Tumor Size Does Not Predict Risk of MetastaticDisease or Prognosis of Small Renal Cell Carcinomas

Tobias Klatte, Jean-Jacques Patard, Michela de Martino, Karim Bensalah, Gregory Verhoest,Alexandre de la Taille, Clément-Claude Abbou, Ernst Peter Allhoff, Giuseppe Carrieri,Stephen B. Riggs, Fairooz F. Kabbinavar, Arie S. Belldegrun and Allan J. Pantuck*From the Departments of Urology (TK, MM, SBR, ASB, AJP) and Medicine (FFK), David Geffen School of Medicine, University ofCalifornia-Los Angeles, Los Angeles, California, Service d’Urologie, Centre Hospitalier Universitaire Pontchaillou, Rennes (JJP, KB, GV),Service d’Urologie, Centre Hospitalier Universitaire Henri Mondor, Créteil (ADT, CCA), France, Urologische Universitätsklinik,Universität Magdeburg, Germany (EPA), and Dipartimento di Scienze Chirurgiche, Divisione di Urologia e Centro Trapianti, Universitàdi Foggia, Italy (GC)

Purpose: We characterized the clinicopathological features and the prognosis of small solid renal tumors defined as tumors4 cm or smaller.Materials and Methods: We identified 1,208 patients who were treated with nephrectomy at 5 international academic centersfor small solid renal tumors. Clinicopathological parameters and outcome data were collected for each patient and analyzed.Results: Of the tumors 88% were renal cell carcinoma and 12% were benign. Of those with renal cell carcinoma 995 (93%)were localized (N0M0) and 72 (7%) presented with metastatic disease. Tumor size did not predict synchronous metastaticdisease. The incidence of metastatic disease in the tumor size ranges 0.1 to 1.0, 1.1 to 2.0, 2.1 to 3.0 and 3.1 to 4.0 cm was7%, 6%, 5% and 8%, respectively (p � 0.322). Survival rates were excellent. The majority of patients who died of renal cellcarcinoma (54%) presented with synchronous metastatic disease, but 3% of patients with localized disease also died of renalcell carcinoma. In patients with localized disease there was a 7% chance of recurrence post nephrectomy at 5 years.Progression-free survival (28 months) was better than for patients with metastatic disease having a primary tumor greaterthan 4 cm (8 months). Tumor size was not retained as an independent prognostic factor of survival in multivariate analyses.The University of California Integrated Staging System and the Karakiewicz nomogram were the best predictors of cancerspecific survival for all renal cell carcinoma stages (c-index 0.87).Conclusions: More than 85% of small solid renal tumors are renal cell carcinoma. The majority of localized small renaltumors can be cured with existing surgical approaches. However, there is a small but not insignificant risk of synchronousand metachronous metastatic disease and cancer associated death. Patients considering experimental therapies such asablation and surveillance should be aware of this. Tumor size alone is not sufficient to distinguish renal cell carcinoma withbenign behavior from aggressive small renal cell carcinoma. Survival of patients with small metastatic renal cell carcinomais better then expected. The biology of these unique tumors should be further studied.

Key Words: kidney neoplasms, prognosis, nomograms

Renal cell carcinoma is the third most common urolog-ical malignancy and accounts for approximately 3% ofall cancers in adults. It has been estimated for 2007

that about 51,000 people will be diagnosed with RCC in theUnited States, and approximately 13,000 will die of thedisease.1 The incidence of RCC has steadily increased dur-ing the last 3 decades, mainly due to the widespread use ofroutine abdominal imaging and the detection of incidental,small solid renal tumors (4 cm or smaller) thereby.2 Fre-

Submitted for publication August 28, 2007.Study received institutional review board approval.* Correspondence and requests for reprints: Department of Urol-

ogy, David Geffen School of Medicine at UCLA, 10833 Le ConteAve., Room B7-298A CHS, Los Angeles, California 90025-1738 (tele-phone: 310-206-2436; FAX: 310-206-408; e-mail: apantuck@mednet.ucla.edu).See Editorial on page 1657.For another article on a related topic see pages 2010

and 2057.

