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Trisomy 4 in acute nonlymphocytic leukemia: The first brazilian case
SHORT COMMUNICATION Trisomy 4 in Acute Nonlymphocytic Leukemia: The First Brazilian Case Enilze M. S. F. Ribeiro, Iglenir J. Cavalli, Alice S. Tokutake, Val ria M. M. Sperandio-Roxo, Mariester Malvezzi, and Ricardo Pasquini
ABSTRACT: We report the first South American case of acute nonlymphocytic leukemia, French-AmericanBritish (FAB) subtype M1, [1] with trisomy 4 as the sole chromosome abnormality. The patient denied exposure to toxic or carcinogenic substances.
INTRODUCTION Since the report of Mecucci et al. [2] in 1986, the occurrence of trisomy 4 in acute nonlymphocytic leukemia (ANLL) has claimed attention due to the recent description of this major chromosome aberration in hematologic disorders. Geographical distribution and occupational history are the principal factors investigated in an attempt to explain this recent description.
Remission was achieved after treatment with cytosine arabinoside (ARA-C) 150 mg/m2/day for 7 days and mitoxantrone 12 mg/m2/day for 3 days. Consolidation consisted of another course with the same drugs after 2 months. She remained well, in complete remission, until January 1992 when she relapsed; she died of bronchopneumonia and septicemia 2 months later. CYTOGENETIC ANALYSIS
CASE REPORT
A 35-year old woman who had been in good health, was admitted to the university hospital of Universidade Federal do Paran~, South Brazil, in July 1991, because of marked leukocytosis. Physical examination on admission showed, pallor, enlargement of the lymph nodes, and no hepatosplenomegaly. She gave no history of exposure to toxic or carcinogenic substances. Hematologic findings were as follows: hemoglobin 10 g/dl, red blood cell count 2.96 × 106/~1, platelets count 77 × 103/td, and white blood cell count 23.3 × 103/td, with 92% blasts, 3% neutrophils, 5% lymphocytes, and few Auer rods. Bone marrow (BM) examination showed an extremely hypercellular marrow due to massive leukemic infiltration, with few normal myeloid cells, 92% blasts, and 4% promyelocytes. One or two nucleoli were noted in most of the blasts. No Auer rods were observed. About 25% of the leukemic cells were positive for myeloperoxidase, and all cells were completely negative for a-naphthyl-acetate-esterase. The hematologic study led to the diagnosis of ANL subtype, M1, according to the French-American-British (FAB) classification.
From the Departemento de Gen~tica do Setor de Ci~ncias Biol6gicas and Servi~o de Hematologia do Hospital de CHnicas, Universidade Federal do Parand, Curitiba-Parand, Brazil. Address reprint requests to: Professor Enilze M. S. F. Bibeiro, Departamento de Gen~tica, Universidade Federal do Parand, Caixa Postal 19071, 81531-970 Curitiba-Parand, Brazil. Received October 1, 1992; accepted February 24, 1993.
