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Refractory anemia with monosomy 2 and a double minute chromosome
Refractory A n e m i a With M o n o s o m y 2 and a Double Minute Chromosome F lix Prieto, Lourdes Badia, Federico Gomis, and Luisa Dieguez
ABSTRACT We present a case of refractory anemia with monosomy 2 in the 41 cells of the bone marrow studied and a double minute chromosome (drain) in 68% of these cells. The illness developed over a period of 3 years and the patient died of cerebral hemorrhage without developing leukemia.
INTRODUCTION
Refractory anemia (RA) is i n c l u d e d in the myelodysplastic syndromes (MDS) [1]. Approximately 45% of MDS cases present cytogenetic alterations [2]. Those cases with an abnormal karyotype are more likely to develop leukemia than those with a normal karyotype [3]. The cytogenetic alterations in these patients may be very diverse and, therefore, cytogenetic studies are of interest in order to gain more knowledge of preleukemia and to be able to better classify these disorders. In this report we present a form of RA in which the cytogenetic study detected m o n o s o m y 2 in all the bone marrow metaphases studied. This numerical abnormality as the sole karyotypic alteration has not been detected in preleukemia states or in any other neoplasia [4]. CASE REPORT
C. P. S., a 50-year-old woman, was sent to our hospital in November 1983 for a study of thrombocytopenia. Her history began 5 years earlier, with pain in the neck and spinal column, which was treated with phenothiazines. On examination in the hospital, paleness of the skin and mucous membranes was detected, as well as hematomas and petechiae, especially in the lower limbs. There was no hepatomegaly or splenomegaly. Study of the blood showed: Hgb 10 g/dl, with a mean corpuscular volume (MCV) of 105 fl, Ht 28.6%, WBC 3.5X109/L (62% segmented neutrophils, 38% lymphocytes), platelets 40X109/L. The serum Bl2 level was 190 pg/ml (normal, 200-800), and serum folate was 5.8 ng/ml. The bone marrow was hypercellular with n u m e r o u s small hypersegmented megakaryocytes. The granulocytic series was well represented with no increase of From the Secci6nde Gen~tica(Serviciode Hematologiay Hemoterapia), Hospital de la Seguridad Social "La Fe", Valencia,Spain. Address requests for reprints to Dr. F61ix Prieto, Secci6n de Gen6tica, Clinica Infantil, Hospital de la Seguridad Social "Lu Fe", Valencia 46009, Spain. Received October 16, 1986, accepted February 2, 1987.
367 © 1987 ElsevierSciencePublishingCo., Inc. 52 VanderbiltAve., New York, NY 10017
Cancer Genet Cytogenet28:367-371 (1987) 0165-4608/87/$03.50
368
v. Prieto et al.
immature cells, but some ot these cells appeared hypogranular. The blast cells represent 4°/,,. The red cell series was hyperplasic and no significant change in the morphology or maturity was evident, nor was there an accumulation of pathologic sideroblasts. The hematologic diagnosis was simple refractory anemia. During 1984, due to frequent metrorrhagia, the patient was u n d e r study in the gynecological department. An e n d o m e t r i u m biopsy showed a functional premenopausal metropathy. Because of repe, ated metrorrhagia, a bysterectomy was performed in September after which the patient contracted hepatitis, possibly postranfusional from which she recovered uneventfully. The ensuing hematologic studies continued to show anemia, leukocytopenia, and trombocytopenia. The bone marrow presented similar characteristics to those observed at diagnosis. In July 1986 a cytogenetic study was carried out taking advantage of bone marrow cells obtained for one of the hematologic controls, the results of which are described later. One month later the patient was admitted to the hospital ill a state of agitation, delirious, disoriented as to time, and place. A cranial CT scan confirmed a hematoma in the left temporoloccipital region due to cerebral hemorrhage; the patient died. CYTOGENETIC STUDY
Cytogenetic studies were carried out on bone marrow cells in July 1986 using a direct method (5) and a 48-hour culture. The metaphases obtained by the direct method were of good quality. Forty-one metaphases were studied and ill all one chromosome 2 was missing (Fig. 1). The identification of the chromosome was established with G b a n d i n g [6]. In addition, in 68% of these metaphases there was a microchromosome (Fig. 2A). Its arms were G band-negative [6] (Fig. 2B) and C b a n d i n g [7] did not detect heterochromatin (Fig. 2C), suggesting that this microchromosome could be a dmin-chromosome. The metaphases obtained from the 48hour bone marrow culture were of poor quality and it was impossible to evaluate the karyotype. DISCUSSION
