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SEMINOMA IN KLINEFELTER'S SYNDROME WITH 47, XXY, 15s+ KARYOTYPE

KOICHIRO ISURUGI, MD, SADAO IMAO, MD, KINJIRO HIROSE, MD AND HIROKO AOKI, BSc*

A 32-year-old man was found to have seminoma of the right testis which had been subjected to orchiopexy for cryptorchism 14 years earlier. The left testis was small and firm, and the patient was further studied for hypogonadism. Chromosome analysis revealed a karyotype of 47, XXY, 15s+ with an extra X chromosome and enlarged and fluorescent satellites on chromosome 1 5 . The satellites were also found in the mother as well as in two sisters and one brother out of his four siblings. Endocrine studies, histological pictures of the biopsied left testis and dermatoglyphic analysis were compatible with Klinefelter's syndrome. To our knowledge this is the first reported case of seminoma associated with the syndrome. Several implications are discussed for the rare occurrence of a germinal cell tumor in Klinefelter's syndrome.

Cancer 39:2041-2047, 1977.

ARIOUS NEOPLASTIC LESIONS H A V E BEEN RE- V ported to occur in patients with Klinefel- ter's syndrome. 2,18,21 In particular, the high incidence of male breast cancer in patients with the syndrome has been emphasized. l 1 Regard- ing the testis as the site of tumor development, however, only occasional cases of benign tumors have been reported. '*' The present paper de- scribes a case of seminoma in a testis of Klinefel- ter's syndrome after orchiopexy. In addition to an extra X chromosome, there were intensively fluorescent materials on satellites of autosome 15 (47, XXY, 15s+).

CASE REPORT

K.T. was 32 years old when he was first seen in May 1971, at the Department of Urology, Bokutoh

From the Ikpartment of Urology, Bokutoh General Hos- pital, Tokyo Metropolitan Government, 4-23-15 Kotobashi, Sumidaku, Tokyo 130.

Address for reprints: Koichiro Isurugi, Department of Urology, The Liniversity of Tokyo Branch Hospital, Mejirodai, Bunkyo-ku, Tokyo 112.

* Department of Cytogenetics. Medical Research In- stitute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, 'Tokyo I 13, Japan.

The authors are grateful to Miss Y. Hayashida, Depart- ment of Legal Medicine, the University of Tokyo School of Medicine, for her kind co-operation in blood group and haptoglobin studies, to Dr. K. Harada, Department of Legal Medicine, Kyorin University School of Medicine for erythrocyte enzyme analyses, and to Dr. S. Nanko, Department of Human Genetics and Criminology, Institute of Brain Re- search, University of Tokyo School of Medicine for dermatoglyphic analysis performed in the present study.

Accepted for publication August 26, 1976.

General Hospital for an enlargement of the right scrota1 content. He was born on January 16, 1939, a t full term after uneventful pregnancy as the first child for the parents who were unrelated and healthy without any known hereditary diseases. No abnormality of the external genitalia was noticed by the parents and physical growth and mental development were said to be normal until puberty except that the patient suf- fered from bronchial asthma in childhood. At the age of 18 (1957), the patient noticed that the right testis was located in the inguinal region and received orchiopexy in a hospital. At this time it was pointed out by the physician that the bilateral testes were small but the patient received no further examination. He stated that development of the secondary sexual char- acteristics had been normal and he had not received any medication before.

At the time of his first visit to our hospital in 1971, the external genitalia were underdeveloped with a small, phimotic penis and the left testis which was small and firm. The prostate was also small on palpa- tion. A female type distribution of the pubic hair was noted. There was no gynecomastia. The right testis was enlarged symmetrically to a hen-egg sized hard tumor. The height was 158.3 cm, the arm span 151.0 cm, and the body weight 54 kg. Blood counts, blood chemistries, liver function studies and the erythrocyte sedimentation rate were all within normal limits. The chest and skull films and excretory urograms were also normal.

The right testicular tumor (6.6 X 4.4 X3.8 cm) was removed on May 18, 1971, and the pathological diagnosis was pure seminoma (Fig. 1). The patient post- operatively received a total of 9000 rads of irradiation. The patient was observed carefully for more than three years without any sign of tumor recurrence or metastasis. Subsequently, for the evaluation of hypogonadism, biopsy of the left testis and chromosome

204 1

2042 CANCER May 1977 Vol. 39

analysis were performed in July 1975. Histologically, the left testis showed mostly hyalinized seminiferous tubules buried in markedly hyperplastic Leydig cells, a finding compatible with Klinefelter’s syndrome (Fig. 2) .

