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Isochromosome (17q) in Philadelphia chromosome (Ph1)-negative juvenile chronic myelocytic leukemia
Isochromosome (17q) in Philadelphia Chromosome (Phl)-negative Juvenile Chronic Myelocytic Leukemia Rosario Casalone, Domenico Francesconi, Francesco Pasquali, Benedetto Comotti, and Francesco Vaccari
A dicentric isochromosome of the long arm of one chromosome # 17 was the only abnormality present in a 12-year-old bay with Philadelphia chromosome (Ph~)-negative juvenile chronic myelocytic leukemia. This association does not seem to have been reported in the literature. It is postulated that the finding of an isochromosome (17q) may also have a negative prognostic value in the Phi-negative type of chronic myelogenaus leukemia.
ABSTRACT:
INTRODUCTION Chronic myelocytic leukemia (CML) is rather infrequent in childhood, i.e., I to 5% of all reported cases of leukemia [1]. It is classified into two different forms: the so-called adult type (ACML), with clinical and hematological features identical to adults' CML, and the juvenile type (JCML), which can be defined on the basis of some peculiarities. These are a rather low WBC, thrombocytopenia, and a myeloid-erythroid cells ratio in bone marrow of between 2 : 1 and 5 : 1 [2]. Several other characteristics may contribute to the diagnosis, although they are less typical. Due to the rarity of the disease, little cytogenetic data are available. The Philadelphia chromosome (Ph 1) is always absent in JCML, whereas ACML is usually Ph'-positive [1,3,4]. In JCML, 80% of reported cases show a normal karyotype. Among the cases with chromosome abnormalities, there is no consistent marker [4]. We report a 12-year-old male patient in whom the absence of a Ph i led to a diagnosis of JCML, although the clinical picture did not coincide with all the peculiarities of this form. The karyotype showed an isochromosome for the long arm of chromosome #17 as the only abnormality. This anomaly has not been described in JCML, nor in Phi-negative CML.
From the Institute of General Biology and Medical Genetics, University of Pavia and the Medical Division, Riuniti Hospital, Bergamo, Italy.
Address requests for reprints to: Dr. Francesco Pasquali, C.P. 217 I - 2 71 O0 Pavia, Italy. Received May 23, 1980; accepted July 29, 1980.
145 Copyright O Elsevier North Holland, Inc., 1981 52 Vanderbilt Ave., New York, NY 1 0 0 1 7
Cancer Genetics and Cytogenetics 3, 145-148 (1981) 0165-4608/81/921450452.50
146
R. Casalone et al.
CASE REPORT
M. C., a male born in 1967, complained of weakness and fever in November 1979. Physical examination revealed enlargement of the spleen (8 cm below the costal margin), but no hepatomegaly or lymph node enlargement. Laboratory data revealed the following: Hb 11.1 g/100 ml, with 4% of fetal Hb; RBC 3,50O,O00/mm~; WBC 124,000/mm 3, neutrophils 50%, eosinophils 1%, basophils 0, lymphocytes 4%, monocytes 0, metamyelocytes 5%, myelocytes 28%, promyelocytes 9%, myeloblasts 3%, platelets 250,000/mm 3. The leukocyte alkaline phosphatase (LAP) score was 8 (normal value: 90 + 50). Serum muramidase value was 10/zg/ml (normal value 3-9) although urinary muramidase was 0 (normal value 0). The bone marrow was hypercellular and showed hyperplasia of the myeloid series with abundant eosinophilic cells. The myeloid-erythroid ratio was 9:1. Megakaryocytes were not increased in number. Therapy was performed with busulfan and 6-mercaptopurine. A reduction of the WBC to 8,900/mm 3 was obtained in 19 days; at that time, Hb level was 13.2 g/100 ml, RBC was 4,680,000/mm 3, and platelets were 130,000/mm 3. The spleen was palpable 2 cm below the costal margin. Therapy was then discontinued. In the following 2 weeks, the WBC rose to 60,O00/mm 3. Busulfan and 6-mercaptopurine therapy was again administered. In February 1980 the patient was in fairly good condition with a WBC of 10,O00/mm3 (neutrophils 59%, eosinophils 1%, basophils 0, lymphocytes 27%, monocytes 3%, metamyelocytes 5%, and myelocytes 5%). CYTOGENETIC FINDINGS Chromosome analyses were performed utilizing Q and G banding on cells from phytohemagglutinin (PHA) stimulated and unstimulated blood cultures and from bone marrow direct preparations. The dates and results of the analyses are shown in Table 1. Both bone marrow and blood cultures showed the presence of a clone with isochromosome (17q) together with karyotypically normal cells. The C-banding technique revealed the i (17q) to be dicentric (Fig. 1). DISCUSSION
