Pediatric Hematology and Oncology, 31:149–156, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.883655
ORIGINAL ARTICLE Myeloid Leukemias and Myeloproliferative Disease
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
A Novel Karyotype in Acute Myeloid Leukemia with Basophilia Marina Servitzoglou,1 Maria Grenzelia,2 Margarita Baka,1 Marietta Harisi,2 Apostolos Pourtsidis,1 Despina Bouhoutsou,1 Maria Varvoutsi,1 Dimitrios Doganis,1 Helen Dana,1 Aspasia Divane,3 and Helen Kosmidis1 1
Oncology Department, Children’s Hospital “P. & A. Kyriakou”, Thivon and Levadias, Athens, Greece; 2 Haematology Laboratory, Children’s Hospital “P. & A. Kyriakou”, Thivon and Levadias, Athens, Greece; 3 Centre of Genetics and Molecular Biology “Life Code”, Karystou 6, Athens, Greece
Acute basophilic leukemia is a distinct entity of Acute Myeloid Leukemia (AML) with primary differentiation to basophils. Increased basophil count has been described in AML cases with translocation t(6;9)(p23;q34) or other chromosomal abnormalities. We describe a 15-year old female teenager with AML and excess peripheral blood and bone marrow basophils. Her white blood cell count at diagnosis was 15.4 G/L with 53% basophils and 17% blasts. The bone marrow cytogenetics analysis did not reveal any of the usual abnormalities. The karyotype showed two closely related leukemic clones: the first (16 metaphases), with a total of 48 chromosomes, had an extra chromosome 8 with deletion of the long arm and an additional 21 (48,XX, +del(8)(q24.2q24.3), t21[16]), while the second clone (2 metaphases), with a total of 47 chromosomes, did not contain the extra 21 chromosome (47, sl, −21[2]). In summary, in this case of AML-M2 with excess basophils, there is a novel chromosomal abnormality, not previously reported in this entity. Keywords Acute Basophilic Leukemia, basophilia
INTRODUCTION The primary malignant disorders of the basophils, like acute basophilic leukemia, are extremely rare. According to the recent WHO classification of Myeloid Malignancies, acute basophilic leukemia has been recognized as a distinct entity of Acute Myeloid Leukemia (AML) with primary differentiation to basophils [1]. Basophilia (absolute basophil count in peripheral blood > 300/μL) is a common finding in various hematological malignancies, like Chronic Myeloid Leukemia, but is rarely found in AML. Increased basophil count in AML has been usually associated with the presence of t(6;9)(p23;q34) translocation. Less often, AML cases with basophilia have been related to other chromosomal abnormalities, like translocations t(8;21)(q22;q22) or t(3;6)(q21;p22) or t(9;22)(q34;q11) or chromosome 12p abnormalities. In terms of prognosis, AML with t(6;9)(p23;q34) has been associated with poor outcome, which Received 23 August 2013; accepted 12 January 2014. Address correspondence to Dr. Marina Servitzoglou, Oncology Department, Children’s Hospital “P. & A. Kyriakou”, Thivon and Levadias, Athens 11527, Greece. E-mail: [email protected]
