Should extragonadal germ cell tumors be included in studies of families with testicular germ cell tumors?
© Guindalini et al.; licensee BioMed Central Ltd. 2013
Received: 21 November 2012
Accepted: 25 February 2013
Published: 4 March 2013
Family history is among the few established risk factors for testicular germ cell tumor (TGCT). Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to six fold and eight- to tenfold increase in TGCT risk, respectively. In twins of men with TGCT the relative risk of testicular cancer is 37.5 (12.3-115.6). Nevertheless, information about the occurrence of TGCT in relatives of patients with extragonadal germ cell tumor is limited.
A 24 year-old male patient was diagnosed with a mediastinum tumor and was submitted to image-guided biopsy, which revealed a seminoma. Two months later, his non-identical asymptomatic twin brother was submitted to an elective ultrasound of the testes, which showed a left testicular mass of 4.2 cm. This patient underwent orchiectomy revealing a seminoma of the left testis. There are no other cases of seminoma or other types of cancers reported in first-degree relatives in this family.
Although familial aggregations of TGCT have been well described, to the best of our knowledge, no data concerning the association of gonadal and extragonadal germ cell tumor in relatives has been previously reported. Further investigation on this association is warranted and may help in improving our knowledge of familial pattern inheritance.
KeywordsGenetic susceptibility Familial testicular germ cell tumor Seminoma
Testicular germ cell tumor (TGCT) is the most common malignancy in males aging 15–35. Known risk factors for TGCT include: cryptorchidism, testicular dysgenesis, infertility, testicular microlithiasis, previously diagnosed TGCT and a family history of the disease .
Familial aggregations of TGCT have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT . Epidemiological studies have shown that there is an eight to ten fold increase in relative risk of TGCT for brothers of patients and a fourfold increased risk for fathers and sons [3, 4]. Moreover, testicular cancer risk was raised in twins of men with testicular cancer (relative risk = 37.5 [12.3-115.6]); risk was greater but not significantly in monozygotic than in dizygotic twins (p = 0.45). The cumulative risk of testicular cancer by the age of 40 years in men whose monozygotic twins had testicular cancer was 14% (4–46) . A previous study using segregation analysis of testicular cancer favored an autosomal recessive model of inheritance  and, although no high-penetrance cancer susceptibility gene has been mapped yet, linkage analyses have identified several genomic regions of modest interest . Y chromosome gr/gr deletion and PDE11A gene mutations have been suggested to modify the risk of familial testicular germ cell tumor (FTGCT) [8, 9]. Phenotypic aspects of FTGCT include 2 cases of TGCT per family, mean age at diagnosis about 2.5 years younger than that observed for sporadic TGCT and greater prevalence of bilateral cancer .
The establishment of a universal screening program using testicular palpation (clinical or patient self-examination) or serum biomarker for healthy young patients lacks clinical evidence . And, although some risk factors for TGCT are well known, effectiveness of high-risk patients screening is controversial. Recent systematic review did not detect published randomized clinical trials comparing screening versus no screening for testicular cancer . On the basis of uncertain benefits and some likelihood of harms, the US Preventive Services Task Force and the American Academy of Family Physicians discourage screening. But others, such as the American Cancer Society and the European Association of Urology, recommend different approaches: testicular examination to be part of a periodic cancer-related checkup  and self-testicular examination for individuals with clinical risk factors , respectively.
Extragonadal germ cell tumors account for fewer than 10% of all germ cell malignancies. All reports of family inheritance focused exclusively in isolated germ cell tumors of testis [4, 6, 7] and the estimation of the contribution of extragonadal germ cell tumor in the familial setting is not known. Therefore, the omission of extragonadal tumors in the published reports may have contributed to the underestimation of the importance of the hereditary factor of germ cell tumors, especially when there is a presence of an affected twin. Here we present a report of simultaneous occurrence of seminomas in dizygotic twins: one in the testicle and the other in the mediastinum.
