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Choriocarcinoma, thyrotoxicosis, and the klinefelter syndrome
Choriocarcinoma, Thyrotoxicosis, and the Klinefelter Syndrome R. Neil Schimke, Coleen M. Madigan, Bradd J. Silver, Carol J. Fabian, and Ronald L. Stephens
ABSTRACT: A patient with the combined features of Klinefelter syndrome, thyrotoxicosis and a primary mediastinal choriocarcinoma is reported. Review of the literature reveals that extragonadal germ cell tumors appear to be significantly associated with the Klinefelter syndrome. The reason for this is presently unclear but may involve an unusual propensity of the extragonadal aneuploid germ cell to undergo malignant degeneration. INTRODUCTION The XXY karyotype characteristic of the Klinefelter syndrome is generally not considered to predispose such i n d i v i d u a l s to malignancy with the exception of breast carcinoma [1]. The relatively few other tumors that have been described could be considered coincidental in view of the relatively high incidence of this chromosome aneuploid state in the general male population. We have recently seen a u n i q u e patient with Klinefelter syndrome, a mediastinal choriocarcinoma, and sim u l t a n e o u s thyrotoxicosis, the latter related to excessive tumor secretion of chorionic gonadotropin (HCG). Review of the literature revaled 19 other patients with the Klinefelter syndrome who also had extragonadal germ cell tumors, most comm o n l y in the mediastinum. It appears that this is a highly significant association.
CASE REPORT The patient, a 26-year-old man, was admitted to the Kansas University'Hospital in August, 1981, with a 2-week history of increasing dyspnea and cough, and a 4-week history of a 36.3 Kg (80 lb) weight loss. His past history revealed long-standing gynecomastia. There was no family history of cancer in parents, grandparents, or sibs. He was married and denied sexual problems but had no children. On physical examination he was found to be an obese, dyspneic white male in obvious distress. He had ample body and facial hair and moderate bilateral gynecomastia. His blood pressure was 140/80 mmHg; his pulse was 120/min; and his respiratory rate 30/min. He had rales in all lung fields, The remaining physical examination was not remarkable except for the presence of small, soft testes bilaterally. From the Department of Medicine, Divisionsof Metabolism,Endocrinologyand Genetics, and Oncology, Kansas UniversityCollege of Health Sciences, KansasCity, Kansas. Address requests for reprints to Dr. R. Nell Schimke, Division Director, Metabolism, Endocrinology and Genetics, Kansas University College of Health Sciences, Kansas City, KS 66103. Received July 5, 1982; accepted August 9, 1982.
1 © Elsevier SciencePublishingCo., Inc., 1983 52 VanderbiltAve.. New York, NY 10017
Cancer Geneticsand Cytogenetics9, 1-8 (1983) 0165-4608/83/$03.00
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R . N . Schimke et al. Table 1
Serum h o r m o n e endocrine profile Hormone
Patient
Normal values (male)
T4 T3 Free T4 Thyroid-stimulating hormone Testosterone Estrone Estradiol
27.5 ~g/dl 473 ng/dl 3.35 ng/dl 1.3 pJU/ml
5-12.5 p~g/dl 90-175 ng/dl 1-2.5 ng/dl 0-6 ~zlU/ml
780 ng/dl 3130 pg/ml 1980 pg/ml
400-1200 ng/dl 25-75 pg/ml 15-40 pg/ml
Chest x ray showed a m a r k e d l y w i d e n e d mediastinum, m u l t i p l e soft tissue nodules in both lungs, and moderate bilateral pleural effusions. A C T scan revealed the mediastinal mass to be attached to the p e r i c a r d i u m and the great vessels. Significant laboratory data confirmed the clinical impression of hypoxemia. His thyroid function studies were compatible with thyrotoxicosis (Table 1). In addition, the serum level of [3-HCG was initially 1.5 × 1 0 6 mIU/ml. His peripheral blood karyotype was 47,XXY. He was treated with 02, bronchodilators, prednisone, and propylthiouracil, the latter at a dose of 100 mg every 6 hr. Hs condition i m p r o v e d and he was subjected to open lung biopsy where the diagnosis of choriocarcinoma was established. Chemotherapy with vinblastine, bleomycin, and c i s - d i a m m i n e d i c h l o r o p l a t i n u m was begun. His initial response to all therapeutic modalities was s y m p t o m a t i c a l l y dramatic. By January 1982, he had no complaints. His T4 was 8.4 ~g/dl, and the [~-HCG level had declined to 6000 mfU/ml. The p r o p y l t h i o u r a c i l was stopped. Chest x ray showed no substantial change. His c h e m o t h e r a p y was modified on two occasions over the next 3 months. In A p r i l 1982, he presented to the Emergency Room with a several-day history of difficulty walking. Physical examination revealed m i l d paraparesis and d i m i n i s h e d sensation below T-8. Myelography confirmed an obstruction at T-6. At operation, he was found to have direct extension of his mediastinal tumor to the extradural space. Decompression was successfully a c c o m p l i s h e d and he was discharged to be followed by the Oncology Clinic for possible future alterations in his chemotherapy. A n attempt to karyotype the tumor was unsuccessful. DISCUSSION
A number of different non-germ-cell malignancies have been reported in patients with the Klinefelter syndrome. Since the s y n d r o m e is relatively common, the simultaneous occurrence of occasional i n d i v i d u a l s with leukemia [2-6], l y m p h o m a [7,8], lung [9], b l a d d e r [10], or prostate carcinoma [11] is likely a coincidence. One unfortunate i n d i v i d u a l suffered m u l t i p l e malignancies: lipomas, a sacral chordoma, spongioblastoma, p a p i l l a r y thyroid carcinoma, and bilateral breast cancer [12]. Heretofore, breast carcinoma has been considered the only malignancy to w h i c h patients with Klinefelter s y n d r o m e showed u n d u e risk, perhaps 20 times greater than that of males in general [1, 13-15]. Testicular tumors have also been seen on occasion i n c l u d i n g teratomas [16], once in brothers with the s y n d r o m e [17], interstitial cell tumors [14,18], and a s e m i n o m a [19]. More puzzling has been the finding that extragonadal germ cell tumors occur with significant frequency in the Klinefelter s y n d r o m e [20-33]. In 18 of 20 patients these tumors have d e v e l o p e d in the m e d i a s t i n u m (Table 2). Two patients have had m i d l i n e central nervous system le-
Klinefelter Syndrome with Extragmadal Tumors
Table 2
E x t r a g o n a d a l g e r m cell t u m o r s in t h e K l i n e f e l t e r s y n d r o m e
Location Mediastinal
Central nervous system Retroperitoneal
Patient
Age [yr)
Tumor Type
Gynecomastia
Precocity
Reference
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ~
5 4/12 7 8 8 8/12 9 6/12 15 16 16 16 19 20 20 21 23 26 26 26 1 16
teratoma teratoma teratocarcinoma teratoma teratoma choriocarcinoma mixed embryonal cell teratocarcinoma choriocarcinoma embryonal cell choriocarcinoma choriocarcinoma embryonal cell yolk sac embryonal cell choriocarcinoma (?) dysgerminoma pineal teratoma
+ + + ? + v
+ + + + + + ?
20 21, 22 23 24 20 25 26 27 28 29 25 28 30 25 30 31 present case 20 32
20
43
seminoma
+
-
33
"This patient also had a dermoid cyst of the testis and an independent mediastinal choriocarcinoma.
sions; o n e c o n s i d e r e d to be a h a m a r t o m a , h i s t o l o g i c a l l y u n v e r i f i e d ; t h e other, a p i n e a l t e r a t o m a . T h e latter p a t i e n t , a 1 6 - y e a r - o l d boy, h a d t h e u n u s u a l d i s t i n c t i o n of h a v i n g t w o a d d i t i o n a l t u m o r s : a d e r m o i d cyst of t h e t e s t i s a n d a m e d i a s t i n a l c h o r i o c a r c i n o m a . All of t h e p a t i e n t s w i t h c e n t r a l or m e d i a s t i n a l i n v o l v e m e n t w e r e c h i l d r e n or y o u n g a d u l t s . T h e o n e r e m a i n i n g p a t i e n t w a s a 4 3 - y e a r - o l d m a l e w i t h a retroperitoneal seminoma. P r i m a r y g e r m cell m a l i g n a n c i e s of t h e m e d i a s t i n u m are an u n c o m m o n n e o p l a s i a [34,35]. M o s t w o r k e r s f a v o r t h e t h e o r y t h a t t h e s e t u m o r s o r i g i n a t e f r o m p r i m o r d i a l g e r m c e l l s t h a t h a v e b e e n a r r e s t e d in t h e i r m i g r a t i o n a l o n g t h e u r o g e n i t a l ridge, w h i c h in t h e e m b r y o e x t e n d s f r o m the s i x t h c e r v i c a l to t h e s e c o n d sacral v e r t e b r a [36]. T h e y are m u c h m o r e c o m m o n i n m a l e s t h a n f e m a l e s [37]. T h e h i s t o l o g y is t h e s a m e as that s e e n i n t e s t i c u l a r c a n c e r w i t h s e m i n o m a s b e i n g by far t h e m o s t