REVIEWS Prognostic factors for upper urinary tract urothelial carcinoma Thomas F. Chromecki, Karim Bensalah, Mesut Remzi, Grégory Verhoest, Eugene K. Cha, Douglas S. Scherr, Giacomo Novara, Pierre I. Karakiewicz and Shahrokh F. Shariat Abstract | Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, which means there are little evidence-based data available to guide clinical decision-making. Although diagnosis and treatment of UTUC have improved significantly over the last 5 years, accurate risk stratification remains a challenge owing to the difficulty of clinical staging. A number of potential prognostic factors have been identified, encompassing clinical characteristics, pathological factors and molecular markers. Tumor stage and lymph node status are the most important predictors of survival in patients with UTUC. Preoperative evaluation for hydronephrosis can identify patients at risk of non-organ-confined disease. In the subgroup of patients with stage ≥pT2 disease, a longer interval between diagnosis and radical nephroureterectomy is associated with a higher risk of disease recurrence and cancer-specific mortality. Extensive tumor necrosis, sessile tumor architecture and lymphovascular invasion are independent predictors of clinical outcomes for patients with UTUC treated with radical nephroureterectomy. The incorporation of such prognosticators into clinical prediction models might help to guide decision-making with regard to timing of surveillance, type of treatment, performance of lymphadenectomy, and consideration of neoadjuvant or adjuvant systemic therapies. Chromecki, T. F. et al. Nat. Rev. Urol. 8, 440–447 (2011); published online 5 July 2011; doi:10.1038/nrurol.2011.96
Department of Urology, Medical University Graz, Auenbruggerplatz 7, 8036 Graz, Austria (T. F. Chromecki). Department of Urology, Rennes University Hospital, Rue Henri Le Guillou, Rennes 35000, France (K. Bensalah, G. Verhoest). Department of Urology, Landeskrankenhaus Weinviertel-Korneuburg, Wiener Ring 3–5, 2100 Korneuburg, Austria (M. Remzi). Department of Urology, Weill Cornell Medical College, New York–Presbyterian Hospital, 525 East 68th Street, Starr 900, New York, NY 10065, USA (E. K. Cha, D. S. Scherr, S. F. Shariat). Department of Urology, University of Padua, Monoblocco Ospedaliero–IV Floor, Via Giustiniani 2, 35128 Padua, Italy (G. Novara). Department of Urology, University of Montreal Health Center, 1058 rue St-Denis, Montreal, QC H2X 3J4, Canada (P. I. Karakiewicz). Correspondence to: S. F. Shariat
[email protected]
Continuing Medical Education online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Nature Publishing Group. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http:// www.medscape.org/journal/nruro; (4) view/print certificate. Released: 5 July 2011; Expires: 5 July 2012
Learning objectives Upon completion of this activity, participants should be able to: 1. Analyze genetic and molecular markers of UTUC. 2. Evaluate patient and disease factors that affect the prognosis of UTUC. 3. Distinguish the most important tumor-related factor affecting the prognosis of UTUC. 4. Describe surgical management of UTUC.
Competing interests The authors, the journal Chief Editor S. Farley and the CME questions author C. P. Vega declare no competing interests.
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Introduction Upper urinary tract urothelial carcinoma (UTUC) accounts for approximately 5% of all urothelial tumors and 10% of all renal tumors. 1 Owing to the highly heterogeneous biology and clinical behavior of this disease—compounded by its relative rarity—clinical decision-making has historically been based on limited data. Indeed, until recently most studies of UTUC were small and retrospective in nature. However, a recent increase in UTUC-related research has led to an explosion of novel information to guide patients, clinicians and researchers. Given that disease recurrence and progression rates are high in patients with UTUC,2 a better understanding of prognostic parameters might lead to the identification, and hence improved counseling, of patients who stand to benefit from intensified therapy and monitoring. In patients with a normal contralateral kidney, open radical nephroureterectomy with bladder cuff excision is the gold standard treatment for large, highgrade, invasive tumors of the renal pelvis and proximal ureter. In cases of low-risk UTUC, conservative management can allow for preservation of the upper urinary renal unit while also sparing the patient the morbidity associated with open radical surgery.3 Absolute indications for conservative management of UTUC include renal insufficiency and solitary functional kidney; elective indications include low-grade, low-stage tumors. The choice of technique (ureteroscopy with endoscopic ablation, percutaneous management, segmental www.nature.com/nrurol
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REVIEWS resection, adjuvant topical agents) depends on technical constraints, the anatomic location of the tumor, and surgeon experience.3 Recent research into clinical factors and the profiling of UTUC at the molecular level has begun to shed light on important mechanisms of pathogenesis, as well as providing a number of potential diagnostic and prog nostic markers. Clinicopathologic and possibly mol ecular markers have the potential to be used clinically to screen for, diagnose, or monitor the activity of diseases and to guide molecular targeted therapy or assess therapeutic response, as has been demonstrated for bladder cancer.4,5 In this Review we will describe the currently available data on a number of suggested prognosticators, including clinical characteristics, pathological factors and mole cular markers, and how they might aid the management of UTUC.