A 24 year-old male patient was first diagnosed with a mediastinal mass. Other lesions were not found elsewhere in the body, including the testicles. A computed tomography-guided transthoracic biopsy led to the diagnosis of primary mediastinal seminoma. Two months after, his non-identical asymptomatic twin brother was then submitted to an elective ultrasound of the testes, which showed a left testicular mass of 4.2 cm. After excluding extragonadal disease, this patient underwent orchiectomy that revealed a pure seminoma of the left testis with rete testis invasion. There are no other cases of seminoma or other types of cancers reported in first-degree relatives of this family. Initially, the first patient received 4 cycles of bleomycin, cisplatin, and etoposide (BEP) and is now following a residual mediastinal mass with serial images. His brother has no evidence of disease after 1 cycle of carboplatin AUC 7 mg/mL.
Although mediastinal germ cell neoplasms account for only 2% to 5% of all germinal tumors, they constitute up to 50% to 70% of all extragonadal tumors. When this mediastinal tumor is identified, it is mandatory to exclude TGCT. Daugaard et al. reported that, while carcinoma in situ testis (CIST) was diagnosed in 42% of germ cell primary tumors of retroperitoneum, indicating that these tumors are probably not truly extragonadal, none of the patients with tumors in mediastinum who underwent biopsy had CIST . Accordingly, the vast majority of patients with mediastinal tumor will not develop testicular tumors and, as a consequence, will not be analyzed in epidemiological studies using population databases. In this sense, although the familial association of gonadal and extragonadal germ cell tumors has not yet been established, based on the present case report it is possible to question if the exclusion of extragonadal germ cell tumors from FTGCT studies may exert a negative influence on the advances of the knowledge regarding the underlying common genetic mechanisms of germ cell tumors.
Furthermore, it is important to note that the decision of performing the investigation on the asymptomatic brother was closely guided by the information provided in previous studies of FTGCT . This initiative permitted an early tumor diagnosis and, consequently, greater chances of successful treatment without an unnecessary exposure to the acute and late toxicities of BEP. In this perspective, we would like to propose the discussion of whether we should start including extragonadal germ cell tumors in studies of families with testicular germ cell tumors.
Nevertheless, further investigations in other clinical and population based studies are necessary and may improve our understanding of familial pattern of inheritance. We believe that future research on the association of testicular and extragonadal germ cell tumors in the familial setting may provide new insights and discoveries in the field and, hopefully, help on the design of strategies for prevention, screening and follow-up of families with germ cell tumors, especially when there is a presence of an affected twin.
Written informed consent was obtained from the patients for publication of this Case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Bleomycin, cisplatin, and etoposide
Carcinoma in situ testis
Familial testicular germ cell tumor
Testicular germ cell tumor.
We thank the patients and their family, without whose cooperation this report would not have been possible.
- Greene MH, Kratz CP, Mai PL, Mueller C, Peters JA, Bratslavsky G, Ling A, Choyke PM, Premkumar A, Bracci J, Watkins RJ, McMaster ML, Korde LA: Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype. Endocr Relat Cancer 2010, 17: R109-R121. 10.1677/ERC-09-0254View ArticlePubMedPubMed CentralGoogle Scholar
- Dieckmann KP, Pichlmeier U: The prevalence of familial testicular cancer: an analysis of two patient populations and a review of the literature. Cancer 1997, 80: 1954–1960. 10.1002/(SICI)1097-0142(19971115)80:10<1954::AID-CNCR12>3.0.CO;2-XView ArticlePubMedGoogle Scholar