M. Servitzoglou et al.
may reflect the higher frequency of dysplasia and FLT3 gene mutations in these patients. We are reporting an adolescent diagnosed with AML-M2 and marked basophilia with a good clinical outcome. In our case, the leukaemic clone showed a chromosomal abnormality, which to our knowledge, has not been previously described in AML with basophilia.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
CASE REPORT A 15-year old female teenager presented to our hospital with high-grade fever for 4 days and acute tonsillitis. She reported fatigue, headache, and dizziness for the last 1.5 month and a rash, a few weeks earlier, which automatically resolved, with no intervention. The full blood count, performed 4 weeks earlier, showed white blood cells 11.7 G/L, hematocrit 31.2%, and platelet count 137 G/L. She was born following in vitro fertilization, full-term gestation, with cesarean section. The perinatal period was complicated by a right humerus fracture. She had been admitted twice in the past, at the age of 6 and 13 years for fainting episodes, but the screening was negative. The family history was positive for malignancy, as maternal grandmother and grandfather had breast and prostatic cancer, respectively. On physical examination, she looked pale and tired but in good general condition. She had soft, palpable, cervical lymph nodes, 2 cm in size, bilaterally, inflammed tonsils and a small ecchymose in the right low eyelid. The full blood count showed white blood cells 15.4 G/L, hemoglobin 102 g/L, and platelet count 130 G/L. The differential showed 14% segmented neutrophils, 8% lymphocytes, 5% monocytes, 3% eosinophils, 53% basophils, and 17% blasts. Renal and liver function tests were normal. The bone marrow aspirate revealed increased cellularity with marked suppression of the erythroid lineage, almost normal megakaryocytes and 40% blasts. Of all bone marrow nucleated cells, 35% were basophils in all stages of maturation, which stained PAS positive, with coarse granulation. Blasts were large in size, with abundant cytoplasm, with few or no granules, some of them with vacuoles, without Auer rods and round or oval nucleus with 2–3 nucleoli (Figure 1). They were PAS (Periodic Acid Schiff ) negative, ANAE diffusely positive (20%), and PEROX (Myeloperoxidase) positive (70%). Immunophenotyping analysis of the blasts CD45int/SS (35%) by flow cytometry showed MPO, CD13, CD117, CD34, CD9, CD38, HLA-DR, CD2, CD15 positivity. B-lymphoid markers CD25, CD23, CD7 were not expressed, while CD33 was present in 6.5% of blasts. Immunophenotyping analysis of the basophils, on the basis of the intension of CD45 expression (more intense fluorescence than myeloblasts and less intense than lymphocytes) showed CD123, CD9, CD38, CD11b, CD13 positivity, while HLA-DR, CD25, CD2, CD117, CD34, CD19, CD15 were negative (Figure 2). Of note, antiCD203c was not available for analysis. Bone marrow cytogenetic analysis, in 16 of the 18 metaphases analyzed, revealed an additional chromosome 8, with deletion of the long arm and a trisomy 21 (48,XX, +del(8)(q24.2q24.3), t21[16]). In the rest two metaphases, the extra chromosome 21 was not detected (47, XX, sl, −21[2]) (Figure 3). FISH analysis for AML1 and ETO genes did not reveal a cryptic t(8;21) translocation, however she had three copies of ETO and three copies of AML1 gene in 91,4% of analyzed, a finding compatible with trisomy 8 and 21 (Figure 4). FISH for FLT3 was also negative. The patient was treated according to AML–BFM 2004 protocol. Her marrow in day 15 of induction was aplastic, but on day 28, showed complete remission, with no Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
Acute Myeloid Leukemia with Basophilia
FIGURE 1
Bone marrow aspirate at diagnosis.
