EUROPEAN UROLOGY 68 (2015) 290–291
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 283–289 of this issue
Translating Testicular Cancer Epidemiology into Clinical Practice Matthew J. Resnick * Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
In this issue of European Urology, Kharazmi and colleagues [1] report an elegant epidemiological analysis of pooled data from five Nordic countries to describe both the absolute and relative risk of testicular cancer in family members of affected individuals. The study confirms findings from prior studies revealing similar relative risk estimates among family members of subjects with testicular cancer [2]. Interestingly, and importantly, however, the study offers the reader estimates of absolute risk that will, undoubtedly, facilitate the use of these data in clinical practice. This study certainly answers questions surrounding estimation of testicular cancer risk in families; however, it also highlights other questions that remain unanswered, including: (1) how do these data fit within contemporary theoretical frameworks of testicular cancer etiology, specifically with respect to the likely complex interplay between genetics and environment? and (2) how might we, as clinicians, translate these research findings into clinical practice? There is increasing evidence that invasive germ-cell tumors nearly universally arise from intratubular germ cell neoplasia (ITGCN), a noninvasive precursor lesion found in association with approximately 90% of invasive germ-cell tumors thought to arise antenatally [3,4]. Subsequent mutations and epigenetic changes, in the context of hormonal changes at puberty, may then result in transformation of ITGCN to invasive testicular cancer [5]. How, then, do the data presented by Kharazmi et al fit within this theoretical framework regarding the etiology of testicular cancer? The fourfold increase observed among brothers of affected individuals translates to an absolute cumulative risk of only 2.3%, indicating a considerable degree of heterogeneity with respect to disease development despite presumed genetic risk. Not surprisingly, the risk of incident
testicular cancer in twin brothers was found to be higher, possibly lending additional support to the transmission of genetic risk. Unfortunately, this study does not permit the reader to untangle the complex relationships between genetics and environment. There remains considerable uncertainty regarding the precise etiology of in utero development of ITGCN. While identical twins share their genetic complement, they also share fetal exposures, rendering identification of the precise contribution of genetics and environmental exposures to the development of ITGCN a challenge. Beyond the development of ITGCN, however, there remains a significant knowledge gap regarding risk factors for the development of invasive testicular cancer. It is well known that ITGCN is a significant risk factor for the development of invasive disease, with an estimated 50% risk of testicular cancer within 5 yr. Nonetheless, not all men with ITGCN will develop testicular cancer, and even though numerous groups have identified candidate genes and epigenetic changes involved in the transformation of ITGCN to invasive disease, the etiology of this transformation remains poorly understood. In the current study, the authors report greater than threefold between-country variation in the risk of testicular cancer among brothers of affected individuals. While this finding may result from the relative rarity of testicular cancer or variation in the fidelity of data collection between registries, it is also possible that the variation reflects variation in the environmental attributes contributing to the development of testicular cancer. How, then, do we translate the authors’ findings into clinical practice? The data presented by Kharazmi et al offer the practicing urologist essential information to use when counseling high-risk patients about the risk of developing
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.12.031. * Department of Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN 37204, USA. Tel. +1 615 3222101; Fax: +1 615 3228990. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.01.016 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 68 (2015) 290–291
testicular cancer. These data can and should be used in the clinical setting to guide discussions with such high-risk individuals. Nonetheless, there remain key unanswered questions regarding the potential role of ultrasound screening in high-risk patients. There is little evidence surrounding the potential benefits of screening for testicular cancer among high-risk patients, including those with a family history. The US Preventive Services Task Force recommends against testicular cancer screening with a Grade D recommendation [6]. Furthermore, the Cochrane Collaboration issued a review on the topic encouraging shared decision-making among high-risk individuals regarding the benefits and harms associated with screening [7] in recognition of the significant knowledge gap. Given the absence of highquality data on which to base clinical decisions, how might we identify the benefits and harms of targeted testicular cancer screening? Certainly, the theoretical benefit of early cancer detection seems relatively straightforward. Nonetheless, we know that nearly 90% of patients present with locoregional disease, and contemporary multimodality therapy has resulted in 5-yr survival rates in excess of 95% among all patients with newly diagnosed testicular cancer [8]. Would the implementation of screening programs for high-risk patients improve the likelihood of cure or reduce the intensity of treatment and long-term sequelae associated with survivorship? Unfortunately, there are few data that specifically answer this question. There are, undoubtedly, harms associated with screening of asymptomatic high-risk men for testicular cancer. Certainly, screening may result in anxiety specifically related to indeterminate or false-positive imaging findings. Furthermore, confirmatory testing in the form of testicular biopsy (or orchiectomy) may indeed result in additional uncertainty specifically regarding the management of ITGCNabsent invasive disease. Taking these points together, there remains considerable uncertainty surrounding the balance
291
of benefit and harm associated with testicular cancer screening in high-risk individuals. How might we reconcile this knowledge gap? Patients at high risk of testicular cancer must be educated regarding their specific risk, as well as signs and symptoms of the disease. While there are few data regarding the effectiveness of testicular self-examination, encouraging high-risk patients to perform regular self-examinations may indeed improve the yield of targeted imaging and reduce the harms associated with ubiquitous ultrasound screening. Finally, offering high-risk men education and reassurance regarding treatment outcomes, particularly for those with localized disease, may ultimately eliminate many of the barriers to seeking medical attention. Conflicts of interest: The author has nothing to disclose.