- Hemminki K, Li X: Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer 2004, 90: 1765–1770. 10.1038/sj.bjc.6601714View ArticlePubMedPubMed CentralGoogle Scholar
- Dong C, Hemminki K: Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families. Int J Cancer 2001, 92: 144–150. 10.1002/1097-0215(200102)9999:9999<::AID-IJC1147>3.0.CO;2-CView ArticlePubMedGoogle Scholar
- Swerdlow AJ, De Stavola BL, Swanwick MA, Maconochie NE: Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet 1997, 350: 1723–1728. 10.1016/S0140-6736(97)05526-8View ArticlePubMedGoogle Scholar
- Heimdal K, Olsson H, Tretli S, Fossa SD, Borresen AL, Bishop DT: A segregation analysis of testicular cancer based on Norwegian and Swedish families. Br J Cancer 1997, 75: 1084–1087. 10.1038/bjc.1997.185View ArticlePubMedPubMed CentralGoogle Scholar
- Crockford GP, Linger R, Hockley S, Dudakia D, Johnson L, Huddart R, Tucker K, Friedlander M, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Chompret A, Bonaïti-Pellié C, Heidenreich A, Albers P, Olah E, Geczi L, Bodrogi I, Ormiston WJ, Daly PA, Guilford P, Fosså SD, Heimdal K, Tjulandin SA, Liubchenko L, Stoll H, Weber W, Forman D, Oliver T, Einhorn L, McMaster M, Kramer J, Greene MH, Weber BL, Nathanson KL, Cortessis V, Easton DF, Bishop DT, Stratton MR, Rapley EA: Genome-wide linkage screen for testicular germ cell tumour susceptibility loci. Hum Mol Genet 2006, 15: 443–451.View ArticlePubMedGoogle Scholar
- Nathanson KL, Kanetsky PA, Hawes R, Vaughn DJ, Letrero R, Tucker K, Friedlander M, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Chompret A, Bonaïti-Pellié C, Heidenreich A, Olah E, Geczi L, Bodrogi I, Ormiston WJ, Daly PA, Oosterhuis JW, Gillis AJ, Looijenga LH, Guilford P, Fosså SD, Heimdal K, Tjulandin SA, Liubchenko L, Stoll H, Weber W, Rudd M, Huddart R, Crockford GP, Forman D, Oliver DT, Einhorn L, Weber BL, Kramer J, McMaster M, Greene MH, Pike M, Cortessis V, Chen C, Schwartz SM, Bishop DT, Easton DF, Stratton MR, Rapley EA: The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet 2005, 77: 1034–1043. 10.1086/498455View ArticlePubMedPubMed CentralGoogle Scholar
- Horvath A, Korde L, Greene MH, Libe R, Osorio P, Faucz FR, Raffin-Sanson ML, Tsang KM, Drori-Herishanu L, Patronas Y, Remmers EF, Nikita ME, Moran J, Greene J, Nesterova M, Merino M, Bertherat J, Stratakis CA: Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Res 2009, 69: 5301–5306. 10.1158/0008-5472.CAN-09-0884View ArticlePubMedPubMed CentralGoogle Scholar
- Mai PL, Friedlander M, Tucker K, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Bonaïti-Pellié C, Heidenreich A, Albers P, Bodrogi I, Geczi L, Olah E, Daly PA, Guilford P, Fosså SD, Heimdal K, Liubchenko L, Tjulandin SA, Stoll H, Weber W, Easton DF, Dudakia D, Huddart R, Stratton MR, Einhorn L, Korde L, Nathanson KL, Bishop DT, Rapley EA, Greene MH: The international testicular cancer linkage consortium: a clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred. Urol Oncol 2010, 28: 492–499. 10.1016/j.urolonc.2008.10.004View ArticlePubMedGoogle Scholar
- Lin K, Sharangpani R: Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2010, 153: 396–399.View ArticlePubMedGoogle Scholar
- Ilic D, Misso ML: Screening for testicular cancer. Cochrane Database Syst Rev 2011. http://dx.doi.org/10.1002/14651858 Google Scholar
- American Cancer Society: American Cancer Society guidelines for the early detection of cancer. http://www.cancer.org/Healthy/FindCancerEarly/CancerScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer
- European Association of Urology: Guidelines on Testicular Cancer. http://uroweb.org/gls/pdf/Testicular%20Cancer%202010.pdf
- Daugaard G, Rorth M, von der Maase H, Skakkebaek NE: Management of extragonadal germ-cell tumors and the significance of bilateral testicular biopsies. Ann Oncol 1992, 3: 283–289.PubMedGoogle Scholar
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