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Concomitant Germ Cell Tumors in Monozygotic Twins
0022-5347/79/1214-0538$02.00/0 Vol. 121, April Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1979 by The Williams & Wilkins Co.
CONCOMITANT GERM CELL TUMORS IN MONOZYGOTIC TWINS HARRY J. WILBUR, MARVIN W. WOODRUFF
AND
MARYS. WELCH
From the Division of Urology, Department of Surgery, Albany Medical Center and Veterans Administration Hospital, Albany, New York
ABSTRACT
Simultaneously occurring embryonal cell tumors in a 38-year-old set of monozygotic twin brothers are reported. This is the eighth documented case of testicular cancer in twins and it is unique since it is the first report to describe bilateral testicular tumors in 1 of the twin brothers. The role of genetics in the development of certain cancers warrants further study. This documentation of testicular tumors in serologically proved identical twins is used as a basis for discussion of the role of heredity as a possible significant factor in germ cell tumor pathogenesis. Germ cell tumors of the testes are rare, accounting for less than 2 per cent of all cancers. Herein we report a unique case of testicular cancer of the same pathological type, occurring concomitantly in identical twins, with 1 of the brothers presenting with bilateral involvement. Understandably, owing to the extreme rarity of germ cell tumors in twins, no incidence figures currently exist of meaningful statistical significance. Since Champlin's 1 first observation of testicular tumors in twins in 1930 only 7 additional cases have been reported (table l). 2- 7 This is the first report to use human leukocyte antigen histocompatibility testing (HLA) and in depth red cell serotyping, in addition to comprehensive chromosomal studies, to confirm monozygosity and the presence of any significant genetic markers. There has been an increasing interest in the role of heredity in the development of certain cancers. 8 This unique case of testicular tumors in identical twins lends for further intellectual consideration of the congenital implications of the occurrence of similar cancers in the same family. Since monozygotic twins are genotypically identical and frequently have environmental similarities, they make excellent subjects for studying the etiology and variables of certain cancers. Epidemiologically, testicular tumors are rare and have an incidence rate of only 2.1 per 100,000 male subjects in the United States. 9 Malignant testicular tumors account for 11 to 13 per cent of all male cancer deaths in the 15 to 34-year age groups9 but diminish rapidly to less than 1 per cent before and after this period. A solid foundation for the hereditary aspects of some malignancies exists today with several familial cancer syndromes reported, such as von Rippel-Lindau disease associated with pheochromocytoma and hypernephroma. 10 The relationship of testicular feminization with seminoma also has been described by Lynch and associates. 8 In addition, several studies are now in progress relating tissue types and genetic markers to a wide spectrum of disorders. 11 Twin studies with further intensive histocompatibility and red cell typing, as well as identification of genetic and immunological markers, may aid in the future evaluation of the significance of hereditary factors in the etiology of certain tumors. METHODS
Monozygosity was confirmed by HLA, red cell typing and chromosomal analysis. The HLA type was determined as A2, All, B15, BW22, CWl, CW3 in both, using the method described by Mittal and associates. 12 Not only did each brother have identical HLA patterns but their reactivity to each type
was similar. Red cell typing was done using standard erythrocyte antisera, with red cells from both twins yielding identical results as seen in table 2. Chromosomal analysis revealed normal 46 XY patterns with identical markers. These combined studies assure monozygosity with greater than 98 per cent certainty. 13 CASE REPORTS
Case 1. A 38-year-old white man presented in May 1977 with painless enlargement of the left testis. A left orchiectomy was done and histological examination revealed embryonal TABLE
Reference
1. Previously reported testicular cancer in twins Monozygosity
Cdftore idism
Ages
Champlin'
Not proved
24 31
Wells2
Not proved
Domrich3
Not proved
Salm and Adlington' Stewart and Bagshaw' Villani"
Not proved
35 39 40
Red cell typing Not reported
Side
No Rt. Rt. No Not reported
37 37 18
Yes Yes Yes Yes No No Yes
Rt. Rt. Rt. Lt. Rt. Lt. Lt.