0022-5347/08/1795-1719/0THE JOURNAL OF UROLOGY®

Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION

1719

quently these tumors are benign or RCC with favorablepathological characteristics and prognosis.3

However, it is known that a subset of small renal tumorsexhibit aggressive properties including synchronous ormetachronous metastatic spread. Patients with synchronousmetastatic disease will be treated with surgery followed bytargeted or immune based therapy. However, the prognosisof patients with small metastatic RCC is yet to be specifi-cally determined. For patients who are treated for localizeddisease (N0M0), prediction of prognosis is critical to providetailored surveillance and patient allocation into adjuvantclinical trials.4 In addition, a better understanding of thebiology of small, localized RCC would allow easier patient

Editor’s Note: This article is the second of 5 publishedin this issue for which category 1 CME credits can beearned. Instructions for obtaining credits are given

with the questions on pages 2070 and 2071.

Vol. 179, 1719-1726, May 2008Printed in U.S.A.

DOI:10.1016/j.juro.2008.01.018

SMALL SOLID RENAL TUMORS1720

counseling for new nonsurgical approaches such as radiofrequency ablation, cryotherapy and active surveillancewhich have been evolved to considerable alternative optionsfor a subset of patients, although surgical extirpation re-mains the standard of care.5

We report on 1,208 patients who presented with asmall solid renal tumor at 5 international institutions.Because all patients underwent surgical extirpation, thisseries allows the definition of the actual incidence of renaltumor types and pathological staging. Analyses wereperformed 1) to define the incidence of benign tumors,localized RCC, metastatic RCC, clinical and pathologicalcharacteristics, and prognosis, 2) to characterize the ma-lignant potential of small renal tumors, defined as theprobability of metachronous metastatic disease after un-dergoing surgery for localized disease, and 3) to evaluatethe performance of prognostic models to predict survivalof small RCC.

PATIENTS AND METHODS

Patient PopulationWe studied retrospectively 1,208 patients, who were diag-nosed with unilateral, sporadic, small solid renal tumorsfrom 1989 to 2006 at 5 international academic urologicalcenters in Créteil, France; Rennes, France; Magdeburg, Ger-many; Foggia, Italy; and Los Angeles, California. A small

TABLE 1. Patient an

Benign Tumor

No. pts 141Mean pt age (SD) 60.3 (14.7)No. gender (%):

Female 65 (46)Male 76 (54)

No. ECOG PS (%):0 127 (90)1 or Greater 14 (10)

No. presentation (%):Incidental 118 (84)Local 21 (15)Systemic 2 (1)

Mean tumor size (SD) 2.7 (0.8)No. cm tumor (%):

0.1–1.0 5 (3)1.1–2.0 32 (23)2.1–3.0 65 (46)3.1–4.0 39 (28)

No. benign tumor type (%):Oncocytoma 75 (53)Angiomyolipoma 33 (23)Complex cyst 16 (11)Other 17 (12)

No. RCC type (%):Clear cellPapillaryChromophobe —Collecting ductUnclassified

No. T stage (%):T1aT3a —T3b

No. N/M stage (%):Nx or N0/M0N�/M0 —N�/M1N0/M1

No. Fuhrman grade (%):G1G2 —

G3–G4 160

solid renal tumor was defined as a solid renal tumor 4 cm orsmaller. The study was approved by the institutional reviewboard at each institution.

Patient charts were reviewed and clinicopathologicaldata recorded. The data that was abstracted included age,gender, symptoms,6 ECOG PS, T, N and M stage accordingto 2002 definitions, Fuhrman grade, and histological type.Pathological examination was performed by 1 anatomicalpathologist at each institution. The type of renal tumor wasdefined according to WHO criteria. For practical purposes,we distinguished between benign and malignant renal tu-mors. Benign tumors were further stratified into oncocy-toma, angiomyolipoma, atypical cyst and other. Malignantrenal tumors were all RCC in this series and were dividedinto clear cell, papillary, chromophobe, collecting duct andunclassified subtype.

