Skip to main content
SpringerLink
Log in

The diagnosis of acute leukemia with undifferentiated or minimally differentiated blasts

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Summary

A small group of acute leukemias can be classified by morphological, cytochemical, or immunological marker analysis neither as acute lymphatic leukemia nor as acute myeloid leukemia. These leukemias are referred to as acute undifferentiated leukemia (AUL) and make up 2%–7% of the acute nonmyeloid leukemias. These leukemias are poorly defined in the literature and are also sometimes referred to as AML-MO. Most of the definitions include in the morphological and cytochemical criteria the expression of myeloid antigens. Here the value of these markers and of other techniques used in the diagnosis of undifferentiated or minimally differentiated leukemia is discussed. More than half of the leukemias that are undifferentiated by morphology and cytochemistry on the light-microscopic level show a positive reaction for myeloperoxidase by electron microscopy, which points to an early myeloid differentiation of those leukemias. Immunological marker analysis in most cases is inconclusive. Most show a positive reaction for CD 13, CD 33 or other myeloid-associated markers. However, in about half of these leukemias co-expression of lymphatic markers is seen. In a small minority, only lymphatic markers are expressed. Cytogenetic abnormalities which are found in these leukemias vary in type, and antigen receptor rearrangements are not lineage specific. Receptor studies, gene expression, and in vitro culture studies may, in the near future, contribute substantially to our knowledge about the commitment of these undifferentiated or minimally differentiated blasts. Recent definitions for AUL and AML-MO based on these different techniques are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Adriaansen HJ, Dongen JJM van, Kappers-Klune MC, Hählen K, Veer MB van't, Wijdenes de Bresser JHFM, Holdrinet ACJM, Harthoorn-Lasthuizen EJ, Abels J, Hooykaas H (1990) Terminal deoxynucleotidyl transferase-positive subpopulations occur in the majority of ANLL: implications for the detection of minimal disease. Leukemia 4: 404–410

    PubMed  Google Scholar 

  2. Bain BJ (1990) Leukemia diagnosis, a guide to the FAB classification. Lippincott, Philadelphia

    Google Scholar 

  3. Benedetto P, Mertelsmann R, Szahowski TH (1986) Prognostic significance of terminal deoxynucleotidyl transferase activity in acute nonlymphoblastic leukemia. J Clin Oncol 4: 489–495

    PubMed  Google Scholar 

  4. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG (1976) Proposals for the classification of the acute leukaemias (FAB cooperative group). Br J Haematol 33: 451–458

    PubMed  Google Scholar 

  5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1985) Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103: 620–629

    PubMed  Google Scholar 

  6. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1985) Criteria for the diagnosis of acute leukemia of megakaryocytic lineage (M7): a report of the French-American-British cooperative group. Ann Intern Med 103: 460–462

    PubMed  Google Scholar 

  7. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1991) Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO). Br J Haematol 78: 325–329

    PubMed  Google Scholar 

  8. Bertazzoni U, Brusamolino E, Isernia P, Scovassi J, Torsello S, Lazzarino M, Bernasconi C (1982) Prognostic significance of terminal transferase and adenosine deaminase in acute and chronic myeloid leukemia. Blood 60: 685–692

    PubMed  Google Scholar 

  9. Boehm TLJ, Werle A, Drakovsky D (1987) Immunoglobulin heavy chain and T-cell receptor beta and gamma chain gene rearrangements in acute myeloid leukemias. Mol Biol Med 4: 51–62

    PubMed  Google Scholar 

  10. Cheng GY, Minden MD, Toyonaga B, Mak TW, McCulloch EA (1986) T-cell receptor and immunoglobulin gene rearrangements in acute myeloblastic leukemia. J Exp Med 163: 14–24

    Google Scholar 

  11. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, Sawitsky A, Stass S, Weinstein H, Woods WG (1990) Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8: 813–819

    PubMed  Google Scholar 

  12. Childs C, Hirsch-Ginsberg C, Walters RD, Andersson BS, Reuben J, Trujilo JM, Cork A, Stass SA, Freireich EJ, Zipf TF (1989) Myeloid surface antigen-positive acute lymphoblastic leukemia (My + ALL): immunophenotypic of ultrastructural, cytogenetic and molecular characteristics. Leukemia 3: 777–783

    PubMed  Google Scholar 

  13. Del Vecchio L, Schiavone EM, Ferrara F, Pace E, Pardo CL, Pacetti M, Russo M, Cirillo D, Vacca C (1989) Immunodiagnosis of acute leukemia displaying ectopic antigens. Am J Hematol 31: 173–180

