Prognostic Factors and Staging Systems for Renal Cell Carcinoma

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1 european urology supplements 6 (2007) available at journal homepage: Prognostic Factors and Staging Systems for Renal Cell Carcinoma Vincenzo Ficarra a, *, Antonio Galfano a, Gregory Verhoest b, Stefano Cavalleri a, Guido Martignoni c, Walter Artibani a, Jean-Jacques Patard b a Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Italy b Department of Urology, University of Rennes, Rennes, France c Department of Pathology, University of Verona, Verona, Italy Article info Keywords: Prognosis Prognostic factors Renal cell carcinoma TNM staging Survival Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Objectives: Primary tumour local extension, lymph-node status, and the presence of metastases have always been considered the most important prognostic factors in renal cell carcinoma (RCC). In recent years, many other clinical, pathological, and molecular factors able to independently predict survival in RCC have been proposed and discussed. The aim of this unsystematic literature review is to describe the most important advances in RCC prognostication. Results: The review provides updated information regarding the most important clinical (performance status, localized or systemic symptoms), pathological (Fuhrman nuclear grade, histological subtypes, sarcomatoid features, tumour necrosis), and molecular (molecules involved in the hypoxia-inducible pathway, proliferation, cell cycle regulation, or cell adhesion) prognostic factors. It also highlights the issues related to RCC staging systems, such as the debate about the ideal cut-off to stratify patients with localized disease into two categories with different survival as well as the different prognostic impact of perinephric fat invasion, ipsilateral adrenal gland involvement, venous axis neoplastic thrombosis, and the possible synergistic role of their association in locally advanced disease. Conclusions: The ongoing development of integrated models combining different features improves the accuracy of survival prediction, thus allowing more detailed patient information, correct follow-up planning, and adequate recruitment and interpretation of clinical trials. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Oncological and Surgical Sciences, Urology Clinic University of Padua, Via Giustiniani 2, Padova, Italy. Tel ; Fax: address: vincenzoficarra@hotmail.com (V. Ficarra) /$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 624 european urology supplements 6 (2007) From anatomical factors to molecular markers: have we made decisive progress? 1.1. The need for reliable prognostic factors In an era of new targeted therapies and with new insights into the molecular pathways involved in renal cell carcinoma (RCC) development and spreading, it is important to define reliable prognostic factors. There are increasing requests from patients to be informed regarding all aspects of the disease, including outcome, risks of recurrence, or metastasis. As prognostic factors become more accurate, we will be able to provide the highest-quality information to our patients. In addition, accurate prognostic factors can help in adapting follow-up algorithms (timing schedule, image and biological tools) to calculate recurrence or progression risk probability. Finally, perhaps the most important need for accurate prognostic classifications is for selecting patients for clinical trials in adjuvant or neoadjuvant settings The current prognostic factors for RCC Basically, prognostic factors can be summarized into anatomical, histological, clinical, molecular, and integrated systems [1]. Anatomical factors that are obviously summarized by the TNM classification include tumour size [2], tumour extension, adrenal invasion, venous invasion, lymph-node invasion, and the presence or absence of distant metastases [3]. Histological prognostic factors include Fuhrman nuclear grade, histological subtype [4], sarcomatoid features, histological necrosis, and collecting system invasion [5,6]. The main clinical prognostic factors include performance status, localized symptoms, and cachexia [7,8]. According to detailed cytogenetic studies, several molecular markers able to identify different RCCs with different outcomes have been identified [9]. Finally, different integrated prognostic systems that aim to improve the predictive accuracy of the usual prognostic factors have been designed [10 12] The prognostic role of molecular markers To date, several potential molecular prognostic factors have been described. They can be summarized into key molecules involved in the hypoxiainducible pathway (VHL, VEGF, HIF, CAIX), proliferation (Ki67), cell cycle regulation (p53, PTEN), or cell adhesion (CD44, E Cadherin). In particular, multivariate analyses have demonstrated that VEGF, CAIX, Ki67, and p53 are independent prognostic factors [9]. However, it is important to understand that although some of these markers are conceptually interesting, none of them has been validated for monitoring