Most of the clinical and laboratory data on our patient are intermediate between those typical of JCML and of ACML, i.e., the WBC was higher than the average value for JCML but in the lower range for ACML [2]. Platelet count was normal, whereas JCML is often thrombocytopenic and ACML is usually thrombocythemic [2]. The myeloid-erythroid cell ratio in bone marrow was intermediate between typical values for JCML and ACML [2]. No skin eruptions or lymphadenopathies were present, which could argue in favor of a diagnosis of JCML [2]. No data are available regarding the obliteration of splenic Malpighian corpuscles. Bone marrow megakaryocytes, which seem to be reduced in number in JCML and increased in ACML [2], were present in normal numbers. The absence of the Ph 1, however, led to a diagnosis of JCML. The alternative would be a diagnosis of Phi-negative ACML, but one should note that in fact most features of JCML are similar to those of phi-negative CML in adults. Hence one could postulate that ACML in childhood corresponds to adult Phl-posi tire CML, whereas JCML corresponds to adult Phi-negative CML. We think that a sharp nosologic distinction between childhood and adult forms is perhaps not justified. Isochromosome (17q) is one of the most frequent anomalies found in addition to the Ph 1 in the blastic phase (BP) of Phi-positive CML; its presence may even be considered as a reliable indicator of the BP [5]. It has been reported in several other hema-
147
i(17q) in phi°negative Juvenile CML Table I
Results of c h r o m o s o m e analysis
Date
Material
Number of analyzed cells
Karyotype
11/21/1979
Unstimulated blood cultures
12 5
46,XY,i dic(17q) 48,XY
PHA-stimulated blood cultures
12
46,XY
Bone marrow
6 26
46,XY,i dic(17q) 46,XY
Unstimulated blood cultures
26
46,XY,i dic(17q)
2/8/1980
PHA stimulated blood cultures
7
46,XY
15
46,XY
tologic disorders such as acute myeloblastic leukemia, erythroleukemia, acute lymphoblastic leukemia, p r e l e u k e m i c m y e l o d y s p l a s i a s , l y m p h o m a s , and isolated cases of e o s i n o p h i l i c leukemia, p l a s m a cells leukemia, chronic l y m p h o c y t i c leukemia, S~zary syndrome, and myelofibrosis [6]. A n i s o c h r o m o s o m e (17q) has also been reported in several solid tumors [7]. In contrast, it was never reported in JCML, nor in Phi-negative CML. Our case seems to be the first reporting of an i(17q) with such a diagnosis. In our case as well as in two p r e v i o u s l y reported ones [8], the i(17q) is dicentric, thus indicating that its origin is due to a break on the short arm followed by joining of the two c h r o m a t i d s containing the centromere. What is the prognostic relevance of the finding of an i s o c h r o m o s o m e (17q) in the course of Phi-negative CML or JCML? No prognostic i m p l i c a t i o n s of c h r o m o s o m a l a n o m a l i e s have been m a d e as yet in JCML, but some data are available for a d u l t Ph ~negative CML w h e r e the presence of c h r o m o s o m e abnormalities is often observed at the time of BP [9]. Furthermore, trisomy 8 seems to be frequent in these BP just as in the BP of the Phi-positive CML [9]. Thus n o n r a n d o m c h r o m o s o m e changes are involved in the evolution of the disease in Phi-negative CML as well. In view of these facts, we t h i n k that in our patient too, the presence of the i(17q) m a y indicate a progression of the l e u k e m i a t o w a r d BP. The fact that this a n o m a l y is one of the most typical of the BP of Phi-positive CML gives further s u p p o r t to the view that it has a negative prognostic value.