Clinical factors Patient characteristics Gender does not seem to affect the histopathologic features of UTUC or outcomes after radical nephro ureterectomy.6–8 This is in contrast to lower tract uro thelial carcinoma, where men are four times more likely to develop bladder cancer than women, although women tend to present with more advanced disease and demonstrate worse survival after radical cystectomy.9,10 Being older at the time of radical nephroureterectomy has been shown to be associated with decreased survival.11 In a recent multi-institutional study of 1,169 patients treated with radical nephroureterectomy, age coded as a categorical variable was an independent predictor of disease recurrence, cancer-specific mortality, and all-cause mortality after adjusting for the effects of standard clinicopathologic characteristics. 12 Patients aged 70 years and older were at increased risk for disease recurrence and patients aged 60 years and older were at increased risk for cancer-specific and all-cause mortality. The same was true for age analyzed as a continuous variable. This finding could be attributed to changes in the biological potential of the tumor, a decrease in the patient’s defense mechanisms, or differences in care patterns.11 However, a large proportion of elderly patients can be cured with nephroureterectomy, suggesting that advanced age alone should not be an exclusion criterion for the aggressive treatment of potentially curable UTUC.11 A recent multi-institutional retrospective study of 216 patients treated with radical nephroureterectomy showed no association between ethnicity and recurrence-free survival, after adjusting for the effects of standard clinicopathological features.13 However, the prognostic value of ethnicity can only be accurately assessed in large, population‑based studies. Disease characteristics The most common primary symptom in patients with UTUC is microscopic or gross hematuria, which is usually painless. Approximately 20–30% of patients present with flank pain.14,15 Systemic symptoms such
Key points ■■ Tumor stage and lymph node status are the most important predictors of survival in patients with upper urinary tract urothelial carcinoma (UTUC) ■■ Preoperative evaluation for hydronephrosis can identify patients at risk of non‑organ-confined UTUC ■■ In the subgroup of patients with stage ≥pT2 disease, a longer interval from diagnosis to radical nephroureterectomy (more than 3 months) is associated with higher risk of disease recurrence and cancer-specific mortality ■■ Tumor location (renal pelvis versus ureter) has no prognostic impact when adjusted for the effects of established features of disease severity ■■ Extensive tumor necrosis (defined as >10% of the tumor area) and sessile tumor architecture are independent predictors of clinical outcomes for patients with UTUC treated with radical nephroureterectomy ■■ Lymphovascular invasion is associated with established features of biologically aggressive UTUC and is a strong predictor of disease recurrence and cancer‑specific mortality
as weight loss, anorexia and bone pain are usually associated with regional or distant metastasis and therefore worse outcomes, even in patients suspected to have clinically localized disease treated with radical nephroureterectomy.16 Preoperative evaluation for hydronephrosis can identify patients at risk of non-organ-confined UTUC and such knowledge might impact treatment choice, including consideration of perioperative chemotherapy.17 In bladder cancer, hydronephrosis is a sign of advanced disease and a predictor of poor outcome.18 With regard to UTUC, studies have shown that hydron ephrosis is associated with worse prognosis after radical nephroureterectomy.19,20
Surgical considerations Similarly to bladder cancer,21,22 a recent study showed that a longer interval from diagnosis of UTUC to radical nephroureterectomy was associated with aggressive pathologic features, such as more advanced stage and higher tumor grade, but not with disease recurrence or cancer-specific mortality.23 However, in the subgroup of patients with stage ≥pT2, longer delay (more than 3 months) was associated with higher risk of disease recurrence and cancer-specific mortality. In patients with a normal contralateral kidney, open radical nephroureterectomy with bladder cuff excision is the gold standard for large, high-grade, invasive tumors of the renal pelvis and proximal ureter.14,24,25 However, laparoscopic nephroureterectomy is now considered an alternative standard of care in centers with expertise in minimally-invasive surgery. Based on the results of several studies, there is no evidence to suggest any differ ence in oncologic outcomes between laparoscopic and open radical nephroureterectomy, providing there is adherence to the same oncological principles.26–29 Tumor location (renal pelvis versus ureter) has no prognostic impact on cancer-specific outcomes when adjusted for the effects of established features of disease severity, such as tumor stage, grade, and lymph node status, according to most recent, large, multicenter, population-based studies.2,30–32
