- Email: [email protected]
Klinefelter Syndrome and Non-Hodgkin Lymphoma
ELSEVIER
Klinefelter Syndrome and Non-Hodgkin Lymphoma Mervyn Humphreys, Philip Lavery, Curly Morris, and Norman Nevin ABSTRACT: Patients with a 47,XXY karyotype (Klinefelter syndrome) appear to have an increased risk
of developing cancer, especially male breast cancer and germ cell tumors, but rarely malignant hematologic disorders. We report a patient with a low grade B-cell non-Hodgkin lymphoma with a 47,XXY karyotype in both the tumor and constitutional cells. This is only the 13th reported case of malignant lymphoma in a patient with Klinefelter syndrome. Although some authors postulate that the 47,XXY karyotype may be a predisposing factor in the development of hematological malignancies, the lack of reported cases suggests that such associations may be no more than chance findings. © Elsevier Science Inc., 1997
INTRODUCTION
Klinefelter syndrome (KS) is a constitutional chromosomal disorder characterized clinically by hypogonadism, azospermia, and gynecomastia [1] and cytogenetically by the constitutional sex chromosome abnormality 47,XXY [2]. The incidence is approximately 1 in 1000 live male births [3]. It has been established that KS patients have an increased cancer predisposition, especially for mate breast cancer [4], and non-gonadal germ cell tumors [5]. There have only been a few reports of hematological malignancies in patients with KS [6-18]. We report a Klinefelter syndrome patient with a low-grade, malignant non-Hodgkin lymphoma with a KS karyotype. The significance of the associations between KS and hematological malignancies is discussed. CASE REPORT
This 81-year-old patient initially presented in January 1990 with a history of night sweats and weight loss of 16.5 kg over the previous two years. On examination, he had a 10 cm palpable splenomegaly with no lymphadenopathy or other findings of note. Initial investigations showed Hb = 109 g/l, Platelets = 111 x 109/1, WBC = 2.8 x 109/1, ESR = 40 mm/hr, IgM paraprotein band of 8 g/1. The bone marrow aspirate showed an infiltrate of lymphoid and lymphoplasmacytoid cells accounting for 50% of all cells. A C T scan showed that there were no mediastinal or para-aortic nodes and that the spleen measured 18 cm x 8 cm. It was
thought that this was isolated splenomegaly with bone marrow tymphocytosis. A splenectomy was therefore carried out in March 1990 and the pathology reported a low grade B cell lymphoma. PCR analysis of DNA extracted from the spleen tissue sections confirmed clonal IgH gene rearrangement. By October 1990, the paraprotein band had fallen to 6 g/1 and the patient remained well apart from gynecomastia noted in October 1991. A repeat CT scan in February 1991 showed lymphodenopathy above and below the diaphragm. A repeat bone marrow biopsy showed infiltration with a population of small lymphocytes forming ill-defined nodules around the bony trabeculae. Immunoperoxidase staining showed positivity for CD45 (LCA) and CD20 (L26), confirming a diagnosis of a low grade Bcell non-Hodgkin lymphoma. MATERIALS AND METHODS
Bone marrow and peripheral blood samples were cultured for 72 hours with the B-cell mitogen tetradecanoyl phorbol acetate (TPA) in RPMI medium containing 20% fetal calf serum. After the addition of colcemid for 1 hour, cells were exposed to KC1 solution (0.075 M) and fixed in absolute alcohol/glacial acetic acid (3:1). Metaphases were trypsin Giemsa banded by conventional techniques. Further PHA-stimulated peripheral blood lymphocytes were cultured to confirm the constitutional karyotype. These cultures were harvested by the same standard techniques. RESULTS
From the Cytogenetic Laboratory, Regional Genetics Centre, and the Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland. Address reprint requests to: M. W. Humphreys, Cytogenetic Laboratory, Regional Genetics Centre, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, Northern Ireland. Received March 26, 1996; accepted October 11, 1996. Cancer Genet Cytogenet 97:111-113 (1997) © Elsevier Science Inc., 1997 655 Avenue of the Americas, N e w York, NY 10010
Cytogenetic analysis of bone marrow metaphases from the TPA-stimnlated cultures revealed a 47,XXY karyotype in all 20 cells examined, while analysis of TPA-stimulated blood cultures showed 13 of the 20 metaphases examined to have a 47,XXY karyotype. Analysis of the PHA-stimulated blood cultures revealed the 47,XXY karyotype in 18
9165-4608/97/$17.00 PII $0165-4608(96)00386-X
112 of the 20 metaphases examined, thus confirming that this c h r o m o s o m e abnormality is a constitutional abnormality associated with Klinefelter syndrome rather than an acquired chromosome abnormality.