    PubMed  Google Scholar 

  14. Drexler HG, Thiel E, Ludwig W-D (1991) Review of the incidence and clinical relevance of myeloid antigen-positive acute lymphoblastic leukemia. Leukemia 5: 637–645

    PubMed  Google Scholar 

  15. Foa R, Casorati G, Giubellino MC, Basso G, Shiro T, Pizzolo G, Lauria F, LeFranc M-P, Rabbits TH, Migone N (1987) Rearrangements of immunoglobulin and T-cell receptor beta and gamma genes are associated with terminal deoxynucleotidyl transferase expression in acute myeloid leukemia. J Exp Med 165: 879–890

    PubMed  Google Scholar 

  16. Fontenay M, Flandrin G, Baurman H, Loiseau P, Valensi F, Daniel M-T, Sigaux F (1990) T-cell receptor delta gene rearrangements occur predominantly in immature myeloid leukemias exhibiting lineage promiscuity. Leukemia 4: 100–105

    PubMed  Google Scholar 

  17. Foon KA, Todd RF (1986) Immunological classification of leukaemia and lymphoma. Blood 68: 1–31

    PubMed  Google Scholar 

  18. Ganser A, Heil G, Böhm Th, Bartram CR, Raghavachar A, Carbonell F, Hoelzer D (1987) Human acute unclassified leukemia with a unique t(14;17) chromosomal translocation expresses T-lymphoid and myeloid surface antigens after in vitro culture. Blood 69: 271–277

    PubMed  Google Scholar 

  19. Goorha R, Bunin N, Mirro J, Murphy SB, Cross AH, Behm FG, Quertermous T, Seidman J, Kitchingman GR (1987) Provocative pattern of rearrangements of the genes for the gamma and beta chains of the T-cell receptor in human leukemias. Proc Natl Acad Sci USA 84: 4547–4551

    PubMed  Google Scholar 

  20. Greaves MF, Chan LC, Furley AJW, Watt SM, Molgaard HV (1986) Lineage promiscuity in hemopoietic differentiation and leukemia. Blood 67: 1–11

    PubMed  Google Scholar 

  21. Gregg SL, Gail-Peczalska KJ, LeBien TW, Bloomfield CD, Brunning R, Sagawa K (1984) Monoclonal antibody MCS-2 as the marker of phorbol diester-induced myeloid differentiation in acute undifferentiated leukemia. Cancer Res 44: 2724–2730

    PubMed  Google Scholar 

  22. Ha K, Minden M, Hozumi-Gelfand EW (1984) Immunoglobulin gene rearrangement in acute myelogenous leukemia. Cancer Res 44: 4658–4660

    PubMed  Google Scholar 

  23. Hara J, Yumura-Yajik K, Tawa A, Ishihara S, Murata M, Terada N, Zumi Y, Champagne E, Takihara Y, Mak TW, Minden M, Kawa-Ha K (1989) Molecular analysis of acute undifferentiated leukemia: two distinct subgroups at the DNA and RNA levels. Blood 74: 1738–1746

    PubMed  Google Scholar 

  24. Heil G, Ganser A, Raghavachar A, Kurrle E, Hert W, Hoelzer D, Heimpel H (1988) Induction of myeloperoxidase in five cases of acute unclassified leukaemia. Br J Haematol 68: 23–32

    PubMed  Google Scholar 

  25. Heil G, Gunsilius E, Raghavachar A, Bartram CR, Ganser A, Kurrle E, Aydemir U, Löffler H, Hoelzer D, Thiel E, Heimpel H (1991) Ultrastructural demonstration of peroxidase expression in acute unclassified leukemias: correlation to immunophenotype and treatment outcome. Blood 77: 1305–1312

    PubMed  Google Scholar 

  26. Imamura N, Kuramoto A (1988) Acute unclassifiable leukaemia in adults, demonstrating myeloid antigens and myeloperoxidase protein. Br J Haematol 69: 427–428

    PubMed  Google Scholar 

  27. Janossy G, Coustan-Smith E, Campana D (1989) The reliability of cytoplasmic CD 3 and CD 22 antigen expression in the immunodiagnosis of acute leukemia: a study of 500 cases. Leukemia 3: 170–181

    PubMed  Google Scholar 

  28. Kantarjian HM, Hirsch-Ginsberg C, Yee G, Huh Y, Freirich EJ, Stass S (1990) Mixed-lineage leukemia revisited: acute lymphocytic leukemia with myeloperoxidase-positive blasts by electron microscopy. Blood 76: 808–813

