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Acute Myeloblastic Leukemia (M0) with an Unusual Chromosomal Abnormality
Acute Myeloblastic Leukemia (M0) with an Unusual Chromosomal Abnormality: Translocation (1;14)(p13;q32) Coskun Tecimer, Brian A. Loy, and Alvin W. Martin
ABSTRACT: We describe a case of acute myeloblastic leukemia, French-American-British subclassification of M0 (AML-M0), with an unusual chromosomal abnormality. The diagnosis of AML-M0 was made morphologically, cytochemically, and immunophenotypically. At the time of diagnosis, cytogenetic studies were performed, revealing a translocation involving chromosomes 1 and 14—specifically t(1;14)(p13;q32). The patient responded to high-dose ARA-C. In our survey of the literature, we were unable to find a reported case of AML-M0 with this chromosomal translocation. © Elsevier Science Inc., 1999. All rights reserved.
INTRODUCTION Acute myeloblastic leukemia-M0 (AML-M0), also called minimally differentiated AML [1], is the least-differentiated subclass of AML, according to the expanded French– American–British (FAB) classification [2]. The diagnosis requires immunologic evidence for myeloid differentiation and demonstration of at least one myeloid-specific antigen (i.e., myeloperoxidase, CD13, CD33) and negativity for lymphoid antigens (except tdt, CD2, CD4, CD7) [3]. Peroxidase-positive granules can be demonstrated by electron microscopy. AML-M0 accounts for approximately 7% of all acute leukemias in adults [1]. This type of leukemia has a less favorable response to combination therapy than do other types of AML [1]. AML-M0 is frequently associated with cytogenetic abnormalities common to myelodysplastic syndrome or secondary AML, such as 25/5q2 or 27/7q2 deletions and trisomies 8, 4, and 13 [3]. We present a case of AML-M0 with t(1;14)(p13;q32), which is the first in the literature. CASE REPORT A 63-year-old woman was admitted to the hematology service at University of Louisville Hospital for malaise and weakness. On admission, physical examination revealed
From the Department of Hematology/Medical Oncology (C. T.) and the Department of Pathology (B. A. L., A. W. M.), University of Louisville School of Medicine, Louisville, Kentucky, USA. Address reprint requests to: Coskun Tecimer, M.D., Ahmet Refik Sok., No: 3/5, Çiftehavuzlar, Göztepe, 81060, Istanbul, Turkey. Received August 5, 1998; accepted September 21, 1998. Cancer Genet Cytogenet 111:175–177 (1999) Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
no hepatosplenomegaly, lymphadenopathy, petechiae, ecchymoses, or fever. Laboratory values included a hemoglobin of 11.1 g/dL, white cell count of 18,000/mL, and platelet count of 194,000/mL. A Wright-Giemsa-stained peripheral blood smear revealed microblasts with a high nuclear-to-cytoplasmic ratio. These blasts contained only scant cytoplasm and no cytoplasmic azurophilic granules or Auer rods. Nuclear features included a fine open chromatin pattern and multiple prominent nucleoli. A subsequent bone marrow biopsy and aspirate revealed multiple microblasts similar to those found in the peripheral smear. Some normoblasts had dysplastic features (e.g., irregular nuclear configurations). Cytochemistry performed on cytospin preparations revealed rare (less than 3% of all blasts) weak, cytoplasmic reactivity. However, no Auer rods were identified. Immunophenotyping by flow cytometry of the bone marrow aspirate revealed a population of cells in the lymphoid region expressing dim CD33, CD13, CD34, HLA-DR, and cytoplasmic myeloperoxidase. Interestingly, the cytoplasmic myeloperoxidase was present in most of the CD33/CD34 events. These events were negative for CD2, CD3, CD4, CD5, CD7, and CD8. Cytogenetic studies performed from bone marrow revealed that 8 of 10 metaphases demonstrated a balanced translocation between chromosomes 1 and 14; that is, 46,XX,t(1;14)(p13;q32) (Figure 1). On diagnosis, the patient was treated with high-dose ARA-C of 1.5 g/m2/12 h for 12 doses and Idarubicin of 12 mg/m2/day for 3 days. The patient responded to treatment and hematologic remission was obtained. Flow cytometric analysis of bone marrow failed to demonstrate residual or recurrent disease. After the hematologic recovery, the patient was discharged with plans to administer a second round of chemotherapy.
