Trisomy 4 in Acute Nonlymphocytic Leukemia Report of Two Cases and Review of the Literature Emilio Donti, Adriana Maccari, Antonio Tabilio, Carmela Ardisia, Nadia Campanari, and Giovanna Venti Donti
ABSTRACT: Two patients with M2 subtype of acute nonlymphocytic leukemia (ANLL) and trisomy 4
as a primary karyotype change are described. The abnormality was observed in 100% of bone marrow (BM) metaphases in both cases. It appeared alone in one case and was associated with trisamy 13 in 94% of metaphases in the other. These are the second and third cases of ANLL with trisomy 4 documented in Italy. Neither patient appears to have incurred any environmental or therapeutic insult.
INTRODUCTION Trisomy 4, as a primary karyotype change, was initially described by Mecucci et al. [1] in patients with a specific subtype of acute nonlymphocytic leukemia {ANLL) with myelomonocytic morphology. In the past 4 years, this anomaly has been found with the same frequence in the M1-M2 and M4 French-American-British (FAB} phenotypes [2-15]. It has also been found in one case of myelodysplastic syndrome (MDS) [1] and, more recently, in one case of biphenotypic acute leukemia [16]. Sandberg et al. [17] proposed an association between trisomy 4 and ANLL and previous exposure to carcinogenic agents. We observed trisomy 4 in 2 of 200 ANLL cases successfully examined between 1986 and 1990. These two patients are the subject of this report. CASE REPORTS Case 1
A 59-year-old woman was referred to our institution in September 1987. She complained of fever and generalized weakness. Past history was unrevealing. Physical examination did not show lymphadenopathy or hepatosplenomegaly. The initial peripheral blood (PB) profile was hemoglobin [Hb) 6.5 g/dl, platelet count 175 x 109/L, and leukocyte count 1.8 x 109/L with 5% mature neutrophils, 65% lymphocytes and 30% myeloid blast cells. Total serum protein, serum albumin, blood urea nitrogen (BUN), creatinine, bilirubin, uric acid, and lactic dehydrogenase
From the First (E. M., C. A., N. C., G. V. D.) and Second Department (A. M.) of Internal Medicine, and Institute of Hematology (A. T.) University of Perugia, Italy. Address reprint requests to: Dr. Emilio Donti, Laboratorio di Citagenetica, Clinica Medica I, Policlinico Monteluce, 06100 Perugia, Italy. Received September 4, 1991; accepted October 10, 1991.
were normal. Levels of fibrinogen and fibrin degradation products were within normal limits. A bone marrow (BM) aspirate showed a hypercellular BM with almost total replacement of the normal hematopoietic tissue by myeloblasts; 8.4% of blast cells contained Auer rods. Cytochemical studies showed that 74% of the myeloblasts were peroxidase positive and 80% Sudan black B-positive. aNaphthyl acetate esterase (ANAE), periodic-acid Schiff (PAS), and naphthol AS-D cloroacetate esterase reactions were negative. A diagnosis of acute myeloblastic leukemia (M2 according to the FAB classification) was made, and the patient was treated with 200 mg/m2/day cytosine arabinoside by continuous infusion on days 1-7 plus 45 mg/m2/day daunorubicin on days 1-3. The patient entered complete remission after the first chemotherapy cycle. Consolidation treatment was started with cytosine arabinoside, 6-thioguanine, and daunorubicin (four cycles). The patient was disease-free at a follow-up of 22 months. Case 2 A 66-year-old man admitted to our institution in October 1988 complained of fever, weakness, and pain in the right upper abdominal quadrant. Past history was unrevealing. Physical examination showed pale mucosa and mild hepatosplenomegaly (2 and 4 cm below the costal margins, respectively). He had no enlarged lymph nodes. The blood indexes were Hb 10.4 g/dl, platelet count 38 x 109/L, and white blood cell count 15.6 x 109/L with a differential count of 4% neutrophils and 96% myeloid blast cells. Total serum protein, serum albumin, BUN, creatinine, bilirubin, uric acid, transaminases, serum alkaline phosphatase, and electrolytes were normal. Prothrombin time was 51%, fibrinogen was 130 mg/dl, and fibrin degradation products were increased (40 7%). Bone marrow aspirate showed that the hematopoietic tissue was almost completely replaced by myeloblasts. Cytochemical studies showed that 10% of blast cells were peroxidase positive, 11% were Sudan black B positive, 6% were naphthol AS-D
195 © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 60:195-197 (1992) 0165-4608/92/$05.00
196
E. Donti et al.
chloroacetate esterase positive; ANAE was negative. A dia g n o s i s o f a c u t e m y e l o b l a s t i c l e u k e m i a ( M 2 a c c o r d i n g to the FAB classification) was made. The patient died of a cerebral hemorrhage during the aplastic phase after chemotherapy with 200 mg/m2/day cytosine arabinoside by continuous i n f u s i o n o n d a y s 1 - 7 p l u s 45 m g / m 2 / d a y daunorubicin on days 1-3.
phology and quality of banding was greatly improved in PB m e t a p h a s e s b y c u l t u r i n g b l a s t c e l l s i n 5 6 3 7 m e d i u m .