excess basophils. She continues to be in remission 12 months from completion of maintenance. DISCUSSION We are reporting a novel case of AML with marked basophilia. According to FAB classification, this leukemia was typed as M2, with 28% blasts and 15% differentiating myeloid lineage in the bone marrow. Characteristically, in our case 35% of bone marrow nucleated cells represented basophils in different stages of differentiation. Bone marrow flow cytometry analysis confirmed the myeloid origin of blast cells (MPO+, CD13+, CD117+, CD34+) but provided no evidence in support of the diagnosis of acute basophilic leukaemia. Specifically, CD25, a marker characteristic for blasts of basophilic origin, was tested negative. Of note, CD203c, a characteristic marker for blasts in acute basophilic leukaemia, was not available and therefore not tested. Basophils also had to be differentiated from mast cells in order AML with mastocytosis to be ruled out. Apart from the bone marrow and peripheral blood morphology, this was based on the differential expression of the CD117 and CD25 markers on basophils and mast cells. Specifically, basophils are CD25 negative and CD117−/lo , whereas, mast cells show a high reactivity for the CD117 and CD25 antigens [2–5]. In our case, the population of interest showed CD25 negativity with the CD117 ranging from negative to positive low, a finding compatible with the presence of basophils at different stages of cell maturation. Basophilia has been described rarely in AML with most of the cases associated with (6;9)(p23;q34) translocation. This translocation has also been reported in patients with AML, aggressive myelodysplastic syndromes, t(9;22) negative chronic myelogenous leukemia, and some cases of acute myelofibrosis [6]. It results to the formation of DEKNUP214 fusion gene in chromosome 6. According to FAB classification, most of these patients were diagnosed with M2 or M4 AML [7]. Although it may be true that the DEKNUP214 fusion gene is responsible for poor prognosis, studies have demonstrated a C Informa Healthcare USA, Inc. Copyright
M. Servitzoglou et al.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
high prevalence (70%) of the fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation among patients with t(6;9) AML than in all other types of AML [7–9]. It is well established that FLT3-ITD gives poor prognosis to patients with AML. It has been shown that patients with t(6;9) and FLT3-ITD mutations present with higher white blood cell counts, higher percentages of bone marrow blasts, and significantly lower rates of complete remission [10–12]. Less often, AML cases with
FIGURE 2
Immunophenotyping analysis. (Continued) Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
Acute Myeloid Leukemia with Basophilia
FIGURE 2
(Continued)
basophilia have been related to other chromosomal abnormalities, like translocations t(8;21)(q22;q22) or t(3;6)(q21;p22) or t(9;22)(q34;q11) or chromosome 12p abnormalities. In our patient, the bone marrow cytogenetics analysis did not reveal any of these, usual for basophilia, abnormalities. The karyotype showed two closely related leukemic clones: the first (16 metaphases), with a total of 48 chromosomes, had an extra chromosome 8 with deletion of the long arm and trisomy 21 (48,XX, +del(8)(q24.2q24.3), t21[16]), while the second clone (2 metaphases), with a total of 47 chromosomes, did not contain the extra 21 chromosome (47, sl, −21[2]). Trisomy 8 is found in about 10–15% of AML cases and in a small percentage is combined with trisomy 21, as part of a complex caryotype [12]. Of interest in our case is the deletion in the long arm of the additional chromosome 8. The prognosis of AML trisomy 8 has been associated with intermediate or poor prognosis in adults, but there are no data for children and adolescents. When it is combined with t(8;21), t(15;17), or inv(16), it does not seem to alter their good prognosis. On the contrary, cases within a context of a complex karyotype exhibit a poor outcome [13, 14]. Because of a previous report of AML with basophilia in a little girl, who presented with AML1-ETO gene rearrangement, on the basis of t(8;21)(q22;q22) cryptic translocation, a FISH analysis for AML1 and ETO genes in bone marrow aspirate was performed. [14] The analysis did not reveal hybridization of these genes, but three copies for each of them, finding obviously mirroring the chromosome 8 and 21 translocations. Two AML cases with t(8;21) and basophilia have been previously reported. In the first, the cytomorphological features were those of AML-M2 and in the second, an additional t(9;22) translocation was present along with clinical and hematological features of CML [15–17]. Our patient was treated according to AML-BFM 2004 protocol, achieved complete remission with induction treatment and remains disease free 1 year after treatment C Informa Healthcare USA, Inc. Copyright
M. Servitzoglou et al.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
FIGURE 3
Cytogenetics analysis.
completion. This good clinical course cannot be attributed to the presence of a recognized favorable prognostic factor although the absence of any adverse genetic markers (FLT3 mutation) also should be noted. Trisomy 8 also has no recognized adverse effect on AML in adolescences. If our unique finding of partial loss of the long arm in the extra 8 chromosome is of prognostic relevance, it is impossible to conclude based on this Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
Acute Myeloid Leukemia with Basophilia
FIGURE 4 (a) Interphase FISH with probes for AML1 (green) and ETO (red) showed three signals for each of the two genes but no fusion between them. (b) Metaphase FISH with no hybridization signal between the AML1 (green) and ETO (red) genes.