0165-4608/99/$–see front matter PII S0165-4608(98)00234-9
176
C. Tecimer et al.
Figure 1 The karyotype of the case showing t(1;14)(p13;q32).
DISCUSSION AML-M0 is a distinct entity described in the recent literature and accounts for 5% of all AMLs [4]. The classification of acute leukemias by the FAB group [2, 5] has provided a framework for the diagnosis of subtypes of AML based on morphology, cytochemistry, and immunophenotyping. The unequivocal diagnosis of AML-M0 may still pose some difficulty, particularly in distinguishing it from early lymphoblastic leukemias with inadequate expression of myeloid markers. The diagnosis of AML-M0 requires immunologic studies to demonstrate at least one lineage-specific myeloid antigen [6]. The morphology, cytochemistry, and immunophenotype of this case fulfilled the FAB criteria to make a diagnosis of AML-M0. In our review of the literature, many different cytogenetic abnormalities have been associated with AML-M0. Cuneo et al. [7] found a higher percentage of abnormal karyotypes (81%) in AML-M0 compared with unselected AML cases. In addition, the type of chromosome changes in AML-M0 differed significantly with respect to the cytogenetic profile, often recalling that of myelodysplasia or secondary AML, which portends an unfavorable outcome. The most frequent abnormalities associated with AML-M0
were 25/5q2 or 27/7q2 deletions or both (42%). Additionally, translocation of 12p has also been associated with AML-M0. Given that translocations of chromosome 12, 5q, and 7q aberrations have been associated with erythroleukemia, some cases of AML-M0 may represent proliferations of immature erythroid precursors [7]. Trisomy 13 was also seen in 19% of their cases. Lee et al. [1] found different complex chromosomal abnormalities in 88% of their cases with involvement of chromosome 7 in 37% of AML-M0 cases and 5 in 12% of the cases. Venditti et al. [8] showed chromosomal abnormalities in 71% of the cases. The most common finding was trisomy 8, trisomy 4, and aberrations of chromosomes 2, 3, 5, 7, 9, 12, and 21. Segeren et al. [9] reported chromosomal abnormalities in 58% of their cases, although no consistent or specific chromosomal aberrations were found. In three patients, an abnormality of chromosome 7 was found, suggesting an earlier myelodysplastic syndrome. Trisomy 13 in one case and trisomy 8 in another case were also found in their study. To our knowledge, no previous association of a case of AML-M0 with t(1;14) has been reported in the English literature. Moreover, this translocation with breakpoints
AML with t(1;14)(p13;q32) similar to those in our case has not been associated with any subtype of AML. 14q32 translocation with different breakpoints of chromosome 1 has been demonstrated in a mixed lineage acute leukemia and a myelodysplastic syndrome case in two studies [10, 11]. This finding in association with the features of dysplastic bone marrow normoblasts in our case may suggest that this leukemic process may have arisen from an underlying myelodysplasia. On the other hand, the closest translocation in our case is the t(1;14)(p22;q32) seen in some cases of mucosally associated lymphoid tissue lymphoma [12]. 14q32 translocation with different breakpoints of any chromosome is seen in B-cell leukemias and lymphomas because the genes encoding the immunoglobulin human heavy chain (IgH) are located in this region [13]. However, 14q32 abnormalities have also been reported in some mixed lineage leukemias [10] and in AML [14] in addition to T-cell lymphoma/leukemia [15, 16]. These findings suggested that some genes other than those encoding IgH may reside in this chromosomal region [10, 14]. Our patient with 14q32 translocation is one of the cases in the literature that supports this idea. REFERENCES 1. Lee EJ, Pollak A, Leavitt RD, Testa JR, Schiffer CA (1987): Minimally differentiated acute nonlymphocytic leukemia: a distinct entity. Blood 70:1400–1406. 2. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1991): Proposals for the recognition of minimally differentiated acute myeloid leukemia. Br J Haematol 78:325–329. 3. Amadori S, Venditti A, Del Poeta G, Stasi R, Buccisano F, Bruno A, Tamburini A, Cox MC, Maffei L, Aronica G, Simone MD, Adorno G, Masi M, Tribalto M, Papa G (1996): Minimally differentiated acute myeloid leukemia (AML-M0): a distinct clinico-biologic entity with poor prognosis. Ann Hematol 72:208–215. 4. Campos L, Guyotat D, Archimbaud E, Devaux Y, Treille D, Larese A, Maupas J, Gentilhomme O, Ehrsam A, Fiere D (1989): Surface marker expression in adult acute myeloid leukemia: correlations with initial characteristics, morphology and response to therapy. Br J Haematol 72:161–166. 5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton AG, Gralnick HR, Sultan C (1985): Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative group. Ann Intern Med 103:626–629.
177 6. 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. 7. Cuneo A, Ferrant A, Michaux JL, Boogaerts M, Demuynck H, Orshoven AV, Criel A, Stul M, Dal Cin P, Hernandez J, Chatelain B, Doyen C, Louwagie A, Castoldi G, Cassiman J, Van den Berghe H (1985): Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinico-biologic findings. Blood 85:3688–3694. 8. Venditti A, Poeta GD, Stasi R, Masi M, Bruno A, Buccisano F, Cox C, Coppetelli U, Aronica G, Simone MD, Papa G, Tribalto M, Amadori S (1994): Minimally differentiated acute myeloid leukemia (AML-M0): cytochemical, immunophenotypic and cytogenetic analysis of 19 cases. Br J Haematol 88:784–793. 9. Segeran CM, De Jong-Gerrits GCMM, Van’t Veer MB, on behalf of the Review Dutch Slide Review Committee of Leukemias in Adults (1995): AML-M0: clinical entity or waste basket for immature blastic leukemias? A description of 14 patients. Ann Hematol 70:297–300. 10. Hayashi Y, Pui CH, Behm FG, Fuchs AH, Raimondi SC, Kitchingman GR, Mirro J, Jr, Williams DL (1990): 14q32 translocations are associated with mixed-lineage expression in childhood acute leukemia. Blood 76:150–156. 11. De Pree C, Cabrol C, Frossard JL, Beris P (1995): Pseudoreticulocytosis in a case of myelodysplastic syndrome with translocation t(1;14)(q42;q32). Sem Hematol 32:232–236. 12. Wotherspoon AC, Pan L, Diss TC, Isaacson PG (1992): Cytogenetic study of B-cell lymphoma of mucosa-associated lymphoid tissue. Cancer Genet Cytogenet 58:35–38. 13. McAlpine PJ, Shows TB, Miller RL, Pakstis AJ (1985): The 1985 Catalogue of Mapped Genes and Report of the Nomenclature Committee: Eighth International Human Gene Mapping Workshop. Cytogenet Cell Genet 40:8–66. 14. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H (1997): Fusion of the platelet-derived growth factor receptor to a novel gene CEV 14 in acute myelogenous leukemia after clonal evolution. Blood 90:4271–4277. 15. The Fifth International Workshop on Chromosomes in Leukemia-Lymphoma (1987): Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin’s lymphoma and adult T cell leukemia-lymphoma. Blood 70:1554–1564. 16. Miyamoto K, Tomita N, Ishii A, Nonaka H, Kondo T, Tanaka T, Kitajima K (1984): Chromosome abnormalities of leukemia cells in adult patients with T-cell leukemia. J Natl Cancer Inst 73:353–363.
