Risk of Contralateral Testicular cancer (TC): A Population-based Study of 29 515 U.S. Men

Risk of Contralateral Testicular cancer (TC): A Population-based Study of 29 515 U.S. Men
Journal of the National Cancer Institute, Vol. 97, No. 14, 1056-1066, July 20, 2005

Introduction

• Increasing numbers of men with unilateral TC are at risk of developing a metachronous contralateral TC, given the high cure rates (approximately 95%) of patients with testicular germ cell tumours and the rising incidence of TC
• The cumulative risks of metachronous contralateral TC 20–25 years after initial diagnosis is from 2.4% to 5.2%
• European men with unilateral TC have a 12- to 38-fold higher risk of developing a new TC compared with men from the general population
• Initial diagnosis before the age of 30 years has been reported to be a risk factor for the development of a metachronous contralateral TC
• Many clinicians recommend routine biopsy of the contralateral testis for patients diagnosed with unilateral TC
• Aim of this study was to evaluate the risk of developing metachronous contralateral TC in a large, population-based cohort of TC patients with respect to age at initial diagnosis, histologic type, and treatment and to examine the prevalence of synchronous contralateral TC in the same cohort

Methods

• For 29 515 TC cases reported to the National Cancer Institute's Surveillance, Epidemiology and End Results Program from 1973 through 2001, we estimated
• prevalence of synchronous contralateral TC
• observed-to-expected ratio (O/E) and 15-year cumulative risk of metachronous contralateral TC
• 10-year overall survival rate of both synchronous and metachronous contralateral TC
• NB Kaplan–Meier method was used for the two latter assessments. Age-adjusted multivariable analyses were used to examine risk according to histological type of the original cancer

Results

• A total of 175 men presented with synchronous contralateral TC
• 287 men developed metachronous contralateral TC (O/E = 12.4 [95% confidence interval {CI} = 11.0 to 13.9]
• 15-year cumulative risk = 1.9% [95% CI = 1.7% to 2.1%])
• In the multivariable analysis, only nonseminomatous histology of the first TC was associated with a statistically significantly decreased risk of metachronous contralateral TC (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.46 to 0.79; P<.001)
• Increasing age at first TC diagnosis was associated with decreasing risk of nonseminomatous metachronous contralateral TC (odds ratio = 0.90, 95% CI = 0.86 to 0.94)
• The 10-year overall survival rate after metachronous contralateral TC diagnosis was 93% (95% CI = 88% to 96%), and that after synchronous contralateral TC was 85% (95% CI = 78% to 90%)

Discussion

• U.S. TC patients have a 12.4-fold increased risk of developing a metachronous contralateral TC compared with the general population
• Risk was highest during the first 5 years after orchidectomy and decreased thereafter
• 15-year cumulative risk of developing a metachronous contralateral TC was 1.9%
• After adjustment for age, patients with seminomatous unilateral TC had a higher risk of metachronous contralateral TC than patients with a nonseminomatous unilateral TC
• Older age at the time of the first TC diagnosis was associated with a reduced risk of nonseminomatous metachronous contralateral TC as compared to seminomatous histology
• Development of a metachronous contralateral TC is not associated with a decrease in overall survival as compared to patients without a metachronous TC
• Development of bilateral TC can be explained by the hypothesis regarding germ cell carcinogenesis
• The malignant process is believed to start during the 7th through 9th weeks of embryonal life
• Environmental factors are believed to cause changes in the male embryo's primordial cells, from which the testes later develop
• These prenatal influences may initiate carcinoma in situ and subsequent development of invasive TC
• Whether carcinogenesis occurs in one or both testes depends on the distribution of cells that were exposed to these prenatal influences
• Cancer development is believed to start earlier and have a higher growth rate in men with nonseminoma than in men with seminoma, which explains the younger age of nonseminoma patients at first presentation
• In some men, the development of TC is also genetically determined, as indicated by the occurrence of familial TC
• This may explain the occurrence of bilateral TC observed in patients with TC – in fact 2%–5% of patients with TC, the germinative epithelium in both testes seems to contain cell clones with pre-malignant changes
• Overall observed-to-expected ratio (12.4) and 15-year cumulative incidence risk (1.9%) of metachronous contralateral TC estimated in this study are lower than the estimates reported by most European studies with comparable information
• The reasons behind this may include:
• European analyses of subsequent testicular cell cancer after a first germ cell cancer diagnosis often include patients with extragonadal germ cell cancer who have a high incidence of metachronous TC
• In some studies, the reported incidence estimates included patients with synchronous contralateral TC and patients with metachronous contralateral TC
• The risk of developing a metachronous contralateral TC may reflect unexplained variations in TC rates between countries
• Routine biopsy of the contralateral testis is controversial
• Some Europeans advise biopsy in all patients with TC, followed by treatment of any carcinoma in situ (on the basis of a 5.4% prevalence of carcinoma in situ in the contralateral testis and a 5%–6% overall cumulative risk of metachronous contralateral TC)
• The current USA paper indicates that patients with unilateral TC are at increased risk of developing metachronous contralateral TC
• Patients with seminomatous tumours had a statistically significantly higher probability of developing metachronous contralateral TC than patients with a nonseminoma, although the risk in both groups decreased with increasing age at first TC diagnosis
• Therefore clinicians should encourage all unilateral TC patients, especially those not receiving chemotherapy, to perform regular self-examination and, possibly, undergo regular testicular ultrasonography, with the aim of detecting a nonmetastatic metachronous contralateral TC while the primary tumour is still small enough to perform testis-sparing surgery
• Biopsy followed by individual counselling and/or treatment of carcinoma in situ may be justified for high-risk patients, ie. Those with a history of testicular maldescent, infertility, or testicular atrophy or a family history of TC
• NB The overall risk of developing a metachronous contralateral TC is low, given that the overall 15-year cumulative incidence in the current population was less than 2%
• NB Patients with metachronous contralateral TC have good prognosis - The current study found a 10-year overall survival rate of 93% in the 287 patients with metachronous contralateral TC
• Also the diagnosis of metachronous contralateral TC did not compromise 10-year overall survival compared with that of patients diagnosed with unilateral TC

Conclusion

• U.S. patients with unilateral TC have a modest 15-year cumulative risk (1.9%) of metachronous contralateral TC and their high long-term survival provide support for continuing the usual clinical practice of not subjecting the contralateral testis to routine biopsy