Klinefelter Syndrome Patient with Ckronic Myelogenous Leukemia
The association between congenital chromosomal abnormalities and predisposition to neoplastic disease is well known. Down syndrome patients are at a high risk of developing leukemia [1]. An association exists between deletion of band 13q14 and retionoblastoma [2] and deletion of band 11q13 and Wilms' tumor [3]. The implications of extra X chromosome anomalies in human neoplasia have been reported [4], and occur in about one in 500-700 live births. Various malignancies such as male breast cancers [5], carcinoma of the bladder [6], and extra gonadal germ cell tumors [7, 8], have been reported in patients with Klinefelter syndrome. Of all these malignancies, occurrence of breast carcinoma was reported to be almost 20 times more frequent in patients with Klinefelter syndrome as compared with normal males [5]. Regarding hematological malignancies, occurrence of lymphoma and various leukemias in patients with 47, XXY has been reported [9-11]. Chronic myelogenous leukemia (CML) has been reported rarely [10 I. We report a case of Klinefelter syndrome with CML. The bone marrow chromosomal complement was 47,XXY, t(9;22)(q34;q11) in all metaphases studied.
CASE REPORT A male patient, aged 35 years, was admitted to M. P. Shah Cancer Hospital, Ahmedabad, in March 1986, with a complaint of generalized weakness. Physical examination showed a pale, poorly built male. No enlarged lymph nodes were palpable. The spleen was markedly enlarged, almost reaching the umbilicus. He had scanty facial hair, and no hair on the chest. The pubic hair had a feminine distribution. The testes were small, and gynecomastia was absent. Systemic examination showed no other abnormality. Chest roentgenogram was normal. Hematological analysis showed a hemoglobin of 75 g/L; the total white blood cell count was 1.2 × 10~I/L, erythrocyte sedimentation rate was 47 mm/h, and platelet count was 2.7 × 1011/L. The peripheral smear showed many premature myeloid cells with a mixed population consisting of 16% promyelocytes, 13% myelocytes, 10% metamyelocytes, 5% band cells, 45% polymorphs, 6% lymphocytes, 2% basophils, and 3% eosinophils. Bone marrow aspiration showed a marked increase in cellularity, with premature myeloid cells dominating the cell population. A diagnosis of CML was made from the peripheral blood smear and bone marrow findings. He was started on Myleran, and successful remission was achieved.
Cytogenetic Study From the bone marrow and peripheral blood without mitogen stimulation, 86 metaphases were studied at diagnosis. All metaphases showed the presence of a Philadelphia (Ph) chromosome, which resulted from the reciprocal translocation between chromosome 9 and 22. Chromosomal constitution of all the cells was 47,XXY,t(9;22)(q34;q11).
135 © 1990 Elsevier Science Publishing Co., Inc. 655 A v e n u e of the Americas, New York, NY 10010
Cancer Genet Cytogenet 4 8 : 1 3 5 - 1 3 7 (1990) 0165-4608/90/$03.59
136
s . G . A d h v a r y u et al. Each of the 36 metaphases from P H A - M - s t i m u l a t e d peripheral blood l y m p h o c t y t e s had a chromosome c o m p l e m e n t of 47,XXY. A Ph chromosome was not observed in the mitogen-stimulated lymphocytes.
DISCUSSION In the case of XXY individuals, breast carcinoma and nongonadal dysgenesis have been reported frequently [5, 7, 8]. Apart from these malignancies, leukemia also has been reported in patients with Klinefelter s y n d r o m e [9-11]. Geraedts et al. [9] reported four cases of Klinefelter s y n d r o m e among 60 patients with acute leukemia and believed these patients to be at a higher risk for leukemia. Their claims, however, have not been substantiated by other investigators; the high incidence reported by Geraedts et al. [9] may have resulted from the small s a m p l e size or the samples may have come from a selected population. So far, we have studied 380 leukemia patients for chromosomal patterns at diagnosis; the present patient was the first to have Klinefelter syndrome. The frequency of occurrence of leukemia is quite comparable to the incidence of Klinefelter s y n d r o m e among normal males, w h i c h is about one in 500-700 live births in this part of the world. This also suggests that these patients are not at an elevated risk of developing leukemia. Our report is in agreement with the report of A l i m e n a et al. [10]. Considering the data of Sandberg [4] and the c o m p i l a t i o n by Mitelman [12], to the best of our knowledge, only three cases of Klinefelter s y n d r o m e with CML have been d o c u m e n t e d in the literature. However, further reports on this type may help elucidate whether leukemogenesis is more frequent in Klinefelter s y n d r o m e patients than in comparable control group subjects.