25
Yes
Rt.
23 23 38
No No No
Rt.
38
No
Bilat.
44
Tumor Type Embryonal Embryonal Seminoma Seminoma Embryonal Embryonal Seminoma Seminoma Seminoma Embryonal Teratoma (benign) Teratocarcinoma
Levey and Grabstald' Present report
TABLE
HLA and red cell typing HLA, red cell and genotyping
Lt.
Lt.
Embryonal Embryonal Embryonal with seminomia Rt. seminoma Lt. embryonal with seminoma
2. HLA serotyping and genotyping ofmonozygotic twins
reported HLA typing: A2, All, B15, BW22, CWl, CW3 (identical in both) Red cell typing (identical in both): Group O M pos. Rh pos. N pos. D (Rho) pos. S neg. C (rh') pos. s pos. E (rh") neg. P neg. c (hr') pos. Le• (Lewis) neg. e (hr") pos. Le• (Lewis) neg.
Kell (K) neg. Duffy (Fy•) neg. Duffy (Fy•) pos. Kidd (Jk) pos.
Antibody screening test (identical in both): Papain screening, neg. Accepted for publication July 7, 1978. Selectogen screening, neg. Read at annual meeting of American Urological Association, Chromosomal analysis, normal 46 XY (identical in both) Washington, D. C., May 21-25, 1978. 538
CONCOMITANT GERM CELL TUMORS IN MONOZYGOTIC TWINS
with seminoma (fig. 1). The patient denied any r
uvM""' examination was unremarkable except for a surgi-
left testicle. Ultrasonography of the remaining testicle, performed because of his brother's bilateral involvement, was interpreted as normal. All laboratory studies, including serum µ human chorionic gonadotropin and afetoprotein, were normal. Metastatic evaluation revealed bilateral lung metastasis, later shown histologically to be embryonal carcinoma. The patient was treated with chemotherapy, including vinblastine, bleomycin and cis-platinum. During treatment for the last 6 months he has shown marked regression of the pulmonary lesions. Case 2. The twin brother of the patient described in case 1 presented 3 months later with a nodule in the right testicle. At the time ofright orchiectomy, which was reported histologically as pure seminoma, examination of the left testis revealed it to be irregular and of increased consistency and, therefore, it was removed. Microscopic examination of the left testis revealed embryonal carcinoma with seminoma similar to that found in his brother (fig. 2). He was referred to the Albany Medical Center for further evaluation and therapy. Metastatic survey was unremarkable and serum µ human chorionic gonadotropin and a-fetoprotein levels were normal. A transabdominal radical bilateral para-aortic lymph node
539
dissection was done and 39 nodes were recovered, all reported as normal. DISCUSSION
Concomitant testicular tumors in twins are statistically rare. Numerous previous attempts have been made to compare concordance rates of various malignancies in twins to the incidence in the general population, with the implication that heredity may have a major role in tumor pathogenesis. 14 Other reports, using data from twin registries, discount significant differences in the incidence of tumors in twins from that of the general population. 13 Obviously, owing to the extreme rarity of testicular tumors in twins, significant statistical deductions cannot be made because of the small incidence figures involved. In an attempt to assign proper significance to the factors involved in tumor pathogenesis there may well be a delicate interrelationship that exists among several variables, including viral agents, cell mutation, altered immunological response, environmental influence and hereditary predisposition. To identify the etiologies of testicular cancer one must give serious consideration to the role of hereditary factors, especially when dealing with a tumor of germ cell origin. Inheritance alone is a complex subject, originating at the cellular or molecular level, and also may involve secondary
Fm. 1. Histologic section of left orchiectomy performed in case 1. Note that germ cell tumor contains embryonal and seminomatous elements.
