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Tetrasomy of Chromosome 8 and +i(8q) as the Sole Chromosome Abnormality in Three Adult Patients with Myelomonocytic Leukemia
Trisomy/Tetrasomy of Chromosome 8 and ⴙi(8q) as the Sole Chromosome Abnormality in Three Adult Patients with Myelomonocytic Leukemia M. T. Ferro, Y. Vázquez-Mazariego, S. Ramiro, M. F. Santiago, J. M. García-Sagredo, R. Nuñez, J. M. Hernández, and C. San Roman
ABSTRACT: We report three cases of tetrasomy 8 associated with myeloid disease. Two patients had chronic myelomonocytic leukemia (CMMoL) and the other had acute monocytic leukemia (AML M5 FAB). Two patients had trisomy/tetrasomy chromosome 8 as the sole abnormality. The other patient with CMMoL had two normal 8 chromosomes plus one isochromosome 8q; this is the first case of long arm chromosome 8 tetrasomy without short arm 8 monosomy. This cytogenetic finding suggests the importance of the genes located in the long arms of chromosome 8. © 2000 Elsevier Science Inc. All rights reserved.
INTRODUCTION
CASE REPORTS
Trisomy of chromosome 8 is one of the most frequent abnormalities associated with malignant diseases of myeloid origin. This 8 trisomy has been found in acute leukemia as well as in myelodysplastic syndromes without relation to any particular type of FAB classification [1]. Tetrasomy 8 has also been found in these malignant processes but with lower frequency. Published cases suggest a strong relationship with monocytic differentiation [2]. We report here three patients, two with chronic myelomonocytic leukemia (CMMoL) and the third with acute myeloid leukemia FAB M5b type. In one of the CMMoL patients and in the M5b patient, a mosaicism of 8 tetrasomy and 8 trisomy was found. In the other CMMoL patient, an i(8)(q10) was found in addition to the two normal 8 chromosomes; therefore, this patient had tetrasomy only for the long arm of chromosome 8.
Case 1 is a 28-year-old woman who presented with fever and anemia. The hemogram showed: Hb 4.6 gm/dL, WBC 4.6 ⫻ 109/L, and platelets 16 ⫻ 109/L. Bone marrow aspirate showed 93% monocytoid blasts. Immunophenotype revealed that 56% of the cells expressed HLA-DR, CD33, CD15, CD38, CD45, and CD4; whereas 18% of the cells were CD65-positive. With the diagnoses of AML-M5b, treatment with idarubicin and ara-C was given, and the patient achieved a complete remission after 26 days. The patient then received consecutive cycles. A peripheral blood stem cell transplantation (PBSCT) was done; after 3 years, the patient remains in remission. The karyotype was established at diagnosis on bone marrow cells with direct methods and on 24-hour cell cultures without stimulation. After 30 minutes of Colcemid exposure, conventional harvesting procedures with KCl hypotonic treatment and Carnoy fixation were accomplished. Identification procedures were done by G-banding. Twenty-two metaphases were analyzed, with the following as the results: 47,XX,⫹8[14]/48,XX,⫹8,⫹8[4]/46,XX[4]. Case 2 is a 73-year-old male diagnosed with duodenal ulcer and gout, who showed anemia and monocytosis in a routine examination. He had a dyspnea as the sole symptom. Physical examination was normal. The hemogram showed: Hb 9.8 gm/dL, WBC 5.1 ⫻ 109/L, with 27% segmented, 30% lymphocytes, 32% monocytes, and 171 ⫻ 109/L platelets. Bone marrow aspirate and biopsy provided a diagnosis of myelodysplastic syndrome of CMMoL type.
From the Department of Medical Genetics (M. T. F., Y. V.-M., S. R., M. F. S., J. M. G.-S., C. S. R.) and the Department of Haematology (R. N.), University Hospital Ramón y Cajal, Madrid, Spain; and the Department of Haematology, University of Medicine (J. M. H.), Salamanca, Spain. Address reprint requests to: María Teresa Ferro, M.D., Department of Medical Genetics, University Hospital Ramón y Cajal, C. Colmenar Km 9.100, Madrid, Spain. Received September 15, 1999; accepted November 29, 1999. Cancer Genet Cytogenet 120:163–165 (2000) 2000 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0165-4608/00/$–see front matter PII S0165-4608(99)00261-7
