Cancer Genetics and Cytogenetics 139 (2002) 9–13

0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.PII: S0165-4608(02)00626-X

Hematologic malignancies and Klinefelter syndrome:a chance association?

Yi-Kong Keung

a,*

, David Buss

b

, Allen Chauvenet

c

, Mark Pettenati

d

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 withKlinefelter 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

Klinefelter syndrome (KS) was first described in 1942 asan endocrine disorder characterized by gynecomastia, hy-pogonadism, small testes, and elevated levels follicle-stimu-lating 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 devel-oping male breast cancer and mediastinal germ cell tumor[2–6]. Leukemia and lymphoma are not infrequent amongthese patients. We report a retrospective study of a series ofunselected patients with KS diagnosed by cytogenetic stud-ies and occurrence of hematologic malignancies.

2. Materials and methods

Patients with KS (i.e., 47,XXY) were identified from thedatabase of the Cytogenetic Laboratory in this institutionfrom January 1992 through April 2001. The medical recordsof these patients were reviewed.

Review of medical literature was performed by searchingMEDLINE using keywords “Klinefelter syndrome” and“lymphoma” or “leukemia” as well as the references quotedin these articles.

3. Results

Forty-two patients were diagnosed with KS by virtue ofthe karyotype of 47,XXY in their peripheral blood or bonemarrow from January 1992 to April 2001. Prenatal cases of47,XXY diagnosed by amniocentesis were excluded in thisstudy. Eleven cases were deemed nonevaluable because theywere referred for cytogenetic studies only and no medicalrecords were available for review. Among these 11 cases, a22-year-old patient had complex cytogenetic abnormalitiesin the bone marrow specimen, 48,XXY

c

,

�

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,XXY

c

[4], consistent with myelodysplas-tic syndrome or acute leukemia.

The medical records of the remaining 31 cases were re-viewed. The median age at the time of diagnosis was 19.7(range 0–68.3). The initial cytogenetic studies were per-formed with peripheral blood specimens in all except fourcases in which KS was established in bone marrow speci-mens. Among the four bone marrow cases, one patient wasdiagnosed with anemia of chronic disease, and the otherthree patients had Ki-1 anaplastic large-cell lymphoma, my-elodysplastic syndrome, and acute lymphoblastic leukemia.The latter three cases are described in further detail below.

3.1. Case 1

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

* Corresponding author. Tel.: (336) 716-7972; fax: (336) 716-5687.

E-mail address

: ykeung@wfubmc.edu (Y.-K. Keung).

10

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

strated CD30

�

anaplastic large-cell lymphoma. Bilateralbone marrow examination at the time of diagnosis was nor-mal. He received six cycles of cyclophosphamide, adriamy-cin, oncovin (vincristine), and prednisone (CHOP) followedby radiation to bilateral inguinal lymph nodes. Pathologicallyconfirmed recurrent disease involving right cervical nodeswas diagnosed a year later. Computerized tomography of thechest, abdomen, and pelvis was normal. He was referred tothis institution for consideration of autologous stem celltransplantation. Physical examination demonstrated enlargedcervical nodes. Genital examination was significant for smalltestes. There was no gynecomastia. Restaging bone marrowexamination was again normal. Cytogenetic study of the bonemarrow demonstrated 47,XXY

c

[20]; the same karyotype wasalso detected in the peripheral blood. Serum luteinizing hor-mone (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). Test-osterone was 223 ng/dL (normal 270–1194). He underwenthigh-dose cyclophosphamide and busulfan followed by autol-ogous stem cell transplant with prompt engraftment by day10. He was free of recurrence 6 months after transplant.

3.2. Case 2

A 2 1/2-year-old male presented with limping gait andspontaneous gingival bleeding. Physical examination re-vealed no lymphadenopathy or hepatosplenomegaly. Whiteblood cell (WBC) count was 3,200/

�

L, with 15% neutro-phils, 70% lymphocytes, and 10% monocytes; hemoglobinwas 8.4 gm/dL and platelet count was 95,000/

�

L. Bonemarrow examination revealed pre-B acute lymphoblasticleukemia. The cytogenetic study of the bone marrow re-vealed 47,XXY

c

[16]/54,XXY

c

,

�

4,

�

8,

�

9,

�

12,

�

17,

�

18,

�

21[3]. Peripheral blood karyotype was 47,XXY

c

, and sowas the bone marrow karyotype that was repeated aftercomplete remission was achieved. He was treated with che-motherapy and has been in remission for 2.75 years.

