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Complex karyotype including chromosomal translocation (8;14) (q24;q32) in one case with B-cell prolymphocytic leukemia
Leukemia Research 31 (2007) 699–701
Case report
Complex karyotype including chromosomal translocation (8;14) (q24;q32) in one case with B-cell prolymphocytic leukemia Ricardo H. Crisostomo, Jose A. Fernandez ∗ , William Caceres San Juan City Hospital, Hematology – Oncology Section, Department of Medicine, San Juan, Puerto Rico 00936-8344 Received 11 May 2006; received in revised form 6 June 2006; accepted 9 June 2006 Available online 25 September 2006
Abstract We report a case of a 64-year-old white female patient, who presented with symptomatic anemia (Hgb: 6.8 g/dl), thrombocytopenia (platelets: 94,000/mcl) and leukocytosis (WBC: 156,000/mcl). Peripheral blood smear revealed markedly increased white blood cell count with predominance of atypical lymphoid cells of intermediate size, moderately dense chromatin, and prominent large single nucleoli. Bone marrow aspirate smear showed predominance (78%) of atypical lymphoid cells morphologically identical to those seen in the peripheral blood. The bone marrow core biopsy was hypercellular and packed with prominent infiltrate of prolymphocytes. Immunophenotypic analysis revealed a population of monoclonal cells (75% of all -erythroid cells) characterized by CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD10−, CD23±, CD38+ and FMC7−. The abnormal cells were restricted to kappa light chain immunoglobulin with low intensity. Cytogenetic study showed an abnormal clone of eight cells with the following karyotype: 45,X,-X,add(8)(p11.2),t(8;14)(q24;q32),add(20)ql3[8]/46,XX[12]. The relative rarity of B-PLL and the heterogeneity of clinical and laboratory parameters make it difficult to define the natural history and prognosis in all cases. The optimal treatment for B-PLL is still unknown and to date there are no reports of chromosomal abnormalities as a prognostic factor. The patient was treated with six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Complete remission was achived according to the criteria defined by National Cancer Institute Working Group for CLL. © 2006 Elsevier Ltd. All rights reserved. Keywords: B-cell prolymphocytic leukemia; t(8; 14); Cytogenetic; Immunophenotyping
1. Introduction B-cell prolymphocytic leukemia (B-PLL) is a chronic lymphoproliferative disorder characterized by prominent splenomegaly, minor involvement of lymph nodes and marked leukocytosis with prolymphocytes representing more than 55% of the circulating lymphoid cells. Prolymphocytes usually are over twice the diameter of a red blood cell, with clumped chromatin and a large, vesicular prominent nucleolus [1]. Immunophenotypic analysis of B-PLL cells reveals a population of monoclonal cells that express surface-membrane immunoglobulin (SmIg), HLA-DR, CD19, CD20, CD22, CD79b, FMC7 and weak to moderate CD5 [2]. ∗
Corresponding author. Tel.: +1 407 452 6161; fax: +1 407 452 6161. E-mail address: [email protected] (J.A. Fernandez).
0145-2126/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2006.06.010
Multiples chromosomal abnormalities have been found in patients with B-PLL, the most frequently reported include deletion of 11q23, deletion of 13q14, mutation of p53, t(11;14) and trisomy 12 [3–5]. The t(8;14) characteristic for Burkitt B-cell lymphoma and B-cell acute lymphoblastic leukemia (FAB-L3) has been observed in rare cases of B-PLL and CLL in prolymphocytic transformation [6,7]. We report a patient with complex karyotype along with t(8;14)(q24;q32).
2. Case report This is a case of a 64-year-old white female patient, who presented with symptomatic anemia (Hgb: 6.8 g/dl), thrombocytopenia (platelets: 94,000/mcl) and leukocytosis (WBC:
700
R.H. Crisostomo et al. / Leukemia Research 31 (2007) 699–701
Fig. 1. Peripheral blood smear.
156,000/mcl). Peripheral blood smear revealed markedly increased white blood cell count with predominance of atypical lymphoid cells of intermediate size, moderately dense chromatin, and prominent large single nucleoli (Fig. 1). Bone marrow aspirate smear showed predominance (78%) of atypical lymphoid cells morphologically identical to those seen in the peripheral blood. The bone marrow core biopsy was hypercellular and packed with prominent infiltrate of prolymphocytes (Fig. 2). Immunophenotypic analysis revealed a population of monoclonal cells (75% of all non-erythroid cells) characterized as CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD 10−, CD23±, CD38+ and FMC7−. The abnormal cells are restricted to kappa light chain immunoglobulin with low intensity. Cytogenetic study showed an abnormal clone of eight cells with the following karyotype: 45, X,-X, add(8)(p11.2), t(8;14)(q24;q32),add(20)(q13)[8]/46,XX[12]. The normal karyotype for females is 46,XX.