Myelodysplastic syndromes (MDS) are characterized by an abnormal development of the hematopoietic cells, i n c l u d i n g preleukemic states in which cytogenetic studies show chromosome alterations similar to those observed in patients with acute n o n l y m p h o c y t i c leukemia (ANLL) [8]. In spite of the similarity between cytogenetic alterations presented in MDS and in ANLL, and in spite of the fact that the MDS with cytogenetic alterations run a greater risk of developing into leukemia, it is not always possible to predict whether or not a specific case will turn into leukemia. The frequency of cytogenetic alterations in patients with simple refractory anemia (RA) is less than in other preleukemic states [3,9]. A group of patients with RA present with a 5 q - chromosome as the sole alteration [10]; these patients, besides having a macrocytic RA, have a normal or high platelet count, a normal or low count in the erythroid series in the bone marrow, and megakaryocytic hypolobulation. The patient presented here had a form of RA in which the chromosome 5 pair were normal, and in addition, in the 41 metaphases studied, a chromosome 2 was missing, and 68% of the cells showed a DM chromosome as well as m o n o s o m y 2. This m o n o s o m y 2 as the sole karyotypic alteration has not been detected in preleukemic states or in any other neoplasia [4]; nevertheless this d m i n chromosome has been detected in leukemia and solid tu-
369
RA with M o n o s o m y 2 and d m i n
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Metaphase and karyotype with 45 chromosomes and monosomy 2 (G-banding).
mors [8]. Although there was only one d m i n c h r o m o s o m e per cell in our patient, as in the case described by Benitez et al. [11], in other cases the DMC may be variable in number, with very marked numerical differences from one cell to another [12]. We do not k n o w if the cytogenetic alterations were present from the beginning of the illness because the cytogenetic study was carried out at the end of the illness
370
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F i g u r e 2. (A) metaphase with 45 chromosomes and a dmin chromosome. (B,C) G- and C banding in two incomplete metaphases. Arrows show dmin chromosome.
RA w i t h M o n o s o m y 2 a n d d m i n
371
(15 d a y s b e f o r e d e a t h ) . T h e h e m a t o l o g i c a n d c l i n i c a l c h a r a c t e r i s t i c s w e r e u n c h a n g e d d u r i n g t h e 3 y e a r s of d e v e l o p m e n t of t h e RA, a n d t h e p a t i e n t d i e d of cerebral hemorrhage without developing leukemia.
REFERENCES 1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (FAB Co-operative Group) (1982): Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189-199. 2. Tricot G, Vlietinck R, Boogaerts MA, Hendrickx B, De Wolf-Peeters C, Van den Berghe H, Verwilghen RL (1985): Prognostic factors in the myelodysplastic syndromes: Importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br J Haematol 60:19-32. 3. Ayraud N, Donzeau M, Raynaud S, Lambert J-C (1983): Cytogenetic study of 88 cases of refractory anemia. Cancer Genet Cytogenet 8:243-248. 4. Heim S, Mitelman F (1986): Numerical chromosome aberrations in h u m a n neoplasia. Cancer Genet Cytogenet 22:99-108. 5. Tjio JH, Whang J (1962): Chromosome preparations of bone marrow ceils without prior in vitro culture or in vivo colchicine adininistration. Stain Technol 37:17-20. 6. Seabright M (1971): A rapid banding technique for h u m a n chromosomes. Lancet ii: 971972. 7. Sumner AT (1972): A simple technique for demonstrating heterochromatin. Exp Cell Res 75:304-306. 8. Sandberg AA (1980): The Chromosomes in Human Cancer and Leukemia. New York, Elsevier Science Publishing. 9. Prieto F, Carbonell F, Badia L, Castel V, P6rez Sirvent ML (1985): Citogen6tica en el estudio de los sfndromes mielodisplfisicos. Sangre 30:669-679. 10. Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G (1974): A distinct hematological disorder with deletion of the long arm of a n" 5 chromosome. Nature 251:437-438. 11. Benitez J, Outerifio J, Bello MJ, Rey J (1985): Acute nonlymphocytic leukemia with severe hypodiploidy and one double minute chromosome. Cancer Genet Cytogenet 18:333-336. 12. Alitalo K, Winqvist R, Keski-Oja J, Ilvonen M, Saksela K, Alitalo R, Laiho M, Knuutila S, de la Chapelle A (1985): Acute myelogenous leukaemia with c-myc amplification and double minute chromosomes. Lancet ii: 1035-1038.