report. Identification of new cases with this cytogenetic finding in the future may allow drawing some conclusions regarding any prognostic significance of this abnormality. To summarize, we have described a case of AML-M2 with excess basophils and a novel chromosomal abnormality, not previously reported in this entity. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES [1] Jaffe ES, Harris NL, Stein H, et al. Pathology and Genetic of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. [2] Han X, Jorgensen JL, Brahmandam, A, et al. Immunophenotypic study of basophils by multiparameter flow cytometry. Arch Pathol Lab Med. 2008;813–819. [3] Schernthaner GH, Hausman AW, Baghestanian M, et al. Detection of differentiation and activation linked cell surface antigens on cultured mast cell progenitors. Allergy. 2005;60:1248–1255. [4] Ghannadan M, Hauswith AW, Schernthaner GH, et al. Detection of novel CD antigens on the surface of human mast cells and basophils. Int Arch Allergy Immunol. 2002;127:299–307. [5] Agis H, Fureder W, Bankl HC, et al. Comparative immunophenotypic analysis of human mast cells, blood basophils and monocytes. Immunology. 1996;87:535–543. [6] Shapira MY, Hirshberg B, Amir G, et al. 6;9 translocation in myelodysplastic syndrome. Cancer Genet Cytogenet. 1999;112:57–59. [7] Garcon L, Libura M, Delabesse E, et al. DEK-CAN molecular monitoring of myeloid malignancies could aid therapeutic stratification. Leukemia. 2005;19:1338–1344. [8] Oyarzo MP, Lin P, Glassman A, et al. Acute myelogenous leukemia with t(6;9)(p23;q34) is associated with dysplasia and a high frequency of FLT3 gene mutations. Am J Clin Pathol. 2004;122:348–358. [9] Slovak ML, Gundacker H, Bloomfield CD, et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia. 2006;20:1295–1297. [10] Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326–4335. [11] Yiqing C, Lindgren V, Quigley S, Gaitonde S. Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia. An overview. Arch Pathol Lab Med. 2008;132:1835–1837. [12] Schoch C, Haase D, Fonatsch C, et al. The significance of trisomy 8 in de novo acute myeloid leukaemia: the accompanying chromosome aberrations determine the prognosis. German AML Cooperative Study Group. Br J Haematol. 1997;99(3):605–611. C Informa Healthcare USA, Inc. Copyright
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[13] Chevallier P, Lapobin M, Nagler A, et al. Outcome after allogeneic transplantation for adult acute myeloid leukemia patients exhibiting isolated or associated trisomy 8 chromosomal abnormality: a survey on behalf of the ALWP of the EBMT. Bone Marrow Transplant. 2009;44(9):589–594. [14] Wolman SR, Gundacker H, Appelbaum FR, et al. Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study. Blood. 2002;100(1):29–35. [15] Gupta R, Jain P, Anand M. Acute basophilic leukemia: a case report. Amer J Hematol. 2004;76: 134–138. [16] Lorsbach RB, McNall R, Mathew S. Marked bone marrow basophilia in a child with acute myeloid leukemia with a cryptic t(8;21)(q22;q22) chromosomal translocation. Leukemia. 2001;15:1799–1801. [17] Xue YQ, Guo Y, Lu DR, et al. A case of basophilic leukemia bearing simultaneous translocations t(8;21) and t(9;22). Cancer Genet Cytogenet. 1991;51:215–221.
