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Tetrasomy of chromosome 8: An interesting and rare cytogenetic phenomenon in acute nonlymphocytic leukemia
Tetrasomy of Chromosome 8: An Interesting and Rare Cytogenetic Phenomenon in Acute Nonlymphocytic Leukemia Sheila N. Jani gait, Azra Raza, and Avery A. Sandberg
ABSTRACT: Trisomy of chromosome #8 is a change commonly associated with acute nonlymphacytic leukemia (ANLL). However, tetrasomy of chromosome #8 in ANLL as a single chromosome change without accompanying abnormalities is extremely rare and, to the best of our knowledge, has not been reported to date. We present here a case of acute monocytic leukemia (AMoL, FAB M5b) with four copies of chromosome #8.
INTRODUCTION Chromosome # 8 is one of the most consistently involved chromosomes in malignant transformation. It is involved in translocations such as t(8;21) in acute myeloblastic leukemia (AML) and t(8;14) and t(8;22) in l y m p h o m a s and l y m p h o c y t i c leukemias. Trisomy of c h r o m o s o m e # 8 is a well k n o w n and c o m m o n p h e n o m e n o n encountered in AML. Trisomy 8 also has been reported as a frequent additional karyotypic abnormality in cases of acute n o n l y m p h o c y t i c leukemia (ANLL). Though tetrasomy 8 has been reported, it is always associated with another c h r o m o s o m e abnormality. To the best of our knowledge, tetrasomy 8 (+ 8, + 8) has not been reported as a single c h r o m o s o m a l abnormality without a c c o m p a n y i n g karyotypic changes in ANLL. CASE REPORT
A 43-year-old white male presented in January 1986 with p a n c y t o p e n i a and generalized l y m p h a d e n o p a t h y . He was also noted to have r a p i d l y enlarging cutaneous lesions all over his body, ranging in size from a few millimeters to greater than 5.0 cm, most m a r k e d on his face, skull, and limbs. On presentation, his peripheral blood e x a m i n a t i o n revealed a white blood count (WBC) 2.1 x 109/L, platelets 27 x 109/L, and hemoglobin 10.3 gm/dl. Biopsy of the skin lesions demonstrated the presence of sheets of m o n o n u c l e a r cells that were nonspecific esterase positive. A bone marrow examination was diagnostic of ANLL, FAB M5b. A l u m b a r p u n c t u r e failed to show any leukemic i n v o l v e m e n t of the central nervous system, He was treated for 7 days with cytosine arabinoside at 100 mg/m2/24 hours by From the Roswell Park Memorial Institute, Buffalo,NY. Address requests for reprints to Dr. Avery A. Sandberg, Department of Genetics end Endocrinology, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N Y 14263. Received October 3, 1986; accepted November 12, 1986.
269 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genet Cytogenet 27:269-271 (1987) 0165-4608/87/$03.50
270
s . N . Jani Sait, A. Raza, and A. A. Sandberg continuous intravenous infusion and 3 days of a d r i a m y c i n at 30 g / m 2 intravenously (7 + 3). The skin lesions showed a dramatic r e d u c t i o n in size and the bone marrow was noted to be in complete remission 4 weeks after treatment; the p e r i p h e r a l blood counts also normalized. However, some scattered skin lesions persisted despite an almost 90% r e d u c t i o n in their size. Biopsy of one of these lesions demonstrated the presence of residual leukemia. The patient was then initiated on whole b o d y electron beam r a d i o t h e r a p y to the skin. He received five courses of 300 rads each and demonstrated further reduction in the size of the remaining cutaneous lesions. At this time, the patient was noted to have a generalized, scaly, erythematous rash diagnosed as radiation dermatitis. Unfortunately, the patient had some lesions on both eyelids where r a d i o t h e r a p y could not be applied, and 3 weeks into therapy these began to show a gradual increase in size. Further r a d i o t h e r a p y was discontinued (total dose given was 1500 rads). He was given a second course of 7 + 3 and again became p a n c y t o p e n i c (WBC less than 0.2 × 109/L). However, the patient was noted to have a marked worsening of the rash, with r a p i d evolution into a bullous, necrotizing erythroderma, marked e d e m a of all extremities, and m u l t i p l e areas of fissuring and cellulitis. Despite vigorous supportive care with antibiotics, WBC transfusions, etc., the patient c o n t i n u e d to have increasing cellulitis, d e v e l o p e d
Figure 1 Karyotype (G-banded) showing the tetrasomy 8 (+ 8, + 8) in the case of M5b presented in this report.
