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Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum
european urology 54 (2008) 1226–1236
Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum Pierre Mongiat-Artus Department of Urology and Paris 7 University, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France [email protected] A small but significant proportion of cancers arise in patients who carry a germline mutation in a cancer-predisposition gene. The most common of such hereditary predisposition to cancer is hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome. Roupreˆt et al give us a nice description of the proven and suspected urologic malignancies involved in this condition [1]. Colorectal carcinoma (63%) and endometrial carcinoma (9%) mostly constitute the tumour spectrum, but nearly 5% of the affected patients develop a urothelial cell carcinoma of the upper urinary tract, sometimes even as a first tumour [2]. The identification of a patient with a hereditary tumour has critical issues both for the patient, because this diagnosis may affect the prognosis and conditions follow-up, and for the family, because the diagnosis certainly conditions followup. Genetic counselling is the name of the diagnostic process for hereditary tumours, and the cornerstone of genetic counselling is to gain an informed consent from the patient to do genetic testing. When a cancer-predisposing mutation is identified in an individual patient, positive genetic testing provides her or his family with an opportunity to receive preventive measures (ie, targeted surveillance); when testing is negative, those who are not at specific risk are spared specific surveillance measures. Numerous controversies and ethical issues arise in the clinical practice of cancer genetics, and the best individual course of action is often not readily apparent [3]. It is surprising that there is still relatively little therapeutic benefit for an individual patient in genetic counselling. There is generally a huge discrepancy between the elaborate diagnostic process for hereditary cancers and the subsequent rudimentary therapeutic options (ie, ‘‘riskreducing’’ surgery or organ-sparing surgery); however, referring patients to a genetic counselling centre must be encouraged. The more patients are referred, the more knowledge is
1235
gained about the disease. Despite the relative rarity of such hereditary conditions, hereditary cancer syndromes have played a crucial role in basic research and have resulted in some therapeutic improvements. For example, the discovery of mutations in the von Hippel-Lindau gene in patients presenting with von Hippel-Lindau disease, the most common hereditary renal cell carcinoma syndrome, led to understanding of the central role of angiogenesis in sporadic renal cell carcinoma. The contemporary use of tyrosine kinase inhibitors for the treatment of metastatic renal cell carcinoma is based on this understanding, reported years ago [4]. I personally see two key messages in the article by Roupreˆt and colleagues, one for urologists and one for geneticists. Urologists should stay aware of any possibility of hereditary cancer in their patients (eg, early onset, multiple synchronous or metachronous tumours, family history), gain acceptance from suspected patients about genetic testing, and refer those patients to a specialised genetic counselling centre. Clinical geneticists should strictly follow the validated guidelines to carry out genetic counselling and to perform genetic testing. In this respect, it is important to use only validated assays allowing accurate evaluation of microsatellite instability status with high sensitivity and specificity. Any improvement or change in the clinical identification and in the genetic testing process for hereditary predisposition to cancer must be validated through a multidisciplinary consensus conference [2]. Due to the complex nature of prostate cancer genetics, genetic testing for urological malignancies is currently restricted to a narrow spectrum of tumours, but it will certainly develop in the future [5]. Urologists should stay directly involved in genetic counselling, which stands at the crossroads of the clinic and the laboratory and the diagnosis and the therapy.
References [1] Roupreˆt M, Yates DR, Comperat E, Cussenot O. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226–36. [2] Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–8.
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european urology 54 (2008) 1226–1236
[3] Patard J-J, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49:633–43. [4] Harris M, Winship I, Spriggs M. Controversies and ethical issues in cancer-genetics clinics. Lancet Oncol 2005;6:301–10.
Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum Maximilian Burger Klinik fu¨r Urologie, Universita¨t Regensburg, Landshuterstr. 65, 93053 Regensburg, Germany [email protected] Urology is special specialty. Urologic malignancies are paramount from an epidemiologic point of view. Three of the 10 most common malignancies are urologic [1]. Major advances have been made in recent years, and yet those malignancies are handled by one of the smallest specialties, consisting of roughly 1% of all physicians. Urology is challenging, and one may easily be absorbed within its boundaries. Those challenges stretch beyond classical urologic organs, as Roupreˆt and coworkers lay out in their excellent overview [2]. The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is interesting from a molecular point of view and clinically highly relevant. HNPCC promotes colorectal cancer via a distinct molecular pathway and is related to extracolonic neoplasias. One feature is outstanding for urologic cancer: There is a 22-fold increased risk of urothelial carcinomas of the upper urinary tract. The molecular analysis of this relation showed that urothelial carcinoma of the upper and lower urinary tracts may not be distinct entities, despite histologic uniformity [3,4]. Although molecular analyses have revealed much and may one day become clinical routine (eg, for the assessment of prognosis) [5], one must recognize the clinical implications at hand. Urologists need to be aware of the relationship of
[5] Gelmann EP. Complexities of prostate-cancer risk. N Engl J Med 2008;358:961–3.
DOI: 10.1016/j.eururo.2008.08.009 DOI of original article: 10.1016/j.eururo.2008.08.008
HNPCC to the upper urinary tract but also to prostate and germ cell cancer, as Roupreˆt and coworkers tell us [2]. They suggest that some of these urologic tumors are still misclassified as sporadic while being hereditary. This finding should alert the urological community. From an academic point of view, those tumor entities are urologic, and urologists should strive to keep pace in respective research. From a clinical point of view, accurate diagnosis of hereditary cancers is vital for families at risk.
References [1] Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18:581–92. [2] Roupreˆt M, Yates DR, Comperat E, Cussenot O. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226–36. [3] van Oers JMM, Zwarthoff EC, Rehman I, et al. FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours. Eur Urol. In press. doi:10.1016/j.eururo.2008.06.013. [4] Burger M, Burger SJ, Denzinger S, et al. Elevated microsatellite instability at selected tetranucleotide repeats does not correlate with clinicopathologic features of bladder cancer. Eur Urol 2006;50:770–6, discussion 776. [5] Burger M, van der Aa MNM, van Oers JMM, et al. Prediction of progression of non–muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 2008; 54:835–44.
DOI: 10.1016/j.eururo.2008.08.010 DOI of original article: 10.1016/j.eururo.2008.08.008
Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum Pierre Mongiat-Artus Department of Urology and Paris 7 University, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France [email protected] A small but significant proportion of cancers arise in patients who carry a germline mutation in a cancer-predisposition gene. The most common of such hereditary predisposition to cancer is hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome. Roupreˆt et al give us a nice description of the proven and suspected urologic malignancies involved in this condition [1]. Colorectal carcinoma (63%) and endometrial carcinoma (9%) mostly constitute the tumour spectrum, but nearly 5% of the affected patients develop a urothelial cell carcinoma of the upper urinary tract, sometimes even as a first tumour [2]. The identification of a patient with a hereditary tumour has critical issues both for the patient, because this diagnosis may affect the prognosis and conditions follow-up, and for the family, because the diagnosis certainly conditions followup. Genetic counselling is the name of the diagnostic process for hereditary tumours, and the cornerstone of genetic counselling is to gain an informed consent from the patient to do genetic testing. When a cancer-predisposing mutation is identified in an individual patient, positive genetic testing provides her or his family with an opportunity to receive preventive measures (ie, targeted surveillance); when testing is negative, those who are not at specific risk are spared specific surveillance measures. Numerous controversies and ethical issues arise in the clinical practice of cancer genetics, and the best individual course of action is often not readily apparent [3]. It is surprising that there is still relatively little therapeutic benefit for an individual patient in genetic counselling. There is generally a huge discrepancy between the elaborate diagnostic process for hereditary cancers and the subsequent rudimentary therapeutic options (ie, ‘‘riskreducing’’ surgery or organ-sparing surgery); however, referring patients to a genetic counselling centre must be encouraged. The more patients are referred, the more knowledge is
1235
gained about the disease. Despite the relative rarity of such hereditary conditions, hereditary cancer syndromes have played a crucial role in basic research and have resulted in some therapeutic improvements. For example, the discovery of mutations in the von Hippel-Lindau gene in patients presenting with von Hippel-Lindau disease, the most common hereditary renal cell carcinoma syndrome, led to understanding of the central role of angiogenesis in sporadic renal cell carcinoma. The contemporary use of tyrosine kinase inhibitors for the treatment of metastatic renal cell carcinoma is based on this understanding, reported years ago [4]. I personally see two key messages in the article by Roupreˆt and colleagues, one for urologists and one for geneticists. Urologists should stay aware of any possibility of hereditary cancer in their patients (eg, early onset, multiple synchronous or metachronous tumours, family history), gain acceptance from suspected patients about genetic testing, and refer those patients to a specialised genetic counselling centre. Clinical geneticists should strictly follow the validated guidelines to carry out genetic counselling and to perform genetic testing. In this respect, it is important to use only validated assays allowing accurate evaluation of microsatellite instability status with high sensitivity and specificity. Any improvement or change in the clinical identification and in the genetic testing process for hereditary predisposition to cancer must be validated through a multidisciplinary consensus conference [2]. Due to the complex nature of prostate cancer genetics, genetic testing for urological malignancies is currently restricted to a narrow spectrum of tumours, but it will certainly develop in the future [5]. Urologists should stay directly involved in genetic counselling, which stands at the crossroads of the clinic and the laboratory and the diagnosis and the therapy.