ABSTRACT We present a case of refractory anemia with monosomy 2 in the 41 cells of the bone marrow studied and a double minute chromosome (drain) in 68% of these cells. The illness developed over a period of 3 years and the patient died of cerebral hemorrhage without developing leukemia.
INTRODUCTION
Refractory anemia (RA) is i n c l u d e d in the myelodysplastic syndromes (MDS) [1]. Approximately 45% of MDS cases present cytogenetic alterations [2]. Those cases with an abnormal karyotype are more likely to develop leukemia than those with a normal karyotype [3]. The cytogenetic alterations in these patients may be very diverse and, therefore, cytogenetic studies are of interest in order to gain more knowledge of preleukemia and to be able to better classify these disorders. In this report we present a form of RA in which the cytogenetic study detected m o n o s o m y 2 in all the bone marrow metaphases studied. This numerical abnormality as the sole karyotypic alteration has not been detected in preleukemia states or in any other neoplasia [4]. CASE REPORT
C. P. S., a 50-year-old woman, was sent to our hospital in November 1983 for a study of thrombocytopenia. Her history began 5 years earlier, with pain in the neck and spinal column, which was treated with phenothiazines. On examination in the hospital, paleness of the skin and mucous membranes was detected, as well as hematomas and petechiae, especially in the lower limbs. There was no hepatomegaly or splenomegaly. Study of the blood showed: Hgb 10 g/dl, with a mean corpuscular volume (MCV) of 105 fl, Ht 28.6%, WBC 3.5X109/L (62% segmented neutrophils, 38% lymphocytes), platelets 40X109/L. The serum Bl2 level was 190 pg/ml (normal, 200-800), and serum folate was 5.8 ng/ml. The bone marrow was hypercellular with n u m e r o u s small hypersegmented megakaryocytes. The granulocytic series was well represented with no increase of From the Secci6nde Gen~tica(Serviciode Hematologiay Hemoterapia), Hospital de la Seguridad Social "La Fe", Valencia,Spain. Address requests for reprints to Dr. F61ix Prieto, Secci6n de Gen6tica, Clinica Infantil, Hospital de la Seguridad Social "Lu Fe", Valencia 46009, Spain. Received October 16, 1986, accepted February 2, 1987.
367 © 1987 ElsevierSciencePublishingCo., Inc. 52 VanderbiltAve., New York, NY 10017
Cancer Genet Cytogenet28:367-371 (1987) 0165-4608/87/$03.50
368
v. Prieto et al.
immature cells, but some ot these cells appeared hypogranular. The blast cells represent 4°/,,. The red cell series was hyperplasic and no significant change in the morphology or maturity was evident, nor was there an accumulation of pathologic sideroblasts. The hematologic diagnosis was simple refractory anemia. During 1984, due to frequent metrorrhagia, the patient was u n d e r study in the gynecological department. An e n d o m e t r i u m biopsy showed a functional premenopausal metropathy. Because of repe, ated metrorrhagia, a bysterectomy was performed in September after which the patient contracted hepatitis, possibly postranfusional from which she recovered uneventfully. The ensuing hematologic studies continued to show anemia, leukocytopenia, and trombocytopenia. The bone marrow presented similar characteristics to those observed at diagnosis. In July 1986 a cytogenetic study was carried out taking advantage of bone marrow cells obtained for one of the hematologic controls, the results of which are described later. One month later the patient was admitted to the hospital ill a state of agitation, delirious, disoriented as to time, and place. A cranial CT scan confirmed a hematoma in the left temporoloccipital region due to cerebral hemorrhage; the patient died. CYTOGENETIC STUDY
Cytogenetic studies were carried out on bone marrow cells in July 1986 using a direct method (5) and a 48-hour culture. The metaphases obtained by the direct method were of good quality. Forty-one metaphases were studied and ill all one chromosome 2 was missing (Fig. 1). The identification of the chromosome was established with G b a n d i n g [6]. In addition, in 68% of these metaphases there was a microchromosome (Fig. 2A). Its arms were G band-negative [6] (Fig. 2B) and C b a n d i n g [7] did not detect heterochromatin (Fig. 2C), suggesting that this microchromosome could be a dmin-chromosome. The metaphases obtained from the 48hour bone marrow culture were of poor quality and it was impossible to evaluate the karyotype. DISCUSSION
Myelodysplastic syndromes (MDS) are characterized by an abnormal development of the hematopoietic cells, i n c l u d i n g preleukemic states in which cytogenetic studies show chromosome alterations similar to those observed in patients with acute n o n l y m p h o c y t i c leukemia (ANLL) [8]. In spite of the similarity between cytogenetic alterations presented in MDS and in ANLL, and in spite of the fact that the MDS with cytogenetic alterations run a greater risk of developing into leukemia, it is not always possible to predict whether or not a specific case will turn into leukemia. The frequency of cytogenetic alterations in patients with simple refractory anemia (RA) is less than in other preleukemic states [3,9]. A group of patients with RA present with a 5 q - chromosome as the sole alteration [10]; these patients, besides having a macrocytic RA, have a normal or high platelet count, a normal or low count in the erythroid series in the bone marrow, and megakaryocytic hypolobulation. The patient presented here had a form of RA in which the chromosome 5 pair were normal, and in addition, in the 41 metaphases studied, a chromosome 2 was missing, and 68% of the cells showed a DM chromosome as well as m o n o s o m y 2. This m o n o s o m y 2 as the sole karyotypic alteration has not been detected in preleukemic states or in any other neoplasia [4]; nevertheless this d m i n chromosome has been detected in leukemia and solid tu-
369
RA with M o n o s o m y 2 and d m i n
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|
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b
q,O
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1
2
4
3
5 4 lr Nm
6
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01
13
8
15
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16 ~
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21 Figure 1.