Chromosome analysis was performed at diagnosis. BM cells were processed by the direct method and after 24-hour incubation without phytohemagglutinin stimulation, according to the method of Williams et al. [3]. G-banding was obtained according to the method of Seabright [4], with modifications. Twenty metaphases corresponding to two cell lines were studied: one was composed of eight metaphases with 46 chromosomes and a normal karyotype, and the other was composed of 12 metaphases with 47 chromosomes with trisomy 4 (Fig. 1). DISCUSSION Only recently the first description of trisomy 4 as a sole chromosome abnormality in hematologic disorders was reported [2] and was preferentially associated with ANLL of type M4 [5]. These findings raise the question as to why this major abnormality was not reported previously, even without banding techniques [5]. Geographic distribution or occupational history such as exposure to new types of environmental agents or toxins are the main factors analyzed to explain the recent description of this trisomy in ANLL. A review of 19 publications showed that three reports were made in England [6-8], three in Japan [9-11], two in the United States [5, 12], two in Australia [13, 14], and one case was reported in each of the following countries, Belgium [2], Spain [15], Germany [16], Canada [17], Italy [18], Austria [19], China [20], India [21], and Brazil (present report). In these 19 reports, 34 cases were described. Twelve (35.3%) were clas-
82 Cancer Genet Cytogenet 68:82-83 (1993) 0165-4608/93/$06.00
© 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Trisomy 4 i n ANNL: First Brazilian Case
Figure 1 Partial karyotype from patient with ANLL M1 showing trisomy 4. sifted as M4 [2, 5, 8, 13, 16, 19]; 10 (29.4%) as M2 [2, 7, 9-11, 15, 17-19, 21], five (14.7%) as M1 [5, 6, 8, 20], and present report, two (5.9%) as M2 or M4 [5, 6]; two (5.9%) as acute undifferentiated leukemia [8, 12]; one as refractory anemia with excess of blasts (RAEB) [2], one as biphenotypic leukemia [14], and one as M5 [20] with a frequency of 2.9% each. In 24 (70.6%) of the cases, trisomy 4 is reported as the sole chromosomal abnormality [2, 5, 6, 8-12, 14, 20] (present report) a n d i n 10 (29.4%) it is associated with other chromosome abnormalities [2, 5-8, 13, 16, 20, 21]. Thus, the reports published demonstrate that trisomy 4 has a wide geographic distribution and that it appears to be preferentially associated with ANLL of M4 and M2 subtypes of the FAB classification a n d frequently as the sole chromosome abnormality. It is described i n both sexes (19 w o m e n and 15 men, X~ = 0.465, P > 0.50) and is distributed throughout life. Only three patients (8.8%) underwent radiotherapy [5, 10, 12], one (2.9%) u n d e r w e n t chemoradiotherapy [5], a n d one (2.9%) was exposed to other agents [18] before the cytogenetic study. Although the available data provide valuable information about important aspects concerning the occurrence of trisomy 4 in ANLL, the reasons why it has been only recently reported is not clear. This investigationwas supported by financial aid from the National Research Council for Scientific and Technologic Development (CNPq).
References 1. Bennett JM, Catovsky D, Daniel NIT, Flandrin G, Galton DAG, Gralnick FIR, Sultan C (1965): Proposed revised criteria for the classification of acute myeloid leukemia: A report of the FrenchAmerican-British Co-operative Group. Ann Intern Med 103: 620-625. 2. Mecucci C, Van Orshoven A, Tricot G, Michaux JL, Delanuroy A, Van Den Berghe H (1986): Trisomy 4 identifies a subset acute nonlymphocytic leukemias. Blood 67:1328-1332. 3. Williams PL, Harris A, Williams KJ, Brosius MJ, Lemonds W {1984): A direct bone marrow chromosome technique for acute lymphoblastic leukemia. Cancer Genet Cytogenet 13:239-257.
83