F i g u r e 1 Normal chromosome 17 (left) and dicentric isochromosome for the long arm of 17 (right) from four different metaphases stained for G (first) and C bands. The two dark bands in C-banded i(17q)'s represent two blocks of cent~omeric heterochromatin.
148
R. C a s a l o n e et el.
This work was supported by a grant from C.N.R., Progetto Finalizzato Controllo della Crescita Neoplastica.
REFERENCES 1. Reisman LE, Trujillo JM (1963): Chronic granulocytic leukemia of childhood. J Pediatr 62, 710-723. 2. Smith KL, Johnson W (1974): Classification of chronic myelocytic leukemia in children. Cancer 34, 6 7 0 - 6 7 9 . 3. Hays T, Morse H, Peakman D, Rose B, Robinson A (1979): Cytogenetic studies of chronic myelocytic leukemia in children and adolescents. Cancer 44, 210-214. 4. Brodeur GM, Down LW, William DL (1979): Cytogenetic features of juvenile chronic myelogenous leukemia. Blood 53, 8 1 2 - 8 1 9 . 5. First International Workshop on Chromosomes in Leukaemia (1978): Chromosomes in Ph ~positive chronic granulocytic leukaemia. Br J Haematol 39, 305-309. 6. Sandberg AA (1980): The chromosomes in h u m a n cancer and leukemia. Elsevier North-Holland, New York, p. 246. 7. Kakati S, Oshimura M, Sandberg AA (1976): The chromosomes and causation of h u m a n cancer and leukaemia. XIX. Common markers in various tumors. Cancer 38, 770 - 777. 8. McDermott A, Romain D, Fraser ID, Scott GL (1978): Isochromosome 17q in two cases of acute blast transformation in myeloproliferative disorders. Hum Genet 45, 215 - 218. 9. Mintz U, Vardiman J, Golomb HM, Rowley JD (1979): Evolution of karyotypes in Philadelphia (Ph l) chromosome-negative chronic myelogenous leukemia. Cancer 4 3 , 4 1 1 - 416.
A dicentric isochromosome of the long arm of one chromosome # 17 was the only abnormality present in a 12-year-old bay with Philadelphia chromosome (Ph~)-negative juvenile chronic myelocytic leukemia. This association does not seem to have been reported in the literature. It is postulated that the finding of an isochromosome (17q) may also have a negative prognostic value in the Phi-negative type of chronic myelogenaus leukemia.
ABSTRACT:
INTRODUCTION Chronic myelocytic leukemia (CML) is rather infrequent in childhood, i.e., I to 5% of all reported cases of leukemia [1]. It is classified into two different forms: the so-called adult type (ACML), with clinical and hematological features identical to adults' CML, and the juvenile type (JCML), which can be defined on the basis of some peculiarities. These are a rather low WBC, thrombocytopenia, and a myeloid-erythroid cells ratio in bone marrow of between 2 : 1 and 5 : 1 [2]. Several other characteristics may contribute to the diagnosis, although they are less typical. Due to the rarity of the disease, little cytogenetic data are available. The Philadelphia chromosome (Ph 1) is always absent in JCML, whereas ACML is usually Ph'-positive [1,3,4]. In JCML, 80% of reported cases show a normal karyotype. Among the cases with chromosome abnormalities, there is no consistent marker [4]. We report a 12-year-old male patient in whom the absence of a Ph i led to a diagnosis of JCML, although the clinical picture did not coincide with all the peculiarities of this form. The karyotype showed an isochromosome for the long arm of chromosome #17 as the only abnormality. This anomaly has not been described in JCML, nor in Phi-negative CML.
From the Institute of General Biology and Medical Genetics, University of Pavia and the Medical Division, Riuniti Hospital, Bergamo, Italy.
Address requests for reprints to: Dr. Francesco Pasquali, C.P. 217 I - 2 71 O0 Pavia, Italy. Received May 23, 1980; accepted July 29, 1980.
