International Journal of Urology (2002) 9, 19–23

Original Article

Recurrence of renal cell carcinoma more than 5 yearsafter nephrectomy

KOHSUKE UCHIDA,1 NORIOMI MIYAO,1 NAOYA MASUMORI,1

ATSUSHI TAKAHASHI,1 TOSHIRO ODA,1 MASAHIRO YANASE,1

HIROSHI KITAMURA,1 NAOKI ITOH,1 MASAAKI SATO2 AND TAIJI TSUKAMOTO1

Departments of 1Urology and 2Laboratory Medicine (Clinical Pathology Division), SapporoMedical University School of Medicine, Sapporo, Japan

Abstract Objectives: We evaluated clinical features and predictive factors for the recurrence of renal cellcarcinoma (RCC) developing more than 5 years after nephrectomy.Methods: We retrospectively reviewed 239 patients with RCC who underwent surgery for the primary lesion. To identify factors that affected recurrence more than 5 years after nephrectomy(delayed recurrence) and its clinical outcomes, we performed a multivariate analysis using Cox’sproportional hazards model and a survival study.Results: Recurrence developing within 5 years after nephrectomy (early recurrence) was found in57 patients and delayed recurrence in 11 patients. The multivariate analysis revealed no clinicaland pathologic features influencing delayed recurrence in 114 patients who survived more than5 years after nephrectomy without having early recurrence. The patients with delayed recurrenceshowed better clinical outcomes than those with early recurrence when the rate was determinedfrom the time of recurrence.Conclusions: Although delayed recurrence is not a rare event for patients with RCC, no clinicaland pathologic factors at the time of the initial treatment can predict the recurrence. Patients whoare free of recurrence for more than 5 years after surgery for a primary lesion should be carefullyfollowed up for delayed recurrence.

Key words delayed recurrence, prognostic factors, renal cell carcinoma.

Introduction

Delayed recurrence is one of the biological behaviorsspecific for renal cell carcinoma (RCC).1 It has beenreported that recurrence may occur many years afternephrectomy.2–11 McNicols et al. reported that 18 of158 patients (11%) developed recurrence 10 years afternephrectomy.2 Nakano et al. reported that among 43patients who received curative nephrectomy, two devel-

oped recurrence more than 10 years after the opera-tion; an incidence of 4.7%.3 However, the risk factorsfor such recurrence have not been fully elucidated.

In this study, we evaluated the clinical characteris-tics and pathologic features of patients who developedrecurrence of RCC more than 5 years after nephrec-tomy. We also studied clinical outcomes of suchpatients after the recurrence.

Methods

Patients

We retrospectively reviewed the medical records of308 patients with RCC who received surgical treatmentat Sapporo Medical University Hospital between 1975

Correspondence: Taiji Tsukamoto M D, Department ofUrology, Sapporo Medical University School of Medicine,S-1, W-16, Chuo-Ku, Sapporo 060-8543, Japan. Email: taijit@sapmed.ac.jp

Received 1 February 2001; revision 27 August 2001;accepted 27 August 2001.

20 K Uchida et al.

and 1995. To evaluate risk factors for recurrence aftersurgery for the primary lesion, 239 patients withoutdistant metastasis at the initial diagnosis were includedin the study. They consisted of 157 men and 82 womenwith ages ranging from 28 to 87 years (median:60 years). Radical nephrectomy was performed in 232patients and the remaining seven underwent nephron-sparing surgery. Patients were followed up for between3 months and 20 years (median; 4.2 years). Patho-logic stage and grade were classified according to theGeneral Rule for Clinical and Pathologic Studies on Renal Cell Carcinoma, 3rd edition, 1999 (JapaneseUrological Association, the Japanese Society ofPathology and Japan Radiological Society), which wasadopted from the system of the International UnionAgainst Cancer (UICC)-TNM classification of RCC.12

Factors affecting recurrence of RCC

Multivariate analysis by Cox’s proportional hazardsmodel was used to determine the factors, as shown inTable 1. All 239 patients were included in the study ofearly recurrence, which was defined as that foundwithin 5 years after nephrectomy. For identifying factors influential in recurrence that developed morethan 5 years after nephrectomy (delayed recurrence),patients who developed early recurrence and those whodid not survive for more than 5 years after nephrec-tomy were excluded, leaving 114 patients in the studyof delayed recurrence. We also included the number of

abnormal findings related to acute-phase proteins inthe analysis of the possible influential factors. Thesewere the erythrocyte sedimentation rate, serum C-reactive protein, alpha-2-globulin and fever ofunknown origin, since we previously demonstrated thatthese abnormalities significantly affected clinical out-comes of patients with RCC.13 The definition of theirabnormalities was already reported in that study.

Survival analysis was performed by theKaplan–Meier method. The differences between the groups were determined by the log–rank test. TheMann–Whitney U-test was used in the analysis of dif-ferences for age, stage and grade between the early anddelayed recurrence groups, and the c2 test in the analy-sis of difference for sex, symptoms, pathologic lymphnode or vein involvement and the number of abnormalfactors related to acute-phase proteins.