4. Seabright M (1971): A rapid banding technique for human chromosomes. Lancet 1:972. 5. Sanberg AA, Morgan R, Jani Sait SN, Berger R, Flandrin G, Schrier S, Hecht F (1987): Trisomy 4: An entity acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:117-125. 6. Hoyle CF, Boughton BJ, Hayhoe FGJ (1988): Two further cases of acute myeloid leukemia with trisomy 4. Cancer Genet Cytogenet 34:29-32. 7. Parry SH, Gibbons B, Czepulkowski BH, Amess JA, Oxley VE (1989): A further case of acute myelogenous leukemia with trisomy 4 and double minutes. Cancer Genet Cytogenet 39: 295-297. 8. Thompson PW, Thompson EN, Whittaker JA (1989): Four cases of acute leukemia with trisomy 4. Cancer Genet Cytogenet 43:211-217. 9. Fujishita M, Miyagi T, Takeuchi T, Kubonishi I, Niiya K, Taguchi H, Ohtsuki Y, Miyoshi I (1986): Trisomy 4 in a case of acute nonlymphocyticleukemia (M2). Cancer Ganet Cytogenet 34:281-284. 10. Yokota S, Taniwaki M, Okuda T, Maekawa T, Nishida K, Misawa S, Takino T, Abe T, Urata Y (1989): Acute nonlymphocytic leukemia (M2) with chromosome abnormality trisomy 4 developing eight years after radiation therapy for breast cancer. Blut 58:27-31. 11. Banno S, Hirashima N, Noda T, Nitta M (1989): Chromosomal abnormality of trisomy 4 in a patient with acute nonlymphocytic leukemia (FAB:M2}. Jpn J Clin Hematol 30:1987-1991. 12. Kao YS, McCormick C, Vial R (1990}: Trisomy 4 in a case of acute undifferentiatedmyeloblastic leukemia with hand-mirror ceils. Cancer Genet Cytogenet 45:265-268. 13. Juneja S, Brown J, Ding JC, Garson OM (1986): Trisomy 4 in acute nonlymphocytic leukemia. An Australian case. Cancer Genet Cytogenet 34:25-28. 14. Britton V, Kwan YL, White L, Yip MY (1990): Trisomy 4 in a case of acute biphenotypic leukemia. Cancer Genet Cytogenet 47:265-269. 15. Prieto F, Badfa L, Orts M.A,Dieguez L, Amigo V (1987): Trisomy 4: Another specific anomaly in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:171-173. 16. Suciu S, Weh HJ, Kuse R, Meier CB, Hossfeld DK (1988): Trisomy 4 in two cases of acute myelomonocytic leukemia. Cancer Genet Cytogenet 33:19-23. 17. Horsman DE, Pantzar JT, Kalousek DK (1988): Trisomy 4 in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 36:155-157. 18. Temperani P, Zucchini P, Artusi T, Sacchi S, Emilia G (1989): Acute nonlymphocytic leukemia with trisomy 4. Cancer Genet Cytogenet 41:203-205. 19. Weber E, Nowotny H, Haas DA, Kasparu H, Grois N, Lntz D (1990): Trisomy 4: A specific karyotype anomaly in primary and secondary acute myeloid leukemia. Leukemia 4:219-221. 20. Kwong YL, Liang R, Chan LC (1991): Trisomy 4 in acute myeloid leukemia. Leukemia 5:354-355. 21. Sundareshan TS, Krishnamurthy M, Yasha TC (1991): Trisomy 4 and 9 in a case of AML-M2 type. Cancer Genet Cytogenet 55:273-275.
ABSTRACT: We report the first South American case of acute nonlymphocytic leukemia, French-AmericanBritish (FAB) subtype M1, [1] with trisomy 4 as the sole chromosome abnormality. The patient denied exposure to toxic or carcinogenic substances.
INTRODUCTION Since the report of Mecucci et al. [2] in 1986, the occurrence of trisomy 4 in acute nonlymphocytic leukemia (ANLL) has claimed attention due to the recent description of this major chromosome aberration in hematologic disorders. Geographical distribution and occupational history are the principal factors investigated in an attempt to explain this recent description.
Remission was achieved after treatment with cytosine arabinoside (ARA-C) 150 mg/m2/day for 7 days and mitoxantrone 12 mg/m2/day for 3 days. Consolidation consisted of another course with the same drugs after 2 months. She remained well, in complete remission, until January 1992 when she relapsed; she died of bronchopneumonia and septicemia 2 months later. CYTOGENETIC ANALYSIS
CASE REPORT
A 35-year old woman who had been in good health, was admitted to the university hospital of Universidade Federal do Paran~, South Brazil, in July 1991, because of marked leukocytosis. Physical examination on admission showed, pallor, enlargement of the lymph nodes, and no hepatosplenomegaly. She gave no history of exposure to toxic or carcinogenic substances. Hematologic findings were as follows: hemoglobin 10 g/dl, red blood cell count 2.96 × 106/~1, platelets count 77 × 103/td, and white blood cell count 23.3 × 103/td, with 92% blasts, 3% neutrophils, 5% lymphocytes, and few Auer rods. Bone marrow (BM) examination showed an extremely hypercellular marrow due to massive leukemic infiltration, with few normal myeloid cells, 92% blasts, and 4% promyelocytes. One or two nucleoli were noted in most of the blasts. No Auer rods were observed. About 25% of the leukemic cells were positive for myeloperoxidase, and all cells were completely negative for a-naphthyl-acetate-esterase. The hematologic study led to the diagnosis of ANL subtype, M1, according to the French-American-British (FAB) classification.