All patients underwent open surgical extirpation. Aradical nephrectomy was performed in 834 patients (69%),while 374 (31%) underwent nephron-sparing surgery.Surgical margins were negative in all patients. No adju-vant therapy was administered postoperatively. Patientswho presented with metastatic disease underwent immu-notherapy following nephrectomy. Postoperative surveil-lance was performed according to guidelines establishedat each institution. Median followup was 3.1 years (range0.1 to 18.0).

or characteristics

ized RCC Metastatic RCC Totals

72.3 (11.9) 60.6 (11.3) 61.2 (12.3)

(38) 21 (29) 466 (39)(62) 51 (71) 742 (61)

(81) 33 (46) 966 (80)(19) 39 (54) 242 (20)

(79) 31 (43) 931 (77)(20) 34 (47) 256 (21)(1) 7 (10) 21 (2)

.9 (0.8) 3.1 (0.9) 2.9 (0.9)

(3) 2 (3) 33 (3)(18) 12 (17) 221 (18)(37) 20 (28) 457 (38)(42) 38 (53) 497 (41)

— — —

(81) 62 (86) 864 (81)(15) 7 (10) 152 (14)(5) 1 (1) 49 (5)(0) 1 (1) 1 (less than 1)(0) 1 (1) 1 (less than 1)

(90) 44 (61) 939 (88)(8) 23 (32) 106 (10)(2) 5 (7) 22 (2)

(100) 0 (0) 995 (93)(0) 8 (11) 8 (less than 1)(0) 8 (11) 8 (less than 1)(0) 56 (78) 56 (5)

(28) 7 (10) 288 (27)(56) 36 (50) 590 (55)

d tum

Local

99561

380615

806189

782201122

26177372420

8021454800

8958317

995000

281554

(16) 29 (40) 189 (18)

SMALL SOLID RENAL TUMORS 1721

Statistical AnalysisThe statistical software R v2.4 (www.r-project.org) was usedfor all analyses. The chi-square and Student t tests wereused to compare categorical and continuous data, respec-tively. The relationship between tumor size and histology(benign tumor vs RCC) as well as metastatic status (local-ized vs metastatic RCC) was further analyzed with logisticregression models.

End points of this study included overall survival, cancerspecific survival, recurrence-free survival and progression-free survival, which were all calculated from the date ofsurgery to the date of death, death from RCC, disease recur-rence in localized disease and disease progression in meta-static disease, respectively. The Kaplan-Meier method wasused to estimate the survivor functions, which were com-pared with the log rank test. Confidence intervals for sur-vival data were determined by the Greenwood method. Mul-tivariate Cox proportional hazard models were performed todetect variables independently associated with survival.

Prognostic assessment was performed according to the 3prognostic models of the UISS,7 the Kattan nomogram8 andthe Karakiewicz nomogram.9 The predictive accuracy ofthese models was measured by the concordance index (c-index). The c-index corresponds to the area under the re-ceiver operating characteristics (ROC) curve adapted forsurvival data and ranges from 0.5 (no predictive accuracy) to1.0 (perfect predictive accuracy).

RESULTS

Of the 1,208 consecutive surgical patients 742 were men(61%) and 466 were women (39%). Mean age at diagnosiswas 61 years (median 62, range 17 to 89). An ECOG PS of 0

FIG. 1. Kaplan-Meier survival estimates for overall survival and 95% CI.than patients with localized RCC (p � 0.008). Numbers of patients at r

was assigned to 80% of the patients. A total of 931 patients(77%) were completely asymptomatic at the time of diagno-sis and had incidentally discovered tumors, 256 (21%) pre-sented with local symptoms, and 21 (2%) had tumors asso-ciated with systemic symptoms.

A total of 1,067 patients (88%) had RCC, of whom 995(93%) presented without evidence of metastatic disease and72 (7%) had lymph node and/or distant metastases. Distantmetastatic disease was confirmed by biopsy in 56% of thepatients. The most frequently assigned histological subtypeswere clear cell (81% of RCCs, 72% of small renal tumors),papillary (14%, 13%), and chromophobe (5%, 4%). Therewere 141 patients (12%) who had benign tumors, most fre-quently oncocytoma (53% of benign tumors, 6% of smallrenal tumors), angiomyolipoma (23%, 3%), complex cysts(11%, 1%), and other entities (12%, 1%). Patient and tumorcharacteristics are summarized in table 1.

Clinicopathological FeaturesBenign renal tumor vs RCC. Tumor size was statisticallysignificant but clinically insignificantly smaller in benigntumors than RCC (mean � SD, 2.7 � 0.8 cm vs 2.9 � 0.9 cm,p � 0.004). The frequency of RCC in the tumor size ranges0.1 to 1.0, 1.1 to 2.0 and 2.1 to 3.0 cm was similar (85%, 86%and 86%, p � 0.987) and increased significantly in tumorsmeasuring 3.1 to 4.0 cm (92%, p � 0.001). Patients withbenign tumors had significantly better ECOG PS (ECOG PS0, 90% vs 79%, p � 0.001) and were more likely to presentwith incidental tumors (84% vs 76%, p � 0.047). Also, benigntumors were more likely to be diagnosed in women (46% vs38%), although this difference did not quite reach statistical

Patients with benign renal tumors had significantly better survivalisk are indicated.