in standard clinical practice settings. Further molecular markers such as CD10, parvalbumin, AMACR, CK7, and S100A1 have been validated as diagnostic markers, but not for their prognostic role [9] Progress regarding tools and methodology in RCC prognostication The literature regarding potential prognostic factors in RCC is abundant and sometimes confusing, although significant progress is being made. First, patient series are getting larger. Research has moved from analyzing a unique marker by conventional immunohistochemistry in a small series to larger series with different molecules involved in different pathways analyzed using tissue macro-arrays [13]. Statistical methods also have evolved, and it is becoming an absolute requirement to present both univariate and multivariate analyses when describing a new potential prognostic marker. Finally, nomograms are becoming increasingly important because they allow the quantification of the predictive accuracy of a prognostic variable [14]. Predictive accuracy is usually expressed as a percentage using Harrell s concordance index, where 50% represents a flip of a coin and 100% represents ideal prediction. Ultimately, the predictive accuracy of each new prognostic system should be compared to that of standard, recognized prognostic systems such as TNM The current status of integrated prognostic systems The three major prognostic factors that are currently used in localized RCC are the 2002 TNM classification [3], nuclear Fuhrman grade [5], and ECOG performance status [15]. When considered individually, however, each of these systems has limited predictive accuracy. Kim et al. [13] reported predictive accuracy index values of 0.73, 0.65, and 0.66 for TNM, Fuhrman grade, and ECOG, respectively. Although the three major integrated prognostic systems that have been described so far are different in their goals (recurrence vs survival, clear cell histology vs all histologies, nomogram vs prognostic algorithm), some of them were successful in improving predictive accuracy compared to TNM classification, while others failed. For example, the predictive accuracy of the Stage Size Grade and Necrosis (SSIGN) score was found to reach as much as 0.88 in an external validation [16], and the UCLA

3 european urology supplements 6 (2007) Fig. 1 Future challenges and strategies in RCC prognostication. RCC = renal cell carcinoma. Integrated Staging System (UISS) was validated in a large European cohort including more than 4000 patients. The predictive accuracy of the UISS was found to be at 0.8 overall [17]. Kattan s nomogram has not been validated as a standard prognostic tool so far, however, and is not proposed for selecting patients for clinical trials, unlike UISS or SSIGN [18,19] The main issues of prognostication in localized RCC Prognostic questions are not the same for small renal masses, locally advanced RCC, or metastatic RCC. Therefore, prognostic tools, including molecular markers, should not be the same in the various settings. Various questions and the different molecular pathways involved require different tools for predicting outcome or response to treatment. It is unreasonable to search for a universal prognostic system, and it makes no sense to search for a unique biological prognostic factor. For example, there are two main challenges that we are currently facing in terms of prognostication in localized RCC. First, the biological behaviour of small renal tumours must be predicted and patients selected for active surveillance, probe ablation techniques, or surgical ablation techniques [20,21]. Second, the risk of cancer-related death after surgery in locally advanced renal tumours must be predicted and patients selected for close follow-up or adjuvant or neoadjuvant clinical trials Future strategies in terms of prognostication in RCC The urological community now has a better understanding of the molecular pathways involved in RCC, which provides a good rationale for exploring specific molecular markers closely related to each step of progression in this disease. In addition, integrated prognostic systems for both localized and metastatic RCC have been validated and proven superior to conventional staging systems. More robust prognostic systems will likely be obtained by combining important key variables. Therefore, these new systems should be prospectively validated either as part of large phase III clinical trials or as part of specifically designed trials. Ultimately, prognostication based on both clinical and molecular information will allow us to guide therapy based on individual patient and tumour characteristics. Fig. 1 summarizes future strategies in terms of prognostication. 2. Staging systems A cancer staging system should effectively communicate critical tumour characteristics, aid the clinician in the appropriate selection of therapeutic options, stratify the patient s risk of cancer progression or cancer death, allow evaluation of treatment results, simplify data comparison from different centres, and determine the selection criteria for clinical trials [3].