164
M. T. Ferro et al.
In this case, 15 metaphases were studied. The karyotype was: 47,XY,⫹8[3]/48,XY,⫹8,⫹8[2]/46,XY[10]. This patient died during blastic transformation 10 months after diagnosis. Case 3 is a 83-year-old diabetic man who showed monocytosis and anemia. Two years later, during a respiratory infection, he showed a leukocytosis of 45.41 ⫻ 109/ L, with 56.7% neutrophils, 11.7% lymphocytes, 24.7% monocytes, 0.1% eosinophils, 3.8% basophils, and 6.5% LUC. The Hb was 9.1 g/dL, the MCV was 98.3, platelets 315 ⫻ 109/L, showing 2.8% of reticulocytes. Trilineal dysplasia was observed. Bone marrow aspirate disclosed 15% agranular blasts, and 39% monocyte macrophages with prevalence of mature forms. Histologically, there was infiltration with myeloid precursors compatible with a CMMoL diagnosis. The bone marrow cytogenetic analysis showed only a single cell line. All 30 metaphases analyzed were abnormal, disclosing an isochromosome of the long arm of chromosome 8. Therefore, the karyotype was: 47,XY,⫹i(8) (q10) (see Fig. 1). Thorax radiography showed a pleural effusion occupying the lower two thirds of the left hemithorax. Abdominal ecography revealed hepatomegaly and splenomegaly. After diagnosis of CMMoL, treatment with antibiotics and a cycle of 7 days subcutaneous citarabine obtained a decrease of monocytes (4.4 ⫻ 109/L). Two weeks after chemotherapy, the amount of leukocytes and monocytes reached similar levels to those at the time of diagnoses. One and a half months after admission, the patient died.
DISCUSSION The three patients described had monocytic differentiation leukemias and showed 8 tetrasomy cells in the bone marrow karyotype. Two of them, case 1 with AML M5b type and case 2 with CMMoL, showed 8 tetrasomy and they had a predominant clone with trisomy 8. There are few reported cases with 8 tetrasomy in AML, and the majority, as in our cases, have a clone with 8 trisomy. Hamey et al. [3] reviewed chromosome 8 polysomies among hematological malignant diseases, reporting 8 pentasomy in one patient with CMMoL and 13 cases with 8 tetrasomy as the single abnormality. Seven patients were diagnosed with AML-M5 and two with AML-M4, demonstrating that the majority of reported cases had monocytic differentiation. Furthermore, in reported cases in which mosaicism of 8 tetrasomy coexisted with 8 trisomy, this association was found also with monocytic differentiation [4–6]. Patients 2 and 3 were diagnosed with CMMoL; patient 2, the tetrasomy involved the whole chromosome 8, in patient 3, the tetrasomy of chromosome 8 was restricted to the long arm, and there was no clone with 8 trisomy. This tetrasomy 8q was produced by an isochromosome of the long arms of chromosome 8, additional to the two normal 8 chromosomes. To our knowledge, there are two reported cases of isochromosome 8q associated with myeloid disorders. One report refers to a woman with myelomonocytic acute leukemia in which the clinical and bone marrow data suggest that the leukemia evolved from a previous myelodysplastic syndrome; this patient showed a double isochromo-
Figure 1 G-banded karyotype showing two chromosomes 8 and i(8)(q10).
165
Multiple Copies of 8q in CMMoL some 8q resulting in a partial tetrasomy, for the long arm, and a monosomy for the short arm. The authors proposed that the critical genes for leukemogenesis may be in the long arm of chromosome 8 [7]. Another report of an isochromosome 8q referred to a patient with refractory anemia with partial erythroblastosis who showed a pentasomy of the long arm of chromosome 8 due to a duplication of the 8q isochromosome. This patient had also two deletions: del(5)(q21) and del(7) (q31), and died 2 months after the diagnosis [8]. There are no reports of an 8q isochromosome associated with CMMoL. This finding supports the relationship between monocytic differentiation and tetrasomy 8, as had been seen in the monocytic type acute leukemias. Our patient showed, like the reported cases of tetrasomy 8 or isochromosome 8q, progressive evolution of the disease, which supports the idea that acute myeloid leukemia or myelodysplasia with 8 tetrasomy has an adverse prognosis, although there are few reported cases to establish a clear relationship. The evolution in the other two patients with trisomy/tetrasomy was different: case 1 is in remission after 3 years of PBSCT; case 2 had an unfavorable evolution and he died 1 month after the diagnosis. The prognosis of AML patients with trisomy 8 has been reviewed by Schoch et al. [9]; they report that patients with ⫹8 as the sole cytogenetic anomaly had an intermediate prognosis. The presence of an isochromosome 8q with two normal chromosomes 8 suggests two leukemogenic possibilities. Either loss of heterozygosity (LOH) of the short arm of chromosome 8 or a proto-oncogene activation by multiple copies of 8q. In our case with an i(8)(q10) plus two copies of chromosome 8, the most likely hypothesis is that leukemogenesis may be related to multiple copies of the long arm of chromosome 8. Our three cases support the hypothesis that 8 tetrasomy
is not a casual finding in myeloid-type disorders, stressing the importance of the genes located in the long arm of chromosome 8.