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septic shock, and d i e d 14 weeks after the initial diagnosis of ANLL. An autopsy revealed no evidence of leukemia; sepsis with p s e u d o m e m b r a n o u s colitis and acute renal failure were noted. CHROMOSOME ANALYSIS Cytogenetic analysis was carried out on bone marrow cells that were cultured for 48 hours and further processed according to procedures previously described [1], All metaphases scored showed the karyotype 48,XY, + 8, + 8 (Fig. 1]. DISCUSSION Chromosome # 8 is c o m m o n l y involved in cytogenetic changes occurring with malignant transformation, especially in ANLL. Extra copies of c h r o m o s o m e # 8 have been reported as both specific and a d d i t i o n a l karyotypic changes in ANLL. Trisomy 8 is regarded as a poor prognostic indicator, the extent d e p e n d i n g on whether it is a specific or additional change. Tetrasomy 8, however, is very rare and usually is associated with other karyotypic changes. Tetrasomy 8 as a sole karyotypic a b n o r m a l i t y has been reported in only two cases in the literature. A case of refractory anemia of Lessard and Le Prise, as reported by Mitelman [2], had a karyotype of 48,XX,+ 8 , + 8 . Berger et al. [3] reported a m i n o r clone of + 8, + 8 in a 50-year-old female with p o l y c y t h e m i a vera. This w o m a n was treated with h y d r o x y u r e a and followed-up for 2 years. Bernard et al. [4], however, reported a case of 4 8 , X Y , + 8 , + 8 / 4 7 , X Y , + 8 , + 8 , - 1 5 in a case of ANLL FAB M5b. The patient described by them was a 78-year-old male who had hyperleukocytosis. All the metaphases e x a m i n e d were abnormal. The prognosis was poor and the patient lived for only 1 month. The patient described by us also had a short survival time and lived only 14 weeks after the initial diagnosis of ANLL. The p h e n o m e n o n of tetrasomy 8 is extremely interesting because it raises the question as to the origin of the extra copies of c h r o m o s o m e #8, i.e., whether there were three copies of one c h r o m o s o m e # 8 and one of the other c h r o m o s o m e # 8 or two copies each of each # 8 chromosome. In other words, because trisomy 8 can be a specific (primary) karyotypic change or an additional event associated with other specific changes, the question arises as to whether the extra chromosomes # 8 in our case represents d u p l i c a t i o n of the specific + 8 change, or one c h r o m o s o m e # 8 the specific karyotypic change and the other an additional change involving the other homolog. Molecular studies m a y possibly yield the answer to this question. Supported in part by Grant CA-412858 from the National Cancer Institute. The authors thank Diane Smith, Joan Schumer, and Kathleen Carr for technical assistance.
REFERENCES 1. Jani Salt SN, Dal Cin P, Sandberg AA (1986): t(Y;18] in acute myeloblastic leukemia FAB type M2. Cancer Genet Cytogenet 22:367-368. 2. Mitelman F (1985): Catalog of chromosome aberrations in cancer. In Progress and Topics in Cytogenetics, Sandberg AA (ed.). Alan R Liss, NY. 3. Berger R, Bernheim A, Le Coniat M, Necchione D, Flandrin G, Dresch C, Nagean Y (1984): Chromosome studies in polycythemia vera patients. Cancer Genet Cytogenet 12:217-223. 4. Bernard P, Reiffers J, Lacombe F, Dachary D, Boisseau MR, Broustet A (1984): A stage classification for prognosis in adult acute myelogenous leukaemia based upon patients' age, bone marrow karyotype and clinical features. Scand J Haematol 32:429-440.
