Late recurrence of renal cell carcinoma >5 years after surgery: clinicopathological characteristics and prognosis

Authors


Cheol Kwak, Department of Urology, College of Medicine, Seoul National University, 101 Daehak-no, Jongno-gu, Seoul 110-744, Korea. e-mail: mdrafael@snu.ac.kr

Abstract

Study Type – Therapy (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

Late recurrence more than five years after the initial treatment is one of the biological behaviours specific for RCC. In our study, late recurrence was observed in 8.8% of the patients. Also, patients with late recurrence had more favorable clinicopathological features and better prognosis with long cancer-specific survival after recurrence. Age and preoperative hs-CRP levels may be independent predictive factors for late recurrence of RCC.

OBJECTIVE

  • • To evaluate the clinicopathological features and prognosis of late recurrence of renal cell carcinoma (RCC).

PATIENTS AND METHODS

  • • A total of 747 patients who had undergone curative surgery for RCC with follow-up of >5 years or recurrence within 5 years were included in the study.
  • • The patients were stratified into four groups based on cancer-free intervals: no recurrence (no recurrence >5 years after surgery, n= 425), synchronous metastasis (n= 138), early recurrence (recurrence within 5 years, n= 143), and late recurrence (recurrence after 5 years, n= 41).
  • • Multivariate analysis was performed to identify the clinicopathological factors affecting late recurrence and its clinical outcome.

RESULTS

  • • The subgroups were significantly different in clinicopathological variables, including age, preoperative haemoglobin, platelet count, high-sensitivity C-reactive protein (hs-CRP) levels, pT stage and nuclear grade.
  • • In multiple logistic regression analysis, age (odds ratio [OR] 1.085, 95% confidence interval [CI] 1.012–1.163, P= 0.022), and preoperative hs-CRP levels (OR 6.211, 95% CI 1.590–24.270, P= 0.009) were independent predictive factors for late recurrence.
  • • In patients with synchronous metastasis, early recurrence and late recurrence, 5-year cancer-specific survival rates after recurrence were 27.0%, 41.1% and 73.7%, respectively (P < 0.001).
  • • Multivariate Cox analysis indicated that cancer-free interval, as well as body mass index, initial symptoms, Fuhrman's nuclear grade, sarcomatoid differentiation, lymphovascular invasion and metastasectomy, were independent predictive factors for cancer-related death.

CONCLUSIONS

  • • Late recurrence of RCC is not a rare event.
  • • Patients with late recurrence had more favourable clinicopathological features and better prognosis with long cancer-specific survival after recurrence.
  • • Age and preoperative hs-CRP levels may be independent predictive factors for late recurrence of RCC.
Abbreviations
OR

odds ratio

UICC

Union Internationale Contre le Cancer

AJCC

American Joint Committee on Cancer

BMI

body mass index

ASA

American Society of Anesthesiologists

hs-CRP

high-sensitivity C-reactive protein

LDH

lactate dehydrogenase

ESR

erythrocyte sedimentation rate.

INTRODUCTION

Recurrence of RCC after initial curative treatment occurs within 5 years in most patients, but late recurrence >5 years after the initial treatment is one of the biological behaviours specific to RCC. It has been reported that 4.7–11% of patients developed a recurrence 10 years after initial nephrectomy [1–3].

Metastatic RCC is a major challenge to clinical management owing to its poor prognosis. Median survival with cytokine therapy is ∼12 months [4]. Although many patients show good clinical response after targeted therapy, this effect is limited and the patients inevitably die from RCC [5]. Thus, an improved ability to predict the risk of recurrence and the appropriate stratification of patients would improve the ability to inform patients about their prognosis, and aid in clinical decision-making, and interpretation of the results. However, clinicopathological features, prognosis, and predictive factors for late recurrence have not been completely defined. In the present study, we aimed to evaluate the clinicopathological features and predictive factors for late recurrence of RCC.

PATIENTS AND METHODS

Between 1989 and 2008, a total of 747 patients who had undergone curative surgery for RCC with follow-up of >5 years, or recurrence within 5 years, were included in the present study. Management in this cohort included radical nephrectomy (n= 605, 81.0%) and nephron-sparing surgery (n= 142, 19.0%). No patient received adjuvant therapy. After approval by the Institutional Review Board at Seoul National University Hospital, comprehensive clinical, preoperative laboratory and final pathological data from the eligible patients were retrieved and reviewed. TNM staging was based on the 7th TNM classification of the Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC) guidelines [6]. Histological subtypes were classified according to the UICC/AJCC and Heidelberg recommendations [7], and tumour grades were determined according to the Fuhrman's grading system [8]. The number and sites of recurrence were determined based on radiological findings at the time of initial diagnosis and postoperative follow-up. Cancer-specific death was attributed to patients with evidence of cancer progression before death by reviewing the patient's medical records and/or the following codes using the International Classification of Diseases 10th revision (ICD-10 code C64) from the database of the Korea National Statistical Office.