ABSTRACT: We describe a case of acute myeloblastic leukemia, French-American-British subclassification of M0 (AML-M0), with an unusual chromosomal abnormality. The diagnosis of AML-M0 was made morphologically, cytochemically, and immunophenotypically. At the time of diagnosis, cytogenetic studies were performed, revealing a translocation involving chromosomes 1 and 14—specifically t(1;14)(p13;q32). The patient responded to high-dose ARA-C. In our survey of the literature, we were unable to find a reported case of AML-M0 with this chromosomal translocation. © Elsevier Science Inc., 1999. All rights reserved.
INTRODUCTION Acute myeloblastic leukemia-M0 (AML-M0), also called minimally differentiated AML [1], is the least-differentiated subclass of AML, according to the expanded French– American–British (FAB) classification [2]. The diagnosis requires immunologic evidence for myeloid differentiation and demonstration of at least one myeloid-specific antigen (i.e., myeloperoxidase, CD13, CD33) and negativity for lymphoid antigens (except tdt, CD2, CD4, CD7) [3]. Peroxidase-positive granules can be demonstrated by electron microscopy. AML-M0 accounts for approximately 7% of all acute leukemias in adults [1]. This type of leukemia has a less favorable response to combination therapy than do other types of AML [1]. AML-M0 is frequently associated with cytogenetic abnormalities common to myelodysplastic syndrome or secondary AML, such as 25/5q2 or 27/7q2 deletions and trisomies 8, 4, and 13 [3]. We present a case of AML-M0 with t(1;14)(p13;q32), which is the first in the literature. CASE REPORT A 63-year-old woman was admitted to the hematology service at University of Louisville Hospital for malaise and weakness. On admission, physical examination revealed
From the Department of Hematology/Medical Oncology (C. T.) and the Department of Pathology (B. A. L., A. W. M.), University of Louisville School of Medicine, Louisville, Kentucky, USA. Address reprint requests to: Coskun Tecimer, M.D., Ahmet Refik Sok., No: 3/5, Çiftehavuzlar, Göztepe, 81060, Istanbul, Turkey. Received August 5, 1998; accepted September 21, 1998. Cancer Genet Cytogenet 111:175–177 (1999) Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
no hepatosplenomegaly, lymphadenopathy, petechiae, ecchymoses, or fever. Laboratory values included a hemoglobin of 11.1 g/dL, white cell count of 18,000/mL, and platelet count of 194,000/mL. A Wright-Giemsa-stained peripheral blood smear revealed microblasts with a high nuclear-to-cytoplasmic ratio. These blasts contained only scant cytoplasm and no cytoplasmic azurophilic granules or Auer rods. Nuclear features included a fine open chromatin pattern and multiple prominent nucleoli. A subsequent bone marrow biopsy and aspirate revealed multiple microblasts similar to those found in the peripheral smear. Some normoblasts had dysplastic features (e.g., irregular nuclear configurations). Cytochemistry performed on cytospin preparations revealed rare (less than 3% of all blasts) weak, cytoplasmic reactivity. However, no Auer rods were identified. Immunophenotyping by flow cytometry of the bone marrow aspirate revealed a population of cells in the lymphoid region expressing dim CD33, CD13, CD34, HLA-DR, and cytoplasmic myeloperoxidase. Interestingly, the cytoplasmic myeloperoxidase was present in most of the CD33/CD34 events. These events were negative for CD2, CD3, CD4, CD5, CD7, and CD8. Cytogenetic studies performed from bone marrow revealed that 8 of 10 metaphases demonstrated a balanced translocation between chromosomes 1 and 14; that is, 46,XX,t(1;14)(p13;q32) (Figure 1). On diagnosis, the patient was treated with high-dose ARA-C of 1.5 g/m2/12 h for 12 doses and Idarubicin of 12 mg/m2/day for 3 days. The patient responded to treatment and hematologic remission was obtained. Flow cytometric analysis of bone marrow failed to demonstrate residual or recurrent disease. After the hematologic recovery, the patient was discharged with plans to administer a second round of chemotherapy.