SMALL SOLID RENAL TUMORS1722

significance (p � 0.051). No difference was detected in age(60.3 � 14.7 years vs 61.3 � 11.9 years, p � 0.436).

The same clinicopathological features were compared be-tween patients with benign tumors and localized RCC (995).Patients with benign tumors had smaller tumor sizes (2.7 �0.8 cm vs 2.9 � 0.8 cm, p � 0.003), corresponding to a 34%increase in risk of RCC by 1 cm increase in tumor size (riskratio 1.34, 95% CI 1.10–1.65). An ECOG PS of 0 was morefrequent in benign tumors (90% vs 81%, p � 0.009), while nodifference was detected in the frequency of incidental tu-mors (84% vs 79%, p � 0.163) or age (p � 0.415). Again, thepercentage of women was higher in patients with benignlesions than in RCC (46% vs 38% p � 0.072).

Localized (N0M0) vs metastatic RCC. A total of 995 pa-tients with RCC (93%) had no evidence of metastatic diseaseat the time of diagnosis, while 72 (7%) had metastatic dis-ease including 56 with N0M1, 8 N�M0 and 8 N�M1 disease.Factors associated with metastatic disease in patients withRCC were an ECOG PS 1 or greater (metastatic vs localized,54% vs 19%, p �0.001), presentation with symptoms (57% vs21%, p �0.001), higher T stage (incidence of metastaticdisease, pT1a 5%, pT3a 22%, pT3b 23%, p �0.001), highergrades (p �0.001) and histological type (p �0.001). Theincidence of clear cell RCC was higher in patients withmetastatic disease (86% vs 81%), while the frequency ofpapillary RCC (10% vs 15%) and chromophobe RCC (1% vs5%) was lower.

Tumor size did not differ between patients with localizedand metastatic disease (2.9 � 0.8 cm vs 3.1 � 0.9 cm,p � 0.096, risk ratio 1.29 [0.96-1.73]). The incidence of met-astatic disease in the tumor size ranges 0.1 to 1.0, 1.1 to 2.0,2.1 to 3.0 and 3.1 to 4.0 cm was 7%, 6%, 5% and 8%,respectively (p � 0.322). Tumor size in patients with meta-static disease ranged from 0.6 cm to 4.0 cm.

PrognosisAt the time of analysis 189 deaths (16%) had occurred in-cluding 61 (32%) from RCC. Of the 61 deaths from RCC 33(54%) occurred in patients with synchronous metastatic dis-ease representing 46% of these patients, while only 28 pa-tients with N0M0 disease died following recurrent RCC.These 28 patients accounted for only 3% of the patients whounderwent surgery for localized RCC.

Overall survival. Five and 10-year overall survival rates(95% CI) for the entire cohort were 83% (80 to 85) and 64%(57 to 69), respectively (fig. 1). Overall survival was signifi-cantly better for patients with benign tumors than for pa-tients with localized RCC (5-year 92% [85 to 96] vs 85% [81to 87], 10-year 85% [71 to 92] vs 63% [55 to 69], p � 0.008,fig. 1). This survival difference was also present when com-paring survival of patients with benign tumors to those withpT1aN0M0 RCC (p � 0.0277). Median overall survival timefor metastatic RCC was 36 months (range 20 to 52), and the1 and 5-year overall survival rates were 74% (62 to 83) and36% (23 to 49) (fig. 1). Factors independently associated withoverall survival included age, gender, ECOG PS and type ofhistology (table 2).

Cancer specific survival. For the entire RCC cohort the 5and 10-year survival probabilities were 92% (90 to 94) and

87% (82 to 91) (fig. 2). Patients with localized RCC had 5 and

10-year cancer specific survival rates of 96% (94 to 98) and91% (85 to 94). For patients who presented with metastaticdisease, median survival time was 45 months (range 26 to64) with corresponding 1 and 5-year survival rates of 76%(64 to 85) and 42% (28 to 56). Multivariate Cox regressionanalysis revealed that ECOG PS, T stage, presence of dis-tant metastases and Fuhrman grade, but not tumor size,were independent prognostic factors of cancer specific sur-vival (table 2).