The patients were stratified into four groups based on cancer-free intervals: no recurrence (no recurrence >5 years after surgery, n= 425), synchronous metastasis (n= 138), early recurrence (recurrence within 5 years, n= 143), and late recurrence (recurrence after 5 years, n= 41). Thus, late recurrence of RCC was observed in 41 of 466 patients (8.8%) who had been cancer-free for >5 years after curative surgery.

Comparison of demographics, clinical and pathological data was performed by the one-way anova test for continuous variables and the chi-squared test for categorical variables. Survival analysis was performed using the Kaplan–Meier method, and the differences among the groups were determined using the log-rank test. Multiple logistic regression analysis was performed to determine the predictive factors of recurrence 5 years after surgery. Cox proportional hazard regression in a forward stepwise regression and Kaplan–Meier analysis were performed to assess the independent prognostic factors of cancer-specific mortality after recurrence. Variables included in the multivariate analysis were age, gender, symptoms at initial diagnosis, body mass index (BMI), American Society of Anesthesiologists (ASA) score, preoperative laboratory data, T-stage, histological subtype, Fuhrman's nuclear grade, variable pathological results (sarcomatoid differentiation, etc.), cancer-free interval, and metastasectomy. A P value of <0.05 was considered to indicate statistical significance and all P values were two-sided.

RESULTS

ANALYSIS OF CLINICAL AND PATHOLOGICAL VARIABLES

Significant differences in clinical characteristics of the patients with different cancer-free intervals are shown in Table 1. The mean age was lowest in patients without recurrence, and BMI was lowest in those with synchronous metastasis. Of the patients with synchronous metastasis or early recurrence, large proportions of the patients (67.4 and 64.3%, respectively) had symptoms at diagnosis.

Table 1. Clinical characteristics according to patient group
 Patient group P
No recurrence, n= 425Synchronous metastasis, n= 138Early recurrence, n= 143Late recurrence, n= 41
Mean (range) follow-up duration, months103.2 (61–264)29.6 (1–202)51.6 (4–176)133.4 (63–234)<0.001
Mean (range) age at surgery, years51.4 (22–78)56.3 (30–78)55.8 (21–80)56.0 (38–76)<0.001
Gender, n (%)    0.777
 Male301 (70.8)104 (75.4)102 (71.3)29 (70.7) 
 Female124 (29.2)34 (24.6)41 (28.7)12 (29.3) 
Mean (range) BMI, kg/m224.4 (15.7–35.8)22.9 (16.4–30.5)24.0 (16.6–31.2)24.6 (19.3–29.7)<0.001
ASA score, n (%)    <0.001
 1193 (45.8)42 (31.8)47 (34.1)14 (35.0) 
 2206 (48.9)71 (53.8)74 (53.6)24 (60.0) 
 321 (5.0)16 (12.1)17 (12.3)1 (2.5) 
Symptoms at diagnosis, n (%)114 (26.8)93 (67.4)92 (64.3)19 (46.3)<0.001
Laterality, n (%)    0.112
 Right218 (51.3)55 (39.9)57 (39.9)19 (46.3) 
 Left206 (48.5)83 (60.1)85 (59.4)22 (53.7) 
 Bilateral1 (0.2)0 (0)1 (0.7)0 (0) 

Significant differences among patients with different cancer-free intervals were observed in several laboratory variables at the time of surgery (Table 2). Relative to patients without recurrence, those with late recurrence had higher serum lactate dehydrogenase (LDH) levels (79.2 vs 223.0 IU/L, P= 0.032) and high-sensitivity C-reactive protein (hs-CRP) levels (0.63 vs 4.2 mg/dL, P= 0.007). Also, relative to patients with early recurrence, those with late recurrence had higher mean haemoglobin levels (13.2 vs 14.2 g/dL, P= 0.030), and lower mean erythrocyte sedimentation rate (ESR) levels (78.1 vs 37.4 mm/h, P= 0.011).

Table 2. Laboratory findings at the time of surgery stratified by patient group
 Patient group P
No recurrence, n= 425Synchronous metastasis, n= 138Early recurrence, n= 143Late recurrence, n= 41
  1. *Significant difference between no recurrence and late recurrence. †Significant difference between early and late recurrence.