References [1] Kharazmi E, Hemminki K, Pukkala E, et al. Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five Nordic countries. Eur Urol 2015;68: 283–9. [2] Hemminki K, Li X. Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer 2004;90:1765–70. [3] Hanna NH, Einhorn LH. Testicular cancer—discoveries and updates. N Engl J Med 2014;371:2005–16. [4] Rajpert-de Meyts E, Hoei-Hansen CE. From gonocytes to testicular cancer: the role of impaired gonadal development. Ann N Y Acad Sci 2007;1120:168–80. [5] Ma YT, Cullen MH, Hussain SA. Biology of germ cell tumors. Hematol Oncol Clin North Am 2011;25:457–71. [6] US Preventive Services Task Force. Screening for testicular cancer: US Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 2011;154:483–6. [7] Ilic D, Misso ML. Screening for testicular cancer. Cochrane Database Syst Rev 2011:CD007853. [8] National Cancer Institute. SEER Stat fact sheets: testis cancer. http://seer.cancer.gov/statfacts/html/testis.html
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 283–289 of this issue
Translating Testicular Cancer Epidemiology into Clinical Practice Matthew J. Resnick * Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
In this issue of European Urology, Kharazmi and colleagues [1] report an elegant epidemiological analysis of pooled data from five Nordic countries to describe both the absolute and relative risk of testicular cancer in family members of affected individuals. The study confirms findings from prior studies revealing similar relative risk estimates among family members of subjects with testicular cancer [2]. Interestingly, and importantly, however, the study offers the reader estimates of absolute risk that will, undoubtedly, facilitate the use of these data in clinical practice. This study certainly answers questions surrounding estimation of testicular cancer risk in families; however, it also highlights other questions that remain unanswered, including: (1) how do these data fit within contemporary theoretical frameworks of testicular cancer etiology, specifically with respect to the likely complex interplay between genetics and environment? and (2) how might we, as clinicians, translate these research findings into clinical practice? There is increasing evidence that invasive germ-cell tumors nearly universally arise from intratubular germ cell neoplasia (ITGCN), a noninvasive precursor lesion found in association with approximately 90% of invasive germ-cell tumors thought to arise antenatally [3,4]. Subsequent mutations and epigenetic changes, in the context of hormonal changes at puberty, may then result in transformation of ITGCN to invasive testicular cancer [5]. How, then, do the data presented by Kharazmi et al fit within this theoretical framework regarding the etiology of testicular cancer? The fourfold increase observed among brothers of affected individuals translates to an absolute cumulative risk of only 2.3%, indicating a considerable degree of heterogeneity with respect to disease development despite presumed genetic risk. Not surprisingly, the risk of incident
testicular cancer in twin brothers was found to be higher, possibly lending additional support to the transmission of genetic risk. Unfortunately, this study does not permit the reader to untangle the complex relationships between genetics and environment. There remains considerable uncertainty regarding the precise etiology of in utero development of ITGCN. While identical twins share their genetic complement, they also share fetal exposures, rendering identification of the precise contribution of genetics and environmental exposures to the development of ITGCN a challenge. Beyond the development of ITGCN, however, there remains a significant knowledge gap regarding risk factors for the development of invasive testicular cancer. It is well known that ITGCN is a significant risk factor for the development of invasive disease, with an estimated 50% risk of testicular cancer within 5 yr. Nonetheless, not all men with ITGCN will develop testicular cancer, and even though numerous groups have identified candidate genes and epigenetic changes involved in the transformation of ITGCN to invasive disease, the etiology of this transformation remains poorly understood. In the current study, the authors report greater than threefold between-country variation in the risk of testicular cancer among brothers of affected individuals. While this finding may result from the relative rarity of testicular cancer or variation in the fidelity of data collection between registries, it is also possible that the variation reflects variation in the environmental attributes contributing to the development of testicular cancer. How, then, do we translate the authors’ findings into clinical practice? The data presented by Kharazmi et al offer the practicing urologist essential information to use when counseling high-risk patients about the risk of developing