From the Departemento de Gen~tica do Setor de Ci~ncias Biol6gicas and Servi~o de Hematologia do Hospital de CHnicas, Universidade Federal do Parand, Curitiba-Parand, Brazil. Address reprint requests to: Professor Enilze M. S. F. Bibeiro, Departamento de Gen~tica, Universidade Federal do Parand, Caixa Postal 19071, 81531-970 Curitiba-Parand, Brazil. Received October 1, 1992; accepted February 24, 1993.
Chromosome analysis was performed at diagnosis. BM cells were processed by the direct method and after 24-hour incubation without phytohemagglutinin stimulation, according to the method of Williams et al. [3]. G-banding was obtained according to the method of Seabright [4], with modifications. Twenty metaphases corresponding to two cell lines were studied: one was composed of eight metaphases with 46 chromosomes and a normal karyotype, and the other was composed of 12 metaphases with 47 chromosomes with trisomy 4 (Fig. 1). DISCUSSION Only recently the first description of trisomy 4 as a sole chromosome abnormality in hematologic disorders was reported [2] and was preferentially associated with ANLL of type M4 [5]. These findings raise the question as to why this major abnormality was not reported previously, even without banding techniques [5]. Geographic distribution or occupational history such as exposure to new types of environmental agents or toxins are the main factors analyzed to explain the recent description of this trisomy in ANLL. A review of 19 publications showed that three reports were made in England [6-8], three in Japan [9-11], two in the United States [5, 12], two in Australia [13, 14], and one case was reported in each of the following countries, Belgium [2], Spain [15], Germany [16], Canada [17], Italy [18], Austria [19], China [20], India [21], and Brazil (present report). In these 19 reports, 34 cases were described. Twelve (35.3%) were clas-
82 Cancer Genet Cytogenet 68:82-83 (1993) 0165-4608/93/$06.00
© 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Trisomy 4 i n ANNL: First Brazilian Case
Figure 1 Partial karyotype from patient with ANLL M1 showing trisomy 4. sifted as M4 [2, 5, 8, 13, 16, 19]; 10 (29.4%) as M2 [2, 7, 9-11, 15, 17-19, 21], five (14.7%) as M1 [5, 6, 8, 20], and present report, two (5.9%) as M2 or M4 [5, 6]; two (5.9%) as acute undifferentiated leukemia [8, 12]; one as refractory anemia with excess of blasts (RAEB) [2], one as biphenotypic leukemia [14], and one as M5 [20] with a frequency of 2.9% each. In 24 (70.6%) of the cases, trisomy 4 is reported as the sole chromosomal abnormality [2, 5, 6, 8-12, 14, 20] (present report) a n d i n 10 (29.4%) it is associated with other chromosome abnormalities [2, 5-8, 13, 16, 20, 21]. Thus, the reports published demonstrate that trisomy 4 has a wide geographic distribution and that it appears to be preferentially associated with ANLL of M4 and M2 subtypes of the FAB classification a n d frequently as the sole chromosome abnormality. It is described i n both sexes (19 w o m e n and 15 men, X~ = 0.465, P > 0.50) and is distributed throughout life. Only three patients (8.8%) underwent radiotherapy [5, 10, 12], one (2.9%) u n d e r w e n t chemoradiotherapy [5], a n d one (2.9%) was exposed to other agents [18] before the cytogenetic study. Although the available data provide valuable information about important aspects concerning the occurrence of trisomy 4 in ANLL, the reasons why it has been only recently reported is not clear. This investigationwas supported by financial aid from the National Research Council for Scientific and Technologic Development (CNPq).