Fm. 2. Histologic section from case 2 after left orchiectomy shows similar embryonal and seminomatous elements
540
WILBUR, WOODRUFF AND WELCH
environmental factors. 13 The question of inborn hereditary versus environmental factors as a causal agent in this case of testicular tumors in monozygotic twins remains unanswered, since both are similar and present simultaneously. With further studies of familial germ cell tumors certain fa~tors shared by specific malignancies may be identified, usmg various forms of histocompatibility testing and newer methods of genetic marker identification. Thus, in the future we may be able to predict that a specific genotype in certain susceptible individuals may predispose various tissues, in this case germ cells, to malignant degeneration. In support of this aspect of testicular tumor pathogenesis is the finding that cryptorchid testes, which have a higher incidence of neoplastic degeneration, predominately display abnormal chromosomal patterns. 15 . The Albany Veterans Administration Hospital Tissue Typmg Laboratory and the Department of Nuclear Medicine the Albany Medical Center Hospital Blood Bank, the New York State Kidney Disease Institute and the New York State Birth Defects Institute assisted with HLA identification, serotyping and genetic evaluation. REFERENCES
1. Champlin, H. W.: Similar tumors of testis occurring in identical twins. J.A.M.A., 95: 96, 1930. 2. Wells, H. G.: Personal communication to Twinem, 1937. Cited by Macklin. 14 3. Domrich, H.: Uber Leistenhodencarcinoma bei Zwillingen. Langenbecks Arch. f. Clin. Chir., 197: 848, 1940. 4. Salm, R. and Adlington, S. R.: Seminoma in identical twins. Brit. Med. J., 2: 964, 1962. 5. Stewart, J. R. and Bagshaw, M. A.: Malignant testicular tumors appearing simultaneously in identical twins: a case report. Cancer, 18: 895, 1965. 6. Villani, U.: Tumore concordante del testicolo in una coppia di gemelli monozigoti. Acta Genet. Med. G., 16: 172, 1967.
7. Levey, S. and Grabstald, H.: Synchronous testicular tumors in identical twins. Urology, 6: 754, 1975. 8. Lynch, H. T., Guirgis, H. A., Lynch, P. M., Lynch, J. F. and Harris, R. E.: Familial cancer syndromes: a survey. Cancer, 39: 1867, 1977. 9. Mostofi, F. K.: Testicular tumors. Epidemiologic, etiologic, and pathologic features. Cancer, 32: 1186, 1973. 10. Greene, L. F. and Rosenthal, M. H.: Multiple hypernephromas of the kidney in association with Lindau's disease. New Engl. J. Med., 244: 634, 1951. 11. Petrakis, N. L. and King, M.-C.: Genetic markers and cancer epidemiology. Cancer, 39: 1861, 1977. 12. Mittal, K. K., Mickey, M. R., Singal, D. P. and Terasaki, P. I.: Serotyping for homotransplantation. 18. Refinement ofmicrodroplet lymphocyte cytotoxicity test. Transplantation, 6: 913, 1968. 13. Harvald, B. and Hague, M.: Hereditary factors elucidated by twin studies. Genetics and the Epidemiology of Chronic Disease. Public Health Service Publication No. 1163, p. 61, 1965. 14. Macklin, M. T.: Analysis of tumors in monozygous and dizygous twins, with a report of 15 unpublished cases. J. Hered., 31: 277, 1940. 15. Mininberg, D. T. and Bingol, N.: Chromosomal abnormalities in undescended testes. Urology, 1: 98, 1973. EDITORIAL COMMENT The hereditary and genetic aspects of testicular neoplasia have not been documented fully. Some 38 years ago Macklin studied more than 100 pairs of twins in whom there was tumor in at least 1 twin (reference 14 in article). He concluded that concordance for tumors is higher in monozygotic twins than in dizygotic twins. Tumors of the same type and site occur more often in monozygotic twins. He thought that monozygotic twins may have hereditary factors involved in the pathogenesis of these tumors. While these tumors are rare, the twin sibling should probably be aware of the possibility. The first reported case of testis tumors in monozygotic twins was in 1930 (reference 1 in article). These tumors were asynchronous, occurring 7 years apart, and were of different types. H.G.
