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Triple X chromosome constitution and acute nonlymphocytic leukemia
Triple X Chromosome Constitution and Acute Nonlymphocytic Leukemia M. Fevzi Ozkaynak, Kuang-Lin Ying, and Walter E. Laug
ABSTRACT: A case of acute nonlymphocytic leukemia occurring in a 15-year-old girl with a triple X sex chromosome constitution is discussed.
INTRODUCTION Acute lymphocytic leukemia (ALL) and acute n o n l y m p h o c y t i c leukemia (ANLL) have been demonstrated to be associated with chromosome changes in the leukemic cells. Often, only one karyotypic event is present in these cells, and in such cases this chromosome change can be assumed to be the primary (specific) one [1]. We detected triple X during routine cytogenetic examination in a 15-year-old girl with ANLL. X chromosome abnormalities are rarely associated with acute leukemias, but when they are, they are generally structural abnormalities. To our knowledge this is the second case report of an association of chromosome XXX with acute leukemia. CASE REPORT
A 15-year-old girl presented with a 3-month history of lethargy, anorexia, easy bruisability, and a weight loss of 8 kg. She was found to have staphylococcal septicemia and was hospitalized in October 1981. Two weeks after being discharged, she experienced an episode of hematemesis and was readmitted to another hospital where she was found to be pancytopenic. Leukemia was diagnosed in December 1981 by bone marrow examination, and she was then transferred to our hospital. Her physical examination on admission was unremarkable except for superficial fluctuant abscesses on the left distal arm, left proximal forearm, right lower quadrant of the abdomen, and right nasal antrum. No hepatosplenomegaly or lymphadenopathy were noted. A complete blood count showed Hbg 10.1 g/dl, platelets 18 × 109/L, and a white cell count of 6.9 × 109/L with 19% neutrophils, 47% lymphocytes, 29% blasts, 2% myelocytes, 2% basophils, and 1% eosinophils. Bone marrow examination showed 50% myeloblasts, 21% promyelocytes, 13% neutrophils, 7% erythroids, 7.2% lymphocytes, 1% plasmacytes, and 0.8% monocytes, and ANLL-M2 morphology (FAB classification) was diagnosed. S u d a n Black, peroxidase, chloroacetyl esterase, and periodic acid-Schiff stains were positive in 55%,
From the Divisionof Hematology-Oncologyand Medical Genetics,Childrens Hospital of Los Angeles, and Universityof Southern California,School of Medicine.Los Angeles.CA. Address requests for reprints to Dr. M. Fevzi Ozkaynak, Division of Hematology-Oncology, Childrens Hospital of Los Angeles, Los Angeles, CA 90027. Received February 24, 1988; accepted April 13, 1988.
1 ~:~1988 ElsevierSciencePublishingCo., Inc. 655 Avenueof the Americas.New York, NY 10010
Cancer Genet Cytogenet 35:1 3 (1988) 0165-4608/88/$03.50
2
M . F . Ozkaynak, K-L. Ying, and W. E. Laug
33%, 35%, and 32% of the blasts, respectively. The blasts were negative for ~-naphthyl esterase. No surface marker studies were done. She was treated intravenously with nafcillin for the skin infection. After the infection cleared, the patient was placed under a laminar flow condition and c h e m o t h e r a p y according to the Children's Cancer Study Group Protocol 251 with 7 days of cytosine arabinoside (araC) and 3 days of d a u n o m y c i n was started. Complete remission was achieved in 2 weeks. Following a second course of ara-C and d a u n o m y c i n , she received prophylactic cranial irradiation together with 6-thioguanine (6-TG), ara-C, and intrathecal methotrexate (MTX) as the intensification phase of treatment. Maintenance consisted of 16-week courses of c h e m o t h e r a p y with alternating cycles of intravenous prednisolone, vincristine, MTX plus oral 6-mercaptopurine, intravenous azacytidine and d a u n o m y c i n ; d a u n o m y c i n and ara-C; intravenous carmustine and cyclop h o s p h a m i d e and 6-TG by mouth plus ara-C subcutaneously. She received five cycles of this maintenance therapy in 2 years. She had several episodes of severe n e u t r o p e n i a with infectious complications necessitating intravenous antibiotics. The patient was taken off c h e m o t h e r a p y in April 1984 and she has remained in remission since that time. She gave birth to a healthy boy on June 27, 1987.