References 1. Bennett JM, Catovsky D, Daniel NIT, Flandrin G, Galton DAG, Gralnick FIR, Sultan C (1965): Proposed revised criteria for the classification of acute myeloid leukemia: A report of the FrenchAmerican-British Co-operative Group. Ann Intern Med 103: 620-625. 2. Mecucci C, Van Orshoven A, Tricot G, Michaux JL, Delanuroy A, Van Den Berghe H (1986): Trisomy 4 identifies a subset acute nonlymphocytic leukemias. Blood 67:1328-1332. 3. Williams PL, Harris A, Williams KJ, Brosius MJ, Lemonds W {1984): A direct bone marrow chromosome technique for acute lymphoblastic leukemia. Cancer Genet Cytogenet 13:239-257.
83
4. Seabright M (1971): A rapid banding technique for human chromosomes. Lancet 1:972. 5. Sanberg AA, Morgan R, Jani Sait SN, Berger R, Flandrin G, Schrier S, Hecht F (1987): Trisomy 4: An entity acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:117-125. 6. Hoyle CF, Boughton BJ, Hayhoe FGJ (1988): Two further cases of acute myeloid leukemia with trisomy 4. Cancer Genet Cytogenet 34:29-32. 7. Parry SH, Gibbons B, Czepulkowski BH, Amess JA, Oxley VE (1989): A further case of acute myelogenous leukemia with trisomy 4 and double minutes. Cancer Genet Cytogenet 39: 295-297. 8. Thompson PW, Thompson EN, Whittaker JA (1989): Four cases of acute leukemia with trisomy 4. Cancer Genet Cytogenet 43:211-217. 9. Fujishita M, Miyagi T, Takeuchi T, Kubonishi I, Niiya K, Taguchi H, Ohtsuki Y, Miyoshi I (1986): Trisomy 4 in a case of acute nonlymphocyticleukemia (M2). Cancer Ganet Cytogenet 34:281-284. 10. Yokota S, Taniwaki M, Okuda T, Maekawa T, Nishida K, Misawa S, Takino T, Abe T, Urata Y (1989): Acute nonlymphocytic leukemia (M2) with chromosome abnormality trisomy 4 developing eight years after radiation therapy for breast cancer. Blut 58:27-31. 11. Banno S, Hirashima N, Noda T, Nitta M (1989): Chromosomal abnormality of trisomy 4 in a patient with acute nonlymphocytic leukemia (FAB:M2}. Jpn J Clin Hematol 30:1987-1991. 12. Kao YS, McCormick C, Vial R (1990}: Trisomy 4 in a case of acute undifferentiatedmyeloblastic leukemia with hand-mirror ceils. Cancer Genet Cytogenet 45:265-268. 13. Juneja S, Brown J, Ding JC, Garson OM (1986): Trisomy 4 in acute nonlymphocytic leukemia. An Australian case. Cancer Genet Cytogenet 34:25-28. 14. Britton V, Kwan YL, White L, Yip MY (1990): Trisomy 4 in a case of acute biphenotypic leukemia. Cancer Genet Cytogenet 47:265-269. 15. Prieto F, Badfa L, Orts M.A,Dieguez L, Amigo V (1987): Trisomy 4: Another specific anomaly in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:171-173. 16. Suciu S, Weh HJ, Kuse R, Meier CB, Hossfeld DK (1988): Trisomy 4 in two cases of acute myelomonocytic leukemia. Cancer Genet Cytogenet 33:19-23. 17. Horsman DE, Pantzar JT, Kalousek DK (1988): Trisomy 4 in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 36:155-157. 18. Temperani P, Zucchini P, Artusi T, Sacchi S, Emilia G (1989): Acute nonlymphocytic leukemia with trisomy 4. Cancer Genet Cytogenet 41:203-205. 19. Weber E, Nowotny H, Haas DA, Kasparu H, Grois N, Lntz D (1990): Trisomy 4: A specific karyotype anomaly in primary and secondary acute myeloid leukemia. Leukemia 4:219-221. 20. Kwong YL, Liang R, Chan LC (1991): Trisomy 4 in acute myeloid leukemia. Leukemia 5:354-355. 21. Sundareshan TS, Krishnamurthy M, Yasha TC (1991): Trisomy 4 and 9 in a case of AML-M2 type. Cancer Genet Cytogenet 55:273-275.