Recurrence-free and progression-free survival. A totalof 52 patients (5%) had RCC recurrence after nephrectomyfor localized RCC (fig. 3). Characteristics of these patientsare shown in table 3. The 5 and 10-year recurrence-freesurvival rates were 93% (90 to 95) and 84% (77 to 89).Stratified by T stage the 5-year recurrence-free rates forpT1aN0M0, pT3aN0M0 and pT3bN0M0 were 96% (93 to 97),69% (52 to 81) and 58% (26 to 80), respectively (fig. 3, A).Multivariate analysis showed that ECOG PS, T stage andFuhrman grade, but not tumor size independently impactedrecurrence-free survival (table 2).

In patients with metastatic disease median progression-free survival was 28 months (range 6 to 50). The 1 and5-year progression-free survival rates were 64% (51 to 74)

TABLE 2. Multivariate analysis for overall survival, cancerspecific survival and recurrence-free survival

Covariate HR 95% CI p Value

Overall survivalAge 1.03 1.02–1.05 �0.001Male 1.57 1.15–2.15 0.005ECOG PS 1 or greater 1.91 1.36–2.68 �0.001Symptomatic presentation 1.19 0.85–1.66 0.320Tumor size 1.14 0.97–1.37 0.098Histology:

Localized RCC 1Benign tumor 0.49 0.27–0.89 0.020Metastatic RCC 4.29 2.89–6.36 �0.001

Ca specific survivalECOG PS 1 or greater 2.26 1.26–4.09 0.006Symptomatic presentation 1.53 0.83–2.81 0.172T stage:

T1a 1T3a 2.78 1.48–5.25 0.002T3b 5.08 2.13–12.1 �0.001

N stage 1 or greater 1.98 0.81–4.87 0.136M stage 1 or greater 10.5 5.94–18.7 �0.001Fuhrman grade:

G1 1G2 3.64 1.09–12.2 0.036G3–4 5.10 1.44–18.0 0.011

Tumor size 1.22 0.85–1.76 0.282Histological subtype 0.98 0.57–1.69 0.942

Recurrence-free survivalECOG PS 1 or greater 2.00 1.06–3.75 0.032Symptomatic presentation 0.87 0.45–1.69 0.681T stage:

T1a 1T3a 6.01 3.27–11.1 �0.001T3b 8.23 3.24–20.9 �0.001

Fuhrman grade:G1 1G2 3.19 1.23–8.24 0.017G3–4 3.36 1.14–9.90 0.028

Tumor size 1.18 0.81–1.71 0.395Histological subtype:*

Clear cell 1Nonclear cell 0.27 0.06–1.12 0.072

* Due to the small number of events, papillary and chromophobe RCC wereclassified as nonclear cell subtype for this analysis.

and 39% (26 to 53) (fig. 3, B). This progression-free survival

, and

SMALL SOLID RENAL TUMORS 1723

time was significantly longer than for patients with meta-static disease and a primary tumor more than 4 cm in size(median progression free survival 8 months, p �0.0001).

Prognostic models for small RCC. We compared the ac-curacy of 3 prognostic models to predict cancer specific sur-vival and recurrence-free survival. The results are reportedin table 4. In terms of cancer specific survival the UISS andthe Karakiewicz nomogram reached a c-index of approxi-mately 0.87. The Kattan nomogram was the best predictor ofcancer specific survival (c-index 0.778) and recurrence-freesurvival (c-index 0.755) in patients with localized disease.

DISCUSSION

The use of routine abdominal imaging modalities has led toincreasing detection of solid renal tumors 4 cm or smaller.Therefore, urologists are increasingly confronted with theirmanagement and followup. We studied 1,208 small renalmasses and found that 88% were RCC and 12% were benigntumors. As others3 we demonstrated a relationship betweentumor size and the risk of localized RCC, which increased by34% by each cm increase in tumor size.