M. W, H u m p h r e y s et al. cytogenetic analysis was supported by the Northern Ireland Leukaemia Research Fund.
REFERENCES DISCUSSION
There is a strong suggestion that patients with constitutional chromosome abnormalities m a y be more susceptible to malignancy; for example, children with trisomy 21 have an 18-fold increased risk of developing acute leukemia [19]. The implications of X-chromosome abnormalities in h u m a n cancer were r e v i e w e d by Sandberg in 1983 [20]. There is a high frequency of distinct malignancies in patients with KS. Tumors are m a i n l y related to hormoned e p e n d e n t tissues such as male breast cancer [4] and germ cell tumors [5]. Male breast cancer has a 20-fold increased frequency in KS patients c o m p a r e d to the n o r m a l population. Some KS patients also have been reported with acute n o n - l y m p h o b l a s t i c leukemia. (ANLL) [6-9], acute lymphoblastic l e u k e m i a (ALL) [10-13], chronic m y e l o i d leukemia [14], m y e l o d y s p l a s t i c s y n d r o m e (MDS) [15], nonHodgkin l y m p h o m a (NHL) [16-18], sarcomas [21], b l a d d e r carcinoma [22], and prostate cancer [23]. Our KS patient represents only the 13th reported case of malignant l y m p h o m a in association with a 47,XXY karyotype. The majority of p r e v i o u s l y reported cases have been high-grade NHL of the B-cell type [16-18]. Although the increased susceptibility to breast cancer and germ cell tumors is well-established in KS, it is unclear w h e t h e r such patients are also prone to hematological malignancies. In a group of 60 males with acute leukemia, Geraedts et al. [7] reported four patients with KS. They suggested that the 47,XXY karyotype increases the risk of AL in KS by 100 times that of the normal population. Subsequent reports have not substantiated Geraedts et al.'s conclusion. In a review of 1200 male patients investigated cytogenetically for actual or suspected hematological malignancy, Horsman [9] found only one patient with acute l e u k e m i a who had a 47,XXY karyotype. From a birth incidence of 1:1000 male births for KS, Horsman estimated that one or two patients with a 47,XXY karyotype w o u l d have been expected among their group of 1200 male patients, Benitez et al. [24] found 59 cases with constitutional c h r o m o s o m e abnormalities among 5500 cases of hematological conditions. Although constitutional chromosomal abnormalities were significantly more prevalent among this group of hematological conditions than in the normal population, there was no significant association between KS and such disorders. With a c h r o m o s o m a l disorder with a frequency as high as KS, cases of l e u k e m i a or l y m p h o m a m a y occur by chance. Although the general consensus suggests that associations between KS and hematological conditions are p u r e l y coincidental, the uncertainty can only be resolved by more data from case reports and hematological cytogenetic studies. The authors gratefully acknowledge D. Ryan for carrying out PCR analysis of DNA extracted from the spleen tissue sections. This