Cytogenetic Findings Four bone marrow specimens were analyzed during a 2-month period. Chromosome preparations were made after 24-hour culture on the first bone marrow s p e c i m e n obtained on 12/10/81. Of 20 cells examined, an extra chromosome was consistently found in the C group. Because of the poor quality of the preparations, it was not possible to identify the extra chromosome. A second bone marrow sample was examined on 1/7/82, and a peripheral blood specimen was also obtained from the patient. The bone marrow was cultured for 24 hours and the blood was cultured for 72 hours in the presence of p h y t o h e m a g g l u t i n i n (PHA). Chromosome analysis from both revealed that an extra chromosome was present in all the cells e x a m i n e d (14 and 25, respectively). Both Q bands by fluorescence using quinacrine and G bands by trypsin using Giemsa revealed that the additional c h r o m o s o m e was an X chromosome. Thus, the patient's constitutional karotype was 47,XXX, w h i c h was also the only cell line found in bone marrow samples. These findings were confirmed on two additional bone marrow specimens examined on 1/18/82 and 2/10/82. Chromosome analysis again revealed 47,XXX in all 14 and 20 cells examined, respectively. No other chromosomal abnormality was found,
DISCUSSION Females with more than two X chromosomes (usually trisomic) were first observed by Jacobs et al. [2, 3] and occur with a frequency of about one in 800-1000 in the female p o p u l a t i o n [4, 5]. Although this chromosomal abnormality is not uncommon, these patients are not easily detected because of a lack of characteristic phenotypic manifestations. Occasional cases of XXX with cancer are encountered, including Hodgkin's l y m p h o m a , endometrial cancer, renal cancer, meningioma, and astrocytoma, but the exact incidence of neoplastic disease in this c o n d i t i o n is unk n o w n [5]. There are only two such acute leukemia patients reported in the literature; they had triple X and XO/XXX mosaicism, respectively [6, 7]. Recent catalogs of c h r o m o s o m e aberrations in cancer lists relatively few cases of structural abnormalities of the X in leukemic cells and none associated with polysomic X [8, 9]. Some leukemias, particularly ALL, may be associated solely with numerical chromosomal changes. H y p e r d i p l o i d ALL cases and ANLL cases with trisomy 8 are examples of such numerical changes in acute leukemias. It appears
T r i p l e X C h r o m o s o m e and A N L L
3
that the p r e s e n c e of o n l y n u m e r i c a l k a r y o t y p i c changes, p a r t i c u l a r l y t h o s e l e a d i n g to h y p e r d i p l o i d y , is a s s o c i a t e d w i t h a m u c h better prognosis t h a n w i t h k a r y o t y p i c c h a n g e s of the m o r p h o l o g i c t y p e [6, 11]. The s a m e m a y be true of ANLL, t h o u g h h e r e the s i t u a t i o n is m o r e c o m p l i c a t e d b e c a u s e the n u m b e r of cases of A N L L w i t h n u m e r i c a l changes o n l y is rather small c o m p a r e d w i t h ALL [1]. T h e s e n u m e r i c a l c h r o m o s o m a l changes s e e n in both ALL and ANLL are a c q u i r e d events. Therefore, one c a n n o t i m p l y an a s s o c i a t i o n w i t h p o l y s o m y X and prognosis in the case pres e n t e d here b e c a u s e the c h r o m o s o m a l a b n o r m a l i t y is c o n s t i t u t i o n a l . T h e r e are two p o s s i b l e e x p l a n a t i o n s for the a s s o c i a t i o n of triple X w i t h ANLL in our patient: 1) it is c o i n c i d e n c e ; 2) triple X m a y p r e d i s p o s e , as does t r i s o m y 21 [12], to acute leukemia. The s e c o n d p o s s i b i l i t y can be e v a l u a t e d by l o o k i n g at a c o n s e c u t i v e large series of females w i t h acute l e u k e m i a for triple X.