Of the patients with RCC, 995 (93%) were localized, but72 (7%) presented with metastatic disease. We could notshow a significant relationship between tumor size and therisk of synchronous metastatic disease and could not iden-tify a tumor size cutoff, under which the risk of concomitantmetastatic disease is negligible. Similarly, in a study of10,420 cases from the Surveillance, Epidemiology, and EndResults database, no significant correlation was observed.10

In this study the risk of synchronous metastatic disease inthe tumor size ranges less than 1, 1 to 2, 2 to 3 and 3 to 4 cm

FIG. 2. Kaplan-Meier survival estimates for cancer specific survivalor M1) RCC. Numbers of patients at risk are indicated.

was 6.3%, 4.7%, 5.2% and 7.2%, respectively. In contrast,

Kunkle et al11 showed in a cohort of 360 patients that theincidence of metastatic disease increases by 22% for each 1cm increase in tumor size, but patients with all tumor sizesand not only those with tumors 4 cm or smaller were in-cluded in their analysis.

In patients with RCC N0M0 disease there was a 7%chance of metachronous metastatic disease at 5 years and a16% chance at 10 years after nephrectomy. However, themajority of localized small RCCs were cured by extirpativesurgery. Minimally invasive therapies such as radio fre-quency ablation and cryotherapy are alternative approachesfor small renal masses. Although early oncological resultsare promising,12,13 long-term data are required. Finally, ac-tive surveillance may be offered to patients who are notsuitable candidates for surgery or minimally invasive ther-apies, or are not willing to accept the risks of these ap-proaches. In a recent meta-analysis the mean growth rate ofenhancing renal masses was 0.28 cm per year and the pro-gression rate to metastatic disease was 1%.14 However, thegrowth rate of small renal tumors under active surveillanceis variable and patient selection criteria need to be im-proved. Taken together, our data should serve as a caution.Patients considering these still experimental therapiesshould be aware of the small but not insignificant risk ofmetastatic disease and cancer associated death. In this re-gard our data clearly showed that tumor size alone does notsufficiently distinguish RCC with benign from RCC withaggressive behavior or independently predict recurrence-free and cancer specific survival, and that there is no safecutoff under which the risk of metastases is negligible.

Outcome data were generally favorable and in agreementwith previous reports.7,8,15 Importantly the majority of pa-

95% CI for patients with localized (N0M0) and metastatic (N�M0

tients who died of RCC (54%) presented with concomitant

ivalcated

SMALL SOLID RENAL TUMORS1724

synchronous metastatic disease and only 3% of those pre-senting with localized disease died of RCC. Survival waseven better than expected for patients with metastatic dis-ease. Median overall, cancer specific and progression-freesurvival for this cohort was 36, 45 and 28 months, respec-tively, which was higher than for the population treated formetastatic RCC and primary tumors larger than 4 cm. Theimpact of T stage on survival of patients with metastaticdisease is not well established and is usually not used forprognostic assessment,7 but our data shows that the size of

FIG. 3. Kaplan-Meier survival estimates for (A) recurrence-free survand 95% confidence intervals. Numbers of patients at risk are indi

the primary tumor may indeed have a prognostic impact.

This survival advantage may reflect a more indolent biologyof small metastatic RCCs. The molecular pathways in thesetumors should therefore be more fully characterized in fu-ture studies.

Prediction of prognosis remains critical for tailoring sur-veillance and patient allocation into clinical trials. Tradi-tionally the TNM staging system has been used for predict-ing patient outcome. However, the different stages compriseheterogeneous populations. Several institutions have re-cently developed prognostic models that may improve the

(N0M0 RCC) and (B) progression-free survival (metastatic disease).

predictive accuracy of TNM. The UISS combines ECOG PS,

SMALL SOLID RENAL TUMORS 1725

T, N and M stage, and Fuhrman grade to predict prognosisof all RCC stages.7 The UISS has been validated in a mul-ticenter study and achieved an average c-index of 0.809 forlocalized and 0.651 for metastatic disease.16 Another prog-nostic model is the stage, size, grade, necrosis (SSIGN) forunilateral clear cell RCC, which reached a c-index of 0.849 inthe original analysis.17 Kattan et al8 constructed a nomo-gram to predict recurrence-free survival in patients withclinically localized RCC combining clinical presentation, his-tological subtype, tumor size and T stage. The calculatedc-index in this report was 0.74. An update of the Kattannomogram was proposed by Sorbellini et al,18 and includedtumor size, T stage, clinical presentation, grade, necrosisand vascular invasion (c-index 0.82). Karakiewicz et al9

recently published a nomogram containing T, N and Mstage, grade, size and symptoms to predict survival of allRCC stages. The predictive accuracy after 5 years was 0.867.Our data showed that this nomogram and the UISS performwell in predicting survival of all RCC stages. For patientswith localized disease, the Kattan nomogram may be betterused to tailor postoperative approaches. However, it is ex-pected that several molecular analyses will have a greaterrole in the future in predicting prognosis and in evaluatingthe biology of small renal tumors.19