Mean (range) haemoglobin, g/L14.0 (7.7–17.6)12.4 (6.7–17.9)13.2 (7.4–20.6)14.2 (9.9–22.5)<0.001
Mean (range) platelet count×103/µL236.3 (51–481)305.5 (128–562)279.7 (62–592)232.2 (129–342)<0.001
Mean (range) neutrophil count,/µL3799 (1 092–13 000)5302 (1 400–12 121)4656 (1 503–15 448)5428 (3 082–15 884)<0.001
Mean (range) LDH, IU/L*79.2 (61–253)118.5 (56–398)113.7 (83–311)223.0 (152–294)0.210
Mean (range) albumin, g/dL4.1 (2.6–4.9)3.6 (2.2–4.7)4.0 (2.6–5.2)4.0 (3.1–5.4)<0.001
Mean (range) calcium, mg/dL8.4 (6.0–11.7)7.4 (5.9–11.3)8.0 (5.8–11.8)9.4 (6.4–10.4)<0.001
Mean (range) ESR, mm/h46.5 (1–263)94.9 (1–203)78.1 (1–241)37.4 (1–139)<0.001
Mean (range) hs-CRP, mg/dL*0.63 (0.1–15)4.8 (0.1–18)3.0 (0.1–25)4.2 (0.1–22)<0.001

Table 3 shows the pathological outcomes according to the duration of recurrence. The pathological T stage was significantly higher in patients with short cancer-free intervals: 7.1% of patients without recurrence were in the pT3 or higher group, 59.4% of those with synchronous metastasis, 44.8% of those with early recurrence, and 29.3% of those with late recurrence (P < 0.001). Likewise, a lower nuclear grade, absence of tumour necrosis, sarcomatoid differentiation and lymphovascular invasion all favoured long cancer-free survival. In multivariate logistic regression analysis, age (odds ratio [OR] 1.085, 95% CI 1.012–1.163, P= 0.022) and serum hs-CRP level (OR 6.211, 95% CI 1.590–24.270, P= 0.009) at the time of surgery were independent predictive factors for late recurrence.

Table 3. Pathological outcomes stratified by patient group
 Patient group P
No recurrence, n= 425Synchronous metastasis, n= 138Early recurrence, n= 143Late recurrence, n= 41
T stage, n (%)    <0.001
 1337 (79.3)35 (25.4)44 (30.8)20 (48.8) 
 258 (13.6)21 (15.2)35 (24.5)9 (22.0) 
 330 (7.1)62 (44.9)54 (37.8)12 (29.3) 
 40 (0)20 (14.5)10 (7.0)0 (0) 
Histological subtype, n (%)    <0.001
 Clear-cell346 (82.4)113 (84.3)126 (90.0)39 (97.5) 
 Chromophobe42 (10.0)2 (1.5)3 (2.1)1 (2.5) 
 Papillary 121 (5.0)4 (3.0)5 (3.6)0 (0) 
Papillary 27 (1.7)7 (5.2)5 (3.6)0 (0) 
 Collecting duct1 (0.2)3 (2.2)0 (0)0 (0) 
 Unclassified3 (0.7)5 (3.7)1 (0.7)0 (0) 
Fuhrman's nuclear grade, n (%)    <0.001
 120 (5.7)0 (0)2 (1.6)3 (8.3) 
 2192 (54.4)23 (20.0)37 (29.6)22 (61.1) 
 3121 (34.3)56 (48.7)65 (52.0)9 (25.0) 
 420 (5.7)36 (31.3)21 (16.8)2 (5.6) 
Tumour necrosis, n (%)102 (28.9)73 (63.5)62 (49.6)14 (38.9)<0.001
Sarcomatoid differentiation, n (%)8 (2.2)23 (20.0)16 (12.8)1 (2.8)<0.001
Lymphovascular invasion, n (%)35 (10.1)59 (51.3)48 (38.4)8 (22.3)<0.001

ANALYSIS OF INITIAL SITES OF RECURRENCE AND TREATMENT METHODS

Of the 322 patients with recurrence during the follow-up period, 93 patients (67.4%) with synchronous metastasis had a solitary site of recurrence, while 115 (80.4%) with early recurrence and 34 (82.9%) with late recurrence had a solitary recurrence (Table 4). Initial sites of recurrence were different according to cancer-free interval. In patients with synchronous metastasis and early recurrence, lung metastases were observed most frequently, followed by liver and bone metastasis. In patients with late recurrence, the lung was also the most frequent site of recurrence; however, the rate of other sites of recurrence was higher, including the pancreas (n= 12), thyroid (n= 4), scalp (n= 3), submandibular gland (n= 1), nasal cavity (n= 1), and big toe (n= 1).