Chromosome analysis has been made in cells de- rived from lymphocyte cultures of the patient, and the presence of an extra C group chromosome and an unusually large satellite on the short arm of one of the D group chromosomes were found in the cells ana- lyzed (Fig. 3). The results of chromosome counts and

FIG. 1. Histological picture of seminoma of the right testis which was removed in 1971. Tumor cells with large nuclei with lymphocytic infiltration are noted.

analyses in the patient together with those in the family are shown in ‘Table 1 . Blood smears examined for drumsticks were found to be chromatin-positive (2.8%). Using the quinacrine fluorescence (Q-banding) technique, the extra C group chromosome was clearly identified as an X and the chromosome having a large satellite was found to be chromosome 15 (Fig. 4 ) . The karyotype of the patient can thus be desig- nated 47, XXY, 1 5 s f .

The large satellite fluoresced brilliantly and dis- tinctly in the metaphase plate. A corresponding fluo-

FIG. 2. Histological picture of the hiopsied left testis. Atrophic or mostly hyalinized seminiferous tubules and markedly hyperplastic Leydig cells.

No. 5 SEMINOMA I N KLINEFELTER’S SYNDROME lsurugi et al.

FIG. 3. The karyotype of the propositus (47, XXY, 15s+) with the unusually enlarged satellite (arrow) on autosome 15.

rescent particle was present in many interphase nuclei, as shown in Fig. 4. The satellite was darkly stained with the C-banding technique (Fig. 5).

In order to clarify the significance of the presence of this fluorescent satellite, chromosome analysis was performed on both parents and four siblings (two brothers and two sisters) by the use of lymphocyte cultures. In addition, the chromosomes of a 7-year- old boy who is a son of one of the two brothers were also studied, since the boy had been noted to have the right testis undescended in the inguinal region. They showed apparently normal karyotypes. With the Q- banding technique, the fluorescent satellite on one of

2043

the chromosome 15 was observed in cells of the mother (Fig. 6), and three members of the siblings, while no such fluorescent satellite was found in the father, in one of the two brothers and in the boy with undescendent testis. (Table I ) . These results may indicate that there is no direct correlation between the clinical conditions of the patient and the presence of the unusually large satellite.

Blood groups, erythrocyte enzyme variants, haptoglobin types and group specific components were studied in the proband and the parents. The results are shown in Tables 2 and 3, and indicate that all genetic expressions were compatible with inheritance

FIG. 4. Q-band staining of the metaphase chromosomes of the propositus showing brightly fluorescent portions of the Y and 15 (arrow) chromosomes. An interphase nucleus (bottom left) shows corresponding fluorescent spots.

2044 CANCER May 1977 Vol. 39

from the parents. From the finding of Xg blood type it can be seen that at least one of the two X chromosomes in the proband was of maternal origin.

Dermatoglyphic analysis revealed a total finger ridge count(TRC) of 118 in the proband. The mean T R C of normal Japanese male and female controls were 151.3 & 46.1 (SD) and 142.2 st 44.8, respectively. I' There were third interdigital loops and hy- pothenar distal loops bilaterally. In hallucal areas, a tibia1 loop on the left and a distal loop with ridge count over 20 on the right were observed. The max- imal d d angle on the left was 37' and on the right 34". No simian line or thenar pattern was found. The finding of a low TRC is considered as compatible with Klinefelter's syndrome.

Endocrine studies performed in July 1975, showed

FIG. 5. C-band patterns of the metaphase chromosome spread in the propositus showing the darkly stained satellite on the 15 chromosome (arrow).

elevated basal levels of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deter- mined by radioimmunoassay." Serum LH was 257.9 ng (LER 907)/ml and FSH was 1219 ng (LER 907)/ml. Normal ranges for adult men (16-39 years of age) in our laboratories are 10-45 ng/ml for LH and 40-180 ng/ml for FSH. lo Exaggerated increases of both LH and FSH levels were observed in response to a n intravenous injection of synthetic luteinizing hormone-releasing hormone (LH-RH, 100 rg), i.e., after 30 minutes of the injection serum LH and FSH levels were increased at 1203.1 and 2138.7 ng/ml, respectively. The serum testosterone level also deter- mined by radioimmunoassay was 133.7 ng/dl, which was decreased compared with normal adult men.'