c o m m o n variety. I n t e r e s t i n g l y , w h e n m e d i a s t i n a l g e r m cell t u m o r s d o o c c u r in f e m a l e s , t h e y are p o o r l y d i f f e r e n t i a t e d . A r e c e n t s u r v e y d o c u m e n t e d 22 s u c h cases; o n l y 5 of w h i c h w e r e s e m i n o m a s ( d y s g e r m i n o m a s ) [38]. T h e p a t i e n t s w i t h t h e K l i n e f e l t e r s y n d r o m e also h a v e l e s i o n s that are m o r e p r i m i t i v e i n type. S e v e n of t h e 19 t u m o r s s h o w n in Table 2 w e r e p u r e c h o r i o c a r c i n o m a s or c o n t a i n e d c h o r i o c a r c i n o m a elem e n t s . T h i s s u b t y p e of m e d i a s t i n a l g e r m cell t u m o r is c o m p a r a t i v e l y rare, o n l y 23 w e l l - d o c u m e n t e d c a s e s h a v i n g b e e n r e p o r t e d i n a 1976 r e v i e w [26]. I n t e r e s t i n g l y , some patients with mediastinal choriocarcinoma have had gynecomastia and small t e s t e s t h a t w h e n b i o p s i e d s h o w e d t u b u l a r a t r o p h y a n d r e l a t i v e L e y d i g cell h y p e r p l a s i a [39-42]. T h e s e f e m i n i z i n g c h a n g e s o c c u r b e c a u s e t h e t u m o r m a s s h a s a trop h o b l a s t i c f u n c t i o n a n d c a n c o n v e r t c i r c u l a t i n g d e h y d r o e p i a n d r o s t e r o n e s u l f a t e to e s t r a d i o l [43]. T h e s e r u m e s t r o g e n l e v e l s in our p a t i e n t w e r e c o m p a t i a b l e w i t h t h i s h y p o t h e s i s as t h e y w e r e e x t r a o r d i n a r i l y h i g h (Table 1). H o w e v e r , t h e t e s t i c u l a r h i s tology d e s c r i b e d is i d e n t i c a l to t h a t s e e n in t h e K l i n e f e l t e r s y n d r o m e ; k a r y o t y p e s w e r e n o t c o n s i s t e n t l y p e r f o r m e d a n d f e w c o r r e l a t i v e h o r m o n a l a s s a y s w e r e pro-
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R . N . Schimke et al. vided in these reports. It is, therefore, conceivable that some of the remaining patients with mediastinal choriocarcinoma also had the Klinefelter syndrome. In general, adult patients with Klinefelter s y n d r o m e and m e d i a s t i n a l germ cell tumors presented w i t h the usual s y m p t o m s of tumor mass and obstruction. More striking, p r e p u b e s e n t boys with extragonadal germ cell tumors all d e v e l o p e d precocious puberty. The excess androgen was assumed to be testes-derived, stimulated by HCG. However, in the patient with the p r e s u m e d central germinoma, this hormone was not detected and a h y p o t h a l a m i c defect could also be postulated. Thyrotoxicosis is an u n u s u a l complication of choriocarcinoma, most of the p r e v i o u s l y described cases having been females w i t h gestational trophoblastic n e o p l a s m s [44-47]. HCG is k n o w n to compete with thyrotropin for thyroid cell m e m b r a n e receptor because of the c o m m o n alpha subunit of the two hormones [47]. W h e n HCG is present in high enough concentration in the serum, i.e., more than 100,000 mlU/ml, excessive thyroxine p r o d u c t i o n can be stimulated, although there is no consistently predictable correlation with serum HCG levels and the d e v e l o p m e n t of thyrotoxicosis [46,48]. Extragonadal, particularly mediastinal, germ cell tumors and the Klinefelter syndrome appear to be strongly associated. W h y the extragonadal germ cells and not the testicular counterparts should show an unusual p r o p e n s i t y for malignancy in this s y n d r o m e is u n k n o w n , but it is reasonable to assume that the c h r o m o s o m e imbalance plays some role. Earlier studies of testicular and extragonadal germ cell tumors in a p p a r e n t l y normal m e n noted the presence of nuclear c h r o m a t i n and double-Y bodies in a substantial proportion [49-51]. Testicular tumor karyotypes are often h y p e r p l o i d even w h e n peripheral blood karyotypes are normal [52]. In one report of six extragonadal teratomas in w h i c h the p e r i p h e r a l karyotype was normal, the tumor chromosome c o m p l e m e n t was also normal in five, the lone except/on being a mediastinal teratocarcinoma in a 23oyear-old man whose tumor was tetraploid (92,XXYY) [53]. Thus, it w o u l d appear that e n d