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REVIEWS Pathological factors Tumor characteristics Tumor stage is one of the most important predictors of survival in patients with UTUC.2 Upper tract urothelial cancers can spread by direct invasion, mucosal seeding, hematologic and lymphatic routes. The metastatic potential increases, and therefore prognosis worsens, with advancing tumor stage.24,33–35 Patients with stage pTa–pT1 tumors generally have a 5‑year estimated cancer‑specific survival of >90%, whereas patients with pT3 and pT4 tumors have a 5‑year estimated cancer-specific survival of 30–50% and 10–20%, respectively.24,33,34 UTUC tumor grade can currently be classified as papillary urothelial neoplasia of low malignant potential, lowgrade carcinoma or high-grade carcinoma. Until 2004, the WHO classification of 1973 was used, which distinguished three grades (G1, G2, G3).36 High-grade tumors are more likely to invade into the underlying connective tissue, muscle, and surrounding tissues and are also more likely to be associated with concomitant carcinoma in situ.17,37 Although several investigators have not found any prognostic impact of tumor grade,34,38 others studies have reported a positive association.39–41 These discrepancies might be related to the similarities between grade 1 and 2 tumors and to the well-known intraobserver and interobserver variabilities in assigning tumor grade. Recent series using the two-tiered 2004 WHO grading system have identified high tumor grade as a strong independent prognostic factor for UTUC.2,24,42 Carcinoma in situ is a cytological lesion of the uro thelium and basal membrane that has invasive potential. In bladder cancer, carcinoma in situ is associated with an increased risk of disease recurrence and progression.43,44 In UTUC, carcinoma in situ has been demonstrated to be a significant independent predictor of subsequent bladder recurrence.45 Furthermore, presence of con comitant carcin oma in situ in patients with organconfined UTUC is associated with worse outcomes and a significantly increased risk of both cancer recurrence and cancer-specific mortality.46,47 The relevance of carcinoma in situ in UTUC remains uncertain. Data suggest that extensive tumor necrosis (defined as >10% of the tumor area) is also an independent predictor of clinical outcomes for patients with UTUC treated with radical nephroureterectomy.48 However, in an external validation study, tumor necrosis was only associated with a worse outcome on univariate analysis; its prognostic value was not independent of standard clinicop athological features.49 Further validation studies are needed before tumor necrosis can be used to guide clinical decision-making after radical nephroureterectomy.50 Lymphovascular invasion Lymphatic vessels serve as the primary pathway for metastatic tumor cell spread, and so lymphovascular invasion (LVI) has an important prognostic role in most malignancies, including UTUC.51,52 Early, small, single-center studies reported that LVI was an independent prognostic factor in UTUC,52–55 which was later confirmed in two 442 | AUGUST 2011 | VOLUME 8
large, independent, multicenter, international, retro spective data sets of patients treated with radical nephro ureterectomy.35,56 LVI was found to be associated with established features of biologically aggressive UTUC, such as advanced stage, high tumor grade, metastasis to lymph nodes, sessile tumor architecture, tumor necrosis, and concomitant carcinoma in situ.35,56 Moreover, LVI has been identified as an independent predictor of disease recurrence and cancer-specific mortality. Addition of LVI to standard pathologic features has been demonstrated to improve predictive accuracy for both disease recurrence and cancer-specific mortality by a statistically significant, but clinically small, margin.35,56 This margin was larger when the analyses were restricted to patients without lymph node metastasis and those who did not undergo a lymphadenectomy. In the future, LVI might be considered for inclusion in the TNM staging system for UTUC, as in hepatic and testicular cancer. However, before this modification can occur, one limitation that needs to be addressed is the inherent variability between pathologists in determining the presence of LVI, in UTUC as in other cancers. Indeed, significant differences in assessing LVI have been observed between local pathologists and central pathology review.57 Because retraction artifacts of the surrounding stromal tissue can mimic vascular invasion, experts have recommended reporting LVI only in unequivocal cases, using immunohistochemistry if neces sary. However, the use of immunohistochemical staining to identify lymphatic vessels remains controversial and is not practical for everyday clinical use. Therefore, it is of utmost importance that strict morphological criteria are established to standardize the diagnosis of LVI.56
Tumor size and architecture Recently, it was reported that tumor diameter is an independ ent predictor of metastasis-free survival and cancer-s pecific survival after radical nephro ureterectomy. 24 The most informative threshold was 3 cm; no metastasis was noted in patients presenting with a tumor diameter 3 months is not associated with a worse clinical outcome. BJU Int. 100, 1015–1020 (2007). Waldert, M. et al. A delay in radical nephroureterectomy can lead to upstaging. BJU Int. 105, 812–817 (2010). Margulis, V. et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 115, 1224–1233 (2009). Scher, H. et al. NCCN urothelial cancer practice guidelines. National Comprehensive Cancer Network. Oncology (Williston Park) 12, 225–271 (1998). Capitanio, U. et al. Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: a multi-institutional analysis of 1249 cases. Eur. Urol. 56, 1–9 (2009).