Pediatric Hematology and Oncology
ORIGINAL ARTICLE Myeloid Leukemias and Myeloproliferative Disease
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
A Novel Karyotype in Acute Myeloid Leukemia with Basophilia Marina Servitzoglou,1 Maria Grenzelia,2 Margarita Baka,1 Marietta Harisi,2 Apostolos Pourtsidis,1 Despina Bouhoutsou,1 Maria Varvoutsi,1 Dimitrios Doganis,1 Helen Dana,1 Aspasia Divane,3 and Helen Kosmidis1 1
Oncology Department, Children’s Hospital “P. & A. Kyriakou”, Thivon and Levadias, Athens, Greece; 2 Haematology Laboratory, Children’s Hospital “P. & A. Kyriakou”, Thivon and Levadias, Athens, Greece; 3 Centre of Genetics and Molecular Biology “Life Code”, Karystou 6, Athens, Greece
Acute basophilic leukemia is a distinct entity of Acute Myeloid Leukemia (AML) with primary differentiation to basophils. Increased basophil count has been described in AML cases with translocation t(6;9)(p23;q34) or other chromosomal abnormalities. We describe a 15-year old female teenager with AML and excess peripheral blood and bone marrow basophils. Her white blood cell count at diagnosis was 15.4 G/L with 53% basophils and 17% blasts. The bone marrow cytogenetics analysis did not reveal any of the usual abnormalities. The karyotype showed two closely related leukemic clones: the first (16 metaphases), with a total of 48 chromosomes, had an extra chromosome 8 with deletion of the long arm and an additional 21 (48,XX, +del(8)(q24.2q24.3), t21[16]), while the second clone (2 metaphases), with a total of 47 chromosomes, did not contain the extra 21 chromosome (47, sl, −21[2]). In summary, in this case of AML-M2 with excess basophils, there is a novel chromosomal abnormality, not previously reported in this entity. Keywords Acute Basophilic Leukemia, basophilia
INTRODUCTION The primary malignant disorders of the basophils, like acute basophilic leukemia, are extremely rare. According to the recent WHO classification of Myeloid Malignancies, acute basophilic leukemia has been recognized as a distinct entity of Acute Myeloid Leukemia (AML) with primary differentiation to basophils [1]. Basophilia (absolute basophil count in peripheral blood > 300/μL) is a common finding in various hematological malignancies, like Chronic Myeloid Leukemia, but is rarely found in AML. Increased basophil count in AML has been usually associated with the presence of t(6;9)(p23;q34) translocation. Less often, AML cases with basophilia have been related to other chromosomal abnormalities, like translocations t(8;21)(q22;q22) or t(3;6)(q21;p22) or t(9;22)(q34;q11) or chromosome 12p abnormalities. In terms of prognosis, AML with t(6;9)(p23;q34) has been associated with poor outcome, which Received 23 August 2013; accepted 12 January 2014. Address correspondence to Dr. Marina Servitzoglou, Oncology Department, Children’s Hospital “P. & A. Kyriakou”, Thivon and Levadias, Athens 11527, Greece. E-mail: [email protected]
M. Servitzoglou et al.
may reflect the higher frequency of dysplasia and FLT3 gene mutations in these patients. We are reporting an adolescent diagnosed with AML-M2 and marked basophilia with a good clinical outcome. In our case, the leukaemic clone showed a chromosomal abnormality, which to our knowledge, has not been previously described in AML with basophilia.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
CASE REPORT A 15-year old female teenager presented to our hospital with high-grade fever for 4 days and acute tonsillitis. She reported fatigue, headache, and dizziness for the last 1.5 month and a rash, a few weeks earlier, which automatically resolved, with no intervention. The full blood count, performed 4 weeks earlier, showed white blood cells 11.7 G/L, hematocrit 31.2%, and platelet count 137 G/L. She was born following in vitro fertilization, full-term gestation, with cesarean section. The perinatal period was complicated by a right humerus fracture. She had been admitted twice in the past, at the age of 6 and 13 years for fainting episodes, but the screening was negative. The family history was positive for malignancy, as maternal grandmother and grandfather had breast and prostatic cancer, respectively. On physical examination, she looked pale and tired but in good general condition. She had soft, palpable, cervical lymph nodes, 2 cm in size, bilaterally, inflammed