Since September 1975; the patient has been receiv-

FIG. 6. Q-band patterns of a metaphase preparation in the mother of the propositus. Note the brilliantly fluorescent satellite (arrow) and the corresponding particle in the interphase nucleus (left).

No. 5 SEMINOMA IN KLINEFELTER'S SYNDROME Isurugi et al. 2045

TABLE 1. Results of Chromosome Analysis in the Propositus and Other Members of the Family

Culture No. of cells Chromosome number Chromosome 47 48 5 constitution time observed 5 4 4 45 46

Propositus

Mother Father Sister Brother' Sister Brother Nephew

50h 72h 72h 72h 72h 72h 72h 72h 72h

56 20 20 20 20 20 20 20 20

1 4' 51 20

19 1' 2 i n

1 19 1 19

20 3 17

1 1 i n

47, XXY. 15s+ 47, XXY, 15s+ 46, XX, 1 5 s f 46. XY 46, XX. 15s+

46, XX, 15s+ 46,XY, 15s+ 46, XY

46, XY

~~ ~

* Random missing of one chromosome other than the C group. t Including an extra C group chromosome. f The father of the cryptorchid nephew.

ing a depot testosterone preparation* (im, 100 mg every two weeks) as a substitution of androgen defi- ciency, and as of August 1976, has been free from tumor recurrence.

DISCUSSION

There is evidence that patients with Klinefel- ter's syndrome are prone to develop neoplastic growths.216 It has been reported that XXY tri- somic cells from an XY/XXY mosaic Klinefel- ter patient were more susceptible to zn uitro transformation by simian papovavirus 40 than XY cells from the patient and those from normal men. Is Besides breast cancer; various types of neoplasms have been reported to occur in Kline- felter's syndrome and some of them were mul- tiple tumors. 2 4 However, the occurrence of testicular tumors in Klinefelter's syndrome is very rare; except for interstitial cell tumors. I' The latter tumors are often difficult to differentiate from massive hyperplasia of Leydig cells which is a common histological characteristic of the testis in the syndrome.

This is in contrast to the well documented high risk of gonadal tumor development in XY individuals with gonadal dysgenesis and mixed gonadal dysgenesis. 420 These tumors are known as gonadoblastomas which are not infrequently overgrown by dysgerminomas, the female coun- terpart of seminoma in the male. The liability of the dysgenetic gonads to neoplasms in these individuals has been ascribed to various factors, i.e., the intraabdominal position of the testis;'

* Enarmon Depot (Teikoku Hormone Mfg. Co., Ltd., Tokyo, Japan), a combination of testosterone enanthate ( I 15.7 mg) and testosterone propionate (20 ma), equivalent to 100 mg of testosterone.

elevated levels of follicle-stimulating hormone (FSH) occurring from early childhood, ''genetic predisposition to tumorigenesis which is probably related to the presence of a Y chromosome;'etc. The dysgenetic gonads are obviously defective in their function of inducing normal male differentiation of the genitalia and the mui- lerian duct systems persist in all of these cases.

O n the other hand, there has been no report of gonadoblastoma associated with Klinefelter's syndrome. This may be related to the facts that cryptorchism is rare in Klinefelter's syndrome and that the fetal function of the testis appears to have been adequate in male differentiation of the genitalia. Furthermore, it has been reported that in prepubertal boys with Klinefelter's syndrome serum LH and FSH levels are not elevated,' a finding which suggests that the hyp- othalamo-pituitary-testicular axis is normal in the syndrome before puberty. Most probably, genetic predisposition to tumorigenesis is quite different between XXY individuals and XY gonadal dysgenesis. It appears that the chance for the occurrence of seminoma in Klinefelter's syndrome is still more decreased, since most of the

TABLE 2. Blood Group Studies in the Propositus and the Parents

Father Propositus Mother Blood type (46, XU) (47, XXY) (46. X X )

ABO MNSs Rh P Kell

Kidd Lewis

Duffy

x g

B MNSs CcDEe P2 K- k + Fy (a+ b-) J k (a+) Le (a-) XR (a-)