4 626 european urology supplements 6 (2007) Table 1 Differences among the 1987, 1997, and 2002 TNM classifications Tumour classification 1987 TNM [25] 1997 TNM [26] 2002 TNM [27] T1 tumour 2.5 cm, limited to kidney tumour 7 cm, limited to kidney T1a T1b tumour 4 cm, limited to kidney tumour >4 cm7 cm, limited to kidney T2 tumour >2.5 cm, limited to kidney tumour >7 cm, limited to kidney tumour >7 cm, limited to kidney T3 tumour extends into major veins or invades adrenal or perinephric tissues but not beyond Gerota s fascia tumour extends into major veins or invades adrenal or perinephric tissues but not beyond Gerota s fascia tumour extends into major veins or invades adrenal or perinephric tissues but not beyond Gerota s fascia T3a perinephric or adrenal extension perinephric or adrenal extension perinephric or adrenal extension T3b renal vein involvement renal vein or vena cava involvement below diaphragm T3c vena cava involvement below diaphragm vena cava involvement above diaphragm renal vein or vena cava involvement below diaphragm vena cava involvement above diaphragm T4 outside Gerota s fascia outside Gerota s fascia T4a outside Gerota s fascia T4b vena cava involvement above diaphragm 2.1. The historical development of staging systems In 1958 Flocks and Kadesky [22] proposed the first classification of RCC according to the anatomical extension of tumours: those limited to the renal capsule (stage I), invasion of the renal pedicle and/or renal fat (stage II), regional lymph-node involvement (stage III), and demonstrable distant metastasis (stage IV). In 1969 Robson et al. [23] proposed a new staging system including all localized RCCs in a single group (stage I). These were distinguished from tumours infiltrating perirenal fat (stage II), those involving renal vein or inferior vena cava (stage IIIA) or lymph nodes (stage IIIB), and those extending outside the Gerota s fascia (stage IVA) or with distant metastasis (stage IVB). This staging system was widely used until the early 1990s, when it was progressively replaced by the Tumour Nodes Metastasis (TNM) system proposed by the Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). RCC found a place in the second edition of the TNM published by the UICC in 1974 [24]. Table 1 summarizes the main changes adopted by UICC/ AJCC to obtain a better patient stratification and to more efficaciously distinguish subgroups of patients with different prognoses [25 27]. Table 2 lists the TNM stages according to the latest 2002 version, which introduced a classification of stage I RCC into two subgroups: T1a 4 cm and T1b > 4 cm but 7 cm. This update was mainly aimed at easier clinical identification of the patients suitable for elective nephron-sparing surgery. Hafez et al. [28] reported on a series of 485 patients who had undergone nephron-sparing surgery, reporting 10-yr cancer-specific survival rates of 90% in 4 cm, 71% in cm, and 62% in >7 cm RCC patients. These data and those from other similar series of elective nephron-sparing surgery supported the last TNM edition. This issue has been assuming larger relevance, considering the major increase in the percentage of incidentally detected kidney cancers, which paralleled the higher number of 4 cm RCC suitable for elective nephron-sparing surgery Prognostic significance Pathological stage is the most important predictor of survival for RCC. Five-year cause-specific survival of patients with localized disease ranged from 90% to 100% for stage I (T1N0M0) and from 74% to 95% for stage II (T2N0M0) [1,29]. Survival data from a recent multicentre European study showed that 5- and 10-yr disease-specific survival probabilities were 95.3% and 91.4%, respectively, for patients with pt1a tumours; 91.4% and 83.4% for patients with pt1b tumours, and 81.6% and 75.2% for patients with pt2 tumours (log rank test, p < ) [30]. Table 2 TNM stage grouping according to the 2002 version [3] Stage T N M Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1, T2, T3 N1 M0 Stage IV T4 N0, N1 M0 any T N2 M0 any T any N M1