    PubMed  Google Scholar 

  29. Lee EJ, Pollak A, Leavitt RD, Testa JR, Schiffer CA (1987) Minimally differentiated acute nonlymphocytic leukemia: a distinct entity. Blood 70: 1400–1406

    PubMed  Google Scholar 

  30. Lee EJ, Yang J, Leavitt RD (1989) The impact of TdT and CD 34 expression on the prognosis of patients with acute myeloid leukemia. Blood 74 [Suppl]: 18

    Google Scholar 

  31. Matutes E, Pombo de Oliveira M, Foroni L, Morilla R, Catovsky D (1988) The role of ultrastructural cytochemistry and monoclonal antibodies in clarifying the nature of undifferentiated cells in acute leukaemia. Br J Haematol 69: 205–211

    PubMed  Google Scholar 

  32. Mirro J, Zipf ThF, Pui CH, Kitchingman G, Williams D, Melvin S, Murphy SB, Stass S (1985) Acute mixed-lineage leukemia: clinicopathologic correlations and prognostic significance. Blood 66: 1115–1123

    PubMed  Google Scholar 

  33. Neame PB, Soamboonsrup P, Browman GP, Meyer RM, Benger A, Wilson WEC, Walker JR, Saeed N, McBride JA (1986) Classifying acute leukemia by immunophenotyping: a combined FAB-immunologic classification of AML. Blood 68: 1355–1362

    PubMed  Google Scholar 

  34. Norton JD, Campana D, Hoffbrand AV (1987) Rearrangement of immunoglobulin and T-cell antigen receptor genes in acute myeloid leukemia with lymphoid-associated markers. Leukemia 1: 757–761

    PubMed  Google Scholar 

  35. Ohta M, Saito M, Suda K, Sakamoto S, Kitagawa S, Miura Y, Takaku F (1983) Differentiation of human leukemia cells and its usefulness for clinical diagnosis. Leuk Res 7: 363–374

    PubMed  Google Scholar 

  36. Oster W, König K, Ludwig W-D, Ganser A, Lindemann A, Mertelsmann R, Herrmann F (1988) Incidence of lineage promiscuity in acute myeloblastic leukemia: diagnostic implications of immunoglobulin and T-cell-receptor gene rearrangement analysis and immunological phenotyping. Leuk Res 12: 887–895

    PubMed  Google Scholar 

  37. Parreira A, Pombo de Oliveira MS, Matutes E (1988) Terminal deoxynucleotidyl transferase-positive acute myeloid leukemia: an association with immature myeloblastic leukaemia. Br J Haematol 69: 219–224

    PubMed  Google Scholar 

  38. Pegoraro L, Abraham J, Cooper RA, Levis A, Lange B, Meo P, Rovera G (1980) Differentiation of human leukemias in response to 12-O-tetradecanoyl phorbol-13 acetate in vitro. Blood 55: 859–862

    PubMed  Google Scholar 

  39. Pui CH, Behm G, Singh B, Rivera GK, Schell MJ, Roberts WM, Crist WM, Mirro J (1990) Myeloid-associated antigen expression lacks prognostic value in childhood acute lymphoblastic leukaemia treated with intensive multiagent chemotherapy. Blood 75: 198–202

    PubMed  Google Scholar 

  40. Reiffers J, Darmendrail V, Larrue J, Villenave I, Bernard Ph, Boisseau M, Braustet A (1981) Ultrastructural cytochemical prospective study of adult acute lymphoblastic leukemia. Cancer 48: 927–931

    PubMed  Google Scholar 

  41. Rovigatti U, Mirro J, Kitchingman G, Dahl G, Ochs J, Murphy S, Stass S (1984) Heavy chain immunoglobulin gene rearrangement in acute nonlymphocytic leukemia. Blood 63: 1023–1027

    PubMed  Google Scholar 

  42. Schachner J, Kantarjian H, Dalton W (1988) Cytogenetic association and prognostic significance of bone marrow blast cell terminal transferase in patients with acute myeloblastic leukemia. Leukemia 2: 667–671

    PubMed  Google Scholar 

  43. Schoot E van der, Visser FJ, Tetteroo PAT, Borne AEGK von dem (1989) In vitro differentiation of cells of patients with acute undifferentiated leukaemia. Br J Haematol 71: 351–355

