Особенности цитогенетической диагностики синхронно протекающих хронического лимфолейкоза и миелодиспластического синдрома: описание клинического случая

При хроническом лимфолейкозе значительно увеличен риск развития вторых опухолей, в том числе опухолевых заболеваний системы крови, с которыми чаще всего связывают применение аналогов пуриновых нуклеозидов и алкилирующих препаратов в терапии хронического лимфолейкоза. Сочетанное выявление данного заболевания и различных гематологических опухолей – редкое событие в гематологической практике. Применение цитогенетического метода исследования позволяет не только дифференцировать 2 опухоли, но и подтверждать различие генетических нарушений в разных клонах и на разных уровнях дифференцировки клеток. В настоящей статье представлен клинический случай синхронного течения хронического лимфолейкоза и миелодиспластического синдрома с 2 клонами с различными цитогенетическими аномалиями – частичной трисомией хромосомы 12 и делецией длинного плеча хромосомы 5, сформированными на разных уровнях дифференцировки клеток.

1. McKenna D.B., Stockton D., Brewster D.H., Doherty V.R. Evidence for an association between cutaneous malignant melanoma and lymphoid malignancy: a population-based retrospective cohort study in Scotland. Br J Cancer 2003;88(1):74–8. DOI: 10.1038/sj.bjc.6600692.

2. Schollkopf C., Rosendahl D., Rostgaard K. et al. Risk of second cancer after chronic lymphocytic leukemia. Int J Cancer 2007;121(1):151–6. DOI: 10.1002/ijc.22672.

3. Royle J.A., Baade P.D., Joske D. et al. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study. Br J Cancer 2011;105(7):1076–81. DOI: 10.1038/bjc.2011.313.

4. Tsimberidou A.M., Wen S., McLaughlin P. et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol 2009;27(6):904– 10. DOI: 10.1200/JCO.2008.17.5398.

5. Chang H., Wechalekar A., Li L., Reece D. Molecular cytogenetic abnormalities in patients with concurrent chronic lymphocytic leukemia and multiple myeloma shown by interphase fluorescence in situ hybridization: evidence of distinct clonal origin. Cancer Genet Cytogenet 2004;148(1):44–8.

6. Obukhova T.N., Drize N., Doronin V. et al. Cytogenetic evidence for lymphomyeloid progenitor cells clonal origin in patient with concurrent chronic lymphocytic leukemia and multiple myeloma. Chromosom Reseach 2013;21:S88.

7. Аль-Ради Л.С., Самойлова Р.С., Тихонова Л.Ю. и др. Сочетание хронического лимфолейкоза и волосатоклеточного лейкоза. Терапевтический архив 2006;78:84–7.

8. Sokol L., Agosti S.J. Simultaneous manifestation of chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL). Am J Hematol 2004;75(2):107–9. DOI: 10.1002/ajh.10459.

9. Martin-Subero J.I., Siebert R., Harder L. et al. Cytogenetic and molecular characterization of a patient with simultaneous B-cell chronic lymphocytic leukemia and peripheral T-cell lymphoma. Am J Hematol 2001;68(4):276–9.

10. Laurenti L., Tarnani M., Nichele I. et al. The coexistence of chronic lymphocytic leukemia and myeloproliperative neoplasms: a retrospective multicentric GIMEMA experience. Am J Hematol 2011;86:1007–12. DOI: 10.1002/ajh.22171.

11. Chavez J.C., Dalia S., Sandoval-Sus J. et al. Second myeloid malignancies in a large cohort of patients with chronic lymphocytic leukemia: a single institution experience. Clin Lymphoma Myeloma Leuk 2015;15:14–8. DOI: 10.1016/j.clml.2015.03.013.

12. Morrison V.A., Rai K.R., Peterson B.L. et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol 2002;20(18):3878–84. DOI: 10.1200/JCO.2002.08.128.

13. Smith M.R., Neuberg D., Flinn I.W. et al. Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood 2011;118(13):3525–7. DOI: 10.1182/blood-2011-03-342485.

14. Florensa L., Vallespi T., Woessner S. et al. Incidence and characteristics of lymphoid malignancies in untreated myelodysplastic syndromes. Leuk Lymphoma 1996;23(5–6):609–12. DOI: 10.3109/10428199609054871.

15. Tambaro F.P., Garcia-Manero G., O’Brien S.M. et al. Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome. Leukemia 2016;30(2):325–30. DOI: 10.1038/leu.2015.227.

16. Kikushige Y., Miyamoto T. Hematopoietic stem cell aging and chronic lymphocytic leukemia pathogenesis. Int J Hematol 2014;100(4):335–40. DOI: 10.1007/s12185-014-1651-6.

17. Mossafa H., Szpiro-tapia S., Pulic M. et al. Chronic lymphocytic leukemia associated with myelodysplastic syndrome and/or chronic myeloid leukemia: evidence for independent clonal chromosomal evolution. Leuk Lymphoma 2008; 41(3–4):337–41. DOI: 10.3109/10428190109057988.

18. Aviv H., Tang D., Das K. et al. Simulta neous appearance of trisomy 8 and tri somy 12 in different cell populations in a patient with untreated B-cell chronic lymphocytic leukemia and myelodysplasia. Leuk Lymphoma 2004;45(6):1279–83.

19. Ornellas De Souza M.H., de Souza Fernandez T., Diamond H.R. et al. Cytogenetic and immunophenotypic evidence of independent clonal origins of concomitant chronic lymphocytic leukaemia and acute myeloid leukaemia. Eur J Haematol 2001;66(4):281–3.