o r e d u p l i c a t i o n is a relatively c o m m o n event in germ cell neoplasms, although whether it is a primary and therefore potentially inciting event or merely an e p i p h e n o m e n o n is not clear. It is of interest, however, that ovarian teratomas and complete h y d a t i d i f o r m moles are considered to be forms of parthenogenetic d e v e l o p m e n t in h u m a n s and thus result from e n d o r e d u p l i c a t i o n [54,55]. Both therefore represent germ cell tumors in w h i c h h a p l o i d chromosomes replicate w i t h o u t cytokinesis. Gestational choriocarcinomas are not so derived since studies have shown them to be heterozygous for certain enzyme p o l y m o r p h i s m s [56]. No such comparable investigation has been performed on nongestational choriocarcinomas or i n d e e d other germ cell neoplasms to see if they demonstrate similar heterozygosity. Nonetheless, it appears that e n d o r e d u p l i cation of varying degrees is c o m m o n in germ cell tumors. Whether the presence of the extra X chromosome in i n d i v i d u a l s with Klinefelter s y n d r o m e confers on their germ cells, particularly those in extragonadal sites, an increased p r o p e n s i t y to undergo aberrant c h r o m o s o m e disjunction, and hence p r e d i s p o s i t i o n to malignancy, is problematic but worthy of further study. Alternatively, since patients with extragonadal germ cell tumors are p r e d o m i nantly male, it may be that the arrested germ cells behave as a form of u n d e s c e n d e d testis, an embryologic event recognizably associated with an increased i n c i d e n c e of malignant degeneration. In addition, patients with Klinefelter s y n d r o m e have dysgenetic testes. It is k n o w n that the risk of malignancy in dysgenetic u n d e s c e n d e d testes is even more substantial. In this context, the extragonadal germ cell in the Ktinefetter s y n d r o m e c o u l d be looked on as a special form of u n d e s c e n d e d dysgenetic testis exposed to an u n u s u a l internal milieu. Whatever the reason, any speculation concerning the etiology of extragonadal germ tumors must take into account
Klinefelter Syndrome with Extragmadal Tumors
5
t h e m a r k e d m a l e p r e p o n d e r a n c e of t h e t u m o r s a n d , p e r h a p s m o r e i m p o r t a n t l y , t h e i r significant association with the Klinefelter syndrome.
ADDENDUM S i n c e s u b m i s s i o n of t h i s m a n u s c r i p t , t w o a d d i t i o n a l p a t i e n t s w i t h K l i n e f e l t e r ' s s y n d r o m e a n d m e d i a s t i n a l g e r m cell t u m o r s h a v e b e e n r e p o r t e d ( P e c h a n s k y L, K r a u s s e JR (1982): A c u t e l e u k e m i a f o l l o w i n g a m a l i g n a n t t e r a t o m a i n a c h i l d w i t h K l i n e f e l t e r ' s s y n d r o m e . C a n c e r 50, 6 8 4 - 6 8 9 . ) .
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47. Davies TF, Taliadouros GS, Catt KJ, Nisula BC (1979): Assessment of urinary thyrotropincompeting activity in choriocarcinoma and thryoid disease: Further evidence for h u m a n chorionic gonadotropin interacting at the thyroid cell membrane. J Clin Endocrinol Metabol 45,353-357. 48. Norman RJ, Green-Thompson RW, Jialal I, Soutter WP, Pillary NL, Joubert SM (1981): Hyperthyroidism in gestational trophoblastic neoplasia. Clin Endocrinol 15, 395-401. 49. Theiss EA, Ashley DJB, Mostofi FK (1960): Nuclear sex of testicular tumors and some related ovarian and extragonadal neoplasms. Cancer 13,323-327. 50. Kock F (1970): The occurrence of sex chromatin in testicular tumors. Acta Pathol Microbiol Scand 70, 45-49. 51. Atkin NG (1973): Y bodies and similar fluorescence chromocentres in h u m a n tumors including teratomata. Br J Cancer 27,183-189. 52. Martineau M (1969): Chromosomes in h u m a n testicular tumours. J Pathol 99,271-282. 53. Kaplan CG, Askin GB, Benirschke K (1979): Cytogenetics of extragonadal tumors. Teratology 19, 261-266. 54. Linder D, McCaw BK, Hecht F (1975): Parthenogenic origin of benign ovarian teratomas. N Engl J Med 292, 63-66. 55. DeGrouchy J (1980): Human parthenogenesis, a fascinating single event. Biomedicine 32, 51-53. 56. Wake N, Tanaka K, Chapman V, Matsui S, Sandberg AA (1981): Chromosomes and cellular origin of choriocarcinoma. Cancer Res 41, 3137-3143.
