Kovač, Viljem

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Radio! 011col 1998; 32(2): 201-5. rev1ew The cause of testicular cancer Viljem Kovač Institute oj Oncology, Ljubljana, Slovenia The cause oj testicular cance1; like oj most other cancers, is unknown, but the groups oj men with higher incidence oj this type oj cancer are being investigated. Familial patterns oj testicular cancer are reported, as well as the influence oj oncogenes, particular predisposition factors oj congenital anomalies oj the urogeni­tal tract, starting with the failure oj the testis descent (cryptorhism). Since the incidence oj cryptorhism is growing in the world, this could prave to be the main cause oj the higher incidence oj testi cul ar cancer. The atrophy oj the germinal epithelium is also ascribed a special role in the incidence oj testicular cancer. The impact oj the oestrogen from environment, possibly affecting the spermatogenesis and probably caus­ing higher incidence oj congenital anomalies oj the urogenital tract, has been lately intensively studied as well. Social factors may prave significant, too, while physical trauma has not been determined as the cause oj testicular cancer, and it could only be considered as one oj the potential co-causes oj the canccr. Key words: testicular neoplasm, ctiology Introduction Since the incidence of testicular cancer has been growing both in the World, 1,2 and inSlovenia,3 the possible causes of this disease have been the subject of many studies. The real cause of the testicular cancer has remained unknown, but the groups of men with higher incidence are being studied. Genetic causes Familial testicular cancer has been debated as a potential and possibly independent risk fac-Correspondence to: Assist . Viljem Kovač, M.D., M.Se., Institute of Oncology, Zaloška 2, 1000 Ljubljana, Slovenia. Phone: +386 611320 06 8. Fax: +386 611314180. tor.4 Familial patterns of testicular cancer can be related to a groups of patients with higher incidence of congenital anomalies, as well as to patients with tumours in the counter-lateral testis5 and to Down's syndrome. Such fami­lies have been reported as displaying a 6 to 10 times higher incidence of testicular cancer. The most frequent chromosomal anomalies have been looked for, those which cause malignant alteration in testicles.6 An international study of 100 families with a familial form of testicular cancer, car­ried out under the auspices of the UK Imperi­al Cancer Research Fund, has revealed con­siderable genetic heterogeneity. There is no evidence of a single genomic region account­ing for the occurrence of testicular cancer, but rather of several such regions.7 Some sole 202 Kovač V cytogenetic abnormalities have nevertheless been found in patients with nonseminoma­tous tumours.8The most frequent chromosomal anom­alies related to malignant alterations in testi­cles are stil! being looked for,6,9 and in partic­ular there are looking for oncogenes. The most frequent oncogenes detected in testicu­lar tumours and related to oncogenesis are K­ras2, PDGFA and N-myc oncogenes. Predisposition factors of congenital anom­alies of urogenital tract The incidence of testicular cancer is higher in patients with the anomalies of the urogenital tract, especially the failure of testis descent (cryptorhism), but also ingvinal hernia, hydrocele and hypospadias. As much as 10% of testicular neoplasm are associated with cryptorhism, in spite of the orchriopexy.10,11 The risk factor for testicular tumours is 40 times higher with the failure of testis descent. The risk is a little lower if the opera­tion of the cryptorhism is performed before the age of six. The risk of cancer is also high in the contralateral descended testis.12 Since the incidence of cryptorhism is growing in the World, this could prove to be the main cause of the higher incidence of tes­ticular cancer.13,14 Patients who have had one testicular tumour are more likely to develop a contralat­eral tumour.15,16 The incidence of carcinomain situ of the contralateral testis in patients who have had one testicular tumour is about 5%, and about 50% of patients with carcino­ma in situ develop invasive malignancy with­in 5 years.17 The atrophy of testis In to the above mentioned factors, the atrophy of the germinal epithelium is supposed to be significant as well, most frequent in the patho­genesis of tumours.18 The reports that theatrophy, as a complication after vasectomy, is a risk factor for testicular tumours, also speak in favour of this theory.19 When a tumour isdiagnosed in a testis, higher levels of FSH would represent a risk factor for a secondary tumour.19 The incidence of testicular cancer isalso higher with fertility disorders, which are closely linked with atrophy of testis.5 Contrary to that, Giwercman and others20 report that the risk of carcinoma in situ of testis is not higher in moderately oligo­zoospermic men. Bilateral testicular biopsies were performed in 207 men of infertile cou­ples. No carcinoma in situ were detected in any of them. Although the authors believe that there is substantial evidence of a fetal origin of carcinoma in situ, patients in whom the biopsy revealed no carcinoma should also be closely monitored. The results presented namely refer to moderately oligozoospremic men only. Hormonal factors The peak incidence of testicular cancer in young men suggests that gestational develop­ment and events during early infancy and puberty are important in the pathogenesis of the disease. There are two potentially signifi­cant events: the transformation of fetal germ cells into carcinoma in situ cells and later conversion of carcinoma in situ cells into fully invasive cancer. Severa! hypotheses sug­gest an endocrinological background of tes­ticular neoplasia. 