20. Crescenzi B., Sacchi S., Marasca R. et al. Distinct genomic events in the myeloid and lymphoid lineages in simultaneous presentation of chronic myeloid leukemia and B-chronic lymphocytic leukemia. Leukemia 2002;16(5):955–6. DOI: 10.1038/sj.leu.2402490.

21. Beaud J., Modot T., Delhommeau F., Suner L. Chronic myelogenous leukemia occurring in a chronic lymphocytic leukemia patient. Clin Case Reports 2018;6(8):1655–6. DOI: 10.1002/ccr3.1572.

22. Ioachim H.L., Medeiros L.J. Composite lymphomas. Ioachim’s Lymph Node Pathol. 4th ed, Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins, 2009. Pp. 452–459.

23. Zimmerman Z., Scott B.L., Gopal A.K. et al. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and concurrent lymphoid malignancy. Bone Marrow Transplant 2012;47(6):804–9. DOI: 10.1038/bmt.2011.180.

24. Gottardi M., Gattei V., Degan M. et al. Concomitant chronic lymphocytic leukemia and acute myeloid leukemia: evidence of simultaneous expansion of two independent clones. Leuk Lymphoma 2006;47(5):885–9. DOI: 10.1080/10428190500404761.

25. Bracey A.W., Maddox A.M., Immken L. et al. Coexistence of myelodysplastic syndrome and untreated chronic lymphocytic leukemia with development of acute myeloid leukemia immediately after treatment of chronic lymphocytic leukemia. Am J Hematol 1989;30(3):174–80.

26. Strati P., Manning J.T., Ok C.Y. et al. Interaction between myelomonocytic and lymphoid cells in a patient with acute myelomonocytic leukemia and chronic lymphocytic leukemia. Leuk Lymphoma 2014;55(6):1425–7. DOI: 10.3109/10428194.2013.838234.

27. Lima M., Porto B., Rodrigues M. et al. Cytogenetic findings in a patient presenting simultaneously with chronic lymphocytic leukemia and acute myeloid leukemia. Cancer Genet Cytogenet 1996;87(1):38–40.

28. Mitterbauer G., Schwarzmeier J., Mitterbauer M. et al. Myelodysplastic syndrome/ acute myeloid leukemia supervening previously untreated chronic B-lymphocytic leukemia: demonstration of the concomitant presence of two different malignant clones by immunologic and molecular analysis. Ann Hematol 1997;74(4):193–7. DOI: 10.1007/s002770050282.

29. Carulli G., Marini A., Baccelli E. et al. Association of B-chronic lymphocytic leukemia and acute myeloid leukemia. J Exp Clin Cancer Res 2007;26(3):421–4.

30. Barresi G.M., Albitar M., O’Brien SM. Acute myeloid leukemia, inversion 16, occurring in a patient with chronic lymphocytic leukemia. Leuk Lymphoma 2000;38(5–6):621–5. DOI: 10.3109/10428190009059282.

31. Miller M.K., Strauchen J.A., Nichols K.T., Phelps R.G. Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL. Am J Dermatopathol 2001;23:334–40.

32. Lu C.M., Murata-Collins J.L., Wang E. et al. Concurrent acute myeloid leukemia with inv(16)(p13.1q22) and chronic lymphocytic leukemia: molecular evidence of two separate diseases. Am J Hematol 2006;81(12):963–8. DOI: 10.1002/ajh.20716.

33. Decker T., Schneller F., Kronschnabl M. et al. Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp Hematol 2000;28(5):558–68. DOI: 10.1016/S0301472X(00)00144-2.

34. Juliusson G., Oscier D.G., Fitchett M. et al. Prognostic subgroups in B-Cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 1990;323(11):720–4. DOI: 10.1056/NEJM199009133231105.

35. Hallek M., Cheson B.D., Catovsky D. et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131(25):2745–60. DOI: 10.1182/blood-2017-09-806398.

36. Schanz J., Tuchler H., Sole F. et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 2012;30(8):820–9. DOI: 10.1200/JCO.2011.35.6394.

37. Dohner H., Stilgenbauer S., Benner A. et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910–6. DOI: 10.1056/NEJM200012283432602.

38. Strati P., Abruzzo L.V., Wierda W.G. et al. Second cancers and Richter transformation are the leading causes of death in patients with trisomy 12 chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2015;15(7):420–7. DOI: 10.1016/j.clml.2015.02.001.

39. Mallo M., Cervera J., Schanz J. et al. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia 2011;25(1):110–20. DOI: 10.1038/leu.2010.231.

40. Volkert S., Kohlmann A., Schnittger S. et al. Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome. Genes Chromosomes Cancer 2014;53(5):402–10. DOI: 10.1002/gcc.22151.

41. Gahn B., Schafer C., Neef J. et al. Detection of trisomy 12 and Rb-deletion in CD34+ cells of patients with B-cell chronic lymphocytic leukemia. Blood 1997;89(12):4275–81.

42. Quijada-Alamo M., Hernandez-Sanchez M., Robledo C. et al. Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia. J Hematol Oncol 2017;10(1):83. DOI: 10.1186/s13045-017-0450-y.

43. Gahn B., Wendenburg B., Troff C. et al. Analysis of progenitor cell involvement in B-CLL by simultaneous immunophenotypic and genotypic analysis at the single cell level. Br J Haematol 1999;105(4):955–9. DOI: 10.1046/j.1365-2141.1999.01471.x.

44. Lazaridou A., Miraxtsi C., Tokmaktsis A. et al. Detection of genetic markers on different populations of hematopoietic progenitor cells in B-cell chronic lymphocytic leukemia. Blood 2000;95(11):3634–5.