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27. Favaretto, R. L. et al. Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of patients: are recurrence and disease-specific survival associated with surgical technique? Eur. rol. 58, 645–651 (2010). 28. Kamihira, O. et al. Laparoscopic radical nephroureterectomy: a multicenter analysis in Japan. Eur. Urol. 55, 1397–1407 (2009). 29. Rouprêt, M. et al. Oncologic control after open or laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: a single center experience. Urology 69, 656–661 (2007). 30. Favaretto, R. L. et al. The effect of tumor location on prognosis in patients treated with radical nephroureterectomy at Memorial Sloan– Kettering Cancer Center. Eur. Urol. 58, 574–580 (2010). 31. Isbarn, H. et al. Location of the primary tumor is not an independent predictor of cancer specific mortality in patients with upper urinary tract urothelial carcinoma. J. Urol. 182, 2177–2181 (2009). 32. Raman, J. D. et al. Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. Eur. Urol. 57, 1072–1079 (2010). 33. Langner, C. et al. pT classification, grade, and vascular invasion as prognostic indicators in urothelial carcinoma of the upper urinary tract. Mod. Pathol. 19, 272–279 (2006). 34. Novara, G. et al. Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multiinstitutional dataset from 3 European centers. Cancer 110, 1715–1722 (2007). 35. Novara, G. et al. Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract: an international validation study. Eur. Urol. 57, 1064–1071 (2010). 36. Lopez-Beltran, A., Bassi, P., Pavone-Macaluso, M. & Montironi, R. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. Eur. Urol. 45, 257–266 (2004). 37. Bolenz, C. et al. Risk stratification of patients with nodal involvement in upper tract urothelial carcinoma: value of lymph-node density. BJU Int. 103, 302–306 (2009). 38. Mullerad, M. et al. Bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. J. Urol. 172, 2177–2181 (2004). 39. Lehmann, J. et al. Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur. Urol. 51, 1281–1288 (2007). 40. Li, W. M. et al. The prognostic predictors of primary ureteral transitional cell carcinoma after radical nephroureterectomy. J. Urol. 182, 451–458 (2009). 41. Li, C. C. et al. Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients. Eur. Urol. 54, 1127–1134 (2008). 42. Remzi, M. et al. Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int. 103, 307–311 (2009). 43. Chade, D. C. et al. Clinical outcome of primary versus secondary bladder carcinoma in situ. J. Urol. 184, 464–469 (2010). 44. Shariat, S. F. et al. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ-confined TCC at radical cystectomy. Eur. Urol. 51, 152–160 (2007).
