Hematologic malignancies and Klinefelter syndrome

Cancer Genetics and Cytogenetics 139 (2002) 9–13

Hematologic malignancies and Klinefelter syndrome: a chance association? Yi-Kong Keunga,*, David Bussb, Allen Chauvenetc, Mark Pettenatid a

Section of Hematology-Oncology, Comprehensive Cancer Center of Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157-1082, USA b Department of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1082 USA c Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1082 USA d Cytogenetic Laboratory, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1082 USA Received 12 April 2002; received in revised form 21 May 2002; accepted 22 May 2002

Abstract

Klinefelter syndrome was first described in 1942 as an endocrine disorder characterized by gynecomastia, hypogonadism, small testes, and elevated levels of follicle-stimulating hormone. An extra X chromosome (i.e., 47,XXY) was subsequently demonstrated in these patients and an increased incidence of leukemia and lymphoma has been described. We report a retrospective study of a series of unselected patients with Klinefelter syndrome diagnosed by cytogenetic studies and the occurrence of hematologic malignancies. The literature is also reviewed. © 2002 Elsevier Science Inc. All rights reserved.

1. Introduction

3. Results

Klinefelter syndrome (KS) was first described in 1942 as an endocrine disorder characterized by gynecomastia, hypogonadism, small testes, and elevated levels follicle-stimulating hormone (FSH). An extra X chromosome (i.e., 47,XXY) was subsequently demonstrated in these patients [1]. These patients tend to have an increased risk of developing male breast cancer and mediastinal germ cell tumor [2–6]. Leukemia and lymphoma are not infrequent among these patients. We report a retrospective study of a series of unselected patients with KS diagnosed by cytogenetic studies and occurrence of hematologic malignancies.

Forty-two patients were diagnosed with KS by virtue of the karyotype of 47,XXY in their peripheral blood or bone marrow from January 1992 to April 2001. Prenatal cases of 47,XXY diagnosed by amniocentesis were excluded in this study. Eleven cases were deemed nonevaluable because they were referred for cytogenetic studies only and no medical records were available for review. Among these 11 cases, a 22-year-old patient had complex cytogenetic abnormalities in the bone marrow specimen, 48,XXYc, der(1)t(1;21) (p11;p11.2),5,der(7)t(1;7)(p11;p11.2), 11,  del(11)(q13), 13, 20[20]/47,XXYc[4], consistent with myelodysplastic syndrome or acute leukemia. The medical records of the remaining 31 cases were reviewed. The median age at the time of diagnosis was 19.7 (range 0–68.3). The initial cytogenetic studies were performed with peripheral blood specimens in all except four cases in which KS was established in bone marrow specimens. Among the four bone marrow cases, one patient was diagnosed with anemia of chronic disease, and the other three patients had Ki-1 anaplastic large-cell lymphoma, myelodysplastic syndrome, and acute lymphoblastic leukemia. The latter three cases are described in further detail below.

2. Materials and methods Patients with KS (i.e., 47,XXY) were identified from the database of the Cytogenetic Laboratory in this institution from January 1992 through April 2001. The medical records of these patients were reviewed. Review of medical literature was performed by searching MEDLINE using keywords “Klinefelter syndrome” and “lymphoma” or “leukemia” as well as the references quoted in these articles.

3.1. Case 1 * Corresponding author. Tel.: (336) 716-7972; fax: (336) 716-5687. E-mail address: [email protected] (Y.-K. Keung).

A 29-year-old male presented in February 2000 with bilateral groin lymphadenopathy. Excisional biopsy demon-

0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S0165-4608(02)00 6 2 6 - X

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Y.K. Keung et al. / Cancer Genetics and Cytogenetics 139 (2002) 9–13

strated CD30 anaplastic large-cell lymphoma. Bilateral bone marrow examination at the time of diagnosis was normal. He received six cycles of cyclophosphamide, adriamycin, oncovin (vincristine), and prednisone (CHOP) followed by radiation to bilateral inguinal lymph nodes. Pathologically confirmed recurrent disease involving right cervical nodes was diagnosed a year later. Computerized tomography of the chest, abdomen, and pelvis was normal. He was referred to this institution for consideration of autologous stem cell transplantation. Physical examination demonstrated enlarged cervical nodes. Genital examination was significant for small testes. There was no gynecomastia. Restaging bone marrow examination was again normal. Cytogenetic study of the bone marrow demonstrated 47,XXYc[20]; the same karyotype was also detected in the peripheral blood. Serum luteinizing hormone (LH) and FSH levels were elevated to 33.3 mIU/mL (normal 0.9–10.6) and 39.6 mIU/mL (normal 2–17.7). Testosterone was 223 ng/dL (normal 270–1194). He underwent high-dose cyclophosphamide and busulfan followed by autologous stem cell transplant with prompt engraftment by day 10. He was free of recurrence 6 months after transplant.

