Japan
  2. 2Department of Clinical Pathology, Tokai University School of Medicine, Isehara-city, Kanagawa, Japan
  3. 3Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
  1. Correspondence to Dr Atsushi Watanabe, Department of Pediatrics, University of Yamanashi, Chuo-city, Yamanashi 409-3898, Japan; awatanabe{at}yamanashi.ac.jp

https://doi.org/10.1136/jclinpath-2016-203915

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Erythrophagocytosis by leukaemic blasts—a poor prognostic feature—is mostly seen in acute myeloid leukaemia (AML), particularly monocytic leukaemia with cytogenetic abnormalities involving t(8;16)(p11;p13);MOZ-CBP or t(16;21)(p11;q22);FUS/TLS-ERG.1 This feature was reported in poorly differentiated leukaemias, including AML-M0, undifferentiated-type leukaemia and mixed lineage-type leukaemia, but very rarely in lineage-determined leukaemia, especially T-cell acute lymphoblastic leukaemia (T-ALL). We present a case of T-ALL with leukaemic blasts showing erythrophagocytosis, which was successfully treated with unrelated cord blood transplantation (uCBT).

    A 11-year-old female child presented with prolonged abdominal distention of 1 month duration. Physical examination revealed both liver and spleen edges at 15 cm below the right and left costal margins, respectively. Abdominal X-ray showed a large mass with displaced intestines and MRI confirmed significant hepatosplenomegaly on low-intensity and high-intensity T1-enhanced and T2-enhanced images, respectively. There was no thymus enlargement. Laboratory examinations of peripheral blood showed the following: white blood cell count, 1.92×109/L with no leukaemic blasts; haemoglobin, 11.4 g/dL; platelet count, 80×109/L and serum lactate dehydrogenase, 541 IU/L. There was no serological evidence of Epstein-Barr virus or cytomegalovirus infection. Morphological evaluation of a bone marrow smear using May-Giemsa staining showed approximately 70% leukaemic blasts with irregular nuclear membranes, few nucleoli and scanty cytoplasm with some vacuoles, classified as L2 according to the French-American-British (FAB) classification; 4.8% of leukaemic blasts showed erythrophagocytosis (figure 1A–D). All blasts were negative for myeloperoxidase and double esterase staining. Immunophenotypic analysis of the surface markers revealed the leukaemic blasts to be positive for CD2, CD3, CD4, CD5, CD7, TCR α/β, cyCD3, CD117, CD58 and CD99 and negative for CD8, TCR γ/δ, cyMPO, CD13, CD33, cyCD79a, CD22 and CD34, which is compatible with T-ALL, and that leukaemic blasts did not fulfil the diagnostic criteria for ambiguous lineage. Although chromosomal analysis by G-banding showed 46, XX [20/20] (figure 2A), the fluorescent in-situ hybridisation (FISH) assay, which was performed with alphoid repetitive DNA (D8Z2) probe specific for the pericentromeric region of chromosome 8, showed two pairs of signals (yellow) in 21.0% cells (figure 2B) and the DNA index was 2.04 (figure 2C), indicating tetraploidy. Molecular genetic analysis using reverse-transcription PCR excluded BCR-ABL, ETV6-RUNX1, E2A-PBX1, MLL-AF4, MLL-AF9, MLL-ENL and SIL-TAL1 fusion genes.

    Figure 1
    Figure 1

    Images showing erythrophagocytosis by a leukaemic cell (A–D) in this study patient. May-Giemsa stain; original magnification, ×1000.

    Figure 2
    Figure 2

    Chromosomal analysis of this study patient is shown. The karyotyping using G-banding (A) showed a normal female pattern. However, the fluorescent in-situ hybridisation assay (B) for chromosome 8 showed two pairs of spots (yellow) and the DNA index (C) standardised with trout red blood cells was 2.04, indicating DNA tetraploidy.