Table 4. Sites of recurrence and treatment methods stratified by patient group
 Patient group P
Synchronous metastasis, n= 138Early recurrence, n= 143Late recurrence, n= 41
  • *

    Some patients had more than one recurrent site.

No. of sites, n (%)   0.019
 Solitary93 (67.4)115 (80.4)34 (82.9) 
 Multiple45 (32.6)28 (19.6)7 (17.1) 
Site of recurrence, n (%)*   <0.001
 Lung96 (48.2)82 (47.1)16 (32.0) 
 Liver27 (13.6)20 (11.5)4 (8.0) 
 Bone29 (14.6)19 (10.9)4 (8.0) 
 Brain6 (3.0)8 (4.6)1 (2.0) 
 Retroperitoneal lymph node23 (11.6)4 (2.3)1 (2.0) 
 Adrenal gland8 (4.0)4 (2.3)2 (4.0) 
 Other10 (5.0)37 (21.3)22 (44.0) 
Metastasectomy, n (%)   0.003
 Complete removal26 (18.8)49 (34.2)18 (43.9) 
 Incomplete removal36 (26.1)24 (16.8)4 (9.8) 
 Not done76 (55.1)70 (49.0)19 (46.3) 
Systemic therapy, n (%)   <0.001
 Immunotherapy103 (74.6)57 (39.9)17 (41.5) 
 Targeted therapy20 (14.5)29 (20.3)9 (22.0) 
 Not done15 (10.9)57 (39.9)15 (36.6) 

Metastasectomy was performed in 157 patients, including complete removal in 93 patients (59.2%) and incomplete removal in 64 (40.8%), and the tumours were confirmed to be the same histological subtype as the primary tumour. Of the 322 patients who had recurrence during follow-up, 235 received salvage systemic therapy. The reasons for not receiving systemic therapy were poor performance status in 34 patients, no evidence of disease after metastasectomy in 29, slow disease progression in eight, patient's refusal in six, loss of follow-up in four, and unknown reasons in six.

CANCER-SPECIFIC SURVIVAL AFTER RECURRENCE

The 5-year cancer-specific survival rates after recurrence for patients with synchronous metastasis, early recurrence, and late recurrence were 27.0%, 41.1%, and 73.7%, respectively (P < 0.001, Fig. 1). Factors significantly influencing cancer-specific survival after recurrence are shown in Table 5. Multivariate analysis by Cox's proportional hazard model retained cancer-free interval, as well as BMI at diagnosis, initial symptoms, Fuhrman's nuclear grade, sarcomatoid differentiation, lymphovascular invasion, and metastasectomy as independent predictive factors for cancer-related death after recurrence (Table 5).

Figure 1.

Cancer-specific survival after recurrence. CSS, cancer-specific survival; Mets, metastasis; Synch. mets, synchronous metastasis.

Table 5. Univariate and multivariate analysis for RCC-related death after recurrence
FactorsUnivariate analysisMultivariate analysis
HR95% CI P HR95% CI P
  1. HR, hazard ratio.

Age at diagnosis      
 <50 years
 50–60 years0.9650.632–1.4750.870
 60–70 years0.9320.623–1.3950.733
 ≥70 years1.9481.147–3.3090.014
BMI at diagnosis      
 Underweight (<18.5 kg/m2)
 Normal (18.5–23.0 kg/m2)0.6330.272–1.4730.2890.2290.076–0.6890.009
 Overweight (23.0–25.0 kg/m2)0.4180.175–1.0020.0510.2480.078–0.7880.018
 Obese (≥25.0 kg/m2)0.3530.148–0.8410.0190.1530.049–0.4720.001
Symptoms at diagnosis1.9291.333–2.792<0.0011.7121.067–2.7480.026
T stage      
 1
 21.9991.235–3.2340.005
 32.1641.414–3.311<0.001
 42.6921.515–4.7820.001
Histological subtype      
 Clear-cell
 Chromophobe0.5270.074–3.7730.524
 Papillary1.9401.070–3.5150.029
 Collecting duct1.2300.171–8.8220.837
 Unclassified3.7001.621–8.4490.002
Fuhrman's nuclear grade      
 1–2
 32.5741.515–4.372<0.0012.1501.196–3.8660.011
 44.8342.719–8.592<0.0013.1921.695–6.010<0.001
Tumour necrosis2.3571.393–3.9880.001
Sarcomatoid differentiation3.0811.838–5.166<0.0014.3082.263–8.201<0.001
Lymphovascular invasion2.2211.529–3.204<0.0012.6301.407–4.9160.002
Metastasectomy      
 Complete removal
 Incomplete removal3.6342.139–6.175<0.0012.3031.149–4.6190.019
 Not done4.3262.730–6.856<0.0013.1161.708–5.687<0.001
Recurrence-free survival      
 Late recurrence
 Early recurrence2.4761.232–4.9760.0116.3230.859–7.5470.070
 Synchronous metastasis4.1582.081–8.312<0.0018.8811.198–16.8150.033