11
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9
12
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18
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22
Metaphase and karyotype with 45 chromosomes and monosomy 2 (G-banding).
mors [8]. Although there was only one d m i n c h r o m o s o m e per cell in our patient, as in the case described by Benitez et al. [11], in other cases the DMC may be variable in number, with very marked numerical differences from one cell to another [12]. We do not k n o w if the cytogenetic alterations were present from the beginning of the illness because the cytogenetic study was carried out at the end of the illness
370
A
4
4
J ,/
F i g u r e 2. (A) metaphase with 45 chromosomes and a dmin chromosome. (B,C) G- and C banding in two incomplete metaphases. Arrows show dmin chromosome.
RA w i t h M o n o s o m y 2 a n d d m i n
371
(15 d a y s b e f o r e d e a t h ) . T h e h e m a t o l o g i c a n d c l i n i c a l c h a r a c t e r i s t i c s w e r e u n c h a n g e d d u r i n g t h e 3 y e a r s of d e v e l o p m e n t of t h e RA, a n d t h e p a t i e n t d i e d of cerebral hemorrhage without developing leukemia.
REFERENCES 1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (FAB Co-operative Group) (1982): Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189-199. 2. Tricot G, Vlietinck R, Boogaerts MA, Hendrickx B, De Wolf-Peeters C, Van den Berghe H, Verwilghen RL (1985): Prognostic factors in the myelodysplastic syndromes: Importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br J Haematol 60:19-32. 3. Ayraud N, Donzeau M, Raynaud S, Lambert J-C (1983): Cytogenetic study of 88 cases of refractory anemia. Cancer Genet Cytogenet 8:243-248. 4. Heim S, Mitelman F (1986): Numerical chromosome aberrations in h u m a n neoplasia. Cancer Genet Cytogenet 22:99-108. 5. Tjio JH, Whang J (1962): Chromosome preparations of bone marrow ceils without prior in vitro culture or in vivo colchicine adininistration. Stain Technol 37:17-20. 6. Seabright M (1971): A rapid banding technique for h u m a n chromosomes. Lancet ii: 971972. 7. Sumner AT (1972): A simple technique for demonstrating heterochromatin. Exp Cell Res 75:304-306. 8. Sandberg AA (1980): The Chromosomes in Human Cancer and Leukemia. New York, Elsevier Science Publishing. 9. Prieto F, Carbonell F, Badia L, Castel V, P6rez Sirvent ML (1985): Citogen6tica en el estudio de los sfndromes mielodisplfisicos. Sangre 30:669-679. 10. Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G (1974): A distinct hematological disorder with deletion of the long arm of a n" 5 chromosome. Nature 251:437-438. 11. Benitez J, Outerifio J, Bello MJ, Rey J (1985): Acute nonlymphocytic leukemia with severe hypodiploidy and one double minute chromosome. Cancer Genet Cytogenet 18:333-336. 12. Alitalo K, Winqvist R, Keski-Oja J, Ilvonen M, Saksela K, Alitalo R, Laiho M, Knuutila S, de la Chapelle A (1985): Acute myelogenous leukaemia with c-myc amplification and double minute chromosomes. Lancet ii: 1035-1038.