Several limitations of our study need to be acknowledgedand addressed. Based on the retrospective nature, thedrawn conclusions have to be treated with reservation andneed to be confirmed in prospective settings. We did notperform a pathological review by a single pathologist, al-though the pathological slides were examined by 1 patholo-gist at each institution. However, it is unlikely that ourresults were profoundly altered through this approach, be-cause we performed an examination of basic pathologicaldata, which are examined in a standardized way worldwide.Another consideration is that there was no standardizationin preoperative imaging or on postoperative surveillance.However, there is currently no clear practice standard thathas been established to guide such endeavors. Finally, nostandardization existed regarding the performance of alymph node dissection and, if performed, to what extent.

TABLE 3. Characteristics of the 52 patients with recurrence aftersurgery for localized (N0M0) RCC

No. ECOG PS (%):0 36 (69)1 or Greater 16 (31)

No. presentation (%):Incidental 38 (73)Local 12 (23)Systemic 2 (4)

Mean tumor size (SD) 3.2 (0.7)No. cm tumor or (%):

0.1–1.0 0 (0)1.1–2.0 5 (10)2.1–3.0 17 (33)3.1–4.0 30 (58)

No. RCC type (%):Clear cell 50 (96)Papillary 2 (4)

No. T stage (%):T1a 27 (52)T3a 19 (37)T3b 6 (12)

No. Fuhrman grade (%):G1 5 (10)G2 35 (67)

G3–G4 12 (23)

Therefore, the actual incidence of patients with pN� diseasecould be underestimated in the current study. However,recent data suggest that combination of pNx and pN0 casesfor outcome modeling in RCC is appropriate.20

CONCLUSIONS

Of patients presenting with small solid renal tumors morethan 85% have RCC and 7% have synchronous metastaticdisease. In those who present with localized disease there isa 7% chance of metachronous metastatic disease at 5 years.The majority of patients who die of RCC present with con-comitant synchronous metastatic disease, but 3% of thosepresenting with localized disease will also die of RCC. Themajority of localized small renal tumors can be cured withexisting surgical approaches. However, patients consideringexperimental therapies such as ablation and surveillanceshould be aware of the small but not insignificant risk ofsynchronous and metachronous metastatic disease and can-cer associated death. Unfortunately, tumor size alone is notsufficient to distinguish RCC with benign behavior fromaggressive small RCC. Progression-free survival for patientswith metastatic small RCC is better than expected. TheUISS, the Karakiewicz nomogram and the Kattan nomo-gram are all reliable predictors of survival for patients withsmall RCC.

Abbreviations and Acronyms

ECOG PS � Eastern Cooperative Oncology Groupperformance status

RCC � renal cell carcinomaUISS � University of California Integrated

Staging System

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2. Chow WH, Devesa SS, Warren JL and Fraumeni JF: Risingincidence of renal cell cancer in the United States. JAMA1999; 281: 1628.

3. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL andZincke H: Solid renal tumors: an analysis of pathological

TABLE 4. Comparison of the accuracy of prognostic modelsto predict survival of small RCC

Prognostic Model

All StagesLocalized RCC (N0M0)

C-index CaSpecificSurvival

(SD)

C-index CaSpecificSurvival

(SD)

C-indexRecurrence-

FreeSurvival

(SD)

UISS7 0.871 (0.029) 0.705 (0.029) 0.706 (0.020)Kattan et al8 Not available* 0.778 (0.047) 0.755 (0.020)Karakiewicz et al9 0.869 (0.030) 0.724 (0.030) 0.704 (0.026)

The Kattan nomogram approached the highest predictive accuracy forcancer specific and recurrence-free survival of localized disease (c-indices0.778 and 0.755, respectively), while the UISS and the Karakiewicz nomo-gram showed high predictive accuracy for all RCC stages.* The Kattan nomogram predicts prognosis for patients with localized

RCC.

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SMALL SOLID RENAL TUMORS1726

4. Lam JS, Leppert JT, Belldegrun AS and Figlin RA: Adjuvanttherapy of renal cell carcinoma: patient selection and ther-apeutic options. BJU Int 2005; 96: 483.

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