REFERENCES 1. Sandberg AA (1986): The chromosomes in human leukemia. Semin Hematol 23:201-217. 2. Jacobs PA, Baikie AG, Court Brown WM, et al. (1960): Evidence of the existence of the human "super female." Lancet ii:423. 3. Jacobs PA, Harnden DG, Court Brown WM, et al. (1960): Abnormalities involving the Xchromosome in women. Lancet i:1213. 4. Maclean N, Harnden GD, Court Brown WM, et al. (1964); Sex chromosome abnormalities in newborn babies. Lancet i:286. 5. Sandberg AA. (1983): The X chromosome m human neoplasia, including sex chromatin and congenital conditions with X-chromosome anomalies. In: Cytogenetics of the Mammalian X-Chromosome, Part B, Sandberg AA, ed. Alan R. Liss, NY, pp. 459-498. 6. Benitez J, Valearcel E, Ramos C, et al. (1987): Frequency of constitutional chromosome alterations in patients with hematologic neoplasias. Cancer Genet Cytogenet 24:345-354. 7. Lewis FJW, Poulding RH, Eastham RD. (1963): Acute leukemia in an XO/XXX mosaic. Lancet ii:306. 8. Chromosomal Variation in Man. Borgaonkar DS ed. New York: Alan R. Liss, 1984. 9. Mitelman F (1985): Catalog of Chromosome Aberrations in Cancer, Second ed. In: Progress and Topics in Cytogenetics, Vol. 5; Sandberg AA, ed, Alan R. Liss, NY. 10. Third International Workshop on Chromosomes in Leukemia, 1980 (1980): Clinical significance of chromosomal abnormalities in acute lymphoblastic leukemia. Cancer Genetic Cytogenet 4:111-137. 11. Williams DL, Anastasios T, Brodeur GM, et al. (1982): Prognostic importance of chromosome number in 136 untreated children with acute lymphoblastic leukemia. Blood 60:864-871. 12. Miller RV (1970): Neoplasia and Down's syndrome. Ann NY Acad Sci 171:637-644.
ABSTRACT: A case of acute nonlymphocytic leukemia occurring in a 15-year-old girl with a triple X sex chromosome constitution is discussed.
INTRODUCTION Acute lymphocytic leukemia (ALL) and acute n o n l y m p h o c y t i c leukemia (ANLL) have been demonstrated to be associated with chromosome changes in the leukemic cells. Often, only one karyotypic event is present in these cells, and in such cases this chromosome change can be assumed to be the primary (specific) one [1]. We detected triple X during routine cytogenetic examination in a 15-year-old girl with ANLL. X chromosome abnormalities are rarely associated with acute leukemias, but when they are, they are generally structural abnormalities. To our knowledge this is the second case report of an association of chromosome XXX with acute leukemia. CASE REPORT
A 15-year-old girl presented with a 3-month history of lethargy, anorexia, easy bruisability, and a weight loss of 8 kg. She was found to have staphylococcal septicemia and was hospitalized in October 1981. Two weeks after being discharged, she experienced an episode of hematemesis and was readmitted to another hospital where she was found to be pancytopenic. Leukemia was diagnosed in December 1981 by bone marrow examination, and she was then transferred to our hospital. Her physical examination on admission was unremarkable except for superficial fluctuant abscesses on the left distal arm, left proximal forearm, right lower quadrant of the abdomen, and right nasal antrum. No hepatosplenomegaly or lymphadenopathy were noted. A complete blood count showed Hbg 10.1 g/dl, platelets 18 × 109/L, and a white cell count of 6.9 × 109/L with 19% neutrophils, 47% lymphocytes, 29% blasts, 2% myelocytes, 2% basophils, and 1% eosinophils. Bone marrow examination showed 50% myeloblasts, 21% promyelocytes, 13% neutrophils, 7% erythroids, 7.2% lymphocytes, 1% plasmacytes, and 0.8% monocytes, and ANLL-M2 morphology (FAB classification) was diagnosed. S u d a n Black, peroxidase, chloroacetyl esterase, and periodic acid-Schiff stains were positive in 55%,
From the Divisionof Hematology-Oncologyand Medical Genetics,Childrens Hospital of Los Angeles, and Universityof Southern California,School of Medicine.Los Angeles.CA. Address requests for reprints to Dr. M. Fevzi Ozkaynak, Division of Hematology-Oncology, Childrens Hospital of Los Angeles, Los Angeles, CA 90027. Received February 24, 1988; accepted April 13, 1988.