tonsils and a small ecchymose in the right low eyelid. The full blood count showed white blood cells 15.4 G/L, hemoglobin 102 g/L, and platelet count 130 G/L. The differential showed 14% segmented neutrophils, 8% lymphocytes, 5% monocytes, 3% eosinophils, 53% basophils, and 17% blasts. Renal and liver function tests were normal. The bone marrow aspirate revealed increased cellularity with marked suppression of the erythroid lineage, almost normal megakaryocytes and 40% blasts. Of all bone marrow nucleated cells, 35% were basophils in all stages of maturation, which stained PAS positive, with coarse granulation. Blasts were large in size, with abundant cytoplasm, with few or no granules, some of them with vacuoles, without Auer rods and round or oval nucleus with 2–3 nucleoli (Figure 1). They were PAS (Periodic Acid Schiff ) negative, ANAE diffusely positive (20%), and PEROX (Myeloperoxidase) positive (70%). Immunophenotyping analysis of the blasts CD45int/SS (35%) by flow cytometry showed MPO, CD13, CD117, CD34, CD9, CD38, HLA-DR, CD2, CD15 positivity. B-lymphoid markers CD25, CD23, CD7 were not expressed, while CD33 was present in 6.5% of blasts. Immunophenotyping analysis of the basophils, on the basis of the intension of CD45 expression (more intense fluorescence than myeloblasts and less intense than lymphocytes) showed CD123, CD9, CD38, CD11b, CD13 positivity, while HLA-DR, CD25, CD2, CD117, CD34, CD19, CD15 were negative (Figure 2). Of note, antiCD203c was not available for analysis. Bone marrow cytogenetic analysis, in 16 of the 18 metaphases analyzed, revealed an additional chromosome 8, with deletion of the long arm and a trisomy 21 (48,XX, +del(8)(q24.2q24.3), t21[16]). In the rest two metaphases, the extra chromosome 21 was not detected (47, XX, sl, −21[2]) (Figure 3). FISH analysis for AML1 and ETO genes did not reveal a cryptic t(8;21) translocation, however she had three copies of ETO and three copies of AML1 gene in 91,4% of analyzed, a finding compatible with trisomy 8 and 21 (Figure 4). FISH for FLT3 was also negative. The patient was treated according to AML–BFM 2004 protocol. Her marrow in day 15 of induction was aplastic, but on day 28, showed complete remission, with no Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
Acute Myeloid Leukemia with Basophilia
FIGURE 1
Bone marrow aspirate at diagnosis.
excess basophils. She continues to be in remission 12 months from completion of maintenance. DISCUSSION We are reporting a novel case of AML with marked basophilia. According to FAB classification, this leukemia was typed as M2, with 28% blasts and 15% differentiating myeloid lineage in the bone marrow. Characteristically, in our case 35% of bone marrow nucleated cells represented basophils in different stages of differentiation. Bone marrow flow cytometry analysis confirmed the myeloid origin of blast cells (MPO+, CD13+, CD117+, CD34+) but provided no evidence in support of the diagnosis of acute basophilic leukaemia. Specifically, CD25, a marker characteristic for blasts of basophilic origin, was tested negative. Of note, CD203c, a characteristic marker for blasts in acute basophilic leukaemia, was not available and therefore not tested. Basophils also had to be differentiated from mast cells in order AML with mastocytosis to be ruled out. Apart from the bone marrow and peripheral blood morphology, this was based on the differential expression of the CD117 and CD25 markers on basophils and mast cells. Specifically, basophils are CD25 negative and CD117−/lo , whereas, mast cells show a high reactivity for the CD117 and CD25 antigens [2–5]. In our case, the population of interest showed CD25 negativity with the CD117 ranging from negative to positive low, a finding compatible with the presence of basophils at different stages of cell maturation. Basophilia has been described rarely in AML with most of the cases associated with (6;9)(p23;q34) translocation. This translocation has also been reported in patients with AML, aggressive myelodysplastic syndromes, t(9;22) negative chronic myelogenous leukemia, and some cases of acute myelofibrosis [6]. It results to the formation of DEKNUP214 fusion gene in chromosome 6. According to FAB classification, most of these patients were diagnosed with M2 or M4 AML [7]. Although it may be true that the DEKNUP214 fusion gene is responsible for poor prognosis, studies have demonstrated a C Informa Healthcare USA, Inc. Copyright