ABSTRACT: A patient with the combined features of Klinefelter syndrome, thyrotoxicosis and a primary mediastinal choriocarcinoma is reported. Review of the literature reveals that extragonadal germ cell tumors appear to be significantly associated with the Klinefelter syndrome. The reason for this is presently unclear but may involve an unusual propensity of the extragonadal aneuploid germ cell to undergo malignant degeneration. INTRODUCTION The XXY karyotype characteristic of the Klinefelter syndrome is generally not considered to predispose such i n d i v i d u a l s to malignancy with the exception of breast carcinoma [1]. The relatively few other tumors that have been described could be considered coincidental in view of the relatively high incidence of this chromosome aneuploid state in the general male population. We have recently seen a u n i q u e patient with Klinefelter syndrome, a mediastinal choriocarcinoma, and sim u l t a n e o u s thyrotoxicosis, the latter related to excessive tumor secretion of chorionic gonadotropin (HCG). Review of the literature revaled 19 other patients with the Klinefelter syndrome who also had extragonadal germ cell tumors, most comm o n l y in the mediastinum. It appears that this is a highly significant association.
CASE REPORT The patient, a 26-year-old man, was admitted to the Kansas University'Hospital in August, 1981, with a 2-week history of increasing dyspnea and cough, and a 4-week history of a 36.3 Kg (80 lb) weight loss. His past history revealed long-standing gynecomastia. There was no family history of cancer in parents, grandparents, or sibs. He was married and denied sexual problems but had no children. On physical examination he was found to be an obese, dyspneic white male in obvious distress. He had ample body and facial hair and moderate bilateral gynecomastia. His blood pressure was 140/80 mmHg; his pulse was 120/min; and his respiratory rate 30/min. He had rales in all lung fields, The remaining physical examination was not remarkable except for the presence of small, soft testes bilaterally. From the Department of Medicine, Divisionsof Metabolism,Endocrinologyand Genetics, and Oncology, Kansas UniversityCollege of Health Sciences, KansasCity, Kansas. Address requests for reprints to Dr. R. Nell Schimke, Division Director, Metabolism, Endocrinology and Genetics, Kansas University College of Health Sciences, Kansas City, KS 66103. Received July 5, 1982; accepted August 9, 1982.
1 © Elsevier SciencePublishingCo., Inc., 1983 52 VanderbiltAve.. New York, NY 10017
Cancer Geneticsand Cytogenetics9, 1-8 (1983) 0165-4608/83/$03.00
2
R . N . Schimke et al. Table 1
Serum h o r m o n e endocrine profile Hormone
Patient
Normal values (male)
T4 T3 Free T4 Thyroid-stimulating hormone Testosterone Estrone Estradiol
27.5 ~g/dl 473 ng/dl 3.35 ng/dl 1.3 pJU/ml
5-12.5 p~g/dl 90-175 ng/dl 1-2.5 ng/dl 0-6 ~zlU/ml
780 ng/dl 3130 pg/ml 1980 pg/ml
400-1200 ng/dl 25-75 pg/ml 15-40 pg/ml
Chest x ray showed a m a r k e d l y w i d e n e d mediastinum, m u l t i p l e soft tissue nodules in both lungs, and moderate bilateral pleural effusions. A C T scan revealed the mediastinal mass to be attached to the p e r i c a r d i u m and the great vessels. Significant laboratory data confirmed the clinical impression of hypoxemia. His thyroid function studies were compatible with thyrotoxicosis (Table 1). In addition, the serum level of [3-HCG was initially 1.5 × 1 0 6 mIU/ml. His peripheral blood karyotype was 47,XXY. He was treated with 02, bronchodilators, prednisone, and propylthiouracil, the latter at a dose of 100 mg every 6 hr. Hs condition i m p r o v e d and he was subjected to open lung biopsy where the diagnosis of choriocarcinoma was established. Chemotherapy with vinblastine, bleomycin, and c i s - d i a m m i n e d i c h l o r o p l a t i n u m was begun. His initial response to all therapeutic modalities was s y m p t o m a t i c a l l y dramatic. By January 1982, he had no complaints. His T4 was 8.4 ~g/dl, and the [~-HCG level had declined to 6000 mfU/ml. The p r o p y l t h i o u r a c i l was stopped. Chest x ray showed no substantial change. His c h e m o t h e r a p y was modified on two occasions over the next 3 months. In A p r i l 1982, he presented to the Emergency Room with a several-day history of difficulty walking. Physical examination revealed m i l d paraparesis and d i m i n i s h e d sensation below T-8. Myelography confirmed an obstruction at T-6. At operation, he was found to have direct extension of his mediastinal tumor to the extradural space. Decompression was successfully a c c o m p l i s h e d and he was discharged to be followed by the Oncology Clinic for possible future alterations in his chemotherapy. A n attempt to karyotype the tumor was unsuccessful. DISCUSSION