DISCUSSION

Late recurrence of RCC developed in 8.8% of patients who had been cancer-free for >5 years after curative surgery in the present study. This finding is similar to that of previous studies. McNichols et al. [1] reported that the incidence of late recurrence was 11% in patients surviving 10 years. Additionally, Miyao et al. [3] reported late recurrence rates of 10.5% and 21.6% at 15 and 20 years, respectively. However, these previous studies were limited by lack of detailed data regarding the clinical and pathological features of these patients. We believe that the present study has an advantage over previous studies because of its thorough analysis of the clinical and pathological variables, which could improve the ability to inform patients about their prognosis, and the interpretation of the results through the proper stratification of patients.

In the present study, compared with the patients with synchronous metastasis or early recurrence, those with late recurrence had higher haemoglobin levels and lower ESR levels, in addition to favourable pathological features, such as lower pT stage, Fuhrman's nuclear grade, tumour necrosis, sarcomatoid differentiation, and lymphovascular invasion. It is not surprising to find patients with a preponderance of better prognostic factors among our long-term survivors; only these patients would be vulnerable to late recurrences of RCC. Consistent with the findings, Adamy et al. [9] recently showed that patients with late recurrence tended to have fewer symptoms at renal cortical tumour presentation (50 vs 62% of patients with symptoms), smaller tumours (7 vs 8.5 cm), and less aggressive disease (pT1 in 39 vs 18%) compared with those with early recurrence. However, the importance of the present results is that these data help define the patient population with risk of late recurrence among the patients with no evidence of disease for 5 years after surgery. In the present study, several clinical and pathological factors strongly influence the risk of late recurrence in patients with RCC, of which the most important are age and serum hs-CRP levels at diagnosis, as assessed in a multivariate analysis. The mean age was higher and serum hs-CRP level was higher in patients with late recurrence compared with those without recurrence after 5 years.

The present data showed that a significant number of patients with late recurrence had recurrence at unusual sites, such as the pancreas, thyroid, scalp, and submandibular gland. The lung, liver and bone were still the usual metastatic sites in patients with late recurrence; however, the proportion of those sites was lower than those in patients with synchronous metastasis or recurrence within 5 years. The question of why these differences in metastatic sites had arisen according to cancer-free interval remains to be answered. Unfortunately, even though analysis of clinicopathological variables for RCC is important in predicting prognosis and guiding treatment, it currently cannot predict the sites of metastasis. In several solid tumours, similar studies have been carried out to obtain the answer for site-specific metastasis. Yerushalmi et al. [10] showed that CA-125 levels varied among the different sites of metastasis, and explained that CA-125 is mainly produced by mesothelial cells and therefore is more likely to be elevated in the setting of abdominal and pleural metastasis [11,12]. Additionally, Koo et al. [13] reported that metastatic breast cancer showed different phenotypes of oestrogen receptor, progesterone receptor, and HER-2 according to the different metastatic sites. Bruin et al. [14] reported that organ-specific metastasis localization can be predicted by specific genomic aberrations in primary colorectal cancer with 80% precision. They showed that primary colorectal cancer that developed liver metastasis was characterized by an amplification of chromosome 20q. Therefore, understanding the molecular and cellular mechanisms underlying RCC, and in particular, progression to sites of metastasis, is of utmost importance.

The potential limitations of the present study should be acknowledged. Notably, this is a retrospective study and is susceptible to all limitations and biases inherent to this study design. A standardized postoperative follow-up protocol was not used, and the quality of imaging techniques has improved recently. These biases might have influenced the present results.

In conclusion, late recurrence of RCC is not a rare event; it is observed in 8.8% of patients who had been cancer-free for >5 years. Age and serum hs-CRP levels at the time of operation may be independent predictive factors for late recurrence of RCC. Patients with late recurrence had more favourable clinical and pathological features and favourable prognosis with long cancer-specific survival after recurrence.

CONFLICT OF INTEREST

The authors have no conflicts of interest or financial ties to disclose.

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