M. Servitzoglou et al.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
high prevalence (70%) of the fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation among patients with t(6;9) AML than in all other types of AML [7–9]. It is well established that FLT3-ITD gives poor prognosis to patients with AML. It has been shown that patients with t(6;9) and FLT3-ITD mutations present with higher white blood cell counts, higher percentages of bone marrow blasts, and significantly lower rates of complete remission [10–12]. Less often, AML cases with
FIGURE 2
Immunophenotyping analysis. (Continued) Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
Acute Myeloid Leukemia with Basophilia
FIGURE 2
(Continued)
basophilia have been related to other chromosomal abnormalities, like translocations t(8;21)(q22;q22) or t(3;6)(q21;p22) or t(9;22)(q34;q11) or chromosome 12p abnormalities. In our patient, the bone marrow cytogenetics analysis did not reveal any of these, usual for basophilia, abnormalities. The karyotype showed two closely related leukemic clones: the first (16 metaphases), with a total of 48 chromosomes, had an extra chromosome 8 with deletion of the long arm and trisomy 21 (48,XX, +del(8)(q24.2q24.3), t21[16]), while the second clone (2 metaphases), with a total of 47 chromosomes, did not contain the extra 21 chromosome (47, sl, −21[2]). Trisomy 8 is found in about 10–15% of AML cases and in a small percentage is combined with trisomy 21, as part of a complex caryotype [12]. Of interest in our case is the deletion in the long arm of the additional chromosome 8. The prognosis of AML trisomy 8 has been associated with intermediate or poor prognosis in adults, but there are no data for children and adolescents. When it is combined with t(8;21), t(15;17), or inv(16), it does not seem to alter their good prognosis. On the contrary, cases within a context of a complex karyotype exhibit a poor outcome [13, 14]. Because of a previous report of AML with basophilia in a little girl, who presented with AML1-ETO gene rearrangement, on the basis of t(8;21)(q22;q22) cryptic translocation, a FISH analysis for AML1 and ETO genes in bone marrow aspirate was performed. [14] The analysis did not reveal hybridization of these genes, but three copies for each of them, finding obviously mirroring the chromosome 8 and 21 translocations. Two AML cases with t(8;21) and basophilia have been previously reported. In the first, the cytomorphological features were those of AML-M2 and in the second, an additional t(9;22) translocation was present along with clinical and hematological features of CML [15–17]. Our patient was treated according to AML-BFM 2004 protocol, achieved complete remission with induction treatment and remains disease free 1 year after treatment C Informa Healthcare USA, Inc. Copyright
M. Servitzoglou et al.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
FIGURE 3
Cytogenetics analysis.
completion. This good clinical course cannot be attributed to the presence of a recognized favorable prognostic factor although the absence of any adverse genetic markers (FLT3 mutation) also should be noted. Trisomy 8 also has no recognized adverse effect on AML in adolescences. If our unique finding of partial loss of the long arm in the extra 8 chromosome is of prognostic relevance, it is impossible to conclude based on this Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by University of Bath on 10/04/14 For personal use only.
Acute Myeloid Leukemia with Basophilia
FIGURE 4 (a) Interphase FISH with probes for AML1 (green) and ETO (red) showed three signals for each of the two genes but no fusion between them. (b) Metaphase FISH with no hybridization signal between the AML1 (green) and ETO (red) genes.
report. Identification of new cases with this cytogenetic finding in the future may allow drawing some conclusions regarding any prognostic significance of this abnormality. To summarize, we have described a case of AML-M2 with excess basophils and a novel chromosomal abnormality, not previously reported in this entity. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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