THE JOURNAL OF UROLOGY
Copyright © 1979 by The Williams & Wilkins Co.
CONCOMITANT GERM CELL TUMORS IN MONOZYGOTIC TWINS HARRY J. WILBUR, MARVIN W. WOODRUFF
AND
MARYS. WELCH
From the Division of Urology, Department of Surgery, Albany Medical Center and Veterans Administration Hospital, Albany, New York
ABSTRACT
Simultaneously occurring embryonal cell tumors in a 38-year-old set of monozygotic twin brothers are reported. This is the eighth documented case of testicular cancer in twins and it is unique since it is the first report to describe bilateral testicular tumors in 1 of the twin brothers. The role of genetics in the development of certain cancers warrants further study. This documentation of testicular tumors in serologically proved identical twins is used as a basis for discussion of the role of heredity as a possible significant factor in germ cell tumor pathogenesis. Germ cell tumors of the testes are rare, accounting for less than 2 per cent of all cancers. Herein we report a unique case of testicular cancer of the same pathological type, occurring concomitantly in identical twins, with 1 of the brothers presenting with bilateral involvement. Understandably, owing to the extreme rarity of germ cell tumors in twins, no incidence figures currently exist of meaningful statistical significance. Since Champlin's 1 first observation of testicular tumors in twins in 1930 only 7 additional cases have been reported (table l). 2- 7 This is the first report to use human leukocyte antigen histocompatibility testing (HLA) and in depth red cell serotyping, in addition to comprehensive chromosomal studies, to confirm monozygosity and the presence of any significant genetic markers. There has been an increasing interest in the role of heredity in the development of certain cancers. 8 This unique case of testicular tumors in identical twins lends for further intellectual consideration of the congenital implications of the occurrence of similar cancers in the same family. Since monozygotic twins are genotypically identical and frequently have environmental similarities, they make excellent subjects for studying the etiology and variables of certain cancers. Epidemiologically, testicular tumors are rare and have an incidence rate of only 2.1 per 100,000 male subjects in the United States. 9 Malignant testicular tumors account for 11 to 13 per cent of all male cancer deaths in the 15 to 34-year age groups9 but diminish rapidly to less than 1 per cent before and after this period. A solid foundation for the hereditary aspects of some malignancies exists today with several familial cancer syndromes reported, such as von Rippel-Lindau disease associated with pheochromocytoma and hypernephroma. 10 The relationship of testicular feminization with seminoma also has been described by Lynch and associates. 8 In addition, several studies are now in progress relating tissue types and genetic markers to a wide spectrum of disorders. 11 Twin studies with further intensive histocompatibility and red cell typing, as well as identification of genetic and immunological markers, may aid in the future evaluation of the significance of hereditary factors in the etiology of certain tumors. METHODS
Monozygosity was confirmed by HLA, red cell typing and chromosomal analysis. The HLA type was determined as A2, All, B15, BW22, CWl, CW3 in both, using the method described by Mittal and associates. 12 Not only did each brother have identical HLA patterns but their reactivity to each type
was similar. Red cell typing was done using standard erythrocyte antisera, with red cells from both twins yielding identical results as seen in table 2. Chromosomal analysis revealed normal 46 XY patterns with identical markers. These combined studies assure monozygosity with greater than 98 per cent certainty. 13 CASE REPORTS
Case 1. A 38-year-old white man presented in May 1977 with painless enlargement of the left testis. A left orchiectomy was done and histological examination revealed embryonal TABLE
Reference
1. Previously reported testicular cancer in twins Monozygosity
Cdftore idism
Ages
Champlin'
Not proved
24 31
Wells2
Not proved
Domrich3
Not proved
Salm and Adlington' Stewart and Bagshaw' Villani"
Not proved
35 39 40
Red cell typing Not reported
Side
No Rt. Rt. No Not reported
37 37 18
Yes Yes Yes Yes No No Yes
Rt. Rt. Rt. Lt. Rt. Lt. Lt.