The authors wish to thank Dr. T. B. Patel, Director, Gujarat Cancer and Research Institute, Ahmedabad, for the facilities provided. SIDDHARTH G. ADHVARYU KALYANI H. JANI DAMODAR B. BALAR* PANKAJ M. SHAH*
Departments of Cancer Biology, *Pathology, and ~:Medical Oncology Gujarat Cancer and Research Institute A h m e d a b a d , 380016 India
REFERENCES 1. Kaneko Y, Rowley JD, Variakojis D, Chilcote RR, Moohr JW, Patel D (1981): Chromosome abnormalities in Down's syndrome patients with acute leukemia. Blood 58:459-466. 2. Knudson AG, Meadows AT, Nichols WW, Hill R (1976]: Chromosome deletion and retinoblastoma. N Engl J Med 295:1120-1124. 3. Riccardi VM, Hittner HM, Francke U, Yunis JJ, Ledbetter D, Borges W (1980J: The aniridia--Wilms' tumor association: The critical role of chromosome band 1l ql 3. Cancer Genet Cytogenet 2:131-137. 4. Sandberg AA (1981}: The Chromosome in Human Cancer and Leukemia. Elsevier Science Publishing Company, New York, pp. 129-131. 5. Dodge OG, Path MC, Jackson AW, Muldal S (1969): Breast cancer and interstitial cell tumor in a patient with Klinefelter's syndrome. Cancer 24:1027-1032. 6. Fnjita K, Fujita HM (1976): Klinefelter's syndrome and bladder cancer, J Urol 116:836-837. 7. Mann BD, Sparkes RS, Kern DH, Morton DL (1983): Chromosomal abnormalities of a mediastinal embryonal cell carcinoma in a patient with 47XXY, Klinefelter's syndrome: Evidence for the premeiotic origin of a germ cell tumor. Cancer Genet Cytogenet 8:191-196. 8. McNeil MM, Leong AS, Sage RE (1981): Primary mediastinal embryonal carcinoma in association with Klinefelter's syndrome. Cancer 47:343-345.
K l i n e f e l t e r S y n d r o m e Patient w i t h CML
13 7
9. Geraedts IP, MoI A, Brier E, Hartgrink-Groeneve[d CA, Ottplander GI (19801: Klinefelter's syndrome: Predisposition to acute non-lymphatic leukemia? [Letterl. Lancet 1:774. 10. Alimena G, Billstrom R, Casalone R, Gallo E, Mitelman F, Pasquali F (1985): Cytogenetic pattern in leukemic cells of patients with constitutional chromosome anomalies. Cancer Genet Cytogenet 16:207-218. 11. Horsman DE, Pantzar JT, Dill FJ, Kalousek DK (1987): Klinefelter's syndrome and acute leukemia. Cancer Genet Cytogenet 26:375-376. 12. Mitelman F (1985): Catalog of Chromosome Aberrations in Cancer. Alan R. Liss, New York, pp 608-615.
The association between congenital chromosomal abnormalities and predisposition to neoplastic disease is well known. Down syndrome patients are at a high risk of developing leukemia [1]. An association exists between deletion of band 13q14 and retionoblastoma [2] and deletion of band 11q13 and Wilms' tumor [3]. The implications of extra X chromosome anomalies in human neoplasia have been reported [4], and occur in about one in 500-700 live births. Various malignancies such as male breast cancers [5], carcinoma of the bladder [6], and extra gonadal germ cell tumors [7, 8], have been reported in patients with Klinefelter syndrome. Of all these malignancies, occurrence of breast carcinoma was reported to be almost 20 times more frequent in patients with Klinefelter syndrome as compared with normal males [5]. Regarding hematological malignancies, occurrence of lymphoma and various leukemias in patients with 47, XXY has been reported [9-11]. Chronic myelogenous leukemia (CML) has been reported rarely [10 I. We report a case of Klinefelter syndrome with CML. The bone marrow chromosomal complement was 47,XXY, t(9;22)(q34;q11) in all metaphases studied.
CASE REPORT A male patient, aged 35 years, was admitted to M. P. Shah Cancer Hospital, Ahmedabad, in March 1986, with a complaint of generalized weakness. Physical examination showed a pale, poorly built male. No enlarged lymph nodes were palpable. The spleen was markedly enlarged, almost reaching the umbilicus. He had scanty facial hair, and no hair on the chest. The pubic hair had a feminine distribution. The testes were small, and gynecomastia was absent. Systemic examination showed no other abnormality. Chest roentgenogram was normal. Hematological analysis showed a hemoglobin of 75 g/L; the total white blood cell count was 1.2 × 10~I/L, erythrocyte sedimentation rate was 47 mm/h, and platelet count was 2.7 × 1011/L. The peripheral smear showed many premature myeloid cells with a mixed population consisting of 16% promyelocytes, 13% myelocytes, 10% metamyelocytes, 5% band cells, 45% polymorphs, 6% lymphocytes, 2% basophils, and 3% eosinophils. Bone marrow aspiration showed a marked increase in cellularity, with premature myeloid cells dominating the cell population. A diagnosis of CML was made from the peripheral blood smear and bone marrow findings. He was started on Myleran, and successful remission was achieved.
Cytogenetic Study From the bone marrow and peripheral blood without mitogen stimulation, 86 metaphases were studied at diagnosis. All metaphases showed the presence of a Philadelphia (Ph) chromosome, which resulted from the reciprocal translocation between chromosome 9 and 22. Chromosomal constitution of all the cells was 47,XXY,t(9;22)(q34;q11).