0165-4608/99/$–see front matter PII S0165-4608(98)00234-9
176
C. Tecimer et al.
Figure 1 The karyotype of the case showing t(1;14)(p13;q32).
DISCUSSION AML-M0 is a distinct entity described in the recent literature and accounts for 5% of all AMLs [4]. The classification of acute leukemias by the FAB group [2, 5] has provided a framework for the diagnosis of subtypes of AML based on morphology, cytochemistry, and immunophenotyping. The unequivocal diagnosis of AML-M0 may still pose some difficulty, particularly in distinguishing it from early lymphoblastic leukemias with inadequate expression of myeloid markers. The diagnosis of AML-M0 requires immunologic studies to demonstrate at least one lineage-specific myeloid antigen [6]. The morphology, cytochemistry, and immunophenotype of this case fulfilled the FAB criteria to make a diagnosis of AML-M0. In our review of the literature, many different cytogenetic abnormalities have been associated with AML-M0. Cuneo et al. [7] found a higher percentage of abnormal karyotypes (81%) in AML-M0 compared with unselected AML cases. In addition, the type of chromosome changes in AML-M0 differed significantly with respect to the cytogenetic profile, often recalling that of myelodysplasia or secondary AML, which portends an unfavorable outcome. The most frequent abnormalities associated with AML-M0
were 25/5q2 or 27/7q2 deletions or both (42%). Additionally, translocation of 12p has also been associated with AML-M0. Given that translocations of chromosome 12, 5q, and 7q aberrations have been associated with erythroleukemia, some cases of AML-M0 may represent proliferations of immature erythroid precursors [7]. Trisomy 13 was also seen in 19% of their cases. Lee et al. [1] found different complex chromosomal abnormalities in 88% of their cases with involvement of chromosome 7 in 37% of AML-M0 cases and 5 in 12% of the cases. Venditti et al. [8] showed chromosomal abnormalities in 71% of the cases. The most common finding was trisomy 8, trisomy 4, and aberrations of chromosomes 2, 3, 5, 7, 9, 12, and 21. Segeren et al. [9] reported chromosomal abnormalities in 58% of their cases, although no consistent or specific chromosomal aberrations were found. In three patients, an abnormality of chromosome 7 was found, suggesting an earlier myelodysplastic syndrome. Trisomy 13 in one case and trisomy 8 in another case were also found in their study. To our knowledge, no previous association of a case of AML-M0 with t(1;14) has been reported in the English literature. Moreover, this translocation with breakpoints
AML with t(1;14)(p13;q32) similar to those in our case has not been associated with any subtype of AML. 14q32 translocation with different breakpoints of chromosome 1 has been demonstrated in a mixed lineage acute leukemia and a myelodysplastic syndrome case in two studies [10, 11]. This finding in association with the features of dysplastic bone marrow normoblasts in our case may suggest that this leukemic process may have arisen from an underlying myelodysplasia. On the other hand, the closest translocation in our case is the t(1;14)(p22;q32) seen in some cases of mucosally associated lymphoid tissue lymphoma [12]. 14q32 translocation with different breakpoints of any chromosome is seen in B-cell leukemias and lymphomas because the genes encoding the immunoglobulin human heavy chain (IgH) are located in this region [13]. However, 14q32 abnormalities have also been reported in some mixed lineage leukemias [10] and in AML [14] in addition to T-cell lymphoma/leukemia [15, 16]. These findings suggested that some genes other than those encoding IgH may reside in this chromosomal region [10, 14]. Our patient with 14q32 translocation is one of the cases in the literature that supports this idea. REFERENCES 1. Lee EJ, Pollak A, Leavitt RD, Testa JR, Schiffer CA (1987): Minimally differentiated acute nonlymphocytic leukemia: a distinct entity. Blood 70:1400–1406. 2. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1991): Proposals for the recognition of minimally differentiated acute myeloid leukemia. Br J Haematol 78:325–329. 3. Amadori S, Venditti A, Del Poeta G, Stasi R, Buccisano F, Bruno A, Tamburini A, Cox MC, Maffei L, Aronica G, Simone MD, Adorno G, Masi M, Tribalto M, Papa G (1996): Minimally differentiated acute myeloid leukemia (AML-M0): a distinct clinico-biologic entity with poor prognosis. Ann Hematol 72:208–215. 4. Campos L, Guyotat D, Archimbaud E, Devaux Y, Treille D, Larese A, Maupas J, Gentilhomme O, Ehrsam A, Fiere D (1989): Surface marker expression in adult acute myeloid leukemia: correlations with initial characteristics, morphology and response to therapy. Br J Haematol 72:161–166. 5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton AG, Gralnick HR, Sultan C (1985): Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative group. Ann Intern Med 103:626–629.
177 6. 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. 7. Cuneo A, Ferrant A, Michaux JL, Boogaerts M, Demuynck H, Orshoven AV, Criel A, Stul M, Dal Cin P, Hernandez J, Chatelain B, Doyen C, Louwagie A, Castoldi G, Cassiman J, Van den Berghe H (1985): Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinico-biologic findings. Blood 85:3688–3694. 8. Venditti A, Poeta GD, Stasi R, Masi M, Bruno A, Buccisano F, Cox C, Coppetelli U, Aronica G, Simone MD, Papa G, Tribalto M, Amadori S (1994): Minimally differentiated acute myeloid leukemia (AML-M0): cytochemical, immunophenotypic and cytogenetic analysis of 19 cases. Br J Haematol 88:784–793. 9. Segeran CM, De Jong-Gerrits GCMM, Van’t Veer MB, on behalf of the Review Dutch Slide Review Committee of Leukemias in Adults (1995): AML-M0: clinical entity or waste basket for immature blastic leukemias? A description of 14 patients. Ann Hematol 70:297–300. 10. Hayashi Y, Pui CH, Behm FG, Fuchs AH, Raimondi SC, Kitchingman GR, Mirro J, Jr, Williams DL (1990): 14q32 translocations are associated with mixed-lineage expression in childhood acute leukemia. Blood 76:150–156. 11. De Pree C, Cabrol C, Frossard JL, Beris P (1995): Pseudoreticulocytosis in a case of myelodysplastic syndrome with translocation t(1;14)(q42;q32). Sem Hematol 32:232–236. 12. Wotherspoon AC, Pan L, Diss TC, Isaacson PG (1992): Cytogenetic study of B-cell lymphoma of mucosa-associated lymphoid tissue. Cancer Genet Cytogenet 58:35–38. 13. McAlpine PJ, Shows TB, Miller RL, Pakstis AJ (1985): The 1985 Catalogue of Mapped Genes and Report of the Nomenclature Committee: Eighth International Human Gene Mapping Workshop. Cytogenet Cell Genet 40:8–66. 14. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H (1997): Fusion of the platelet-derived growth factor receptor to a novel gene CEV 14 in acute myelogenous leukemia after clonal evolution. Blood 90:4271–4277. 15. The Fifth International Workshop on Chromosomes in Leukemia-Lymphoma (1987): Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin’s lymphoma and adult T cell leukemia-lymphoma. Blood 70:1554–1564. 16. Miyamoto K, Tomita N, Ishii A, Nonaka H, Kondo T, Tanaka T, Kitajima K (1984): Chromosome abnormalities of leukemia cells in adult patients with T-cell leukemia. J Natl Cancer Inst 73:353–363.