3. Discussion
Fig. 2. Core bone marrow biopsy at 40× magnification.
The diagnosis of B-PLL was based on morphologic examination of peripheral blood smear using the criteria of Melo et al. [1]. Also, the patient did not have documented any prior lymphoproliferative disorder. Nevertheless, the diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) that transformed into B-PLL was considered due to the diminished expression of immunoglobulin light chain and CD23±. The antibody FMC-7 is useful for identification of B-PLL or prolymphocytoid changes of B-CLL. Increased number of FMC7+ cells are sometimes noted in patients with B-CLL in the absence of morphologic changes of prolymphocytic leukemia [8]. On the other hand, Ruchlemer et al. found that CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)− group (30%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but in only 45% of the t(11;14)− cases [9]. It appears that immunologic changes are regulated independent of morphology. Genetic studies investigating the presence of translocations are an important diagnostic tool which can be used in combination with morphology and immunophenotyping to discriminate between B-PLL de novo and B-CLL in prolymphocytic transformation. The absence of t(11;14) could explain why the case reported had low expression of immunoglobulin light chain. The molecular genetic events involved in the pathogenesis of mature B-cell leukemias with more than 55% of prolymphocytes are not well characterized [7]. Many chromosomal abnormalities have been described. One of the most common cytogenetic abnormalities is t(11;14), together with trisomy 12 [5]. Nevertheless, rare cases of B-PLL with t(8;14) have been reported [6,7]. Translocations of 8q24 involve the cMyc locus, and in all instances, cMyc transcription is deregulated as a result of the juxtaposition of the locus with
R.H. Crisostomo et al. / Leukemia Research 31 (2007) 699–701
strong immunoglobulin gene enhancers, producing constitutive high-level expression [10]. The mechanism by which cMyc promotes cellular transformation is not clear. cMyc exists in cells as a heterodimer with another protein called MAX. This heterodimer tends to activate gene transcription [11–13]. On the other hand, cMyc deregulation has been associated with reduction in the expression of cyclin D-Cdk4 and -Cdk6 [14]. Also, cMyc can directly induce the telomerase reverse transcriptase whose increased expression demonstrated to immortalize rodent cells [15]. The relative rarity of the disease and the heterogeneity of clinical and laboratory parameters make it difficult to define the natural history and prognosis in all cases [16]. Relevant prognostic factors in B-PLL include the spleen size, the absolute number of prolymphocytes, intensity of SmIg staining, and hemoglobin level bellow 11 g/dl [16,17]. The optimal treatment for B-PLL is still unknown and to date there is no report of chromosomal abnormalities as a prognosis factor. Treatment regimens of patients with BPLL could possibly be enhanced if we took into account which particular chromosomal abnormalities were present. The case described in the present report was treated with six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). The patient achieved a complete remission according to the criteria defined by National Cancer Institute Working Group for CLL [18].
References [1] Melo JV, Catovsky D, Gallon DA. The relationship between chronic lymphocytic leukemia and prolymphocytic leukaemia. Clinical and laboratory features of 300 patients and characterization of an intermediate group. Br J Haematol 1986;63:377–87. [2] Matutes E, Polliack A. Morphological and immunophenotypic features of chronic lymphocytic leukemia. Rev Din Exp Hematol 2000;4:22–47. [3] Lens D, Matutes E, Catovsky D, et al. Frequent deletions at 11q23 and 13ql4 in B-cell prolymphocytic leukemia (B-PLL). Leukemia 2000;14:427–30.