Follow-up of patients

Routine follow-up consisted of a physical examinationand imaging studies such as abdominal and chest com-puted tomographies and chest X-rays every 6 monthsduring the first 5 years and every 12 months after5 years.

Post-nephrectomy adjuvant therapy

Although the efficacy of adjuvant therapies is contro-versial, a variety of adjuvant therapies were attemptedin the past. Of the 239 patients, 118 received interferoninjections and 31 were treated with a combination ofvarious drugs such as medroxyprogesterone acetate,fluorouracil and other chemotherapeutic agents. Forty-eight patients received radiation therapy at the site ofthe primary lesion with or without various chemother-apeutic agents as adjuvant therapy. The 42 most recentpatients did not receive any adjuvant therapies.

Post-recurrence treatment

When patients had early or delayed recurrence, theyreceived interferon injections, interleukin-2 infusion orvarious chemotherapeutic agents, or a combination ofthese. Surgical treatment for metastasis was attemptedwhen it was indicated. Radiation therapy was done forpatients with bone metastasis or brain metastasis.

Results

Of the 239 patients who had no distant metastasis atthe time of initial diagnosis, 68 patients (28.8%) had

Table 1 Factors evaluated for recurrence by Cox’s propor-tional hazards model

Factors Categories

Age Chronological yearSex Male/FemaleSymptoms

gross hematuriapalpable mass None/1 or moreback pain

Pathologic stage pT1/pT2/pT3/pT4Pathologic lymph node pN (–)/pN (+)

involvementPathologic venous involvement pV (–)/pV (+)Grade G1/G2/G3Adjuvant therapy Yes/NoNumber of abnormal factors Less than 3 factors/3

related to acute-phase proteins factors or more

pT1, Pathologic stage T1; pT2, pathologic stage T2;pT3, pathologic stage T3; pT4, pathologic stage T4; pN,pathologic lymph node; pV, pathologic veins; G1, grade 1;G2, grade 2; G3, grade 3.

Delayed recurrence of renal cell carcinoma after nephrectomy 21

recurrence after nephrectomy. Fifty-seven patients hadrecurrence within 5 years postoperatively (early recur-rence group) and 11 after more than 5 years (delayedrecurrence group). Disease-free survival rates at 5, 10and 15 years were 74%, 64% and 57%, respectively.While the early recurrence group apparently had ahigher pathologic stage than the delayed-recurrencegroup (P = 0.047 by Mann–Whitney U- test), other fac-tors were not significantly different between the twogroups (Table 2). All 12 patients who had a pathologicinvolvement of the regional lymph nodes had recur-rence within 5 years after nephrectomy. Multivariateanalysis by Cox’s proportional hazards model indicatedthat pathologic findings of regional lymph nodes (pN), veins (pV) and gender were independent riskfactors for early recurrence (data not shown). In theanalysis of delayed recurrence, ‘pathologic lymph node

involvement’ was excluded from the factors to be ana-lyzed, since none of the 114 patients that were studiedhad such an involvement. However, no clinical andpathologic factors responsible for delayed recurrencewere identified (Table 3). Internal correlations amongfactors did not affect the results in the studies on earlyand delayed recurrence (r < 0.4).

The delayed recurrence group had a favorable prognosis after recurrence compared to the early recur-rence group (Fig. 1, P = 0.045 by log–rank test).Indeed, cause-specific survival rates at 3 and 5 yearsafter recurrence were 65% and 49% in the delayedrecurrence group, respectively and 30% and 23% inthe early recurrence group, respectively. The initialsites of recurrence in the delayed recurrence groupincluded the lung in five patients, the contra-lateralkidney in two, the liver in one, the brain in one, thy-roid in one and the axillar lymph nodes in one (Table4). Four patients subsequently developed recurrence invarious organs. Of 11 patients, six developed solitarymetastasis in one organ as the initial recurrence andwere treated with surgery. Four of these six patientswere alive and free of disease at the time of this study.The five patients who had multiple metastases in oneorgan received non-surgical adjuvant treatment includ-ing interferon administration, but four died of cancer.Patients who had a solitary metastasis and receivedsurgical treatment tended to have a higher survival ratethan those who had multiple metastases and receivednon-surgical treatment (3-year and 5-year survivalrates after treatment for recurrence: 100% vs 40% and66% vs 40%, respectively), although there was a selec-tion bias for surgery and no significant statistical difference between the two groups (P = 0.112 by thelog–rank test).

Table 2 Clinical characteristics in the early and delayedrecurrence groups

Early Delayed- P-valuerecurrence recurrence

group group

Age 38–79 42–68 0.092†

(median) (62) (58)Sex

male 42 6 0.202‡

female 15 5Symptoms

none 23 6 0.383‡

1 or more 34 5Stage

pT1 2 0pT2 22 9 0.047†

pT3 30 2pT4 3 0

GradeGrade 1 14 5Grade 2 31 5 0.145†

Grade 3 12 1pN

pN (–) 40 10 0.091‡

pN (+) 12 0pV

pV (–) 19 5 0.441‡

pV (+) 38 6No. of abnormalfindings related toacute-phase proteins

0–2 38 10 0.106‡

3–4 19 1Total 57 11

† Using the Mann–Whitney U-test. ‡ Using c2 test.pN, Pathologic lymph node; pV, pathologic veins.