ABSTRACT: Trisomy of chromosome #8 is a change commonly associated with acute nonlymphacytic leukemia (ANLL). However, tetrasomy of chromosome #8 in ANLL as a single chromosome change without accompanying abnormalities is extremely rare and, to the best of our knowledge, has not been reported to date. We present here a case of acute monocytic leukemia (AMoL, FAB M5b) with four copies of chromosome #8.
INTRODUCTION Chromosome # 8 is one of the most consistently involved chromosomes in malignant transformation. It is involved in translocations such as t(8;21) in acute myeloblastic leukemia (AML) and t(8;14) and t(8;22) in l y m p h o m a s and l y m p h o c y t i c leukemias. Trisomy of c h r o m o s o m e # 8 is a well k n o w n and c o m m o n p h e n o m e n o n encountered in AML. Trisomy 8 also has been reported as a frequent additional karyotypic abnormality in cases of acute n o n l y m p h o c y t i c leukemia (ANLL). Though tetrasomy 8 has been reported, it is always associated with another c h r o m o s o m e abnormality. To the best of our knowledge, tetrasomy 8 (+ 8, + 8) has not been reported as a single c h r o m o s o m a l abnormality without a c c o m p a n y i n g karyotypic changes in ANLL. CASE REPORT
A 43-year-old white male presented in January 1986 with p a n c y t o p e n i a and generalized l y m p h a d e n o p a t h y . He was also noted to have r a p i d l y enlarging cutaneous lesions all over his body, ranging in size from a few millimeters to greater than 5.0 cm, most m a r k e d on his face, skull, and limbs. On presentation, his peripheral blood e x a m i n a t i o n revealed a white blood count (WBC) 2.1 x 109/L, platelets 27 x 109/L, and hemoglobin 10.3 gm/dl. Biopsy of the skin lesions demonstrated the presence of sheets of m o n o n u c l e a r cells that were nonspecific esterase positive. A bone marrow examination was diagnostic of ANLL, FAB M5b. A l u m b a r p u n c t u r e failed to show any leukemic i n v o l v e m e n t of the central nervous system, He was treated for 7 days with cytosine arabinoside at 100 mg/m2/24 hours by From the Roswell Park Memorial Institute, Buffalo,NY. Address requests for reprints to Dr. Avery A. Sandberg, Department of Genetics end Endocrinology, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N Y 14263. Received October 3, 1986; accepted November 12, 1986.
269 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genet Cytogenet 27:269-271 (1987) 0165-4608/87/$03.50
270
s . N . Jani Sait, A. Raza, and A. A. Sandberg continuous intravenous infusion and 3 days of a d r i a m y c i n at 30 g / m 2 intravenously (7 + 3). The skin lesions showed a dramatic r e d u c t i o n in size and the bone marrow was noted to be in complete remission 4 weeks after treatment; the p e r i p h e r a l blood counts also normalized. However, some scattered skin lesions persisted despite an almost 90% r e d u c t i o n in their size. Biopsy of one of these lesions demonstrated the presence of residual leukemia. The patient was then initiated on whole b o d y electron beam r a d i o t h e r a p y to the skin. He received five courses of 300 rads each and demonstrated further reduction in the size of the remaining cutaneous lesions. At this time, the patient was noted to have a generalized, scaly, erythematous rash diagnosed as radiation dermatitis. Unfortunately, the patient had some lesions on both eyelids where r a d i o t h e r a p y could not be applied, and 3 weeks into therapy these began to show a gradual increase in size. Further r a d i o t h e r a p y was discontinued (total dose given was 1500 rads). He was given a second course of 7 + 3 and again became p a n c y t o p e n i c (WBC less than 0.2 × 109/L). However, the patient was noted to have a marked worsening of the rash, with r a p i d evolution into a bullous, necrotizing erythroderma, marked e d e m a of all extremities, and m u l t i p l e areas of fissuring and cellulitis. Despite vigorous supportive care with antibiotics, WBC transfusions, etc., the patient c o n t i n u e d to have increasing cellulitis, d e v e l o p e d
Figure 1 Karyotype (G-banded) showing the tetrasomy 8 (+ 8, + 8) in the case of M5b presented in this report.