References [1] Roupreˆt M, Yates DR, Comperat E, Cussenot O. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226–36. [2] Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–8.
1236
european urology 54 (2008) 1226–1236
[3] Patard J-J, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49:633–43. [4] Harris M, Winship I, Spriggs M. Controversies and ethical issues in cancer-genetics clinics. Lancet Oncol 2005;6:301–10.
Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum Maximilian Burger Klinik fu¨r Urologie, Universita¨t Regensburg, Landshuterstr. 65, 93053 Regensburg, Germany [email protected] Urology is special specialty. Urologic malignancies are paramount from an epidemiologic point of view. Three of the 10 most common malignancies are urologic [1]. Major advances have been made in recent years, and yet those malignancies are handled by one of the smallest specialties, consisting of roughly 1% of all physicians. Urology is challenging, and one may easily be absorbed within its boundaries. Those challenges stretch beyond classical urologic organs, as Roupreˆt and coworkers lay out in their excellent overview [2]. The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is interesting from a molecular point of view and clinically highly relevant. HNPCC promotes colorectal cancer via a distinct molecular pathway and is related to extracolonic neoplasias. One feature is outstanding for urologic cancer: There is a 22-fold increased risk of urothelial carcinomas of the upper urinary tract. The molecular analysis of this relation showed that urothelial carcinoma of the upper and lower urinary tracts may not be distinct entities, despite histologic uniformity [3,4]. Although molecular analyses have revealed much and may one day become clinical routine (eg, for the assessment of prognosis) [5], one must recognize the clinical implications at hand. Urologists need to be aware of the relationship of
[5] Gelmann EP. Complexities of prostate-cancer risk. N Engl J Med 2008;358:961–3.
DOI: 10.1016/j.eururo.2008.08.009 DOI of original article: 10.1016/j.eururo.2008.08.008
HNPCC to the upper urinary tract but also to prostate and germ cell cancer, as Roupreˆt and coworkers tell us [2]. They suggest that some of these urologic tumors are still misclassified as sporadic while being hereditary. This finding should alert the urological community. From an academic point of view, those tumor entities are urologic, and urologists should strive to keep pace in respective research. From a clinical point of view, accurate diagnosis of hereditary cancers is vital for families at risk.
References [1] Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18:581–92. [2] Roupreˆt M, Yates DR, Comperat E, Cussenot O. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226–36. [3] van Oers JMM, Zwarthoff EC, Rehman I, et al. FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours. Eur Urol. In press. doi:10.1016/j.eururo.2008.06.013. [4] Burger M, Burger SJ, Denzinger S, et al. Elevated microsatellite instability at selected tetranucleotide repeats does not correlate with clinicopathologic features of bladder cancer. Eur Urol 2006;50:770–6, discussion 776. [5] Burger M, van der Aa MNM, van Oers JMM, et al. Prediction of progression of non–muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 2008; 54:835–44.
DOI: 10.1016/j.eururo.2008.08.010 DOI of original article: 10.1016/j.eururo.2008.08.008