25
Yes
Rt.
23 23 38
No No No
Rt.
38
No
Bilat.
44
Tumor Type Embryonal Embryonal Seminoma Seminoma Embryonal Embryonal Seminoma Seminoma Seminoma Embryonal Teratoma (benign) Teratocarcinoma
Levey and Grabstald' Present report
TABLE
HLA and red cell typing HLA, red cell and genotyping
Lt.
Lt.
Embryonal Embryonal Embryonal with seminomia Rt. seminoma Lt. embryonal with seminoma
2. HLA serotyping and genotyping ofmonozygotic twins
reported HLA typing: A2, All, B15, BW22, CWl, CW3 (identical in both) Red cell typing (identical in both): Group O M pos. Rh pos. N pos. D (Rho) pos. S neg. C (rh') pos. s pos. E (rh") neg. P neg. c (hr') pos. Le• (Lewis) neg. e (hr") pos. Le• (Lewis) neg.
Kell (K) neg. Duffy (Fy•) neg. Duffy (Fy•) pos. Kidd (Jk) pos.
Antibody screening test (identical in both): Papain screening, neg. Accepted for publication July 7, 1978. Selectogen screening, neg. Read at annual meeting of American Urological Association, Chromosomal analysis, normal 46 XY (identical in both) Washington, D. C., May 21-25, 1978. 538
CONCOMITANT GERM CELL TUMORS IN MONOZYGOTIC TWINS
with seminoma (fig. 1). The patient denied any r
uvM""' examination was unremarkable except for a surgi-
left testicle. Ultrasonography of the remaining testicle, performed because of his brother's bilateral involvement, was interpreted as normal. All laboratory studies, including serum µ human chorionic gonadotropin and afetoprotein, were normal. Metastatic evaluation revealed bilateral lung metastasis, later shown histologically to be embryonal carcinoma. The patient was treated with chemotherapy, including vinblastine, bleomycin and cis-platinum. During treatment for the last 6 months he has shown marked regression of the pulmonary lesions. Case 2. The twin brother of the patient described in case 1 presented 3 months later with a nodule in the right testicle. At the time ofright orchiectomy, which was reported histologically as pure seminoma, examination of the left testis revealed it to be irregular and of increased consistency and, therefore, it was removed. Microscopic examination of the left testis revealed embryonal carcinoma with seminoma similar to that found in his brother (fig. 2). He was referred to the Albany Medical Center for further evaluation and therapy. Metastatic survey was unremarkable and serum µ human chorionic gonadotropin and a-fetoprotein levels were normal. A transabdominal radical bilateral para-aortic lymph node
539
dissection was done and 39 nodes were recovered, all reported as normal. DISCUSSION
Concomitant testicular tumors in twins are statistically rare. Numerous previous attempts have been made to compare concordance rates of various malignancies in twins to the incidence in the general population, with the implication that heredity may have a major role in tumor pathogenesis. 14 Other reports, using data from twin registries, discount significant differences in the incidence of tumors in twins from that of the general population. 13 Obviously, owing to the extreme rarity of testicular tumors in twins, significant statistical deductions cannot be made because of the small incidence figures involved. In an attempt to assign proper significance to the factors involved in tumor pathogenesis there may well be a delicate interrelationship that exists among several variables, including viral agents, cell mutation, altered immunological response, environmental influence and hereditary predisposition. To identify the etiologies of testicular cancer one must give serious consideration to the role of hereditary factors, especially when dealing with a tumor of germ cell origin. Inheritance alone is a complex subject, originating at the cellular or molecular level, and also may involve secondary
Fm. 1. Histologic section of left orchiectomy performed in case 1. Note that germ cell tumor contains embryonal and seminomatous elements.