135 © 1990 Elsevier Science Publishing Co., Inc. 655 A v e n u e of the Americas, New York, NY 10010
Cancer Genet Cytogenet 4 8 : 1 3 5 - 1 3 7 (1990) 0165-4608/90/$03.59
136
s . G . A d h v a r y u et al. Each of the 36 metaphases from P H A - M - s t i m u l a t e d peripheral blood l y m p h o c t y t e s had a chromosome c o m p l e m e n t of 47,XXY. A Ph chromosome was not observed in the mitogen-stimulated lymphocytes.
DISCUSSION In the case of XXY individuals, breast carcinoma and nongonadal dysgenesis have been reported frequently [5, 7, 8]. Apart from these malignancies, leukemia also has been reported in patients with Klinefelter s y n d r o m e [9-11]. Geraedts et al. [9] reported four cases of Klinefelter s y n d r o m e among 60 patients with acute leukemia and believed these patients to be at a higher risk for leukemia. Their claims, however, have not been substantiated by other investigators; the high incidence reported by Geraedts et al. [9] may have resulted from the small s a m p l e size or the samples may have come from a selected population. So far, we have studied 380 leukemia patients for chromosomal patterns at diagnosis; the present patient was the first to have Klinefelter syndrome. The frequency of occurrence of leukemia is quite comparable to the incidence of Klinefelter s y n d r o m e among normal males, w h i c h is about one in 500-700 live births in this part of the world. This also suggests that these patients are not at an elevated risk of developing leukemia. Our report is in agreement with the report of A l i m e n a et al. [10]. Considering the data of Sandberg [4] and the c o m p i l a t i o n by Mitelman [12], to the best of our knowledge, only three cases of Klinefelter s y n d r o m e with CML have been d o c u m e n t e d in the literature. However, further reports on this type may help elucidate whether leukemogenesis is more frequent in Klinefelter s y n d r o m e patients than in comparable control group subjects.
The authors wish to thank Dr. T. B. Patel, Director, Gujarat Cancer and Research Institute, Ahmedabad, for the facilities provided. SIDDHARTH G. ADHVARYU KALYANI H. JANI DAMODAR B. BALAR* PANKAJ M. SHAH*
Departments of Cancer Biology, *Pathology, and ~:Medical Oncology Gujarat Cancer and Research Institute A h m e d a b a d , 380016 India
REFERENCES 1. Kaneko Y, Rowley JD, Variakojis D, Chilcote RR, Moohr JW, Patel D (1981): Chromosome abnormalities in Down's syndrome patients with acute leukemia. Blood 58:459-466. 2. Knudson AG, Meadows AT, Nichols WW, Hill R (1976]: Chromosome deletion and retinoblastoma. N Engl J Med 295:1120-1124. 3. Riccardi VM, Hittner HM, Francke U, Yunis JJ, Ledbetter D, Borges W (1980J: The aniridia--Wilms' tumor association: The critical role of chromosome band 1l ql 3. Cancer Genet Cytogenet 2:131-137. 4. Sandberg AA (1981}: The Chromosome in Human Cancer and Leukemia. Elsevier Science Publishing Company, New York, pp. 129-131. 5. Dodge OG, Path MC, Jackson AW, Muldal S (1969): Breast cancer and interstitial cell tumor in a patient with Klinefelter's syndrome. Cancer 24:1027-1032. 6. Fnjita K, Fujita HM (1976): Klinefelter's syndrome and bladder cancer, J Urol 116:836-837. 7. Mann BD, Sparkes RS, Kern DH, Morton DL (1983): Chromosomal abnormalities of a mediastinal embryonal cell carcinoma in a patient with 47XXY, Klinefelter's syndrome: Evidence for the premeiotic origin of a germ cell tumor. Cancer Genet Cytogenet 8:191-196. 8. McNeil MM, Leong AS, Sage RE (1981): Primary mediastinal embryonal carcinoma in association with Klinefelter's syndrome. Cancer 47:343-345.
K l i n e f e l t e r S y n d r o m e Patient w i t h CML
13 7
9. Geraedts IP, MoI A, Brier E, Hartgrink-Groeneve[d CA, Ottplander GI (19801: Klinefelter's syndrome: Predisposition to acute non-lymphatic leukemia? [Letterl. Lancet 1:774. 10. Alimena G, Billstrom R, Casalone R, Gallo E, Mitelman F, Pasquali F (1985): Cytogenetic pattern in leukemic cells of patients with constitutional chromosome anomalies. Cancer Genet Cytogenet 16:207-218. 11. Horsman DE, Pantzar JT, Dill FJ, Kalousek DK (1987): Klinefelter's syndrome and acute leukemia. Cancer Genet Cytogenet 26:375-376. 12. Mitelman F (1985): Catalog of Chromosome Aberrations in Cancer. Alan R. Liss, New York, pp 608-615.