701
[4] Lens D, de Schouwer PJ, Hamoudi RA, et al. p53 abnormalities in B-cell prolymphocytic leukemia. Blood 1997;89:2015–23. [5] Juliusson G, Gahrton G. Cytogenetics in CLL and related disorders. Bailliere Clin Haem 1993;6(4):821–48. [6] Kuriakose P, Perveen N, Maeda K, et al. Translocation (8; 14) (q24;q32) as the sole cytogenetic abnormality in B-cell prolymphocytic leukemia. Cancer Genet Cytogenet 2004;150:156–8. [7] Merchant S, Schlette E, Sanger W, et al. Mature B-cell leukemias with more than [55%] prolymphocytes: report of 2 cases with Burkitt lymphoma-type chromosomal translocations involving c-myc. Arch Pathol Lab Med 2003;127:305–9. [8] Scott CS, Limbert HJ, Roberts BE, Stark AN. Prolymphocytoid variants of chronic lymphocytic leukemia: an immunological and morphological survey. Leuk Res 1987;11:135–40. [9] Ruchlemer R, Parry-Jones N, Brito-Babapulle V, et al. Bprolymphocytic leukemia with t(11;14) revisited: a splenomegalic form of mantle cell lymphoma evolving with leukemia. Br J Haematol 2004;125:330–6. [10] Rosenwald A, Staudt LM, Duyster JG, Morris SW. Molecular aspects of non-hodgkin lymphomagenesis. In: Wintrobe’s clinical hematology. Lippincott: Williams & Wilkins; 2004. p. 2326–61. [11] Blackwood EM, Eisenman RN. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 1991;251:1211–7. [12] Prendergast GC, Lawe D, Ziff EB. Association of Myn, The murine homolog of Max, with c-Myc stimulates methylation-sensitive DNA binding and Ras cotransformation. Cell 1991;65:395–407. [13] Grandori C, Mac J, Siebelt F, et al. Myc-Max heterodimers activate a DEAD box gene and interact with multiple E box-related sites in vivo. EMBO J 1996;15:4344–57. [14] Mateyak MK, Obaya AJ, Sedivy JM. C-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol 1999;19:4672–83. [15] Wu KJ, Grandori C, Amacker M, et al. Direct activation of TERT by c-MYC. Nat Genet 1999;21(2):220–4. [16] Shvidel L, Shalrid M, Bassous L, et al. B-cell prolymphocytic leukemia: a survey of 35 patients emphasizing heterogeneity, prognostic factors and evidence for a group with an indolent course. Leukemia Lymphoma 1999;33:169–79. [17] Melo JV, Catovsky D, Gregory WM, et al. The relationship between chronic lymphocytic leukemia and prolymphocytic leukemia. Br J Haematol 1987;65:23–9. [18] Cheson BD, Bennett JM, Rai KP, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: Recommendations of the National Cancer Institute-Sponsored Working Group. Am J Hematol 1988;29:152–63.
Case report
Complex karyotype including chromosomal translocation (8;14) (q24;q32) in one case with B-cell prolymphocytic leukemia Ricardo H. Crisostomo, Jose A. Fernandez ∗ , William Caceres San Juan City Hospital, Hematology – Oncology Section, Department of Medicine, San Juan, Puerto Rico 00936-8344 Received 11 May 2006; received in revised form 6 June 2006; accepted 9 June 2006 Available online 25 September 2006
Abstract We report a case of a 64-year-old white female patient, who presented with symptomatic anemia (Hgb: 6.8 g/dl), thrombocytopenia (platelets: 94,000/mcl) and leukocytosis (WBC: 156,000/mcl). Peripheral blood smear revealed markedly increased white blood cell count with predominance of atypical lymphoid cells of intermediate size, moderately dense chromatin, and prominent large single nucleoli. Bone marrow aspirate smear showed predominance (78%) of atypical lymphoid cells morphologically identical to those seen in the peripheral blood. The bone marrow core biopsy was hypercellular and packed with prominent infiltrate of prolymphocytes. Immunophenotypic analysis revealed a population of monoclonal cells (75% of all -erythroid cells) characterized by CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD10−, CD23±, CD38+ and FMC7−. The abnormal cells were restricted to kappa light chain immunoglobulin with low intensity. Cytogenetic study showed an abnormal clone of eight cells with the following karyotype: 45,X,-X,add(8)(p11.2),t(8;14)(q24;q32),add(20)ql3[8]/46,XX[12]. The relative rarity of B-PLL and the heterogeneity of clinical and laboratory parameters make it difficult to define the natural history and prognosis in all cases. The optimal treatment for B-PLL is still unknown and to date there are no reports of chromosomal abnormalities as a prognostic factor. The patient was treated with six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Complete remission was achived according to the criteria defined by National Cancer Institute Working Group for CLL. © 2006 Elsevier Ltd. All rights reserved. Keywords: B-cell prolymphocytic leukemia; t(8; 14); Cytogenetic; Immunophenotyping
1. Introduction B-cell prolymphocytic leukemia (B-PLL) is a chronic lymphoproliferative disorder characterized by prominent splenomegaly, minor involvement of lymph nodes and marked leukocytosis with prolymphocytes representing more than 55% of the circulating lymphoid cells. Prolymphocytes usually are over twice the diameter of a red blood cell, with clumped chromatin and a large, vesicular prominent nucleolus [1]. Immunophenotypic analysis of B-PLL cells reveals a population of monoclonal cells that express surface-membrane immunoglobulin (SmIg), HLA-DR, CD19, CD20, CD22, CD79b, FMC7 and weak to moderate CD5 [2]. ∗
Corresponding author. Tel.: +1 407 452 6161; fax: +1 407 452 6161. E-mail address: [email protected] (J.A. Fernandez).