Case 2 Cell cultures and cytogenetic examinations were perf o r m e d a s f o r c a s e 1. G T G - b a n d i n g a n a l y s i s s h o w e d t h a t 94% of all 50 metaphases had a 48-chromosome set with additional chromosomes 4 a n d 13 a n d 6 % 4 7 c h r o m o somes with trisomy 4 only.
METHODS AND RESULTS Case 1
Chromosome preparations were obtained from BM cultured for 24 hours without mitogens and separated PB blast cells cultured in conditioned medium. Karyotype analysis was made after trypsin-Giemsa treatment (GTGbanding). A karyotype with 47 chromosomes, due to an additional chromosome 4, was observed in all 30 metaphases obtained from both samples. Chromosome mor-
Table 1
n
Cases of malignant
Sex/age (yr}
Country of origin
hematologic
FAB
DISCUSSION Trisomy 4 was detected at diagnosis in the leukemic cells o f t w o p a t i e n t s w i t h M 2 s u b t y p e o f A N L L . It w a s t h e o n l y k a r y o t y p e a l t e r a t i o n i n t h e first p a t i e n t , b u t w a s a s s o c i a t e d w i t h t r i s o m y 13 i n t h e s e c o n d , b u t b e c a u s e t h r e e o f t h e m e t a p h a s e s d i d n o t d i s p l a y t r i s o m y 13, t r i s o m y 4 a p p e a r s
diseases associated with trisomy 4 WBC (x 109/L)
Survival (mo)
Remission
Karyotype
cells (%) 67 93 92 8 62 100 96 87 100 50 100 43 78 100 100 68 36 64 84 70 13 100
94
16 24 4 15
No Yes No Yes
M0
92.1
12+
Yes
M/42 F/5 F/59
England Canada Japan Lybia Austria U.S.A. Italy Japan Australia Italy
M4 M2 M2 M2 M4 M2 M2 M2 --° M2
154 65,0 1.9 20.0 230.0 4.2 34.0 8.1 22.8 1.8
1+ 2 16+ 22 1 -?+ 4 22 +
-Yes Yes Yes No No Yes No Yes Yes
+4 +4 +4 +4, +7 +4 +4 +4 +4 +4, dmin +4 +4 +4, dmin +4 +4, +13 +4 +4 +4 +4, drain +4, del(3) +4 (relapse} +4, - Y +4 +4, +11 {relapse} t(1;10;11) t{1;10;11}, +4 +4 +4 +4 +4 {relapse} +4 +4, drain +4 +4 +4 (relapse) +4
M/66
Italy
M2
15.6
ABSTRACT: Two patients with M2 subtype of acute nonlymphocytic leukemia (ANLL) and trisomy 4
as a primary karyotype change are described. The abnormality was observed in 100% of bone marrow (BM) metaphases in both cases. It appeared alone in one case and was associated with trisamy 13 in 94% of metaphases in the other. These are the second and third cases of ANLL with trisomy 4 documented in Italy. Neither patient appears to have incurred any environmental or therapeutic insult.
INTRODUCTION Trisomy 4, as a primary karyotype change, was initially described by Mecucci et al. [1] in patients with a specific subtype of acute nonlymphocytic leukemia {ANLL) with myelomonocytic morphology. In the past 4 years, this anomaly has been found with the same frequence in the M1-M2 and M4 French-American-British (FAB} phenotypes [2-15]. It has also been found in one case of myelodysplastic syndrome (MDS) [1] and, more recently, in one case of biphenotypic acute leukemia [16]. Sandberg et al. [17] proposed an association between trisomy 4 and ANLL and previous exposure to carcinogenic agents. We observed trisomy 4 in 2 of 200 ANLL cases successfully examined between 1986 and 1990. These two patients are the subject of this report. CASE REPORTS Case 1
A 59-year-old woman was referred to our institution in September 1987. She complained of fever and generalized weakness. Past history was unrevealing. Physical examination did not show lymphadenopathy or hepatosplenomegaly. The initial peripheral blood (PB) profile was hemoglobin [Hb) 6.5 g/dl, platelet count 175 x 109/L, and leukocyte count 1.8 x 109/L with 5% mature neutrophils, 65% lymphocytes and 30% myeloid blast cells. Total serum protein, serum albumin, blood urea nitrogen (BUN), creatinine, bilirubin, uric acid, and lactic dehydrogenase
From the First (E. M., C. A., N. C., G. V. D.) and Second Department (A. M.) of Internal Medicine, and Institute of Hematology (A. T.) University of Perugia, Italy. Address reprint requests to: Dr. Emilio Donti, Laboratorio di Citagenetica, Clinica Medica I, Policlinico Monteluce, 06100 Perugia, Italy. Received September 4, 1991; accepted October 10, 1991.