REFERENCES 1. Mitelman F (1994): Catalog of Chromosome Aberrations in Cancer, 5th Ed. Wiley-Liss, New York. 2. Sait SNJ, Raza A, Sandberg A (1987): Tetrasomy of chromosome 8: an interesting and rare cytogenetic phenomenon in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 27:269–271. 3. Hamey Y, Dean N, Catalano JV, Campbell JL (1998): Pentasomy of chromosome 8 in chronic myelomonocytic leukemia. Cancer Genet Cytogenet 103:164–166. 4. La Starza R, Crescenci BB, Matteucci, Martelli MF, Meccuci C (1995): Cytogenetic and FISH investigation on tetrasomy 8 in ANLL. Cancer Genet Cytogenet 79:153–163. 5. Trautman U, Gramatzki M, Krauss M, Friz A, Liehr T, Gebhart (1994): Tetrasomy 8 as a clonal anomaly in myeloid neoplasias. Cancer Genet Cytogenet 72:101–104. 6. Marosi C, Muhm M, Argyriou Tirita A, Pehamberger H, Pirc Danoewinata H, Geissler K, Locker G, Grois N, Hass OA (1993): Tetrasomy 8 in acute monoblastic leukemia AML-M5 with myelosarcomatosis of the skin. Cancer Genet Cytogenet 71:50–54. 7. Vicari L, Sebastiao L, Cirigliano V, Pugliese MT, Ferrara F (1995): Double isochromosome 8q as single cytogenetic aberration in acute myelo-monocytic leukemia. Leuk Lymphoma 19:351–353. 8. Kwong L, Chan TK (1998): Pentasomy 8q in myelodysplasia. Cancer Genet Cytogenet 100:179–181. 9. Schoch C, Haase D, Fonatsch CH, Haferlach T, Loffler H, Schlegelberger S, Hossfeld DK, Becher R, Saverland MC, Heinecke A. Wörmann B, Buchner T, Hiddemann W (1997): The significance of trisomy 8 in de novo acute myeloid leukaemia: The accompanying chromosome aberrations determine the prognosis. Br J Haematol 99:605–611.
ABSTRACT: We report three cases of tetrasomy 8 associated with myeloid disease. Two patients had chronic myelomonocytic leukemia (CMMoL) and the other had acute monocytic leukemia (AML M5 FAB). Two patients had trisomy/tetrasomy chromosome 8 as the sole abnormality. The other patient with CMMoL had two normal 8 chromosomes plus one isochromosome 8q; this is the first case of long arm chromosome 8 tetrasomy without short arm 8 monosomy. This cytogenetic finding suggests the importance of the genes located in the long arms of chromosome 8. © 2000 Elsevier Science Inc. All rights reserved.
INTRODUCTION
CASE REPORTS
Trisomy of chromosome 8 is one of the most frequent abnormalities associated with malignant diseases of myeloid origin. This 8 trisomy has been found in acute leukemia as well as in myelodysplastic syndromes without relation to any particular type of FAB classification [1]. Tetrasomy 8 has also been found in these malignant processes but with lower frequency. Published cases suggest a strong relationship with monocytic differentiation [2]. We report here three patients, two with chronic myelomonocytic leukemia (CMMoL) and the third with acute myeloid leukemia FAB M5b type. In one of the CMMoL patients and in the M5b patient, a mosaicism of 8 tetrasomy and 8 trisomy was found. In the other CMMoL patient, an i(8)(q10) was found in addition to the two normal 8 chromosomes; therefore, this patient had tetrasomy only for the long arm of chromosome 8.