Table 3 Multivariate analysis of factors associated withdelayed recurrence by Cox’s proportional hazards model

Factors Hazard 95% confidence P-valueratio interval

Age 0.985 0.054–5.305 0.255Sex 0.585 0.155–2.212 0.429Symptoms 0.945 0.225–3.977 0.938pT 0.752 0.274–2.063 0.580Grade 1.046 0.322–3.399 0.940pV 1.114 0.307–4.264 0.841Adjuvant therapy 0.521 0.059–4.891 0.568No. abnormal 0.533 0.054–5.305 0.591

findings relatedto acute phaseproteins

22 K Uchida et al.

Discussion

When patients with RCC who undergo nephrectomydevelop recurrence, it usually occurs within 5 yearsafter the operation. However, recurrence also occursvery late after nephrectomy. In this study, we examinedthe characteristics and factors responsible in patientswho had recurrence more than 5 years after nephrec-tomy. Various factors have been reported to be signi-ficant predictors of recurrence of RCC, in particular, of

early recurrence.14,15 The present study showed that pN, pV and gender were independent prognostic fac-tors responsible for early recurrence that developedwithin 5 years after nephrectomy. These factors havealready been reported to be prognostic factors inpatients with RCC. However, risk factors for delayedrecurrence have not been clarified. Our results indic-ated that recurrence more than 5 years after nephrec-tomy might be unpredictable because multivariateanalysis failed to identify clinicopathologic featuresthat influenced delayed recurrence. Thus, while mostrecurrence of the disease develops within 5 years afterthe operation, we must be careful to look for delayedrecurrence as well when patients survive for more than5 years after surgery.

In our study, survival rates were clearly differentbetween the early and delayed recurrence groups. Thedelayed recurrence group showed a more favorableprognosis than the early recurrence group. Maldazysand DeKernion indicated that the interval betweennephrectomy and the development of metastasis wascorrelated with prognosis in patients with RCC, whichmay be supported by our results.16 It has been reportedthat survival after late recurrence is improved with sur-gical treatment for patients with solitary metastasiswhen it is confined in one organ.9–11 Surgical treatment,whenever delayed recurrence is resectable, representsthe most appropriate therapeutic option. Indeed, McNicols et al. reported that two of 18 patients who developed recurrence more than 10 years after

Table 4 Clinical outcomes of patients with delayed recurrence

Case number, Interval to Initial Treatment Subsequent Survival afterage and sex initial rec. (years) rec. site for initial rec. rec. site(s) initial rec. (years)

1, 61, F 8.9 lung (multi.) IFN-alpha none 0.5 (cancer death)or IFN-gamma

2, 64, M 7.6 lung (multi.) IFN-alpha none 2.7 (cancer death)or IFN-gamma

3, 53, M 5.7 lung (multi.) IFN-alpha none 3.8 (AWD)or IFN-gamma

4, 57, F 8.2 lung surgical resection pancreas, adrenal 6.1 (cancer death)and brain

5, 59, F 6.4 lung surgical resection none 1.2 (NED)6, 57, M 9.4 kidney partial Nx. none 6.7 (NED)7, 42, F 6.9 kidney partial Nx. none 1.3 (NED)8, 58, M 12.3 brain surgical resection kidney and lung 4.0 (cancer death)9, 68, M 10.5 liver (multi.) IFN-alpha none 2.1 (cancer death)10, 62, M 8.0 thyroid resection surgical none 1.8 (NED)11, 46, F 7.4 lymph nodes IFN-alpha lung and renal fossa 6.5 (cancer death)

or IFN-gamma

rec., Recurrence; multi., multiple; Nx., nephrectomy; IFN, interferon; AWD, alive with disease; NED, no evidence of disease.

Fig. 1 Cause-specific survival rate after recurrence inthe early and delayed recurrence groups (number ofpatients at risk). Early versus delayed recurrence group;P = 0.045 by log-rank test. (–), Early recurrence group; (--), delayed recurrence group.

Delayed recurrence of renal cell carcinoma after nephrectomy 23

nephrectomy, underwent resection of a solitary pul-monary recurrence.2 These patients were alive 6 and9 years after that surgical treatment, respectively. Ourstudy may support this option, as four of the sixpatients who received surgical treatment for delayedrecurrence were free of the disease during follow-up 1.2–6.7 years after recurrence. Thus, although ourstudy consisted of a limited number of patients, it indi-cated that survival might be improved when an aggres-sive surgical approach is employed for patients withsolitary metastasis in one organ.

Conclusion

Recurrence of RCC more than 5 years followingnephrectomy is not a rare event and is one of the par-ticular characteristics of RCC. However, delayed recur-rence cannot be predicted at the time of treatment forthe primary lesion. Thus, careful long-term follow-upis necessary for RCC patients when they survive formore than 5 years. Surgical treatment may be consid-ered for patients with delayed recurrence when thelesion is solitary and confined to one organ. In suchcases, the treatment may favorably contribute to theclinical outcome of patients with the disease.

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