21 Since the inhibin B, which is considerably higher in the first year of life, could not be traced in boys with anorhism, this hormone could prove to be especially significant for the occurrence of testicular cancer. After puberty, relatively higher levels of oestrogen and androgen receptors could be relevant for the etiology of testicular cancer.13 The cnuse of /eslirn/nr cnncer 203 Estrogens probably play an important role in the etiopathogenesis of testicular cancer. This was the conclusion of the study by Nakazuma,22 which revealed that the serum levels of estradiol and hCG were significantly above normal values both in systemic and spermatic veins of patients with nonsernino­ma gerrn celi turnours. Higher levels of estro­gens in the serum could, on the other hand, be the consequence of thc tumour and not its cause, as the production of hCG is the conse­quence of thc growth of the germ celi tumours.23 The oestrogen in thc environment are con­sidcred to be the most important cause of the low quality of sperm in the last 20 years, 24and they are also blamed for a highcr inci­dence of innate malformations and possibly for the incidcncc of testicular cancer. Women, who were on estrogen diethyl­stilbestrol during pregnancy, have been stud­ied. Since the drug has estrogenic effect, it was presumed a possib\e cause of testicular cancer. But a detailed review of the effect of the in-utero exposure to diethylstilbestrol showed only an adverse effect on the repro­ductive tract in male progeny.25 Tcsts on ani­mals showed that while prenatal estrogen exposure does induce more severe and earlier testicular abnormalities, manifesting them­selves as regressive changcs in the germinal cpithelium and Sertoli's cells, atrophied sem­iniferous tubules and dysplasia of the rete testis epithelium, the presence of neoplasrn has never been confirmed.26 The impact of diethylstilbestol, taken by pregnant women, on the incidence of vagi­na! cancer in their daughters has been con­firrned, and the estrogens from the environ­rnent are likely responsible for a higher inci­dence of breast cancer. The hypothesis of these estrogens prornoting testicular cancer is stili viable, 27,28 and the development of serum markers determining the exposure of an individual to estrogens in the environ­ment is very important.29 The investigation into the impact of estrogens on the inci­dence of testicular cancer is very inscnsi­tive. Oestrogen has been related to the lower quality of sperm and to thc higher incidence of hypogonadism and cryp­torhism. 27,28,30 Since estrogens are related to the genesis of other types of cancer, over 2200 mothers of the boys who developed testicular cancer, were studied in Denmark. The study revealed no higher incidence of breast cancer, of endo­metric or of ovarian cancer in them, so that these women did not represent a higher risk group of oestrogen related cancers. 3-i Indi­rectly, this cou\d mean that estrogens may not play a role as important as was thought in the genesis of testicular cancer. Such a con­clusion would be premature, however, since countries with a higher incidence of breast cancer (which is likely estrogen related can­ccr) also report a higher incidence of testicu­lar cancer, and it would suggest some relation between the two. Social factors The incidence of testicular cancer is higher in men of higher social status. 1 We detected arelatively high percentage (40.2%) of patients with college or university education.10 A bet­ter social status may be related to more fre­quent diaper changes and consequently high­er temperature in the genital area during the first months of life. The influence of tempera­ture on the incidence of testicular cancer has not been studied enough. The impact of trauma The impact of trauma on the development of testicular cancer has not been cleared. Most probably, trauma does not raise the incidence of testicular cancer. The fact that a larger nurnber of patients mention trauma in their 204 Kovač V anamnesis can be ascribed to the acute atten­tion paid to a blows received in the genital area. Patients may discover at that point tis­sue hardening or swellings.10,32 Despite the above, certain sports (cycling and horse riding) could cause injuries related to the development of testicular cancer.33 It is possible that any type of injury could act as an additional conducive factor to the already existing cause. Swerdlow reports an increa­sed incidence of testicular cancer when biop­sy was performed in addition to orchido­pexy.34 References 1. Shottenfeld D, Warshauer ME. Testis. In: Schot­tenfeld D, Fraumeni JF, eds. Cancer Epidemiologynnd Prevention. Philadelphia: Saunders, 1982: 947-57. 