1. Klinefelter HF Jr, Reinfenstein EC Jr, Albright F (1942): Syndrome characterized by gynaecomastia, azospermatogenesis without aleydigism and increased excretion of follicularstimulating hormone. J Clin Endocrinol 2:615. 2. Jacob PA, Strong JA (1959): A case of human intersexuality having a possible XXY-sex determining mechanism. Nature 183:302. 3. Hook EB, Hamerton JL (1977): The frequency of chromosome abnormalities detected in consecutive newborn studies. In: Population Cytogenetics. EB Hook, IH Porter, eds. Academic Press, NY. 4. Jackson AW, Muldal S, Ockey CH, O'Conner PJ (1965): Carcinoma of male breast in association with Klinefelter syndrome. Br Med J 1:223-225. 5. McNeil MM, Leong AS-Y, Sage RE (1981): Primary mediastihal embryonal carcinoma in association with Klinefelter syndrome. Cancer 47:343-345. 6. Mamunes P, Lapidus PH, Abbot JA, Roath S (1961): Acute leukaemia and Klinefelter's syndrome. Lancet ii:26-27. 7. Geraedts JPM, Mol A, Bri~t E, Hartgrink-Groeneveld CA, den Ottolander GJ (1980): Klinefelter syndrome: predisposition to acute non-lymphoblastic leukemia? Lancet i:744. 8. Muts-Homsma SJ, Muller HP, Geraedst Jp (1982): Klinefelter's syndrome and acute non-lymphocytic leukaemia. Blut 44:15. 9. Horsman DE, Pantzar JT, Dell FJ, Kalousek DK (1987): Klinefelter syndrome and acute leukemia. Cancer Genet Cytogenet 26:375-376. 10. Gale GB, Toledano SR (1984): Congenital acute lymphocytic leukemia in a newborn with Klinefelter syndrome. Am J Pediat Hematol/Oncol 6:338-339. 11. Borges WH, Nicklas JW, Hamm CW (1967): Prezygotic determinants of acute leukemia. J Pediatr 70:180-184. 12. Sohn KY, Boggs DR (1974): Klinefelter's syndrome. LSD usage and acute lymphoblastic leukemia. Clin Genet. 6:20-22. 13. Shaw MP, Eden OB, Grace E, Ellis PM (1992): Acute lymphoblastic leukemia and Klinefelter's syndrome. Pediatr Hematol/Oncol 9:81-85. 14. Tough IM, Court Brown WM, Baikie MG, Buckton KE, Harnden DG, Jacobs PA, King MJ, McBride JA (1961): Cytogenetic studies in chronic myeloid and acute leukaemia associated with mongolism. Lancet i:411-417. 15. Abidi SM, Griffiths M, Oscier DG, Mufti GJ, Hamblin TJ (1986): Primary myelodysplatic syndrome with complex chromosomal rearrangements in a patient with Klinefelter's syndrome. J Med Genet 23:183-185. 16. Becher R (1986): Klinefelter's syndrome and malignant lymphoma. Cancer Genet Cytogenet 21:271-273. 17. Koyama M, Uejima K, Konishi T, Ishida M, Kato M, Nishigaki M, Mizutani H, Matsumoto K, Kawasw M, Tamaki T (1992): A case of malignant lymphoma accompanied by Klinefelter syndrome. Internal Medicine 31:496-499. 18. Attard-Montalto SP, Schuller I, Lastowska MA, Gibbons B, Kingston JE, Eden OB (1994): Non-Hodgkin's lymphoma and Klinefelter syndrome. Pedi Hematol Oncol 11:197-200. 19. Miller RW (1970): Neoplasia and Down's syndrome. Ann NY Acad Sci 171:637. 20. Sandberg AA (1983): The X chromosome in human neopla-
Klinefelter Syndrome and Non-Hodgkin L y m p h o m a
sia, including sex chromatin and congenital conditions with X chromosome anomalies. In: Cytogenetics of the Mammalian X chromosome: X chromosome Anomalies and their Clinical Manifestations. AA Sandberg, ed. Alan R. Liss, New York, p. 459. 21. MacSween RNM (1965): Reticulum-cell sarcoma and rheumatoid arthritis in a patient with XY/XXY/XXXY Klinefelter's syndrome and normal intelligence. Lancet i:460-461.
113
22. Fujita K, Fujita HM (1976): Klinefelter's syndrome and bladder cancer. J Urol 116:836. 23. Arduino LJ (1967): Carcinoma of the prostate in sex chromatin positive (XXY/XY) Klinefelter's syndrome. J Urol 98:234. 24. Benitez J, Valcarcel E, Ramos C, Ayuso C, Cascas AS (1987): Frequency of constitutional chromosome alterations in patients with hematologic neoplasias. Cancer Genet Cytogenet 24:345-354.