45. Pieras, E. et al. Concomitant carcinoma in situ and tumour size are prognostic factors for bladder recurrence after nephroureterectomy for upper tract transitional cell carcinoma. BJU Int. 106, 1319–1323 (2010). 46. Wheat, J. C. et al. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ confined urothelial carcinoma following radical nephroureterectomy. Urol. Oncol. doi:10.1016/j.urolonc.2010.01.001. 47. Otto, W. et al. Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. World J. Urol. doi:10.1007/ s00345-011-0645-8. 48. Langner, C. et al. Tumor necrosis as prognostic indicator in transitional cell carcinoma of the upper urinary tract. J. Urol. 176, 910–913 (2006). 49. Zigeuner, R. et al. Tumour necrosis is an indicator of aggressive biology in patients with urothelial carcinoma of the upper urinary tract. Eur. Urol. 57, 575–581 (2010). 50. Seitz, C. et al. Association of tumor necrosis with pathological features and clinical outcome in 754 patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma: an international validation study. J. Urol. 184, 1895–1900 (2010). 51. Hong, B. et al. Prognostic value of lymphovascular invasion in transitional cell carcinoma of upper urinary tract. Urology 65, 692–696 (2005). 52. Kim, D. S. et al. Lymphovascular invasion and pT stage are prognostic factors in patients treated with radical nephroureterectomy for localized upper urinary tract transitional cell carcinoma. Urology 75, 328–332 (2010). 53. Saito, K. et al. Lymphovascular invasion is independently associated with poor prognosis in patients with localized upper urinary tract urothelial carcinoma treated surgically. J. Urol. 178, 2291–2296 (2007). 54. Bolenz, C. et al. Lymphangiogenesis occurs in upper tract urothelial carcinoma and correlates with lymphatic tumour dissemination and poor prognosis. BJU Int. 103, 1040–1046 (2009). 55. Chung, S. D. et al. Lymphovascular invasion predicts poor outcome of urothelial carcinoma of renal pelvis after nephroureterectomy. BJU Int. 103, 1047–1051 (2009). 56. Kikuchi, E. et al. Lymphovascular invasion predicts clinical outcomes in patients with nodenegative upper tract urothelial carcinoma. J. Clin. Oncol. 27, 612–618 (2009). 57. Margulis, V., Lotan, Y., Montorsi, F. & Shariat, S. F. Predicting survival after radical cystectomy for bladder cancer. BJU Int. 102, 15–22 (2008). 58. Simone, G. et al. Independent prognostic value of tumour diameter and tumour necrosis in upper urinary tract urothelial carcinoma. BJU Int. 103, 1052–1057 (2009). 59. Langner, C., Hutterer, G., Chromecki, T., Rehak, P. & Zigeuner, R. Patterns of invasion and histological growth as prognostic indicators in urothelial carcinoma of the upper urinary tract. Virchows Arch. 448, 604–611 (2006). 60. Fritsche, H. M. et al. Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. Urol. Oncol. doi:10.1016/j.urolonc.2010.07.010. 61. Fromont, G. et al. Tissue microarray analysis of the prognostic value of E‑cadherin, Ki67, p53, p27, survivin and MSH2 expression in upper urinary tract transitional cell carcinoma. Eur. Urol. 48, 764–770 (2005).
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REVIEWS 62. Winkler, A. et al. CD24 expression in urothelial carcinoma of the upper urinary tract correlates with tumour progression. Virchows Arch. 450, 59–64 (2007). 63. Nakanishi, K. et al. Expression of hypoxiainducible factor-1alpha protein predicts survival in patients with transitional cell carcinoma of the upper urinary tract. Clin. Cancer Res. 11, 2583–2590 (2005). 64. Kamai, T. et al. Prognostic significance of p27Kip1 and Ki‑67 expression in carcinoma of the renal pelvis and ureter. BJU Int. 86, 14–19 (2000). 65. Barbieri, C. E. et al. Tissue-based molecular markers for bladder cancer. Minerva Urol. Nefrol. 62, 241–258 (2010). 66. Zigeuner, R. et al. Prognostic impact of p63 and p53 expression in upper urinary tract transitional cell carcinoma. Urology 63, 1079–1083 (2004). 67. Nakanishi, K. et al. Expression of bcl‑2 oncoprotein in transitional cell carcinoma of the upper urinary tract. Virchows Arch. 432, 445–450 (1998). 68. Nakanishi, K. et al. Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. Virchows Arch. 441, 559–563 (2002). 69. Nakanishi, K. et al. Expression of telomerase mRNA component (hTR) in transitional cell carcinoma of the upper urinary tract. Cancer 86, 2109–2116 (1999). 70. Leibl, S. et al. EGFR expression in urothelial carcinoma of the upper urinary tract is associated with disease progression and metaplastic morphology. APMIS 116, 27–32 (2008). 71. Youssef, R. F. et al. Prognostic effect of urinary bladder carcinoma in situ on clinical outcome of subsequent upper tract urothelial carcinoma. Urology 77, 861–866 (2010). 72. Eltz, S., Comperat, E., Cussenot, O. & Rouprêt, M. Molecular and histological markers in urothelial carcinomas of the upper urinary tract. BJU Int. 102, 532–535 (2008). 73. Akkad, T. et al. Fluorescence in situ hybridization for detecting upper urinary tract tumors—a preliminary report. Urology 70, 753–757 (2007). 74. Luo, B. et al. Utility of fluorescence in situ hybridization in the diagnosis of upper urinary tract urothelial carcinoma. Cancer Genet. Cytogenet. 189, 93–97 (2009).