Fm. 2. Histologic section from case 2 after left orchiectomy shows similar embryonal and seminomatous elements
540
WILBUR, WOODRUFF AND WELCH
environmental factors. 13 The question of inborn hereditary versus environmental factors as a causal agent in this case of testicular tumors in monozygotic twins remains unanswered, since both are similar and present simultaneously. With further studies of familial germ cell tumors certain fa~tors shared by specific malignancies may be identified, usmg various forms of histocompatibility testing and newer methods of genetic marker identification. Thus, in the future we may be able to predict that a specific genotype in certain susceptible individuals may predispose various tissues, in this case germ cells, to malignant degeneration. In support of this aspect of testicular tumor pathogenesis is the finding that cryptorchid testes, which have a higher incidence of neoplastic degeneration, predominately display abnormal chromosomal patterns. 15 . The Albany Veterans Administration Hospital Tissue Typmg Laboratory and the Department of Nuclear Medicine the Albany Medical Center Hospital Blood Bank, the New York State Kidney Disease Institute and the New York State Birth Defects Institute assisted with HLA identification, serotyping and genetic evaluation. REFERENCES
1. Champlin, H. W.: Similar tumors of testis occurring in identical twins. J.A.M.A., 95: 96, 1930. 2. Wells, H. G.: Personal communication to Twinem, 1937. Cited by Macklin. 14 3. Domrich, H.: Uber Leistenhodencarcinoma bei Zwillingen. Langenbecks Arch. f. Clin. Chir., 197: 848, 1940. 4. Salm, R. and Adlington, S. R.: Seminoma in identical twins. Brit. Med. J., 2: 964, 1962. 5. Stewart, J. R. and Bagshaw, M. A.: Malignant testicular tumors appearing simultaneously in identical twins: a case report. Cancer, 18: 895, 1965. 6. Villani, U.: Tumore concordante del testicolo in una coppia di gemelli monozigoti. Acta Genet. Med. G., 16: 172, 1967.
7. Levey, S. and Grabstald, H.: Synchronous testicular tumors in identical twins. Urology, 6: 754, 1975. 8. Lynch, H. T., Guirgis, H. A., Lynch, P. M., Lynch, J. F. and Harris, R. E.: Familial cancer syndromes: a survey. Cancer, 39: 1867, 1977. 9. Mostofi, F. K.: Testicular tumors. Epidemiologic, etiologic, and pathologic features. Cancer, 32: 1186, 1973. 10. Greene, L. F. and Rosenthal, M. H.: Multiple hypernephromas of the kidney in association with Lindau's disease. New Engl. J. Med., 244: 634, 1951. 11. Petrakis, N. L. and King, M.-C.: Genetic markers and cancer epidemiology. Cancer, 39: 1861, 1977. 12. Mittal, K. K., Mickey, M. R., Singal, D. P. and Terasaki, P. I.: Serotyping for homotransplantation. 18. Refinement ofmicrodroplet lymphocyte cytotoxicity test. Transplantation, 6: 913, 1968. 13. Harvald, B. and Hague, M.: Hereditary factors elucidated by twin studies. Genetics and the Epidemiology of Chronic Disease. Public Health Service Publication No. 1163, p. 61, 1965. 14. Macklin, M. T.: Analysis of tumors in monozygous and dizygous twins, with a report of 15 unpublished cases. J. Hered., 31: 277, 1940. 15. Mininberg, D. T. and Bingol, N.: Chromosomal abnormalities in undescended testes. Urology, 1: 98, 1973. EDITORIAL COMMENT The hereditary and genetic aspects of testicular neoplasia have not been documented fully. Some 38 years ago Macklin studied more than 100 pairs of twins in whom there was tumor in at least 1 twin (reference 14 in article). He concluded that concordance for tumors is higher in monozygotic twins than in dizygotic twins. Tumors of the same type and site occur more often in monozygotic twins. He thought that monozygotic twins may have hereditary factors involved in the pathogenesis of these tumors. While these tumors are rare, the twin sibling should probably be aware of the possibility. The first reported case of testis tumors in monozygotic twins was in 1930 (reference 1 in article). These tumors were asynchronous, occurring 7 years apart, and were of different types. H.G.