3.3. Case 3

A 31-year-old male presented in April 1996 with generalmalaise, vomiting, and dehydration. WBC was 8800/

�

L, with16% neutrophils, 62% lymphocytes, and 14% blasts; hemoglo-bin was 13.8 and platelet count was 206,000/

�

L. Serumsodium was 150 mg/dL, creatinine 1.3 mg/dL, blood urea ni-trogen 12 mg/dL, and uric acid 9.5 mg/dL. Bone marrow ex-amination revealed a hypocellular marrow with 20% myelo-blasts and trilineage dysplasia, consistent with refractory ane-mia with excess of blasts in transformation. Cytogenetic studyof the bone marrow showed 46,XXY

c

, inv(3)(q21q26),

�

7[18]/47,XXY

c

[2]. His disease failed to respond to induction of che-motherapy with cytarabine and doxorubicin. He was then re-ferred to this institution for further management. On presenta-tion, serum sodium was 157 mg/dL, creatinine 2.1 mg/dL, anduric acid 9.1 mg/dL. Central diabetes insipidus (DI) was subse-quently diagnosed and was successfully treated with desmo-pressin (DDAVP

)

. Magnetic resonance imaging of the braindid not reveal any pituitary or hypothalamic lesion. Cere-brospinal fluid analysis and cytology were normal. Serum LHlevel was 27.3 mIU/mL. Complete remission was obtained af-ter reinduction with high-dose cytarabine, mitoxantrone, and

L

-asparaginase. Bone marrow cytogenetic study at the time ofremission revealed 47, XXY

c

[20]. The patient received high-dose cyclophosphamide and fractionated total body radiationfollowed by HLA-matched bone marrow transplantation inOctober 1996 from an unrelated male donor. By day 36 aftertransplant, he developed refractory graft versus host disease ofthe skin and gastrointestinal tract despite vigorous immunosup-pressive therapies and he finally succumbed to pneumonia 2months after transplant.

Thirty-seven case reports of hematologic malignancies(7 cases of lymphoma and 30 cases of leukemia and myelo-dysplastic syndrome) are identified and summarized in Ta-bles 1 and 2, respectively. The median age at diagnosis oflymphoma is 39 years (range 3.75–81), acute leukemia/

Table 1Case reports of lymphoma associated with Klinefelter syndrome

Year Age HistologyKS pre- orpostdate NHL BM involved

Karyotype Referenceno.PB BM Tumor

1965 53 y RCS Same

�

46,XY/47,XXY/48,XXXY

� �

[16]

1974 46 y Low grade lymphoma Post

�

46,XY/47,XXY

� �

[17]

1986 47 y High grade B-cell Same

�

46,XY/47,XXY

� �

[18]

1987 10 y MGCT, 6wk after, malignanthistiocytosis

Same Yes 47,XXY 48,XXY,

�

mar

�

[19]

1990 33 y Immunoblastic B-cell lymphoma Pre No

� � �

[20]1994 40 m B-lymphoblastic lymphoma Same No

�

47,XXY 47,XXY [21]1997 81 y Low grade B-cell lymphoma Same Yes 46,XY/

47,XXY47,XXY

�

[22]

Current 31 Anaplastic Ki-1 lymphoma Same No 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; —, notreported.

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

11

MDS is 16 years (range 9 days–68 years), and chronic leu-kemia is 43 years (range 27–69). In 29 cases (78%), the di-agnosis of KS was made concomitantly with the diagnosisof hematologic malignancies. Five cases were known tohave KS before the diagnosis of malignancy.

4. Discussion

Mamunes et al. described the first case of acute leukemiain a patient with KS [7]. Sporadic reports of leukemia andother hematologic malignancies have been reported sincethen, and these cases are summarized in this review. Amongpatients 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 cytogeneticstudies of more than 1200 male patients in British Columbia(population of 2 million) and found only one case of KS as-sociated with acute myelomonocytic leukemia. They con-cluded that acute leukemia and KS was a chance association[9]. Price et al. followed 466 patients with KS prospectivelyfor 25 years and found that 15 died of malignancies (9 lung,2 breast, 1 anal, and 1 pancreatic cancer; one multiple my-eloma; one lymphoma). No cases of leukemia were identi-fied [10]. Hasle et al. studied the incidence of cancer amonga cohort of 696 men with KS and found only one case ofchronic lymphocytic leukemia [11].

Table 2Case reports of leukemia associated with Klinefelter syndrome

YearAge(Y)

KS pre- or postdated leukemia FAB Peripheral blood Bone marrow

Referenceno.