75. Mian, C. et al. Fluorescence in situ hybridisation in the diagnosis of upper urinary tract tumours. Eur. Urol. 58, 288–292 (2010). 76. Herman, M. P., Svatek, R. S., Lotan, Y., Karakiewicz, P. I. & Shariat, S. F. Urine-based biomarkers for the early detection and surveillance of non-muscle invasive bladder cancer. Minerva Urol. Nefrol. 60, 217–235 (2008). 77. Nieder, A. M., Soloway, M. S. & Herr, H. W. Should we abandon the FISH test? Eur. Urol. 51, 1469–1471 (2007). 78. Chen, A. A. & Grasso, M. Is there a role for FISH in the management and surveillance of patients with upper tract transitional-cell carcinoma? J. Endourol. 22, 1371–1374 (2008). 79. Johannes, J. R., Nelson, E., Bibbo, M. & Bagley, D. H. Voided urine fluorescence in situ hybridization testing for upper tract urothelial carcinoma surveillance. J. Urol. 184, 879–882 (2010). 80. Rouprêt, M. et al. Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma. J. Med. Genet. 41, e91 (2004). 81. Acher, P., Kiela, G., Thomas, K. & O’Brien, T. Towards a rational strategy for the surveillance of patients with Lynch syndrome (hereditary non-polyposis colon cancer) for upper tract transitional cell carcinoma. BJU Int. 106, 300–302 (2010). 82. Rouprêt, M., Yates, D. R., 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. 54, 1226–1236 (2008). 83. Rouprêt, M. et al. Checkup and management of upper urinary tract tumours in 2010: An update from the committee of cancer from the French National Association of Urology [French]. Prog. Urol. 20, 260–271 (2010). 84. Rouprêt, M., Azzouzi, A. R. & Cussenot, O. Microsatellite instability and transitional cell carcinoma of the upper urinary tract. BJU Int. 96, 489–492 (2005). 85. Saito, K. et al. The impact of preoperative serum C‑reactive protein on the prognosis of patients with upper urinary tract urothelial carcinoma treated surgically. BJU Int. 100, 269–273 (2007). 86. Elstein, A. S. Heuristics and biases: selected errors in clinical reasoning. Acad. Med. 74, 791–794 (1999).
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87. Vlaev, I. & Chater, N. Game relativity: how context influences strategic decision making. J. Exp. Psychol. Learn. Mem. Cogn. 32, 131–149 (2006). 88. Hogarth, R. M. & Karelaia, N. Heuristic and linear models of judgment: matching rules and environments. Psychol. Rev. 114, 733–758 (2007). 89. Ross, P. L. et al. Comparisons of nomograms and urologists’ predictions in prostate cancer. Semin. Urol. Oncol. 20, 82–88 (2002). 90. Ross, P. L., Scardino, P. T. & Kattan, M. W. A catalog of prostate cancer nomograms. J. Urol. 165, 1562–1568 (2001). 91. Specht, M. C., Kattan, M. W., Gonen, M., Fey, J. & Van Zee, K. J. Predicting nonsentinel node status after positive sentinel lymph biopsy for breast cancer: clinicians versus nomogram. Ann. Surg. Oncol. 12, 654–659 (2005). 92. Walz, J. et al. Clinicians are poor raters of lifeexpectancy before radical prostatectomy or definitive radiotherapy for localized prostate cancer. BJU Int. 100, 1254–1258 (2007). 93. Shariat, S. F., Capitanio, U., Jeldres, C. & Karakiewicz, P. I. Can nomograms be superior to other prediction tools? BJU Int. 103, 492–495 (2009). 94. Shariat, S. F., Karakiewicz, P. I., Suardi, N. & Kattan, M. W. Comparison of nomograms with other methods for predicting outcomes in prostate cancer: a critical analysis of the literature. Clin. Cancer Res. 14, 4400–4407 (2008). 95. Bensalah, K., Montorsi, F. & Shariat, S. F. Challenges of cancer biomarker profiling. Eur. Urol. 52, 1601–1609 (2007). Acknowledgments C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article. Author contributions T. F. Chromecki was responsible for researching the data and writing the article. T. F Chromecki, K. Bensalah, M. Remzi, G. Verhoest, E. K. Cha, D. S. Scherr, G. Novara, P. I. Karakiewicz and S. F. Shariat contributed equally to the discussion of content and reviewing the manuscript before submission.
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