A number of different non-germ-cell malignancies have been reported in patients with the Klinefelter syndrome. Since the s y n d r o m e is relatively common, the simultaneous occurrence of occasional i n d i v i d u a l s with leukemia [2-6], l y m p h o m a [7,8], lung [9], b l a d d e r [10], or prostate carcinoma [11] is likely a coincidence. One unfortunate i n d i v i d u a l suffered m u l t i p l e malignancies: lipomas, a sacral chordoma, spongioblastoma, p a p i l l a r y thyroid carcinoma, and bilateral breast cancer [12]. Heretofore, breast carcinoma has been considered the only malignancy to w h i c h patients with Klinefelter s y n d r o m e showed u n d u e risk, perhaps 20 times greater than that of males in general [1, 13-15]. Testicular tumors have also been seen on occasion i n c l u d i n g teratomas [16], once in brothers with the s y n d r o m e [17], interstitial cell tumors [14,18], and a s e m i n o m a [19]. More puzzling has been the finding that extragonadal germ cell tumors occur with significant frequency in the Klinefelter s y n d r o m e [20-33]. In 18 of 20 patients these tumors have d e v e l o p e d in the m e d i a s t i n u m (Table 2). Two patients have had m i d l i n e central nervous system le-
Klinefelter Syndrome with Extragmadal Tumors
Table 2
E x t r a g o n a d a l g e r m cell t u m o r s in t h e K l i n e f e l t e r s y n d r o m e
Location Mediastinal
Central nervous system Retroperitoneal
Patient
Age [yr)
Tumor Type
Gynecomastia
Precocity
Reference
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ~
5 4/12 7 8 8 8/12 9 6/12 15 16 16 16 19 20 20 21 23 26 26 26 1 16
teratoma teratoma teratocarcinoma teratoma teratoma choriocarcinoma mixed embryonal cell teratocarcinoma choriocarcinoma embryonal cell choriocarcinoma choriocarcinoma embryonal cell yolk sac embryonal cell choriocarcinoma (?) dysgerminoma pineal teratoma
+ + + ? + v
+ + + + + + ?
20 21, 22 23 24 20 25 26 27 28 29 25 28 30 25 30 31 present case 20 32
20
43
seminoma
+
-
33
"This patient also had a dermoid cyst of the testis and an independent mediastinal choriocarcinoma.
sions; o n e c o n s i d e r e d to be a h a m a r t o m a , h i s t o l o g i c a l l y u n v e r i f i e d ; t h e other, a p i n e a l t e r a t o m a . T h e latter p a t i e n t , a 1 6 - y e a r - o l d boy, h a d t h e u n u s u a l d i s t i n c t i o n of h a v i n g t w o a d d i t i o n a l t u m o r s : a d e r m o i d cyst of t h e t e s t i s a n d a m e d i a s t i n a l c h o r i o c a r c i n o m a . All of t h e p a t i e n t s w i t h c e n t r a l or m e d i a s t i n a l i n v o l v e m e n t w e r e c h i l d r e n or y o u n g a d u l t s . T h e o n e r e m a i n i n g p a t i e n t w a s a 4 3 - y e a r - o l d m a l e w i t h a retroperitoneal seminoma. P r i m a r y g e r m cell m a l i g n a n c i e s of t h e m e d i a s t i n u m are an u n c o m m o n n e o p l a s i a [34,35]. M o s t w o r k e r s f a v o r t h e t h e o r y t h a t t h e s e t u m o r s o r i g i n a t e f r o m p r i m o r d i a l g e r m c e l l s t h a t h a v e b e e n a r r e s t e d in t h e i r m i g r a t i o n a l o n g t h e u r o g e n i t a l ridge, w h i c h in t h e e m b r y o e x t e n d s f r o m the s i x t h c e r v i c a l to t h e s e c o n d sacral v e r t e b r a [36]. T h e y are m u c h m o r e c o m m o n i n m a l e s t h a n f e m a l e s [37]. T h e h i s t o l o g y is t h e s a m e as that s e e n i n t e s t i c u l a r c a n c e r w i t h s e m i n o m a s b e i n g by far t h e m o s t c o m m o n variety. I n t e r e s t i n g l y , w h e n m e d i a s t i n a l g e r m cell t u m o r s d o o c c u r in f e m a l e s , t h e y are p o o r l