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.12.031. * Department of Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN 37204, USA. Tel. +1 615 3222101; Fax: +1 615 3228990. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.01.016 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 68 (2015) 290–291
testicular cancer. These data can and should be used in the clinical setting to guide discussions with such high-risk individuals. Nonetheless, there remain key unanswered questions regarding the potential role of ultrasound screening in high-risk patients. There is little evidence surrounding the potential benefits of screening for testicular cancer among high-risk patients, including those with a family history. The US Preventive Services Task Force recommends against testicular cancer screening with a Grade D recommendation [6]. Furthermore, the Cochrane Collaboration issued a review on the topic encouraging shared decision-making among high-risk individuals regarding the benefits and harms associated with screening [7] in recognition of the significant knowledge gap. Given the absence of highquality data on which to base clinical decisions, how might we identify the benefits and harms of targeted testicular cancer screening? Certainly, the theoretical benefit of early cancer detection seems relatively straightforward. Nonetheless, we know that nearly 90% of patients present with locoregional disease, and contemporary multimodality therapy has resulted in 5-yr survival rates in excess of 95% among all patients with newly diagnosed testicular cancer [8]. Would the implementation of screening programs for high-risk patients improve the likelihood of cure or reduce the intensity of treatment and long-term sequelae associated with survivorship? Unfortunately, there are few data that specifically answer this question. There are, undoubtedly, harms associated with screening of asymptomatic high-risk men for testicular cancer. Certainly, screening may result in anxiety specifically related to indeterminate or false-positive imaging findings. Furthermore, confirmatory testing in the form of testicular biopsy (or orchiectomy) may indeed result in additional uncertainty specifically regarding the management of ITGCNabsent invasive disease. Taking these points together, there remains considerable uncertainty surrounding the balance
291
of benefit and harm associated with testicular cancer screening in high-risk individuals. How might we reconcile this knowledge gap? Patients at high risk of testicular cancer must be educated regarding their specific risk, as well as signs and symptoms of the disease. While there are few data regarding the effectiveness of testicular self-examination, encouraging high-risk patients to perform regular self-examinations may indeed improve the yield of targeted imaging and reduce the harms associated with ubiquitous ultrasound screening. Finally, offering high-risk men education and reassurance regarding treatment outcomes, particularly for those with localized disease, may ultimately eliminate many of the barriers to seeking medical attention. Conflicts of interest: The author has nothing to disclose.
References [1] Kharazmi E, Hemminki K, Pukkala E, et al. Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five Nordic countries. Eur Urol 2015;68: 283–9. [2] Hemminki K, Li X. Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer 2004;90:1765–70. [3] Hanna NH, Einhorn LH. Testicular cancer—discoveries and updates. N Engl J Med 2014;371:2005–16. [4] Rajpert-de Meyts E, Hoei-Hansen CE. From gonocytes to testicular cancer: the role of impaired gonadal development. Ann N Y Acad Sci 2007;1120:168–80. [5] Ma YT, Cullen MH, Hussain SA. Biology of germ cell tumors. Hematol Oncol Clin North Am 2011;25:457–71. [6] US Preventive Services Task Force. Screening for testicular cancer: US Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 2011;154:483–6. [7] Ilic D, Misso ML. Screening for testicular cancer. Cochrane Database Syst Rev 2011:CD007853. [8] National Cancer Institute. SEER Stat fact sheets: testis cancer. http://seer.cancer.gov/statfacts/html/testis.html