1 ~:~1988 ElsevierSciencePublishingCo., Inc. 655 Avenueof the Americas.New York, NY 10010
Cancer Genet Cytogenet 35:1 3 (1988) 0165-4608/88/$03.50
2
M . F . Ozkaynak, K-L. Ying, and W. E. Laug
33%, 35%, and 32% of the blasts, respectively. The blasts were negative for ~-naphthyl esterase. No surface marker studies were done. She was treated intravenously with nafcillin for the skin infection. After the infection cleared, the patient was placed under a laminar flow condition and c h e m o t h e r a p y according to the Children's Cancer Study Group Protocol 251 with 7 days of cytosine arabinoside (araC) and 3 days of d a u n o m y c i n was started. Complete remission was achieved in 2 weeks. Following a second course of ara-C and d a u n o m y c i n , she received prophylactic cranial irradiation together with 6-thioguanine (6-TG), ara-C, and intrathecal methotrexate (MTX) as the intensification phase of treatment. Maintenance consisted of 16-week courses of c h e m o t h e r a p y with alternating cycles of intravenous prednisolone, vincristine, MTX plus oral 6-mercaptopurine, intravenous azacytidine and d a u n o m y c i n ; d a u n o m y c i n and ara-C; intravenous carmustine and cyclop h o s p h a m i d e and 6-TG by mouth plus ara-C subcutaneously. She received five cycles of this maintenance therapy in 2 years. She had several episodes of severe n e u t r o p e n i a with infectious complications necessitating intravenous antibiotics. The patient was taken off c h e m o t h e r a p y in April 1984 and she has remained in remission since that time. She gave birth to a healthy boy on June 27, 1987.
Cytogenetic Findings Four bone marrow specimens were analyzed during a 2-month period. Chromosome preparations were made after 24-hour culture on the first bone marrow s p e c i m e n obtained on 12/10/81. Of 20 cells examined, an extra chromosome was consistently found in the C group. Because of the poor quality of the preparations, it was not possible to identify the extra chromosome. A second bone marrow sample was examined on 1/7/82, and a peripheral blood specimen was also obtained from the patient. The bone marrow was cultured for 24 hours and the blood was cultured for 72 hours in the presence of p h y t o h e m a g g l u t i n i n (PHA). Chromosome analysis from both revealed that an extra chromosome was present in all the cells e x a m i n e d (14 and 25, respectively). Both Q bands by fluorescence using quinacrine and G bands by trypsin using Giemsa revealed that the additional c h r o m o s o m e was an X chromosome. Thus, the patient's constitutional karotype was 47,XXX, w h i c h was also the only cell line found in bone marrow samples. These findings were confirmed on two additional bone marrow specimens examined on 1/18/82 and 2/10/82. Chromosome analysis again revealed 47,XXX in all 14 and 20 cells examined, respectively. No other chromosomal abnormality was found,
DISCUSSION Females with more than two X chromosomes (usually trisomic) were first observed by Jacobs et al. [2, 3] and occur with a frequency of about one in 800-1000 in the female p o p u l a t i o n [4, 5]. Although this chromosomal abnormality is not uncommon, these patients are not easily detected because of a lack of characteristic phenotypic manifestations. Occasional cases of XXX with cancer are encountered, including Hodgkin's l y m p h o m a , endometrial cancer, renal cancer, meningioma, and astrocytoma, but the exact incidence of neoplastic disease in this c o n d i t i o n is unk n o w n [5]. There are only two such acute leukemia patients reported in the literature; they had triple X and XO/XXX mosaicism, respectively [6, 7]. Recent catalogs of c h r o m o s o m e aberrations in cancer lists relatively few cases of structural abnormalities of the X in leukemic cells and none associated with polysomic X [8, 9]. Some leukemias, particularly ALL, may be associated solely with numerical chromosomal changes. H y p e r d i p l o i d ALL cases and ANLL cases with trisomy 8 are examples of such numerical changes in acute leukemias. It appears