Klinefelter Syndrome and Non-Hodgkin Lymphoma Mervyn Humphreys, Philip Lavery, Curly Morris, and Norman Nevin ABSTRACT: Patients with a 47,XXY karyotype (Klinefelter syndrome) appear to have an increased risk
of developing cancer, especially male breast cancer and germ cell tumors, but rarely malignant hematologic disorders. We report a patient with a low grade B-cell non-Hodgkin lymphoma with a 47,XXY karyotype in both the tumor and constitutional cells. This is only the 13th reported case of malignant lymphoma in a patient with Klinefelter syndrome. Although some authors postulate that the 47,XXY karyotype may be a predisposing factor in the development of hematological malignancies, the lack of reported cases suggests that such associations may be no more than chance findings. © Elsevier Science Inc., 1997
INTRODUCTION
Klinefelter syndrome (KS) is a constitutional chromosomal disorder characterized clinically by hypogonadism, azospermia, and gynecomastia [1] and cytogenetically by the constitutional sex chromosome abnormality 47,XXY [2]. The incidence is approximately 1 in 1000 live male births [3]. It has been established that KS patients have an increased cancer predisposition, especially for mate breast cancer [4], and non-gonadal germ cell tumors [5]. There have only been a few reports of hematological malignancies in patients with KS [6-18]. We report a Klinefelter syndrome patient with a low-grade, malignant non-Hodgkin lymphoma with a KS karyotype. The significance of the associations between KS and hematological malignancies is discussed. CASE REPORT
This 81-year-old patient initially presented in January 1990 with a history of night sweats and weight loss of 16.5 kg over the previous two years. On examination, he had a 10 cm palpable splenomegaly with no lymphadenopathy or other findings of note. Initial investigations showed Hb = 109 g/l, Platelets = 111 x 109/1, WBC = 2.8 x 109/1, ESR = 40 mm/hr, IgM paraprotein band of 8 g/1. The bone marrow aspirate showed an infiltrate of lymphoid and lymphoplasmacytoid cells accounting for 50% of all cells. A C T scan showed that there were no mediastinal or para-aortic nodes and that the spleen measured 18 cm x 8 cm. It was
thought that this was isolated splenomegaly with bone marrow tymphocytosis. A splenectomy was therefore carried out in March 1990 and the pathology reported a low grade B cell lymphoma. PCR analysis of DNA extracted from the spleen tissue sections confirmed clonal IgH gene rearrangement. By October 1990, the paraprotein band had fallen to 6 g/1 and the patient remained well apart from gynecomastia noted in October 1991. A repeat CT scan in February 1991 showed lymphodenopathy above and below the diaphragm. A repeat bone marrow biopsy showed infiltration with a population of small lymphocytes forming ill-defined nodules around the bony trabeculae. Immunoperoxidase staining showed positivity for CD45 (LCA) and CD20 (L26), confirming a diagnosis of a low grade Bcell non-Hodgkin lymphoma. MATERIALS AND METHODS
Bone marrow and peripheral blood samples were cultured for 72 hours with the B-cell mitogen tetradecanoyl phorbol acetate (TPA) in RPMI medium containing 20% fetal calf serum. After the addition of colcemid for 1 hour, cells were exposed to KC1 solution (0.075 M) and fixed in absolute alcohol/glacial acetic acid (3:1). Metaphases were trypsin Giemsa banded by conventional techniques. Further PHA-stimulated peripheral blood lymphocytes were cultured to confirm the constitutional karyotype. These cultures were harvested by the same standard techniques. RESULTS
From the Cytogenetic Laboratory, Regional Genetics Centre, and the Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland. Address reprint requests to: M. W. Humphreys, Cytogenetic Laboratory, Regional Genetics Centre, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, Northern Ireland. Received March 26, 1996; accepted October 11, 1996. Cancer Genet Cytogenet 97:111-113 (1997) © Elsevier Science Inc., 1997 655 Avenue of the Americas, N e w York, NY 10010
Cytogenetic analysis of bone marrow metaphases from the TPA-stimnlated cultures revealed a 47,XXY karyotype in all 20 cells examined, while analysis of TPA-stimulated blood cultures showed 13 of the 20 metaphases examined to have a 47,XXY karyotype. Analysis of the PHA-stimulated blood cultures revealed the 47,XXY karyotype in 18
9165-4608/97/$17.00 PII $0165-4608(96)00386-X
112 of the 20 metaphases examined, thus confirming that this c h r o m o s o m e abnormality is a constitutional abnormality associated with Klinefelter syndrome rather than an acquired chromosome abnormality.