2. Boyle P. Kaye SB, Robertson AG. Changes in tes­ticular cancer in Scotland. Eur J Cnncer Ciin Oncol 1987; 23: 827-30.3. Onkološki inštitut v Ljubljani, Register raka za Slovenijo. lncidenca raka v Sloveniji 1981 - 1995. Ljubljana: Onkološki inštitut v Ljubljani, 1984 -1998.4. Pate! SR, Kvols LK, Richardson RL. Familial testic­ular cancer: report of six cases and review of the literature. Mayo Ciin Proc 1990; 65(6): 804-8.5. Jrgensen N, Muller J, Giwercman A, SkakkebaekNE. Clinical and biological significance of carcino­ma in situ of the testis. Cancer Surv 1990; 9(2): 287-302. 6. Muller J, Skakkebaek NE. Gonadal malignancy inindividuals with sex chromosome anomalies. BirthDefects 1990; 26(4): 247-55. 7. Ginsburg J, Okolo S, Prelevic G, Hardiman P. Res­idence in the London area and sperm density.Lnncet 1994; 343: 230.8. Gibas Z, Prout GR, Sandberg AA. Malignant ter­atoma of the testis with an isochromosome No. 12,1(12p), as the sole structural cytogenetic abnor­mality. J Urol 1984; 13: 372-5. 9. Duncan MV. Isochromosome of chromosome 12: clinically useful marker for male germ celi tumors.J Natl Cancer lnst 1990; 82: 1433. 10. Kovač V. Vpliv onkološke terapije na fertilnostmoških. Magisterska naloga. Zagreb, 1996.11. Henderson BE, Benton B, Jing J, et al. Risk factorsfor cancer of the testis in young men. lnt J Cnncer1979, 23: 598-602.12. Palmer JM. The undescended testicle. EndocrinoMetab Ciin Norih A11 1991; 20(1): 231-40.13. Ginsburg J. Unanswered questions in carcinomaof the testis [Commentary]. Lnncet 1997; 349:1785-6.14. Giwercman A, Skakkebaek NE. The human testis:an organ at risk? lnt J Androl 1992; 15: 373-75.15. Osterlind A, Berthelson JG, Abeldgaard N. Inci­dence of bilateral testicular germ celi cancer in Denmark 1960-1984. lnt J Androl 1987; 10: 203- 8.16. Sokol M, Peckham MJ, Hendry WF. Bilateral germ celi tumours of the testis. Br J Urol 1987; 52: 258-63. 17. von der Maase H, Givercman A, Miller J, et al. Management of carcinoma in situ of the testis. lntJ Androl 1987; 10: 209-13.18. Oliver RT. Atrophy, hormones, genes and virusesin aetiology germ celi tumours. Cancer Surv 1990;9(2):263-86. 19. Oliver RT. Testicular cancer. Curr Opin Oncol 1991; 3(3):559-64.20. Giwercman A, Thomsen JK, Hertz J, BerthelsenJG, Jensen V, Meinecke B, Thormann L, StormHH, Skakkebaek NE. Prevalence of carcinoma insitu of the testis in 207 oligozoospermic men frominfertile couples: prospective study of testicular biopsies. Br Med J 1997; 315: 989-90.21. Rajpert De Meyts E, Skakkebaek NE. The possiblerole of sex hormones in the development of testic­ular cancer. Eur Uro/ 1993; 23(1): 54-9. 22. Nakazumi H, Sasano H, MaeharaI, Ozaki M, Tezuka F, Orikasa S. Estrogen metabolism andimpaired spermatogenesis in germ celi tumors of the testis. J Ciin Endocrinol Metnb 1996; 81(3): 1289-95. 23. Berthelsen JG, Skakkebaek NE. Gonadal function in men with testis cancer. Fertil Sferi/ 1983; 39: 68-71. 24. Auger J, Kunstmann JM, Czyglik F, Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med 1995; 332: 281-5. Tile cause of leslicular ca11cer 205 25. Stillman RJ. In utero exposure to diethylstilbe­strol: Adverse effects on the reproductive tractand reproductive performance in male and femaleoffspring. A111 J 0/Jstel Gyneco/ 1982; 142: 905-21.26. Perez Martinez C, Ferreras Estrada MC, GarciaIglesias MJ, Bravo Moral AM, Espinosa Alvarez J, Escudero Diez A. Effects of in utero exposure to nonsteroidal estrogens on mousc testis. Can J Vel Res 1997; 61(2): 94-8.27. Jensen TK, Toppari J, Keiding N, Skakkebaek NE.Do environmental estrogens contribute to thedecline in male reproductive health? Cli11 Che1111995; 41(12): 1896-901.28. Sharpe RM, Skakkebaek NE. Are oestrogensinvolved in falling sperm counts and disorders ofthe male reproductive tract? Lancel 1993; 341:1392-5.29. Soto AM, Fernandez MF, Luizzi MF, Oles KaraskoAS, Sonnenschein C. Developing a marker of exposure to xenoestrogen mixtures in humanserum. E11viro11 Hea/111 Perspecl 1997; 105 (Suppl 3):647-54.30. Giwercman A. Declining semen quality andincreasing incidence of abnormalities in malereproductive organs - fact or fiction?. H11111 Reprod1995; 10 (Suppl 1): 158-64. 31. Kroman N, frisch M, Olsen JH, Westergaard T,Melbye M. Oestrogen-related cancer risk in moth­ers of testicular-cancer patients. 1111 J Cancer 1996. 66(4): 438-40.32. Thomas GM, Williams SO. Testis. In: Perez CA,Luther WB, editors. Principles m1d practice of radia­/ion 011cology. 2nd ed. New York: J.B. LippincottCompany, 1992. p. 1117-31.33. Coldman AJ, Elwood JM. Gallagher R. Sport activ­ities and risk of testicular cancer. Br J Cancer 1982;46: 749-56.34. Swerdlow AJ, Higgins CD, Pike MC. Risk of testic­ular cancer in cohort of boys with cryp­torchidisms. Br Med J 1997; 314: 1507-11. 

[Vzroki za nastanek raka testisov]

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[Vzroki za nastanek raka testisov]

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