    PubMed  Google Scholar 

  44. Schwarzinger J, Valent P, Köller K (1990) Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia. J Clin Oncol 8: 423–430

    PubMed  Google Scholar 

  45. Serementis SV, Pelicci PG, Tabilio A, Ubriaco A, Grignani F, Cuttner J, Winchester RJ, Knowles II DM, Dalla-Favera R (1987) High frequency of clonal immunoglobulin or T-cell-receptor gene rearrangements in acute myelogenous leukemia expressing terminal deoxynucleotidyl transferase. J Exp Med 165: 1703–1712

    PubMed  Google Scholar 

  46. Skolnick T, Schlossmann SF, Griffin JD (1985) Acute undifferentiated leukemia: induction of partial differentiation by phorbol ester. Leuk Res 9: 11–17

    PubMed  Google Scholar 

  47. Sobol RE, Mick R, Royston J, Davey FR, Ellison RR, Newman R, Cuttner J, Griffin JD, Collins H, Nelson DA, Bloomfield C (1987) Clinical importance of myeloid antigen expression in adult acute lymphoblastic leukemia. N Engl J Med 316: 1111–1117

    PubMed  Google Scholar 

  48. Tricot G, Broekaert-van Orshoven A, Hoof A van, Verwilghen RL (1982) Sudan-black B positivity in acute lymphoblastic leukemia. Br J Haematol 51: 615–621

    PubMed  Google Scholar 

  49. Vaenchenker W, Villeval JL, Tabilio A, Matanis H, Karianakis G, Gruchard J, Henri A, Vernant JP, Roeland H, Breton-Gorius J (1988) Immunophenotype of leukemic blasts with small peroxidase-positive granules detected by electron microscopy. Leukemia 2: 274–281

    PubMed  Google Scholar 

  50. Vaughan WP, Civin CI, Weisenburger DD, Karp JE, Graham ML, Sanger WG, Grierson HL, Joshi SS, Burke PJ (1988) Acute leukemia expressing the normal human haematopoietic stem cell membrane glycoprotein CD34 (MylO). Leukemia 2: 661–666

    PubMed  Google Scholar 

  51. Veer MB van't, Kluin-Nelemans JC, Schoot E van der, Putten WLJ van, Adriaansen HJ, Wering ER (1992) Quality assessment of immunological marker analysis in the diagnosis of leukaemia and lymphoma: a multicenter study. Br J Haematol 10: 450–465

    Google Scholar 

  52. Wainscoat JS, Fey MF, Pilkington S, Summers C, Oscier DG (1988) Absence of immunoglobulin and T-cell-receptor gene rearrangements in myelodysplastic syndromes and acute non-lymphocytic leukemias. Am J Hematol 28: 95–97

    PubMed  Google Scholar 

  53. Wering ER van, Brederoo P, Dijk de Leeuw JHS van, Meulen J van der, Veer MB van't (1990) Electron microscopy: a contribution to further classification of acute unclassifiable childhood leukemia. Blut 60: 291–296

    PubMed  Google Scholar 

  54. Wiersma SR, Ortega J, Sobel E, Weinberg KJ (1991) Clinical importance of myeloid-antigen expression in acute lymphoblastic leukemia in childhood. N Engl J Med 324: 800–808

    PubMed  Google Scholar 

  55. Williere G, Stockinger H, Koller U, Majdic O, Schnabl E, Lutz D, Bettelheim P, Knapp W (1990) Terminal deoxynucleotidyl transferase and CD7 expression in acute myeloid leukemias are not associated with a high frequency of immunoglobulin and/ or T-cell-receptor gene rearrangements. Leukemia 4: 278–281

    PubMed  Google Scholar 

  56. Yarden T, Kuang W, Yang-Feng T, Ulbricht A (1987) Human proto-oncogene c-kit: a new cell-surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6: 3341–3349

    PubMed  Google Scholar 

  57. Youness E, Trujillo JM, Ahearn MJ, McCredie KB, Cork A (1980) Acute unclassified leukemia. A clinical pathological study with diagnostic implications of electron microscopy. Am J Hematol 9: 79–88

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Dr. Daniel den Hoed Cancer Center, Groene Hilledijk 301, NL-3075, EA Rotterdam, The Netherlands

    M. B. van't Veer

Authors
  1. M. B. van't Veer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

van't Veer, M.B. The diagnosis of acute leukemia with undifferentiated or minimally differentiated blasts. Ann Hematol 64, 161–165 (1992). https://doi.org/10.1007/BF01696217

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01696217

Key words

Search

Navigation