5 european urology supplements 6 (2007) Moreover, this study demonstrated that the application of the 2002 TNM staging system allowed statistically significant stratification of the cancerrelated outcome in the subgroup of patients with clear cell RCC (log rank test, p < ). Conversely, the 2002 TNM staging system did not appropriately stratify the cancer-related outcome of patients with papillary RCC (log rank test, p = 0.08). The invasion of perinephric or renal sinus fat and/ or ipsilateral adrenal gland, the involvement of renal vein or inferior vena cava, and the presence of metastasis in a single lymph node (stage III) significantly worsen prognosis. The 5-yr causespecific survival of patients with stage III RCC ranges from 60% to 70% [29,31]. In particular, perinephric or renal sinus fat invasion causes a 15 20% reduction in survival in comparison with organ-confined tumours. In this subgroup of patients, 5-yr cancer-specific survival decreases to 51 68% [31]. Neoplastic extension to the renal vein or to the inferior vena cava is found in 10 20% and 4 10% of RCC cases, respectively. In a high percentage of patients, venous involvement is associated with the simultaneous presence of perirenal fat or adrenal gland invasion or involvement of regional lymph nodes. Moreover, cranial extension of the tumour thrombus into the vena cava is reported to be associated with a higher probability of metastatic spread. Complete removal of the tumour thrombus in the absence of other unfavourable prognostic factors is associated with 5-yr cause-specific survival rates of 47 68% [29,32]. An additional negative prognostic factor in this stage of the disease is the infiltration of the venous wall by the neoplastic thrombus. In this subcategory of patients 5-yr cancer-specific survival is lower than 25%, although surgical removal of the caval infiltrated segment could increase 5-yr survival rates to 57% [31]. The involvement of regional lymph nodes affects survival more than the previously mentioned anatomical factors. The 5-yr cancer-specific survival rate in patients with lymph-node involvement is only 8 35% [1,33]. Metastatic spread of the disease is the worst prognostic factor. The 5- and 10-yr cancer-specific survival rates are 5 10% and 0 7%, respectively. Patients with single metastasis have a better longterm prognosis [34] Future perspectives Despite all the implemented and proposed modifications to staging systems, the optimal stratification of RCC patients in the context of the TNM staging system is still controversial, both for localized and locally advanced tumours [35]. Some authors proposed an ideal breakpoint ranging from 4.5 to 5.5 cm to stratify outcomes in patients with organ-confined RCC [36]. Moreover, in addition to tumour size, recent data supported the integration of symptoms into the primary tumour classification of localized RCC [37]. Moreover, based on data from a multicentre European study analyzing clinical records of 1138 patients with a mean follow-up of 87 mo after partial or radical nephrectomy, the authors proposed classifying organconfined RCC into three subgroups according to tumour size and mode of presentation: (1) patients with 5.5 cm, incidentally detected RCC; (2) patients with 5.5 cm, symptomatic RCC; and (3) patients with >5.5 cm RCC [38]. Moreover, refinements are being made for the classification of locally advanced tumours. Local tumour extension into the ipsilateral adrenal gland is currently classified as pt3a, as is RCC invading perinephric or renal sinus fat. Many studies suggest that RCC with direct ipsilateral adrenal invasion behaves more aggressively than tumours involving perinephric or renal sinus fat [39 41]. RCCs invading the adrenal gland have outcomes similar to those of tumours extending beyond Gerota s fascia or into adjacent organs. Recently, some authors proposed classifying them as pt4 [41,42] (Table 3). Studies have yet to establish whether invasion of only renal sinus fat provides the same prognostic information as does perinephric fat invasion. The renal sinus contains numerous veins and lymphatics. Tumour invasion into this compartment could be associated with a higher potential dissemination than the extension into the perinephric fat, where veins and lymphatics are less abundant [43]. In fact, a recent analysis on 205 patients who underwent radical nephrectomy for pt3a clear cell carcinoma without direct adrenal invasion revealed that tumours invading the renal sinus fat were more aggressive than those with perinephric fat involvement [44]. Another critical point in the TNM classification concerns patients with venous involvement. The 2002 version of TNM did not distinguish between patients with tumour thrombus involving the renal vein only and those with inferior vena cava tumour thrombus below the diaphragm (pt3b). In a series of 422 pt3b patients, Leibovich et al. [45] demonstrated that patients with thrombus involvement of only the renal vein were less likely to die from RCC than patients harbouring a larger tumour thrombus burden. Moreover, the primary tumour classification made no distinction according to the