0145-2126/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2006.06.010
Multiples chromosomal abnormalities have been found in patients with B-PLL, the most frequently reported include deletion of 11q23, deletion of 13q14, mutation of p53, t(11;14) and trisomy 12 [3–5]. The t(8;14) characteristic for Burkitt B-cell lymphoma and B-cell acute lymphoblastic leukemia (FAB-L3) has been observed in rare cases of B-PLL and CLL in prolymphocytic transformation [6,7]. We report a patient with complex karyotype along with t(8;14)(q24;q32).
2. Case report This is a case of a 64-year-old white female patient, who presented with symptomatic anemia (Hgb: 6.8 g/dl), thrombocytopenia (platelets: 94,000/mcl) and leukocytosis (WBC:
700
R.H. Crisostomo et al. / Leukemia Research 31 (2007) 699–701
Fig. 1. Peripheral blood smear.
156,000/mcl). Peripheral blood smear revealed markedly increased white blood cell count with predominance of atypical lymphoid cells of intermediate size, moderately dense chromatin, and prominent large single nucleoli (Fig. 1). Bone marrow aspirate smear showed predominance (78%) of atypical lymphoid cells morphologically identical to those seen in the peripheral blood. The bone marrow core biopsy was hypercellular and packed with prominent infiltrate of prolymphocytes (Fig. 2). Immunophenotypic analysis revealed a population of monoclonal cells (75% of all non-erythroid cells) characterized as CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD 10−, CD23±, CD38+ and FMC7−. The abnormal cells are restricted to kappa light chain immunoglobulin with low intensity. Cytogenetic study showed an abnormal clone of eight cells with the following karyotype: 45, X,-X, add(8)(p11.2), t(8;14)(q24;q32),add(20)(q13)[8]/46,XX[12]. The normal karyotype for females is 46,XX.
3. Discussion
Fig. 2. Core bone marrow biopsy at 40× magnification.
The diagnosis of B-PLL was based on morphologic examination of peripheral blood smear using the criteria of Melo et al. [1]. Also, the patient did not have documented any prior lymphoproliferative disorder. Nevertheless, the diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) that transformed into B-PLL was considered due to the diminished expression of immunoglobulin light chain and CD23±. The antibody FMC-7 is useful for identification of B-PLL or prolymphocytoid changes of B-CLL. Increased number of FMC7+ cells are sometimes noted in patients with B-CLL in the absence of morphologic changes of prolymphocytic leukemia [8]. On the other hand, Ruchlemer et al. found that CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)− group (30%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but in only 45% of the t(11;14)− cases [9]. It appears that immunologic changes are regulated independent of morphology. Genetic studies investigating the presence of translocations are an important diagnostic tool which can be used in combination with morphology and immunophenotyping to discriminate between B-PLL de novo and B-CLL in prolymphocytic transformation. The absence of t(11;14) could explain why the case reported had low expression of immunoglobulin light chain. The molecular genetic events involved in the pathogenesis of mature B-cell leukemias with more than 55% of prolymphocytes are not well characterized [7]. Many chromosomal abnormalities have been described. One of the most common cytogenetic abnormalities is t(11;14), together with trisomy 12 [5]. Nevertheless, rare cases of B-PLL with t(8;14) have been reported [6,7]. Translocations of 8q24 involve the cMyc locus, and in all instances, cMyc transcription is deregulated as a result of the juxtaposition of the locus with
R.H. Crisostomo et al. / Leukemia Research 31 (2007) 699–701
strong immunoglobulin gene enhancers, producing constitutive high-level expression [10]. The mechanism by which cMyc promotes cellular transformation is not clear. cMyc exists in cells as a heterodimer with another protein called MAX. This heterodimer tends to activate gene transcription [11–13]. On the other hand, cMyc deregulation has been associated with reduction in the expression of cyclin D-Cdk4 and -Cdk6 [14]. Also, cMyc can directly induce the telomerase reverse transcriptase whose increased expression demonstrated to immortalize rodent cells [15]. The relative rarity of the disease and the heterogeneity of clinical and laboratory parameters make it difficult to define the natural history and prognosis in all cases [16]. Relevant prognostic factors in B-PLL include the spleen size, the absolute number of prolymphocytes, intensity of SmIg staining, and hemoglobin level bellow 11 g/dl [16,17]. The optimal treatment for B-PLL is still unknown and to date there is no report of chromosomal abnormalities as a prognosis factor. Treatment regimens of patients with BPLL could possibly be enhanced if we took into account which particular chromosomal abnormalities were present. The case described in the present report was treated with six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). The patient achieved a complete remission according to the criteria defined by National Cancer Institute Working Group for CLL [18].