M. W, H u m p h r e y s et al. cytogenetic analysis was supported by the Northern Ireland Leukaemia Research Fund.
REFERENCES DISCUSSION
There is a strong suggestion that patients with constitutional chromosome abnormalities m a y be more susceptible to malignancy; for example, children with trisomy 21 have an 18-fold increased risk of developing acute leukemia [19]. The implications of X-chromosome abnormalities in h u m a n cancer were r e v i e w e d by Sandberg in 1983 [20]. There is a high frequency of distinct malignancies in patients with KS. Tumors are m a i n l y related to hormoned e p e n d e n t tissues such as male breast cancer [4] and germ cell tumors [5]. Male breast cancer has a 20-fold increased frequency in KS patients c o m p a r e d to the n o r m a l population. Some KS patients also have been reported with acute n o n - l y m p h o b l a s t i c leukemia. (ANLL) [6-9], acute lymphoblastic l e u k e m i a (ALL) [10-13], chronic m y e l o i d leukemia [14], m y e l o d y s p l a s t i c s y n d r o m e (MDS) [15], nonHodgkin l y m p h o m a (NHL) [16-18], sarcomas [21], b l a d d e r carcinoma [22], and prostate cancer [23]. Our KS patient represents only the 13th reported case of malignant l y m p h o m a in association with a 47,XXY karyotype. The majority of p r e v i o u s l y reported cases have been high-grade NHL of the B-cell type [16-18]. Although the increased susceptibility to breast cancer and germ cell tumors is well-established in KS, it is unclear w h e t h e r such patients are also prone to hematological malignancies. In a group of 60 males with acute leukemia, Geraedts et al. [7] reported four patients with KS. They suggested that the 47,XXY karyotype increases the risk of AL in KS by 100 times that of the normal population. Subsequent reports have not substantiated Geraedts et al.'s conclusion. In a review of 1200 male patients investigated cytogenetically for actual or suspected hematological malignancy, Horsman [9] found only one patient with acute l e u k e m i a who had a 47,XXY karyotype. From a birth incidence of 1:1000 male births for KS, Horsman estimated that one or two patients with a 47,XXY karyotype w o u l d have been expected among their group of 1200 male patients, Benitez et al. [24] found 59 cases with constitutional c h r o m o s o m e abnormalities among 5500 cases of hematological conditions. Although constitutional chromosomal abnormalities were significantly more prevalent among this group of hematological conditions than in the normal population, there was no significant association between KS and such disorders. With a c h r o m o s o m a l disorder with a frequency as high as KS, cases of l e u k e m i a or l y m p h o m a m a y occur by chance. Although the general consensus suggests that associations between KS and hematological conditions are p u r e l y coincidental, the uncertainty can only be resolved by more data from case reports and hematological cytogenetic studies. The authors gratefully acknowledge D. Ryan for carrying out PCR analysis of DNA extracted from the spleen tissue sections. This
