INTRODUCTION
- Top of page
- Abstract
- INTRODUCTION
- PATIENTS AND METHODS
- RESULTS
- DISCUSSION
- CONFLICT OF INTEREST
- REFERENCES
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
- Top of page
- Abstract
- INTRODUCTION
- PATIENTS AND METHODS
- RESULTS
- DISCUSSION
- CONFLICT OF INTEREST
- REFERENCES
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.
DISCUSSION
- Top of page
- Abstract
- INTRODUCTION
- PATIENTS AND METHODS
- RESULTS
- DISCUSSION
- CONFLICT OF INTEREST
- REFERENCES
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.
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