T r i p l e X C h r o m o s o m e and A N L L
3
that the p r e s e n c e of o n l y n u m e r i c a l k a r y o t y p i c changes, p a r t i c u l a r l y t h o s e l e a d i n g to h y p e r d i p l o i d y , is a s s o c i a t e d w i t h a m u c h better prognosis t h a n w i t h k a r y o t y p i c c h a n g e s of the m o r p h o l o g i c t y p e [6, 11]. The s a m e m a y be true of ANLL, t h o u g h h e r e the s i t u a t i o n is m o r e c o m p l i c a t e d b e c a u s e the n u m b e r of cases of A N L L w i t h n u m e r i c a l changes o n l y is rather small c o m p a r e d w i t h ALL [1]. T h e s e n u m e r i c a l c h r o m o s o m a l changes s e e n in both ALL and ANLL are a c q u i r e d events. Therefore, one c a n n o t i m p l y an a s s o c i a t i o n w i t h p o l y s o m y X and prognosis in the case pres e n t e d here b e c a u s e the c h r o m o s o m a l a b n o r m a l i t y is c o n s t i t u t i o n a l . T h e r e are two p o s s i b l e e x p l a n a t i o n s for the a s s o c i a t i o n of triple X w i t h ANLL in our patient: 1) it is c o i n c i d e n c e ; 2) triple X m a y p r e d i s p o s e , as does t r i s o m y 21 [12], to acute leukemia. The s e c o n d p o s s i b i l i t y can be e v a l u a t e d by l o o k i n g at a c o n s e c u t i v e large series of females w i t h acute l e u k e m i a for triple X.
REFERENCES 1. Sandberg AA (1986): The chromosomes in human leukemia. Semin Hematol 23:201-217. 2. Jacobs PA, Baikie AG, Court Brown WM, et al. (1960): Evidence of the existence of the human "super female." Lancet ii:423. 3. Jacobs PA, Harnden DG, Court Brown WM, et al. (1960): Abnormalities involving the Xchromosome in women. Lancet i:1213. 4. Maclean N, Harnden GD, Court Brown WM, et al. (1964); Sex chromosome abnormalities in newborn babies. Lancet i:286. 5. Sandberg AA. (1983): The X chromosome m human neoplasia, including sex chromatin and congenital conditions with X-chromosome anomalies. In: Cytogenetics of the Mammalian X-Chromosome, Part B, Sandberg AA, ed. Alan R. Liss, NY, pp. 459-498. 6. Benitez J, Valearcel E, Ramos C, et al. (1987): Frequency of constitutional chromosome alterations in patients with hematologic neoplasias. Cancer Genet Cytogenet 24:345-354. 7. Lewis FJW, Poulding RH, Eastham RD. (1963): Acute leukemia in an XO/XXX mosaic. Lancet ii:306. 8. Chromosomal Variation in Man. Borgaonkar DS ed. New York: Alan R. Liss, 1984. 9. Mitelman F (1985): Catalog of Chromosome Aberrations in Cancer, Second ed. In: Progress and Topics in Cytogenetics, Vol. 5; Sandberg AA, ed, Alan R. Liss, NY. 10. Third International Workshop on Chromosomes in Leukemia, 1980 (1980): Clinical significance of chromosomal abnormalities in acute lymphoblastic leukemia. Cancer Genetic Cytogenet 4:111-137. 11. Williams DL, Anastasios T, Brodeur GM, et al. (1982): Prognostic importance of chromosome number in 136 untreated children with acute lymphoblastic leukemia. Blood 60:864-871. 12. Miller RV (1970): Neoplasia and Down's syndrome. Ann NY Acad Sci 171:637-644.