    The patient was treated with T-ALL-oriented chemotherapy, despite erythrophagocytosis being a paradoxical feature. During induction therapy, physical examination revealed significant liver and spleen shrinkage and the bone marrow smear showed complete remission, with 0.02% of minimal residual disease by flow cytometry and no detection by PCR of T-cell receptor and immunoglobulin heavy-chain gene rearrangement. However, hepatosplenomegaly was evident on ultrasonography and MRI even after early consolidation therapy, indicating treatment-refractory leukaemic cells. Thus, we considered this as induction failure and conducted myeloid-oriented chemotherapy comprising high-dose cytarabine, etoposide, L-asparaginase and dexamethasone, resulting in shrinkage of the liver and spleen to normal size. After complete remission, she underwent uCBT from a female donor with a 2-locus mismatch in the human leucocyte antigen (HLA). Her conditioning regimen comprised 12 Gy total body irradiation fractionated four times, etoposide 180 mg/m2×1 and cyclophosphamide 60 mg/kg×2. She developed grade I acute graft-versus-host disease (GVHD) of the skin and limited-type chronic GVHD under prophylaxis with tacrolimus and short-term methotrexate. Donor engraftment was confirmed by HLA-microsatellite polymorphism analysis of bone marrow mononuclear cells on day 15. She remains alive at 808 days after uCBT.

    Erythrophagocytosis by leukaemic blasts is very rare and has been reported in <1% of acute leukaemia cases. It is frequently associated with myeloid features, especially FAB M4 and M5. The most common chromosomal aberration is t(8;16)(p11;p13) translocation coding the CMOZ/CBP chimeric transcript and there are a few cases with t(16;21)(p11;q22), inv(8)(p11;q13) or del 20q. We have summarised 20 case reports of erythrophagocytosis by leukaemic blasts in table 1.

    View this table:
    Table 1

    Reports of leukaemia with erythrophagocytosis

    There were 10 cases (50%) of AML, including one of M4 (5.0%) and two each of M5a and M5b (10%). There were some reports of erythrophagocytosis in monocytic lineage leukaemia and in three cases of AML-M0,2–4 one case of B-cell leukaemia and myeloid hybrid mixed-lineage leukaemia1 and one case of unclassified-lineage leukaemia.5 These cases indicate that leukaemic blasts in the very early haematopoietic developmental stage, even before lineage restriction, can show this erythrophagocytosis feature. There were five reports on ALL; however, one was reported in the 1970s,6 so the lineage could not have been sufficiently assessed by cell surface markers and two were B-cell lineage.7 ,8 Erythrophagocytosis is a known phenomenon in hepatosplenic γ/δ T-cell lymphomas.9 ,10 Two cases were reported as T-lymphoma, which was compatible with the criteria of T-ALL.11 ,12 Of 20 patients, 13 patients (65%) with erythrophagocytosis by leukaemic blasts had died or relapsed, suggesting poor prognosis.

    Another salient aspect of our case is chromosomal near-tetraploidy by FISH and DNA index. Pui et al13 reported only 20 cases (1.1%) of near-tetraploid leukaemia among 1791 patients with ALL, with rather poor prognosis for tetraploid cases. Near-tetraploid blast cells in 40% of patients expressed CD13, CD15 and CD33 (indicating a monocytic feature) and were more often associated with T-cell immunophenotype (47%), FAB L2 morphology (30%) and older age at diagnosis (median age, 8.6 years). Pang et al14 reported 13 cases of near-tetraploidy/tetraploidy in AML. The morphological feature was predominantly large blasts and there were 9 cases (69%) of FAB M2 and one case each (7.7%) of M0, M1, M4 and M6. Table 1 also shows chromosomal aberrations and four instances (20%) of tetraploidy among the cases of leukaemia with erythrophagocytosis, demonstrating a significantly high incidence.

    The mechanism of tetraploidy remains unclear; however, loss or inactivation of the p53 protein, which is implicated in a G1 checkpoint of cell division and maintains diploidy, was associated with tetraploidy development.15 In addition, G-banding that analyses the chromosome in the metaphase showed normal female karyotype in this patient, whereas DNA index using flow cytometry and FISH showed tetraploidy. This discrepancy suggests that the leukaemic blasts did not enter the metaphase and have less proliferative capability in culture.16 The MOZ protein, which is coded on 8p16, functions as a coactivator for AML1 and PI.1 and controls the acetylation and transcriptional activity of p5317 and MOZ-CBP fusion derived from t(8;16)(p11;p13) and has been strongly associated with erythrophagocytosis by AML blasts. There were two cases of inv(8)(p11;q13), indicating inactivation of the MOZ gene, and two cases of t(16;21)(p11;q22) of the AML1 gene, both resulting in loss of p53 function, possibly leading to near-tetraploidy.