3.3. Case 3 A 31-year-old male presented in April 1996 with general malaise, vomiting, and dehydration. WBC was 8800/L, with 16% neutrophils, 62% lymphocytes, and 14% blasts; hemoglobin was 13.8 and platelet count was 206,000/L. Serum sodium was 150 mg/dL, creatinine 1.3 mg/dL, blood urea nitrogen 12 mg/dL, and uric acid 9.5 mg/dL. Bone marrow examination revealed a hypocellular marrow with 20% myeloblasts and trilineage dysplasia, consistent with refractory anemia with excess of blasts in transformation. Cytogenetic study of the bone marrow showed 46,XXYc, inv(3)(q21q26),7[18]/ 47,XXYc[2]. His disease failed to respond to induction of chemotherapy with cytarabine and doxorubicin. He was then referred to this institution for further management. On presentation, serum sodium was 157 mg/dL, creatinine 2.1 mg/dL, and uric acid 9.1 mg/dL. Central diabetes insipidus (DI) was subsequently diagnosed and was successfully treated with desmopressin (DDAVP). Magnetic resonance imaging of the brain did not reveal any pituitary or hypothalamic lesion. Cerebrospinal fluid analysis and cytology were normal. Serum LH level was 27.3 mIU/mL. Complete remission was obtained after reinduction with high-dose cytarabine, mitoxantrone, and L-asparaginase. Bone marrow cytogenetic study at the time of remission revealed 47, XXYc[20]. The patient received highdose cyclophosphamide and fractionated total body radiation followed by HLA-matched bone marrow transplantation in October 1996 from an unrelated male donor. By day 36 after transplant, he developed refractory graft versus host disease of the skin and gastrointestinal tract despite vigorous immunosuppressive therapies and he finally succumbed to pneumonia 2 months after transplant. Thirty-seven case reports of hematologic malignancies (7 cases of lymphoma and 30 cases of leukemia and myelodysplastic syndrome) are identified and summarized in Tables 1 and 2, respectively. The median age at diagnosis of lymphoma is 39 years (range 3.75–81), acute leukemia/

3.2. Case 2 A 2 1/2-year-old male presented with limping gait and spontaneous gingival bleeding. Physical examination revealed no lymphadenopathy or hepatosplenomegaly. White blood cell (WBC) count was 3,200/ L, with 15% neutrophils, 70% lymphocytes, and 10% monocytes; hemoglobin was 8.4 gm/dL and platelet count was 95,000/L. Bone marrow examination revealed pre-B acute lymphoblastic leukemia. The cytogenetic study of the bone marrow revealed 47,XXYc[16]/54,XXYc,4,8,9,12,17,18, 21[3]. Peripheral blood karyotype was 47,XXYc, and so was the bone marrow karyotype that was repeated after complete remission was achieved. He was treated with chemotherapy and has been in remission for 2.75 years. Table 1 Case reports of lymphoma associated with Klinefelter syndrome

Karyotype

Year

Age

Histology

KS pre- or postdate NHL

BM involved

PB

BM

Tumor

Reference no.

1965

53 y

RCS

Same







[16]

1974

46 y

Low grade lymphoma

Post







[17]

1986

47 y

High grade B-cell

Same







[18]

1987

10 y

Same

Yes

48,XXY,mar



[19]

1990 1994 1997

33 y 40 m 81 y

MGCT, 6wk after, malignant histiocytosis Immunoblastic B-cell lymphoma B-lymphoblastic lymphoma Low grade B-cell lymphoma

46,XY/ 47,XXY/ 48,XXXY 46,XY/ 47,XXY 46,XY/ 47,XXY 47,XXY

Pre Same Same

No No Yes

 47,XXY 47,XXY

 47,XXY 

[20] [21] [22]

Current

31

Anaplastic Ki-1 lymphoma

Same

No

  46,XY/ 47,XXY 47,XXY

47,XXY



Case no.