References [1] Melo JV, Catovsky D, Gallon DA. The relationship between chronic lymphocytic leukemia and prolymphocytic leukaemia. Clinical and laboratory features of 300 patients and characterization of an intermediate group. Br J Haematol 1986;63:377–87. [2] Matutes E, Polliack A. Morphological and immunophenotypic features of chronic lymphocytic leukemia. Rev Din Exp Hematol 2000;4:22–47. [3] Lens D, Matutes E, Catovsky D, et al. Frequent deletions at 11q23 and 13ql4 in B-cell prolymphocytic leukemia (B-PLL). Leukemia 2000;14:427–30.
701
[4] Lens D, de Schouwer PJ, Hamoudi RA, et al. p53 abnormalities in B-cell prolymphocytic leukemia. Blood 1997;89:2015–23. [5] Juliusson G, Gahrton G. Cytogenetics in CLL and related disorders. Bailliere Clin Haem 1993;6(4):821–48. [6] Kuriakose P, Perveen N, Maeda K, et al. Translocation (8; 14) (q24;q32) as the sole cytogenetic abnormality in B-cell prolymphocytic leukemia. Cancer Genet Cytogenet 2004;150:156–8. [7] Merchant S, Schlette E, Sanger W, et al. Mature B-cell leukemias with more than [55%] prolymphocytes: report of 2 cases with Burkitt lymphoma-type chromosomal translocations involving c-myc. Arch Pathol Lab Med 2003;127:305–9. [8] Scott CS, Limbert HJ, Roberts BE, Stark AN. Prolymphocytoid variants of chronic lymphocytic leukemia: an immunological and morphological survey. Leuk Res 1987;11:135–40. [9] Ruchlemer R, Parry-Jones N, Brito-Babapulle V, et al. Bprolymphocytic leukemia with t(11;14) revisited: a splenomegalic form of mantle cell lymphoma evolving with leukemia. Br J Haematol 2004;125:330–6. [10] Rosenwald A, Staudt LM, Duyster JG, Morris SW. Molecular aspects of non-hodgkin lymphomagenesis. In: Wintrobe’s clinical hematology. Lippincott: Williams & Wilkins; 2004. p. 2326–61. [11] Blackwood EM, Eisenman RN. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 1991;251:1211–7. [12] Prendergast GC, Lawe D, Ziff EB. Association of Myn, The murine homolog of Max, with c-Myc stimulates methylation-sensitive DNA binding and Ras cotransformation. Cell 1991;65:395–407. [13] Grandori C, Mac J, Siebelt F, et al. Myc-Max heterodimers activate a DEAD box gene and interact with multiple E box-related sites in vivo. EMBO J 1996;15:4344–57. [14] Mateyak MK, Obaya AJ, Sedivy JM. C-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol 1999;19:4672–83. [15] Wu KJ, Grandori C, Amacker M, et al. Direct activation of TERT by c-MYC. Nat Genet 1999;21(2):220–4. [16] Shvidel L, Shalrid M, Bassous L, et al. B-cell prolymphocytic leukemia: a survey of 35 patients emphasizing heterogeneity, prognostic factors and evidence for a group with an indolent course. Leukemia Lymphoma 1999;33:169–79. [17] Melo JV, Catovsky D, Gregory WM, et al. The relationship between chronic lymphocytic leukemia and prolymphocytic leukemia. Br J Haematol 1987;65:23–9. [18] Cheson BD, Bennett JM, Rai KP, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: Recommendations of the National Cancer Institute-Sponsored Working Group. Am J Hematol 1988;29:152–63.