    Leukaemia with erythrophagocytosis and near-tetraploidy is quite rare. Previously, two cases showing both erythrophagocytosis and near-tetraploid karyotype have been reported. Galeotti et al18 reported plasma cell myeloma, which relapsed even after autologous stem cell transplantation (SCT). Yeh et al3 reported AML-M0, which was refractory to idarubicin plus cytarabine, and discussed that the great variety of chromosomal numbers suggests a global defect of cell cycle control, including checkpoints and arrest of proliferation in cancer cells, which can evolve into highly unstable genomes related to the poor drug sensitivity. Our case also displayed the overlapping of erythrophagocytosis and near-tetraploidy, which is a very dismal prognostic feature; however, the patient was successfully treated. Thus, high-dose chemotherapy and donor-derived immunity by allogeneic SCT might have feasible treatment effect. Further study of this unique overlapping feature may possibly provide new insights into cellular lineage determination and leukaemogenesis.

    References

    1. ↵
      1. de Leeuw DC,
      2. van den Ancker W,
      3. Westers TM, et al
      . Challenging diagnosis in a patient with clear lymphoid immunohistochemical features and myeloid morphology: mixed phenotype acute leukemia with erythrophagocytosis. Leuk Res 2011;35:693–6. doi:10.1016/j.leukres.2011.01.024
      OpenUrlCrossRefPubMed
    2. ↵
      1. Mori H,
      2. Tawara M,
      3. Yoshida Y, et al
      . Minimally differentiated acute myeloid leukemia (AML-M0) with extensive erythrophagocytosis and del(20)(q11) chromosome abnormality. Leuk Res 2000;24: 87–90. doi:10.1016/S0145-2126(99)00145-9
      OpenUrlCrossRefPubMed
    3. ↵
      1. Yeh SP,
      2. Wang Y,
      3. Su J, et al
      . Near-tetraploid minimally differentiated acute myeloid leukemia with extensive erythrophagocytosis by leukemic blasts. Ann Hematol 2000;79:36–9. doi:10.1007/s002770050006
      OpenUrlCrossRefPubMed
    4. ↵
      1. Li L,
      2. Li J,
      3. Li G, et al
      . A tetraploid minimally differentiated acute myeloblastic leukemia with extensive erythrophagocytosis: a case report and literature review. Int J Hematol 2012;96:801–5. doi:10.1007/s12185-012-1179-6
      OpenUrlCrossRefPubMed
    5. ↵
      1. Ortuño FJ,
      2. Castilla C,
      3. Moreno MJ, et al
      . Erythrophagocytosis in de novo-Philadelphia-positive acute leukemia of ambiguous lineage. Haematologica 2006;91:ECR43.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Foadi MD,
      2. Slater AM,
      3. Pegrum GD
      . Erythrophagocytosis by acute lymphoblastic leukaemic cells. Scand J Haematol 1978;20:85–8. doi:10.1111/j.1600-0609.1978.tb01558.x
      OpenUrlPubMed
    7. ↵
      1. Colon-Otero G,
      2. Li CY,
      3. Dewald GW, et al
      . Erythrophagocytic acute lymphocytic leukemia with B-cell markers and with a 20q—chromosome abnormality. Mayo Clin Proc 1984;59:678–82. doi:10.1016/S0025-6196(12)62056-4
      OpenUrlCrossRefPubMed
    8. ↵
      1. Park JE,
      2. Park IJ,
      3. Lim YA, et al
      . Hemophagocytosis by leukemic blasts in B lymphoblastic leukemia with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1): a case report. Ann Clin Lab Sci 2013;43: 186–9.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Kadin ME,
      2. Kamoun M,
      3. Lamberg J
      . Erythrophagocytic T gamma lymphoma: a clinicopathologic entity resembling malignant histiocytosis. N Engl J Med 1981;304:648–53. doi:10.1056/NEJM198103123041106
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Weidmann E
      . Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia 2000;14: 991–7. doi:10.1038/sj.leu.2401784
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Kim KJ,
      2. Jeon IS,
      3. Kim CW, et al
      . A case of erythrophagocytosis in a T-cell lymphoblastic lymphoma. Seoul J Med 1990;31:57–60.
      OpenUrl
    12. ↵
      1. Berceanu S,
      2. Roman S,
      3. Moldoveanu E, et al
      . A case of erythrophagocytic T4 lymphoma. Immunological and morphological peculiarities. Folia Haematol 1990;117:15–21.
      OpenUrl
    13. ↵
      1. Pui CH,
      2. Carroll AJ,
      3. Head D, et al
      . Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood. Blood 1990;76:590–6.
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Pang CS,
      2. Pettenati MJ,
      3. Pardee TS
      . Clinicopathological analysis of near-tetraploidy/tetraploidy acute myeloid leukemia. J Clin Pathol 2015;68:236–40. doi:10.1136/jclinpath-2014-202697
      OpenUrlAbstract/FREE Full Text
    15. ↵
      1. Cross SM,
      2. Sanchez CA,
      3. Morgan CA, et al
      . A p53-dependent mouse spindle checkpoint. Science 1995;267:1353–6. doi:10.1126/science.7871434
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Tanaka K,
      2. Arif A,
      3. Eguchi M, et al
      . Interphase fluorescence in situ hybridization overcomes pitfalls of G-banding analysis with special reference to underestimation of chromosomal aberration rates. Cancer Genet Cytogenet 1999;115:32–8. doi:10.1016/S0165-4608(99)00079-5
      OpenUrlCrossRefPubMed
    17. ↵
      1. Rokudai S,
      2. Aikawa Y,
      3. Tagata Y, et al
      . Monocytic leukemia zinc finger (MOZ) interacts with p53 to induce p21 expression and cell-cycle arrest. J Biol Chem 2009;284:237–44. doi:10.1074/jbc.M805101200
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Galeotti J,
      2. Wu B,
      3. Wang E
      . Erythrophagocytosis in a cyclin D1 positive plasma cell myeloma with near-tetraploid karyotypic abnormalities and cryptic MYC/IGH fusion. Ann Hematol 2016;95:515–16. doi:10.1007/s00277-015-2551-4
      OpenUrlCrossRefPubMed
      1. Sharma M,
      2. Dayama A,
      3. Jain S, et al
      . AML associated with extensive erythrophagocytosis and tetraploidy. Eur J Haematol 2011;87:286. doi:10.1111/j.1600-0609.2011.01630.x
      OpenUrlCrossRefPubMed
      1. Hui CH,
      2. Suttle J
      . Erythrophagocytosis associated with AML-M5 and t(8;16). Br J Haematol 2001;113:845. doi:10.1046/j.1365-2141.2001.02770.x
      OpenUrlCrossRefPubMed
      1. Imashuku S,
      2. Hibi S,
      3. Kuriyama K, et al
      . Hemophagocytosis by leukaemic blasts in a case of acute megakaryoblastic leukemia with t(16;21)(p11;q22). Int J Hematol 1999;70(1):36–9.
      OpenUrlPubMed
      1. Coulthard S,
      2. Chase A,
      3. Orchard K, et al
      . Two cases of inv(8)(p11q13) in AML with erythrophagocytosis: a new cytogenetic variant. Br J Haematol 1998;100:561–3. doi:10.1046/j.1365-2141.1998.00587.x
      OpenUrlCrossRefPubMed
      1. Clarke MR,
      2. Lynch EF,
      3. Contis LC, et al
      . Near-tetraploidy in adult acute myelogenous leukemia. Cancer Genet Cytogenet 1996;86:107–15. doi:10.1016/0165-4608(95)00184-0
      OpenUrlCrossRefPubMedWeb of Science
      1. Marosi C,
      2. Bettelheim P,
      3. Geissler K, et al
      . Translocation (16;21)(p11;q22) in acute monoblastic leukemia with erythrophagocytosis. Cancer Genet Cytogenet 1991;54:61–6. doi:10.1016/0165-4608(91)90030-X
      OpenUrlCrossRefPubMed

    Footnotes

    • Competing interests None declared.

    • Patient consent Parental/guardian consent obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.