145 Copyright O Elsevier North Holland, Inc., 1981 52 Vanderbilt Ave., New York, NY 1 0 0 1 7
Cancer Genetics and Cytogenetics 3, 145-148 (1981) 0165-4608/81/921450452.50
146
R. Casalone et al.
CASE REPORT
M. C., a male born in 1967, complained of weakness and fever in November 1979. Physical examination revealed enlargement of the spleen (8 cm below the costal margin), but no hepatomegaly or lymph node enlargement. Laboratory data revealed the following: Hb 11.1 g/100 ml, with 4% of fetal Hb; RBC 3,50O,O00/mm~; WBC 124,000/mm 3, neutrophils 50%, eosinophils 1%, basophils 0, lymphocytes 4%, monocytes 0, metamyelocytes 5%, myelocytes 28%, promyelocytes 9%, myeloblasts 3%, platelets 250,000/mm 3. The leukocyte alkaline phosphatase (LAP) score was 8 (normal value: 90 + 50). Serum muramidase value was 10/zg/ml (normal value 3-9) although urinary muramidase was 0 (normal value 0). The bone marrow was hypercellular and showed hyperplasia of the myeloid series with abundant eosinophilic cells. The myeloid-erythroid ratio was 9:1. Megakaryocytes were not increased in number. Therapy was performed with busulfan and 6-mercaptopurine. A reduction of the WBC to 8,900/mm 3 was obtained in 19 days; at that time, Hb level was 13.2 g/100 ml, RBC was 4,680,000/mm 3, and platelets were 130,000/mm 3. The spleen was palpable 2 cm below the costal margin. Therapy was then discontinued. In the following 2 weeks, the WBC rose to 60,O00/mm 3. Busulfan and 6-mercaptopurine therapy was again administered. In February 1980 the patient was in fairly good condition with a WBC of 10,O00/mm3 (neutrophils 59%, eosinophils 1%, basophils 0, lymphocytes 27%, monocytes 3%, metamyelocytes 5%, and myelocytes 5%). CYTOGENETIC FINDINGS Chromosome analyses were performed utilizing Q and G banding on cells from phytohemagglutinin (PHA) stimulated and unstimulated blood cultures and from bone marrow direct preparations. The dates and results of the analyses are shown in Table 1. Both bone marrow and blood cultures showed the presence of a clone with isochromosome (17q) together with karyotypically normal cells. The C-banding technique revealed the i (17q) to be dicentric (Fig. 1). DISCUSSION
Most of the clinical and laboratory data on our patient are intermediate between those typical of JCML and of ACML, i.e., the WBC was higher than the average value for JCML but in the lower range for ACML [2]. Platelet count was normal, whereas JCML is often thrombocytopenic and ACML is usually thrombocythemic [2]. The myeloid-erythroid cell ratio in bone marrow was intermediate between typical values for JCML and ACML [2]. No skin eruptions or lymphadenopathies were present, which could argue in favor of a diagnosis of JCML [2]. No data are available regarding the obliteration of splenic Malpighian corpuscles. Bone marrow megakaryocytes, which seem to be reduced in number in JCML and increased in ACML [2], were present in normal numbers. The absence of the Ph 1, however, led to a diagnosis of JCML. The alternative would be a diagnosis of Phi-negative ACML, but one should note that in fact most features of JCML are similar to those of phi-negative CML in adults. Hence one could postulate that ACML in childhood corresponds to adult Phl-posi tire CML, whereas JCML corresponds to adult Phi-negative CML. We think that a sharp nosologic distinction between childhood and adult forms is perhaps not justified. Isochromosome (17q) is one of the most frequent anomalies found in addition to the Ph 1 in the blastic phase (BP) of Phi-positive CML; its presence may even be considered as a reliable indicator of the BP [5]. It has been reported in several other hema-
147
i(17q) in phi°negative Juvenile CML Table I
Results of c h r o m o s o m e analysis
Date
Material