Case 1 is a 28-year-old woman who presented with fever and anemia. The hemogram showed: Hb 4.6 gm/dL, WBC 4.6 ⫻ 109/L, and platelets 16 ⫻ 109/L. Bone marrow aspirate showed 93% monocytoid blasts. Immunophenotype revealed that 56% of the cells expressed HLA-DR, CD33, CD15, CD38, CD45, and CD4; whereas 18% of the cells were CD65-positive. With the diagnoses of AML-M5b, treatment with idarubicin and ara-C was given, and the patient achieved a complete remission after 26 days. The patient then received consecutive cycles. A peripheral blood stem cell transplantation (PBSCT) was done; after 3 years, the patient remains in remission. The karyotype was established at diagnosis on bone marrow cells with direct methods and on 24-hour cell cultures without stimulation. After 30 minutes of Colcemid exposure, conventional harvesting procedures with KCl hypotonic treatment and Carnoy fixation were accomplished. Identification procedures were done by G-banding. Twenty-two metaphases were analyzed, with the following as the results: 47,XX,⫹8[14]/48,XX,⫹8,⫹8[4]/46,XX[4]. Case 2 is a 73-year-old male diagnosed with duodenal ulcer and gout, who showed anemia and monocytosis in a routine examination. He had a dyspnea as the sole symptom. Physical examination was normal. The hemogram showed: Hb 9.8 gm/dL, WBC 5.1 ⫻ 109/L, with 27% segmented, 30% lymphocytes, 32% monocytes, and 171 ⫻ 109/L platelets. Bone marrow aspirate and biopsy provided a diagnosis of myelodysplastic syndrome of CMMoL type.
From the Department of Medical Genetics (M. T. F., Y. V.-M., S. R., M. F. S., J. M. G.-S., C. S. R.) and the Department of Haematology (R. N.), University Hospital Ramón y Cajal, Madrid, Spain; and the Department of Haematology, University of Medicine (J. M. H.), Salamanca, Spain. Address reprint requests to: María Teresa Ferro, M.D., Department of Medical Genetics, University Hospital Ramón y Cajal, C. Colmenar Km 9.100, Madrid, Spain. Received September 15, 1999; accepted November 29, 1999. Cancer Genet Cytogenet 120:163–165 (2000) 2000 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0165-4608/00/$–see front matter PII S0165-4608(99)00261-7
164
M. T. Ferro et al.
In this case, 15 metaphases were studied. The karyotype was: 47,XY,⫹8[3]/48,XY,⫹8,⫹8[2]/46,XY[10]. This patient died during blastic transformation 10 months after diagnosis. Case 3 is a 83-year-old diabetic man who showed monocytosis and anemia. Two years later, during a respiratory infection, he showed a leukocytosis of 45.41 ⫻ 109/ L, with 56.7% neutrophils, 11.7% lymphocytes, 24.7% monocytes, 0.1% eosinophils, 3.8% basophils, and 6.5% LUC. The Hb was 9.1 g/dL, the MCV was 98.3, platelets 315 ⫻ 109/L, showing 2.8% of reticulocytes. Trilineal dysplasia was observed. Bone marrow aspirate disclosed 15% agranular blasts, and 39% monocyte macrophages with prevalence of mature forms. Histologically, there was infiltration with myeloid precursors compatible with a CMMoL diagnosis. The bone marrow cytogenetic analysis showed only a single cell line. All 30 metaphases analyzed were abnormal, disclosing an isochromosome of the long arm of chromosome 8. Therefore, the karyotype was: 47,XY,⫹i(8) (q10) (see Fig. 1). Thorax radiography showed a pleural effusion occupying the lower two thirds of the left hemithorax. Abdominal ecography revealed hepatomegaly and splenomegaly. After diagnosis of CMMoL, treatment with antibiotics and a cycle of 7 days subcutaneous citarabine obtained a decrease of monocytes (4.4 ⫻ 109/L). Two weeks after chemotherapy, the amount of leukocytes and monocytes reached similar levels to those at the time of diagnoses. One and a half months after admission, the patient died.
DISCUSSION The three patients described had monocytic differentiation leukemias and showed 8 tetrasomy cells in the bone marrow karyotype. Two of them, case 1 with AML M5b type and case 2 with CMMoL, showed 8 tetrasomy and they had a predominant clone with trisomy 8. There are few reported cases with 8 tetrasomy in AML, and the majority, as in our cases, have a clone with 8 trisomy. Hamey et al. [3] reviewed chromosome 8 polysomies among hematological malignant diseases, reporting 8 pentasomy in one patient with CMMoL and 13 cases with 8 tetrasomy as the single abnormality. Seven patients were diagnosed with AML-M5 and two with AML-M4, demonstrating that the majority of reported cases had monocytic differentiation. Furthermore, in reported cases in which mosaicism of 8 tetrasomy coexisted with 8 trisomy, this association was found also with monocytic differentiation [4–6]. Patients 2 and 3 were diagnosed with CMMoL; patient 2, the tetrasomy involved the whole chromosome 8, in patient 3, the tetrasomy of chromosome 8 was restricted to the long arm, and there was no clone with 8 trisomy. This tetrasomy 8q was produced by an isochromosome of the long arms of chromosome 8, additional to the two normal 8 chromosomes. To our knowledge, there are two reported cases of isochromosome 8q associated with myeloid disorders. One report refers to a woman with myelomonocytic acute leukemia in which the clinical and bone marrow data suggest that the leukemia evolved from a previous myelodysplastic syndrome; this patient showed a double isochromo-
Figure 1 G-banded karyotype showing two chromosomes 8 and i(8)(q10).