were normal. Levels of fibrinogen and fibrin degradation products were within normal limits. A bone marrow (BM) aspirate showed a hypercellular BM with almost total replacement of the normal hematopoietic tissue by myeloblasts; 8.4% of blast cells contained Auer rods. Cytochemical studies showed that 74% of the myeloblasts were peroxidase positive and 80% Sudan black B-positive. aNaphthyl acetate esterase (ANAE), periodic-acid Schiff (PAS), and naphthol AS-D cloroacetate esterase reactions were negative. A diagnosis of acute myeloblastic leukemia (M2 according to the FAB classification) was made, and the patient was treated with 200 mg/m2/day cytosine arabinoside by continuous infusion on days 1-7 plus 45 mg/m2/day daunorubicin on days 1-3. The patient entered complete remission after the first chemotherapy cycle. Consolidation treatment was started with cytosine arabinoside, 6-thioguanine, and daunorubicin (four cycles). The patient was disease-free at a follow-up of 22 months. Case 2 A 66-year-old man admitted to our institution in October 1988 complained of fever, weakness, and pain in the right upper abdominal quadrant. Past history was unrevealing. Physical examination showed pale mucosa and mild hepatosplenomegaly (2 and 4 cm below the costal margins, respectively). He had no enlarged lymph nodes. The blood indexes were Hb 10.4 g/dl, platelet count 38 x 109/L, and white blood cell count 15.6 x 109/L with a differential count of 4% neutrophils and 96% myeloid blast cells. Total serum protein, serum albumin, BUN, creatinine, bilirubin, uric acid, transaminases, serum alkaline phosphatase, and electrolytes were normal. Prothrombin time was 51%, fibrinogen was 130 mg/dl, and fibrin degradation products were increased (40 7%). Bone marrow aspirate showed that the hematopoietic tissue was almost completely replaced by myeloblasts. Cytochemical studies showed that 10% of blast cells were peroxidase positive, 11% were Sudan black B positive, 6% were naphthol AS-D
195 © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 60:195-197 (1992) 0165-4608/92/$05.00
196
E. Donti et al.
chloroacetate esterase positive; ANAE was negative. A dia g n o s i s o f a c u t e m y e l o b l a s t i c l e u k e m i a ( M 2 a c c o r d i n g to the FAB classification) was made. The patient died of a cerebral hemorrhage during the aplastic phase after chemotherapy with 200 mg/m2/day cytosine arabinoside by continuous i n f u s i o n o n d a y s 1 - 7 p l u s 45 m g / m 2 / d a y daunorubicin on days 1-3.
phology and quality of banding was greatly improved in PB m e t a p h a s e s b y c u l t u r i n g b l a s t c e l l s i n 5 6 3 7 m e d i u m .
Case 2 Cell cultures and cytogenetic examinations were perf o r m e d a s f o r c a s e 1. G T G - b a n d i n g a n a l y s i s s h o w e d t h a t 94% of all 50 metaphases had a 48-chromosome set with additional chromosomes 4 a n d 13 a n d 6 % 4 7 c h r o m o somes with trisomy 4 only.
METHODS AND RESULTS Case 1
Chromosome preparations were obtained from BM cultured for 24 hours without mitogens and separated PB blast cells cultured in conditioned medium. Karyotype analysis was made after trypsin-Giemsa treatment (GTGbanding). A karyotype with 47 chromosomes, due to an additional chromosome 4, was observed in all 30 metaphases obtained from both samples. Chromosome mor-
Table 1
n
Cases of malignant
Sex/age (yr}
Country of origin
hematologic
FAB
DISCUSSION Trisomy 4 was detected at diagnosis in the leukemic cells o f t w o p a t i e n t s w i t h M 2 s u b t y p e o f A N L L . It w a s t h e o n l y k a r y o t y p e a l t e r a t i o n i n t h e first p a t i e n t , b u t w a s a s s o c i a t e d w i t h t r i s o m y 13 i n t h e s e c o n d , b u t b e c a u s e t h r e e o f t h e m e t a p h a s e s d i d n o t d i s p l a y t r i s o m y 13, t r i s o m y 4 a p p e a r s
diseases associated with trisomy 4 WBC (x 109/L)
Survival (mo)
Remission
Karyotype
cells (%) 67 93 92 8 62 100 96 87 100 50 100 43 78 100 100 68 36 64 84 70 13 100
94
16 24 4 15
No Yes No Yes
M0
92.1
12+
Yes
M/42 F/5 F/59
England Canada Japan Lybia Austria U.S.A. Italy Japan Australia Italy
M4 M2 M2 M2 M4 M2 M2 M2 --° M2
154 65,0 1.9 20.0 230.0 4.2 34.0 8.1 22.8 1.8
1+ 2 16+ 22 1 -?+ 4 22 +
-Yes Yes Yes No No Yes No Yes Yes
+4 +4 +4 +4, +7 +4 +4 +4 +4 +4, dmin +4 +4 +4, dmin +4 +4, +13 +4 +4 +4 +4, drain +4, del(3) +4 (relapse} +4, - Y +4 +4, +11 {relapse} t(1;10;11) t{1;10;11}, +4 +4 +4 +4 +4 {relapse} +4 +4, drain +4 +4 +4 (relapse) +4
M/66
Italy
M2
15.6