1. Klinefelter HF Jr, Reinfenstein EC Jr, Albright F (1942): Syndrome characterized by gynaecomastia, azospermatogenesis without aleydigism and increased excretion of follicularstimulating hormone. J Clin Endocrinol 2:615. 2. Jacob PA, Strong JA (1959): A case of human intersexuality having a possible XXY-sex determining mechanism. Nature 183:302. 3. Hook EB, Hamerton JL (1977): The frequency of chromosome abnormalities detected in consecutive newborn studies. In: Population Cytogenetics. EB Hook, IH Porter, eds. Academic Press, NY. 4. Jackson AW, Muldal S, Ockey CH, O'Conner PJ (1965): Carcinoma of male breast in association with Klinefelter syndrome. Br Med J 1:223-225. 5. McNeil MM, Leong AS-Y, Sage RE (1981): Primary mediastihal embryonal carcinoma in association with Klinefelter syndrome. Cancer 47:343-345. 6. Mamunes P, Lapidus PH, Abbot JA, Roath S (1961): Acute leukaemia and Klinefelter's syndrome. Lancet ii:26-27. 7. Geraedts JPM, Mol A, Bri~t E, Hartgrink-Groeneveld CA, den Ottolander GJ (1980): Klinefelter syndrome: predisposition to acute non-lymphoblastic leukemia? Lancet i:744. 8. Muts-Homsma SJ, Muller HP, Geraedst Jp (1982): Klinefelter's syndrome and acute non-lymphocytic leukaemia. Blut 44:15. 9. Horsman DE, Pantzar JT, Dell FJ, Kalousek DK (1987): Klinefelter syndrome and acute leukemia. Cancer Genet Cytogenet 26:375-376. 10. Gale GB, Toledano SR (1984): Congenital acute lymphocytic leukemia in a newborn with Klinefelter syndrome. Am J Pediat Hematol/Oncol 6:338-339. 11. Borges WH, Nicklas JW, Hamm CW (1967): Prezygotic determinants of acute leukemia. J Pediatr 70:180-184. 12. Sohn KY, Boggs DR (1974): Klinefelter's syndrome. LSD usage and acute lymphoblastic leukemia. Clin Genet. 6:20-22. 13. Shaw MP, Eden OB, Grace E, Ellis PM (1992): Acute lymphoblastic leukemia and Klinefelter's syndrome. Pediatr Hematol/Oncol 9:81-85. 14. Tough IM, Court Brown WM, Baikie MG, Buckton KE, Harnden DG, Jacobs PA, King MJ, McBride JA (1961): Cytogenetic studies in chronic myeloid and acute leukaemia associated with mongolism. Lancet i:411-417. 15. Abidi SM, Griffiths M, Oscier DG, Mufti GJ, Hamblin TJ (1986): Primary myelodysplatic syndrome with complex chromosomal rearrangements in a patient with Klinefelter's syndrome. J Med Genet 23:183-185. 16. Becher R (1986): Klinefelter's syndrome and malignant lymphoma. Cancer Genet Cytogenet 21:271-273. 17. Koyama M, Uejima K, Konishi T, Ishida M, Kato M, Nishigaki M, Mizutani H, Matsumoto K, Kawasw M, Tamaki T (1992): A case of malignant lymphoma accompanied by Klinefelter syndrome. Internal Medicine 31:496-499. 18. Attard-Montalto SP, Schuller I, Lastowska MA, Gibbons B, Kingston JE, Eden OB (1994): Non-Hodgkin's lymphoma and Klinefelter syndrome. Pedi Hematol Oncol 11:197-200. 19. Miller RW (1970): Neoplasia and Down's syndrome. Ann NY Acad Sci 171:637. 20. Sandberg AA (1983): The X chromosome in human neopla-
Klinefelter Syndrome and Non-Hodgkin L y m p h o m a
sia, including sex chromatin and congenital conditions with X chromosome anomalies. In: Cytogenetics of the Mammalian X chromosome: X chromosome Anomalies and their Clinical Manifestations. AA Sandberg, ed. Alan R. Liss, New York, p. 459. 21. MacSween RNM (1965): Reticulum-cell sarcoma and rheumatoid arthritis in a patient with XY/XXY/XXXY Klinefelter's syndrome and normal intelligence. Lancet i:460-461.
113
22. Fujita K, Fujita HM (1976): Klinefelter's syndrome and bladder cancer. J Urol 116:836. 23. Arduino LJ (1967): Carcinoma of the prostate in sex chromatin positive (XXY/XY) Klinefelter's syndrome. J Urol 98:234. 24. Benitez J, Valcarcel E, Ramos C, Ayuso C, Cascas AS (1987): Frequency of constitutional chromosome alterations in patients with hematologic neoplasias. Cancer Genet Cytogenet 24:345-354.