1961 36 Pre AML 47,XXY

�

[7]1981 30 Pre AML-M2 47,XXY

�

[23],[24] 64 Same AML-M1 47,XXY 47,XXY[10]34 Same AML-M2 – 47,XXY[14]/48,XXY,

�

8 [5]/48,XXY,20q

�

,

�

21[5]40 Same AML-M4 47,XXY[23] 47,XXY[26]

1986 10 m Same AML-M7 47,XXY 47,XXY [25]1987 16 Same AMML 47,XXY 47,XXY [9]1992 7 m Same AML-M5a 47,XXY 46,XXY,

�

Y,t(10;11)(p13;q14) [26]1967 2.5 Same Acute leukemia,

undifferentiated 47,XXY

a

46,XY[3]/47,XXY[23]/hyperploidy

�

47[3] [27]

1974 19 Same ALL 48,XXXY

�

[28]1984 9d Same ALL-L2 47,XXY

�

[29]1992 21 m Same ALL 47,XXY 47,XXY [30]

42 m Same ALL 46,XY/47,XXY 46,XY/47,XXY1994 4 Same ALL-L2 47,XXY 47,XXY [31]2000 49 Same ALL-L2 46,XY/47,XXY 47,XXY,t(9;22;11)(q34;q11.2;q13) [32]1986 68 Same MDS, RARS 47,XXY 47,XXY/45

�

46,XXY,

�

5,

�

7,

�

12,

�

21,del(3p),

�

21,t(7;21),t(3;12),

�

mar1,

�

mar2[cp] [33]

1993 40 Same MDS, 1 m later 2

�

AML 47,XXY

b

47,XXY/47,XXY,del(2)(q13),del(3)(q12),del(5)(q13q33),

�

7,

�

12,der(17)(p11),

�

3mar [34]

1981 51 Same PRV, 14 y later 2

�

AML-M4 47,XXY 47,XXY[20] [23],[24]1982 14 Same MGCT, 18 m later 2

�

AML 47,XXY/50,XY,

�

A,

�

A,

�

D,

�

D47,XXY/50,XY,

�

A,

�

A,

�

D,

�

D [35]

1990 16 Same MGCT concomitant with AML-M5

�

47,XXY/48,XXY,

�

i(12p) [36]

1994 15 Same MGCT, 6 m later 2

�

AML-M6 47,XXY 50,XXY,

�

4,

�

5,

�

11,

�

17,

�

21,

�

4mar [37]1961 59 Same CML 47,XXY

c

46,XY[3]/47,XXY [5] 46,XY,Ph[14]/47,XXY,Ph[2](peripheral blood)

[38]

1971 69 Same CML 46,XY/47,XXY 46,XY,Ph/47,XXY [39]1985 41

�

CML 47,XXY 47,XXY,Ph/53,XXY,Ph,

�

X,

�

4,

�

8,

�

18,

�

18,

�

22q

�

[8]1986 43 Post CML blast crisis

�

47,XXY,Ph,

�

Ph,

�

mar/47,XXY,Ph [40]1989 27 Pre CML 46,XY/47,XXY 47,XXY,t(9;22)(q34;q11) [41]1990 35 Same CML 47,XXY 47,XXY,t(9;22)(q34;q11) [42]1978 69 Same MPD 46,XY/47,XXY 47,XXY/47,XXY,20q

�

[43]1991 41 Pre Prostate CA, 2 y later CLL 47,XXY 47,XXY [44]1978 60 Same T-CLL 47,XXY

a

47,XXY,-8,

�

14,

�

18,

�

t(3;8),

�

t(11;14),

�

i(18q),11q

�

[45]Current 2.5 Same ALL-L1 47,XXY 47,XXY[16]/54,XXY,

�

4,

�

8,

�

9,

�

12,

�

17,

�

18,

�

21[3] Case 2Current 32 Same RAEB

�

47,XXY[2]/46,XXY,inv(3)(q21q26),

�

7[18] Case 3

a

Buccal smear.

b

Bone marrow fibroblast.

cSkin 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.

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

In the current study of 31 patients with KS, two cases ofacute leukemia were encountered. This apparent increase inthe prevalence of acute leukemia is intriguing. We believe,however, that this increase is at least partly due to of the in-creased frequency of cytogenetic studies in the patients withhematologic malignancies.

From January 1992 to April 2001, 517 male patients withacute leukemia have been diagnosed and treated in this in-stitution. Every patient had at least one cytogenetic study ofthe bone marrow. Assuming the incidence of KS in a nor-mal male population is 1:500 [12–14], one would expect tosee one case of KS among our male patients with acute leu-kemia. Furthermore, as demonstrated in Tables 1 and 2,78% of cases had KS diagnosed concomitantly with lym-phoma or leukemia. It is conceivable that KS is more likelyto be “discovered” in medical conditions such as leukemiaand lymphoma, which routinely require cytogenetic studies.

The covert nature of KS is further supported by recentstudy. While the prevalence of KS in male breast cancer wasestimated to be 2.6%, Hultborn et al. detected a threefold in-crease in the prevalence (7.5%) by using a more sensitive fluo-rescent in situ hybridization technique in 93 male breast cancerpatients [3,4,15]. In view of KS being easily underdiagnosed,the current epidemiologic studies should be interpreted withcaution. Larger studies are required to confirm or disprove theassociation of KS and hematologic malignancies.

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