6 628 european urology supplements 6 (2007) Table 3 Proposals to update the locally advanced renal cell carcinoma TNM staging system Stage TNM 2002 [3] Thompson et al [41] Ficarra et al [42] T3a perirenal fat invasion renal vein thrombosis perirenal fat infiltration adrenal invasion renal vein thrombosis subdiaphragmatic vena cava thrombosis T3b renal vein or infradiaphagmetic vena cava thrombosis perirenal fat infiltration renal vein thrombosis + perirenal fat infiltration subdiaphragmatic vena cava thrombosis + perirenal fat infiltration T3c supradiaphragmatic vena cava thrombosis renal vein thrombosis + perirenal fat infiltration subdiaphragmatic vena cava thrombosis T3d subdiaphragmatic vena cava thrombosis + perirenal fat infiltration supradiaphragmatic inferior vena cava thrombosis T4 extension beyond the Gerota s fascia extension beyond the Gerota s fascia ipsilateral adrenal invasion ipsilateral adrenal invasion extension beyond the Gerota s fascia supradiaphragmatic inferior vena cava thrombosis level of inferior vena cava thrombus below the diaphragm. Moinzadeh and Libertino [46] reported that the level of tumour thrombus into the inferior vena cava did not significantly affect long-term survival. The most relevant finding regarding venous involvement is that patients with tumour thrombus in the inferior vena cava below the level of the diaphragm have a significantly decreased survival compared to those with tumour thrombus in the renal vein. Even the classification of lymph-node involvement has undergone several changes over the years. The most important controversy concerns the ability to stratify patients with lymph-node involvement into different prognostic categories. Some authors suggested that outcome is not significantly different between patients with pn1 and pn2 disease and proposed different tools to subclassify patients with lymph-node involvement according to different criteria [34,47]. 3. Conclusions Numerous clinical, pathological, and molecular variables have been studied in the field of RCC prognostication. Local extension of the primary tumour, lymph-node status, and the presence of metastases have always been considered the most important factors. The combination of different variables into integrated mathematical models provides a more accurate prediction of survival in patients with RCC. Nevertheless, the continuous evolution of RCC staging systems and prognostic factors requires constant updating of the proposed models. References [1] Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173: [2] Karakiewicz PI, Lewinshtein DJ, Chun FK-H, et al. Tumor size improves the accuracy of TNM predictions in patients with renal cancer. Eur Urol 2006;50: [3] Sobin LH. TNM classification of malignant tumours. ed. 6. New York: Wiley-Liss; p [4] Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z WHO classification of the renal tumors of the adults. Eur Urol 2006;49: [5] Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6: [6] Lang H, Lindner V, de Fromont M, et al. Multicenter determination of optimal interobserver agreement using the Fuhrman grading system for renal cell carcinoma: assessment of 241 patients with >15-year follow-up. Cancer 2005;103: [7] Kim HL, Belldegrun AS, Freitas DG, et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol 2003;170: [8] Patard JJ, Leray E, Cindolo L, et al. Multi-institutional validation of a symptom-based classification for renal cell carcinoma. J Urol 2004;172: [9] Martignoni G, Brunelli M, Gobbo S, et al. Role of molecular markers in diagnosis and prognosis of renal cell carcinoma. Anal Quant Cytol Histol 2007;29:41 9. [10] Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001;166:63 7. [11] Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical

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