Abbreviations: BM, bone marrow; m, months; MGCT, mediastinal germ cell tumor; PB, peripheral blood; RCS, reticulum cell sarcoma; y, years; —, not reported.

Y.K. Keung et al. / Cancer Genetics and Cytogenetics 139 (2002) 9–13

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Table 2 Case reports of leukemia associated with Klinefelter syndrome Age (Y)

KS pre- or post dated leukemia

36 30 64 34 40 10 m 16 7m 2.5

Pre Pre Same Same Same Same Same Same Same

1994 2000 1986

19 9d 21 m 42 m 4 49 68

1993

Year

Reference no.

FAB

Peripheral blood

Bone marrow

47,XXY 47,XXY 47,XXY – 47,XXY[23] 47,XXY 47,XXY 47,XXY 47,XXYa

  47,XXY[10] 47,XXY[14]/48,XXY,8 [5]/48,XXY,20q,21[5] 47,XXY[26] 47,XXY 47,XXY 46,XXY,Y,t(10;11)(p13;q14) 46,XY[3]/47,XXY[23]/hyperploidy 47[3]

[7] [23],[24]

Same Same Same Same Same Same Same

AML AML-M2 AML-M1 AML-M2 AML-M4 AML-M7 AMML AML-M5a Acute leukemia, undifferentiated ALL ALL-L2 ALL ALL ALL-L2 ALL-L2 MDS, RARS

48,XXXY 47,XXY 47,XXY 46,XY/47,XXY 47,XXY 46,XY/47,XXY 47,XXY

[28] [29] [30]

40

Same

MDS, 1 m later 2 AML

47,XXYb

1981 1982

51 14

Same Same

PRV, 14 y later 2 AML-M4 MGCT, 18 m later 2 AML

  47,XXY 46,XY/47,XXY 47,XXY 47,XXY,t(9;22;11)(q34;q11.2;q13) 47,XXY/4546,XXY,5,7,12,21,del(3p),21, t(7;21),t(3;12),mar1,mar2[cp] 47,XXY/47,XXY,del(2)(q13),del(3)(q12), del(5)(q13q33),7,12,der(17)(p11),3mar 47,XXY[20] 47,XXY/50,XY,A,A,D,D

1990

16

Same

47,XXY 47,XXY/50,XY, A,A,D,D  47,XXY/48,XXY,i(12p)

1994 1961

15 59

Same Same

MGCT concomitant with AML-M5 MGCT, 6 m later 2 AML-M6 47,XXY CML 47,XXYc

1971 1985 1986 1989 1990 1978 1991 1978 Current Current

69 41 43 27 35 69 41 60 2.5 32

Same  Post Pre Same Same Pre Same Same Same

CML CML CML blast crisis CML CML MPD Prostate CA, 2 y later CLL T-CLL ALL-L1 RAEB

1961 1981

1986 1987 1992 1967 1974 1984 1992

46,XY/47,XXY 47,XXY  46,XY/47,XXY 47,XXY 46,XY/47,XXY 47,XXY 47,XXYa 47,XXY 

[25] [9] [26] [27]

[31] [32] [33] [34] [23],[24] [35] [36]

50,XXY,4,5,11,17,21,4mar [37] 46,XY[3]/47,XXY [5] 46,XY,Ph[14]/47,XXY,Ph[2] [38] (peripheral blood) 46,XY,Ph/47,XXY [39] 47,XXY,Ph/53,XXY,Ph,X, 4,8,18,18,22q [8] 47,XXY,Ph,Ph,mar/47,XXY,Ph [40] 47,XXY,t(9;22)(q34;q11) [41] 47,XXY,t(9;22)(q34;q11) [42] 47,XXY/47,XXY,20q [43] 47,XXY [44] 47,XXY,-8,14,18,t(3;8),t(11;14),i(18q),11q [45] 47,XXY[16]/54,XXY,4,8,9,12,17,18,21[3] Case 2 47,XXY[2]/46,XXY,inv(3)(q21q26),7[18] Case 3

a

Buccal smear. Bone marrow fibroblast. c Skin fibroblasts. Abbreviations: FAB, French–American–British classification; m, months; MGCT, mediastinal germ cell tumor; MPD, myeloproliferative disorder; Ph, Philadelphia chromosome; PRV, polycthemia rubra vera; y, years. b

MDS is 16 years (range 9 days–68 years), and chronic leukemia is 43 years (range 27–69). In 29 cases (78%), the diagnosis of KS was made concomitantly with the diagnosis of hematologic malignancies. Five cases were known to have KS before the diagnosis of malignancy.