y d i f f e r e n t i a t e d . A r e c e n t s u r v e y d o c u m e n t e d 22 s u c h cases; o n l y 5 of w h i c h w e r e s e m i n o m a s ( d y s g e r m i n o m a s ) [38]. T h e p a t i e n t s w i t h t h e K l i n e f e l t e r s y n d r o m e also h a v e l e s i o n s that are m o r e p r i m i t i v e i n type. S e v e n of t h e 19 t u m o r s s h o w n in Table 2 w e r e p u r e c h o r i o c a r c i n o m a s or c o n t a i n e d c h o r i o c a r c i n o m a elem e n t s . T h i s s u b t y p e of m e d i a s t i n a l g e r m cell t u m o r is c o m p a r a t i v e l y rare, o n l y 23 w e l l - d o c u m e n t e d c a s e s h a v i n g b e e n r e p o r t e d i n a 1976 r e v i e w [26]. I n t e r e s t i n g l y , some patients with mediastinal choriocarcinoma have had gynecomastia and small t e s t e s t h a t w h e n b i o p s i e d s h o w e d t u b u l a r a t r o p h y a n d r e l a t i v e L e y d i g cell h y p e r p l a s i a [39-42]. T h e s e f e m i n i z i n g c h a n g e s o c c u r b e c a u s e t h e t u m o r m a s s h a s a trop h o b l a s t i c f u n c t i o n a n d c a n c o n v e r t c i r c u l a t i n g d e h y d r o e p i a n d r o s t e r o n e s u l f a t e to e s t r a d i o l [43]. T h e s e r u m e s t r o g e n l e v e l s in our p a t i e n t w e r e c o m p a t i a b l e w i t h t h i s h y p o t h e s i s as t h e y w e r e e x t r a o r d i n a r i l y h i g h (Table 1). H o w e v e r , t h e t e s t i c u l a r h i s tology d e s c r i b e d is i d e n t i c a l to t h a t s e e n in t h e K l i n e f e l t e r s y n d r o m e ; k a r y o t y p e s w e r e n o t c o n s i s t e n t l y p e r f o r m e d a n d f e w c o r r e l a t i v e h o r m o n a l a s s a y s w e r e pro-
4
R . N . Schimke et al. vided in these reports. It is, therefore, conceivable that some of the remaining patients with mediastinal choriocarcinoma also had the Klinefelter syndrome. In general, adult patients with Klinefelter s y n d r o m e and m e d i a s t i n a l germ cell tumors presented w i t h the usual s y m p t o m s of tumor mass and obstruction. More striking, p r e p u b e s e n t boys with extragonadal germ cell tumors all d e v e l o p e d precocious puberty. The excess androgen was assumed to be testes-derived, stimulated by HCG. However, in the patient with the p r e s u m e d central germinoma, this hormone was not detected and a h y p o t h a l a m i c defect could also be postulated. Thyrotoxicosis is an u n u s u a l complication of choriocarcinoma, most of the p r e v i o u s l y described cases having been females w i t h gestational trophoblastic n e o p l a s m s [44-47]. HCG is k n o w n to compete with thyrotropin for thyroid cell m e m b r a n e receptor because of the c o m m o n alpha subunit of the two hormones [47]. W h e n HCG is present in high enough concentration in the serum, i.e., more than 100,000 mlU/ml, excessive thyroxine p r o d u c t i o n can be stimulated, although there is no consistently predictable correlation with serum HCG levels and the d e v e l o p m e n t of thyrotoxicosis [46,48]. Extragonadal, particularly mediastinal, germ cell tumors and the Klinefelter syndrome appear to be strongly associated. W h y the extragonadal germ cells and not the testicular counterparts should show an unusual p r o p e n s i t y for malignancy in this s y n d r o m e is u n k n o w n , but it is reasonable to assume that the c h r o m o s o m e imbalance plays some role. Earlier studies of testicular and extragonadal germ cell tumors in a p p a r e n t l y normal m e n noted the presence of nuclear c h r o m a t i n and double-Y bodies in a substantial proportion [49-51]. Testicular tumor karyotypes are often h y p e r p l o i d even w h e n peripheral blood karyotypes are normal [52]. In one report of six extragonadal teratomas in w h i c h the p e r i p h e r a l karyotype was normal, the tumor chromosome c o m p l e m e n t was also normal in five, the lone except/on being a mediastinal teratocarcinoma in a 23oyear-old man whose tumor was tetraploid (92,XXYY) [53]. Thus, it w o u l d appear that e n d o r e d u p l i c a t i o n is a relatively c o m m o n event in germ cell neoplasms, although whether it is a primary and