AB MNSS CcDEe P2 K- k+ Fy (a+ b-) J k (a+) Le (a-) XR (a+)

A MMSs CCDee P2 K- k + Fy (a+ b-)

Le (a-) Jk ( a + )

Xg (a+ 1

2046 CANCER May 1977

TABLE 3. Erythrocyte Enzyme and Serum Type Studies in the Propositus and the Parents

Father Propositus Mother Marker (46 ,XY) ( 4 7 , X X Y ) (46. XX) ~

ADA 6-PGD ACP PGM G P T Esl) UM PK GLO

GC HP

1 AC B 1 2- 1 1 1 1 2-2 1-1

2- 1 A B 2- 1 1 2- 1 1 I 2-2 1-1

2- 1 A BA 2-1 1 2 1 1 2-2 1-1

ADA: adenosine deaminase; 6-PGD: 6-phosphogluconate dehydrogenase; ACP: acid phosphatase; PGM: phos- phoglucomutase; GPT: glutamic-pyruvic transaminase; EsD: esterase D; UMPK: uridine monophosphate kinase; GI.0: glyoxalase I ; Hp: haptoglobin; Gc: group specifir component.

germ cells degenerate and disappear before puberty in these patients, while most of seminomas in men develop after puberty. Marked eleva- tion of FSH secretion is considered to play a role in aggravating the degeneration process of germ cells" in the Klinefelter testis and in this regard it suppresses the chance, if any, of possible development of seminoma. There may perhaps be immunological factors involved, 24 22 through some kind of autoantibodies genetically deter- mined or produced against degeneration prod- ucts of the seminiferous tubules. Whether such immune mechanism play a role in preventing germ cell tumors remains to be examined.

Then, how could the development of seminoma in our patient be explained? The possi- bility would be that a number of conditions had superimposed which eventually effected in- fluences in favor of the tumor development. First of all, the germ cells must have survived the degeneration process beyond puberty as seen in occasional cases of the syndrome with fairly pre- served spermatogenesis. That our patient had claimed to have been unaware of his hypogo- nadal state may have some bearings on the rela- tively undamaged testicular architectures before tumor development. Secondly, the fact that the tumor bearing right testis had originally been in a cryptorchid position, though later subjected to

orchiopexy, should naturally be considered as related to the tumor occurrence.

Thirdly, genetic factors predisposing to tumorigenesis might have been involved in this particular case, although the significance of the unusually enlarged and fluorescent chromosomal satellites found in the proband is not clear. In this regard, similar brightly fluorescent chromosomal satellites on chromosome 15 have been reported by Khudr et d . l a in relatives of a woman with habitual abortions and probable Y to X translocation. Hahneman and Eiberg7 also described a kindred with the same chromosomal abnormality and suggested that the fluorescent material was a translocation product from a Y chromosome (Y/ 15 translocation). These reported cases and ours with abnormal chromosomes 15 were apparently normal except for the index cases. Since the heterochromatic fluorescent part of the Y chromosome is regarded as genetically inactive, it is understandable that individuals with the marker chromosome exhibit no obvious phenotypical abnormalities. How- ever, as pointed out by Hamerton' the presence of such minor chromosomal aberrations may effect an increased risk of non-disjunction, re- sulting in the pathogenesis of Down's syndrome. The chromosomal aneuploidy of the Klinefelter type in our patient may have been causally related to the presence of the extra material on the chromosome 15. It is not clear whether the presence of the autosomal aberration in our patient had any bearings on the occurrence of seminoma, while no tumor incidence was mentioned in the reported pedigrees cited above.

I n any event, all the members with the marker chromosome in the pedigree should be carefully followed in the future for possible production in their descendants of chromosomal aberrations by nondisjunctional events, e.g., Klinefelter's or Down's syndrome. Regarding tumor development, the cryptorchid nephew of the propositus should be considered as a high risk, though he was found to have no chromosomal aneuploidy or satellites. Under such circumstances or- chiectomy rather than orchiopexy may be the procedure of choice in view of the observation that orchiopexy does not prevent malignant degeneration of the cryptorchid testis unless performed before five years of

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No. 5 SEMINOMA IN KLINEFELTER’S SYNDROME Isurugt et al. 2047

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