Number of analyzed cells
Karyotype
11/21/1979
Unstimulated blood cultures
12 5
46,XY,i dic(17q) 48,XY
PHA-stimulated blood cultures
12
46,XY
Bone marrow
6 26
46,XY,i dic(17q) 46,XY
Unstimulated blood cultures
26
46,XY,i dic(17q)
2/8/1980
PHA stimulated blood cultures
7
46,XY
15
46,XY
tologic disorders such as acute myeloblastic leukemia, erythroleukemia, acute lymphoblastic leukemia, p r e l e u k e m i c m y e l o d y s p l a s i a s , l y m p h o m a s , and isolated cases of e o s i n o p h i l i c leukemia, p l a s m a cells leukemia, chronic l y m p h o c y t i c leukemia, S~zary syndrome, and myelofibrosis [6]. A n i s o c h r o m o s o m e (17q) has also been reported in several solid tumors [7]. In contrast, it was never reported in JCML, nor in Phi-negative CML. Our case seems to be the first reporting of an i(17q) with such a diagnosis. In our case as well as in two p r e v i o u s l y reported ones [8], the i(17q) is dicentric, thus indicating that its origin is due to a break on the short arm followed by joining of the two c h r o m a t i d s containing the centromere. What is the prognostic relevance of the finding of an i s o c h r o m o s o m e (17q) in the course of Phi-negative CML or JCML? No prognostic i m p l i c a t i o n s of c h r o m o s o m a l a n o m a l i e s have been m a d e as yet in JCML, but some data are available for a d u l t Ph ~negative CML w h e r e the presence of c h r o m o s o m e abnormalities is often observed at the time of BP [9]. Furthermore, trisomy 8 seems to be frequent in these BP just as in the BP of the Phi-positive CML [9]. Thus n o n r a n d o m c h r o m o s o m e changes are involved in the evolution of the disease in Phi-negative CML as well. In view of these facts, we t h i n k that in our patient too, the presence of the i(17q) m a y indicate a progression of the l e u k e m i a t o w a r d BP. The fact that this a n o m a l y is one of the most typical of the BP of Phi-positive CML gives further s u p p o r t to the view that it has a negative prognostic value.
F i g u r e 1 Normal chromosome 17 (left) and dicentric isochromosome for the long arm of 17 (right) from four different metaphases stained for G (first) and C bands. The two dark bands in C-banded i(17q)'s represent two blocks of cent~omeric heterochromatin.
148
R. C a s a l o n e et el.
This work was supported by a grant from C.N.R., Progetto Finalizzato Controllo della Crescita Neoplastica.
REFERENCES 1. Reisman LE, Trujillo JM (1963): Chronic granulocytic leukemia of childhood. J Pediatr 62, 710-723. 2. Smith KL, Johnson W (1974): Classification of chronic myelocytic leukemia in children. Cancer 34, 6 7 0 - 6 7 9 . 3. Hays T, Morse H, Peakman D, Rose B, Robinson A (1979): Cytogenetic studies of chronic myelocytic leukemia in children and adolescents. Cancer 44, 210-214. 4. Brodeur GM, Down LW, William DL (1979): Cytogenetic features of juvenile chronic myelogenous leukemia. Blood 53, 8 1 2 - 8 1 9 . 5. First International Workshop on Chromosomes in Leukaemia (1978): Chromosomes in Ph ~positive chronic granulocytic leukaemia. Br J Haematol 39, 305-309. 6. Sandberg AA (1980): The chromosomes in h u m a n cancer and leukemia. Elsevier North-Holland, New York, p. 246. 7. Kakati S, Oshimura M, Sandberg AA (1976): The chromosomes and causation of h u m a n cancer and leukaemia. XIX. Common markers in various tumors. Cancer 38, 770 - 777. 8. McDermott A, Romain D, Fraser ID, Scott GL (1978): Isochromosome 17q in two cases of acute blast transformation in myeloproliferative disorders. Hum Genet 45, 215 - 218. 9. Mintz U, Vardiman J, Golomb HM, Rowley JD (1979): Evolution of karyotypes in Philadelphia (Ph l) chromosome-negative chronic myelogenous leukemia. Cancer 4 3 , 4 1 1 - 416.