therefore potentially inciting event or merely an e p i p h e n o m e n o n is not clear. It is of interest, however, that ovarian teratomas and complete h y d a t i d i f o r m moles are considered to be forms of parthenogenetic d e v e l o p m e n t in h u m a n s and thus result from e n d o r e d u p l i c a t i o n [54,55]. Both therefore represent germ cell tumors in w h i c h h a p l o i d chromosomes replicate w i t h o u t cytokinesis. Gestational choriocarcinomas are not so derived since studies have shown them to be heterozygous for certain enzyme p o l y m o r p h i s m s [56]. No such comparable investigation has been performed on nongestational choriocarcinomas or i n d e e d other germ cell neoplasms to see if they demonstrate similar heterozygosity. Nonetheless, it appears that e n d o r e d u p l i cation of varying degrees is c o m m o n in germ cell tumors. Whether the presence of the extra X chromosome in i n d i v i d u a l s with Klinefelter s y n d r o m e confers on their germ cells, particularly those in extragonadal sites, an increased p r o p e n s i t y to undergo aberrant c h r o m o s o m e disjunction, and hence p r e d i s p o s i t i o n to malignancy, is problematic but worthy of further study. Alternatively, since patients with extragonadal germ cell tumors are p r e d o m i nantly male, it may be that the arrested germ cells behave as a form of u n d e s c e n d e d testis, an embryologic event recognizably associated with an increased i n c i d e n c e of malignant degeneration. In addition, patients with Klinefelter s y n d r o m e have dysgenetic testes. It is k n o w n that the risk of malignancy in dysgenetic u n d e s c e n d e d testes is even more substantial. In this context, the extragonadal germ cell in the Ktinefetter s y n d r o m e c o u l d be looked on as a special form of u n d e s c e n d e d dysgenetic testis exposed to an u n u s u a l internal milieu. Whatever the reason, any speculation concerning the etiology of extragonadal germ tumors must take into account
Klinefelter Syndrome with Extragmadal Tumors
5
t h e m a r k e d m a l e p r e p o n d e r a n c e of t h e t u m o r s a n d , p e r h a p s m o r e i m p o r t a n t l y , t h e i r significant association with the Klinefelter syndrome.
ADDENDUM S i n c e s u b m i s s i o n of t h i s m a n u s c r i p t , t w o a d d i t i o n a l p a t i e n t s w i t h K l i n e f e l t e r ' s s y n d r o m e a n d m e d i a s t i n a l g e r m cell t u m o r s h a v e b e e n r e p o r t e d ( P e c h a n s k y L, K r a u s s e JR (1982): A c u t e l e u k e m i a f o l l o w i n g a m a l i g n a n t t e r a t o m a i n a c h i l d w i t h K l i n e f e l t e r ' s s y n d r o m e . C a n c e r 50, 6 8 4 - 6 8 9 . ) .
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Klinefelter Syndrome with Extragmadal Tumors
7
47. Davies TF, Taliadouros GS, Catt KJ, Nisula BC (1979): Assessment of urinary thyrotropincompeting activity in choriocarcinoma and thryoid disease: Further evidence for h u m a n chorionic gonadotropin interacting at the thyroid cell membrane. J Clin Endocrinol Metabol 45,353-357. 48. Norman RJ, Green-Thompson RW, Jialal I, Soutter WP, Pillary NL, Joubert SM (1981): Hyperthyroidism in gestational trophoblastic neoplasia. Clin Endocrinol 15, 395-401. 49. Theiss EA, Ashley DJB, Mostofi FK (1960): Nuclear sex of testicular tumors and some related ovarian and extragonadal neoplasms. Cancer 13,323-327. 50. Kock F (1970): The occurrence of sex chromatin in testicular tumors. Acta Pathol Microbiol Scand 70, 45-49. 51. Atkin NG (1973): Y bodies and similar fluorescence chromocentres in h u m a n tumors including teratomata. Br J Cancer 27,183-189. 52. Martineau M (1969): Chromosomes in h u m a n testicular tumours. J Pathol 99,271-282. 53. Kaplan CG, Askin GB, Benirschke K (1979): Cytogenetics of extragonadal tumors. Teratology 19, 261-266. 54. Linder D, McCaw BK, Hecht F (1975): Parthenogenic origin of benign ovarian teratomas. N Engl J Med 292, 63-66. 55. DeGrouchy J (1980): Human parthenogenesis, a fascinating single event. Biomedicine 32, 51-53. 56. Wake N, Tanaka K, Chapman V, Matsui S, Sandberg AA (1981): Chromosomes and cellular origin of choriocarcinoma. Cancer Res 41, 3137-3143.