!3
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20
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Tetrasomy 8 in ANLL
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septic shock, and d i e d 14 weeks after the initial diagnosis of ANLL. An autopsy revealed no evidence of leukemia; sepsis with p s e u d o m e m b r a n o u s colitis and acute renal failure were noted. CHROMOSOME ANALYSIS Cytogenetic analysis was carried out on bone marrow cells that were cultured for 48 hours and further processed according to procedures previously described [1], All metaphases scored showed the karyotype 48,XY, + 8, + 8 (Fig. 1]. DISCUSSION Chromosome # 8 is c o m m o n l y involved in cytogenetic changes occurring with malignant transformation, especially in ANLL. Extra copies of c h r o m o s o m e # 8 have been reported as both specific and a d d i t i o n a l karyotypic changes in ANLL. Trisomy 8 is regarded as a poor prognostic indicator, the extent d e p e n d i n g on whether it is a specific or additional change. Tetrasomy 8, however, is very rare and usually is associated with other karyotypic changes. Tetrasomy 8 as a sole karyotypic a b n o r m a l i t y has been reported in only two cases in the literature. A case of refractory anemia of Lessard and Le Prise, as reported by Mitelman [2], had a karyotype of 48,XX,+ 8 , + 8 . Berger et al. [3] reported a m i n o r clone of + 8, + 8 in a 50-year-old female with p o l y c y t h e m i a vera. This w o m a n was treated with h y d r o x y u r e a and followed-up for 2 years. Bernard et al. [4], however, reported a case of 4 8 , X Y , + 8 , + 8 / 4 7 , X Y , + 8 , + 8 , - 1 5 in a case of ANLL FAB M5b. The patient described by them was a 78-year-old male who had hyperleukocytosis. All the metaphases e x a m i n e d were abnormal. The prognosis was poor and the patient lived for only 1 month. The patient described by us also had a short survival time and lived only 14 weeks after the initial diagnosis of ANLL. The p h e n o m e n o n of tetrasomy 8 is extremely interesting because it raises the question as to the origin of the extra copies of c h r o m o s o m e #8, i.e., whether there were three copies of one c h r o m o s o m e # 8 and one of the other c h r o m o s o m e # 8 or two copies each of each # 8 chromosome. In other words, because trisomy 8 can be a specific (primary) karyotypic change or an additional event associated with other specific changes, the question arises as to whether the extra chromosomes # 8 in our case represents d u p l i c a t i o n of the specific + 8 change, or one c h r o m o s o m e # 8 the specific karyotypic change and the other an additional change involving the other homolog. Molecular studies m a y possibly yield the answer to this question. Supported in part by Grant CA-412858 from the National Cancer Institute. The authors thank Diane Smith, Joan Schumer, and Kathleen Carr for technical assistance.
REFERENCES 1. Jani Salt SN, Dal Cin P, Sandberg AA (1986): t(Y;18] in acute myeloblastic leukemia FAB type M2. Cancer Genet Cytogenet 22:367-368. 2. Mitelman F (1985): Catalog of chromosome aberrations in cancer. In Progress and Topics in Cytogenetics, Sandberg AA (ed.). Alan R Liss, NY. 3. Berger R, Bernheim A, Le Coniat M, Necchione D, Flandrin G, Dresch C, Nagean Y (1984): Chromosome studies in polycythemia vera patients. Cancer Genet Cytogenet 12:217-223. 4. Bernard P, Reiffers J, Lacombe F, Dachary D, Boisseau MR, Broustet A (1984): A stage classification for prognosis in adult acute myelogenous leukaemia based upon patients' age, bone marrow karyotype and clinical features. Scand J Haematol 32:429-440.