4. Discussion Mamunes et al. described the first case of acute leukemia in a patient with KS [7]. Sporadic reports of leukemia and other hematologic malignancies have been reported since then, and these cases are summarized in this review. Among patients with constitutional chromosomal abnormalities, Al-

imena et al. reported an increased frequency of leukemia; however, only one case of KS was included in that study [8]. Horsman et al. reviewed the bone marrow cytogenetic studies of more than 1200 male patients in British Columbia (population of 2 million) and found only one case of KS associated with acute myelomonocytic leukemia. They concluded that acute leukemia and KS was a chance association [9]. Price et al. followed 466 patients with KS prospectively for 25 years and found that 15 died of malignancies (9 lung, 2 breast, 1 anal, and 1 pancreatic cancer; one multiple myeloma; one lymphoma). No cases of leukemia were identified [10]. Hasle et al. studied the incidence of cancer among a cohort of 696 men with KS and found only one case of chronic lymphocytic leukemia [11].

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In the current study of 31 patients with KS, two cases of acute leukemia were encountered. This apparent increase in the prevalence of acute leukemia is intriguing. We believe, however, that this increase is at least partly due to of the increased frequency of cytogenetic studies in the patients with hematologic malignancies. From January 1992 to April 2001, 517 male patients with acute leukemia have been diagnosed and treated in this institution. Every patient had at least one cytogenetic study of the bone marrow. Assuming the incidence of KS in a normal male population is 1:500 [12–14], one would expect to see one case of KS among our male patients with acute leukemia. Furthermore, as demonstrated in Tables 1 and 2, 78% of cases had KS diagnosed concomitantly with lymphoma or leukemia. It is conceivable that KS is more likely to be “discovered” in medical conditions such as leukemia and lymphoma, which routinely require cytogenetic studies. The covert nature of KS is further supported by recent study. While the prevalence of KS in male breast cancer was estimated to be 2.6%, Hultborn et al. detected a threefold increase in the prevalence (7.5%) by using a more sensitive fluorescent in situ hybridization technique in 93 male breast cancer patients [3,4,15]. In view of KS being easily underdiagnosed, the current epidemiologic studies should be interpreted with caution. Larger studies are required to confirm or disprove the association of KS and hematologic malignancies. References [1] Klinefelter HF. Klinefelter syndrome: historical background and development. South Med J 1986;79:1089–93. [2] Harnden DG, Maclean N, Langlands AO. Carcinoma of the breast and Klinefelter syndrome. J Med Genet 1971;8:460–1. [3] Scheike O, Visfeldt J, Petersen B. Male breast cancer. 3. Breast carcinoma in association with the Klinefelter syndrome. Acta Pathol Microbiol Scand [A] 1973;81:352–8. [4] Evans DB, Crichlow RW. Carcinoma of the male breast and Klinefelter syndrome: is there an association? CA Cancer J Clin 1987;37:246–51. [5] Nichols CR. Mediastinal germ cell tumors. Semin Thorac Cardiovasc Surg 1992;4:45–50. [6] Nichols CR, Heerema NA, Palmer C, Loehrer PJ Sr, Williams SD, Einhorn LH. Klinefelter syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 1987;5:1290–4. [7] Mamunes P. Acute leukemia and Klinefelter syndrome. Lancet 1961; ii:26–7. [8] Alimena G, Billstrom R, Casalone R, Gallo E, Mitelman F, Pasquali F. Cytogenetic pattern in leukemic cells of patients with constitutional chromosome anomalies. Cancer Genet Cytogenet 1985;16:207–18. [9] Horsman DE, Pantzar JT, Dill FJ, Kalousek DK. Klinefelter syndrome and acute leukemia. Cancer Genet Cytogenet 1987;26:375–6. [10] Price WH, Clayton JF, Wilson J, Collyer S, De Mey R. Causes of death in X chromatin positive males (Klinefelter syndrome). J Epidemiol Community Health 1985;39:330–6. [11] Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer 1995;71:416–20. [12] Jacobs PA. The incidence and etiology of sex chromosome abnormalities in man. Birth Defects Orig Artic Ser 1979;15:3–14. [13] Gerald PS. Sex chromosome disorders. N Engl J Med 1976;294:706–8. [14] Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus. Birth Defects Orig Artic Ser 1990;26:209–23.

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