165
Multiple Copies of 8q in CMMoL some 8q resulting in a partial tetrasomy, for the long arm, and a monosomy for the short arm. The authors proposed that the critical genes for leukemogenesis may be in the long arm of chromosome 8 [7]. Another report of an isochromosome 8q referred to a patient with refractory anemia with partial erythroblastosis who showed a pentasomy of the long arm of chromosome 8 due to a duplication of the 8q isochromosome. This patient had also two deletions: del(5)(q21) and del(7) (q31), and died 2 months after the diagnosis [8]. There are no reports of an 8q isochromosome associated with CMMoL. This finding supports the relationship between monocytic differentiation and tetrasomy 8, as had been seen in the monocytic type acute leukemias. Our patient showed, like the reported cases of tetrasomy 8 or isochromosome 8q, progressive evolution of the disease, which supports the idea that acute myeloid leukemia or myelodysplasia with 8 tetrasomy has an adverse prognosis, although there are few reported cases to establish a clear relationship. The evolution in the other two patients with trisomy/tetrasomy was different: case 1 is in remission after 3 years of PBSCT; case 2 had an unfavorable evolution and he died 1 month after the diagnosis. The prognosis of AML patients with trisomy 8 has been reviewed by Schoch et al. [9]; they report that patients with ⫹8 as the sole cytogenetic anomaly had an intermediate prognosis. The presence of an isochromosome 8q with two normal chromosomes 8 suggests two leukemogenic possibilities. Either loss of heterozygosity (LOH) of the short arm of chromosome 8 or a proto-oncogene activation by multiple copies of 8q. In our case with an i(8)(q10) plus two copies of chromosome 8, the most likely hypothesis is that leukemogenesis may be related to multiple copies of the long arm of chromosome 8. Our three cases support the hypothesis that 8 tetrasomy
is not a casual finding in myeloid-type disorders, stressing the importance of the genes located in the long arm of chromosome 8.
REFERENCES 1. Mitelman F (1994): Catalog of Chromosome Aberrations in Cancer, 5th Ed. Wiley-Liss, New York. 2. Sait SNJ, Raza A, Sandberg A (1987): Tetrasomy of chromosome 8: an interesting and rare cytogenetic phenomenon in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 27:269–271. 3. Hamey Y, Dean N, Catalano JV, Campbell JL (1998): Pentasomy of chromosome 8 in chronic myelomonocytic leukemia. Cancer Genet Cytogenet 103:164–166. 4. La Starza R, Crescenci BB, Matteucci, Martelli MF, Meccuci C (1995): Cytogenetic and FISH investigation on tetrasomy 8 in ANLL. Cancer Genet Cytogenet 79:153–163. 5. Trautman U, Gramatzki M, Krauss M, Friz A, Liehr T, Gebhart (1994): Tetrasomy 8 as a clonal anomaly in myeloid neoplasias. Cancer Genet Cytogenet 72:101–104. 6. Marosi C, Muhm M, Argyriou Tirita A, Pehamberger H, Pirc Danoewinata H, Geissler K, Locker G, Grois N, Hass OA (1993): Tetrasomy 8 in acute monoblastic leukemia AML-M5 with myelosarcomatosis of the skin. Cancer Genet Cytogenet 71:50–54. 7. Vicari L, Sebastiao L, Cirigliano V, Pugliese MT, Ferrara F (1995): Double isochromosome 8q as single cytogenetic aberration in acute myelo-monocytic leukemia. Leuk Lymphoma 19:351–353. 8. Kwong L, Chan TK (1998): Pentasomy 8q in myelodysplasia. Cancer Genet Cytogenet 100:179–181. 9. Schoch C, Haase D, Fonatsch CH, Haferlach T, Loffler H, Schlegelberger S, Hossfeld DK, Becher R, Saverland MC, Heinecke A. Wörmann B, Buchner T, Hiddemann W (1997): The significance of trisomy 8 in de novo acute myeloid leukaemia: The accompanying chromosome aberrations determine the prognosis. Br J Haematol 99:605–611.