The detection of CTCs provides a new powerful tool to evaluate tumor load and invasiveness. In recent years, more and more studies have been conducted on CTCs of RCC, which play an important role in the detection of early recurrence and metastasis.22 Our results showed that preoperative CTC counts was higher in the tumor size ≥ 5cm group and reduced by surguical treatment. Besides, preoperative CTC counts was correlated to proliferation marker Ki-67.
At present, there are few studies on CTCs in renal cell carcinoma. Here, we determined the change of perioperative CTC counts and positive rate, and evaluated whether they were correlated with clinicopathological features. The statistical analyses results demonstrated that only tumor diameter affected preoperative CTC counts. Our findings are not identical to previous studies which found that the TNM-Staging are related to the positive rate and level of CTCs.23, 24 One reason could be included that most patients were diagnosised with early clinical TNM Stage.
Surgical resection is the best treatment for local renal cell carcinoma, The results of this study showed that the positive rate of CTCs in RCC patients slightly increased immediately after surgery but rapidly decreased one week after surgery, however, the difference was not statistically significant. The mean level of CTCs gradually decreased during perioperative period. Some studies have shown that in the surgical treatment of non-small cell lung cancer and prostate cancer CTCs may fall off due to invasive operation, leading to blood-derived spillover of cancer cells.25, 26 Zhang et al [21] showed that the levels of CTC in breast cancer patients was higher on the 3rd day after surgery than that before surgery, but decreased significantly on the 7th day after surgery.27 Invasive operation might result in a transiently increase in CTCs due to squeeze the tumor. Overall, our findings are consistent with the previous studies, complete removal of the tumor will reduce CTC counts after surgery.
RN and PN are the main surgical approaches for renal cell carcinoma. According to the literature, different surgical methods may affect periopretive CTC counts. Haga et al28 compared four surgical approaches, laparoscopic RN, laparoscopic PN, open RN, and open PN. They found open RN resulted in a significantly more postoperative CTC counts than in the laparoscopic RN group or in the open or the laparoscopic PN group. Our data suggested that the RN group showed a tendency to have higher positive rate of CTCs and more preoperative CTC counts than PN group. The reason may be that patients had greater tumor diameter and TNM stage, which resulted in a higher preoperative CTC counts and positive rate in the RN group. However, the perioperative change in positive rate of CTCs or CTC counts did not differ significantly among the surgical methods. The laparoscopic surgery was used for all patients in this study. Fine manipulation could be more possible in laparoscopic kidney surgery than in open surgery. Thus, laparoscopic kidney surgery might be preferable from preventing blood-derived spillover of cancer cells.
Does preoperative CTC counts affect the change of CTCs after surgery? At present, there is no uniform definition of CTCs positivity.29 Some studies have reported that CTCs ≥ 5 is an independent risk factor for recurrence and metastasis of breast cancer and non-small cell lung cancer.27, 30 Using a CTCs of 5 as the cutoff value, the present study demonstated that, in the high CTCs group, more patients showed CTC counts decreased at one week after surgery compared to low CTCs group. To some extent, the high CTCs group may receive extra benefit from surgical treatment.
Ki67 is a nuclear antigen that is present in almost all human malignancies. A growing body of research on lymphomas,31 bladder cancer,32 colorectal cancer33 and gastric cancer,34 have shown that overexpression of Ki-67 is associated with tumor cell growth, biological aggressiveness and the prognosis of these malignancies. Moreover, In RCC labeling indexes of Ki67 was found to be positively associated with advanced tumour stage and grade, and provide an additional prognostic indication of biological aggressiveness.35, 36 Tollefson et al37 reported that patients with high Ki67 expression were 68% more likely to die from RCC. Then, we analyzed the correlation between CTC counts and Ki-67 index and evaluate the prognostic value of CTCs in RCC. Our results indicated that a higher Ki-67 expression was significantly correlated positively with the absolute number of preoprative CTCs using the linear regression analyses. In addition, A higher Ki-67 express has been found in high CTCs group (CTCs ≥ 5). Therefore, CTCs≥5 may be an prognostic indicator of renal cell carcinoma. This finding was consistent with these reports that demonstrated in breast cancer and non-small cell lung cancer.27, 30
The methods of detecting CTCs should be noted for this study. The CellSearch system was approved by the FDA as a CTCs detection platform, which analyzes CTCs by detecting epithelial cellular adhesion molecule (EpCAM) expression in individual tumors. However, the expression of EpCAM in RCC is not high,38 so this method has a low detection rate of CTCs in RCC.39 In this study, a semi-automatic CTCs detection system based on ISET technology, namely the CTC-BIOPSY device, was used to analyze CTCs. Compared with the CellSearch system, ISET has a higher detection rate for CTCs of RCC and more advantages in detecting renal cancer CTCs with low expression of EpCAM.23 In recent studies, markers of G250 antigen40, 41 or CA9 combined with CD14742 showed good prospects in the detection of CTCs in RCC patients.
A few limitations of the this study need to be considered. First, in order to execute the inclusion and exclusion criteria in strict rotation, the number of cases enrolled in this study was small. Second, although preoperative CTC counts was correlated to proliferative marker Ki-67 in the current study, the prognostic and predictive impact of CTCs in the perioperative period would need more than several years of observation because the follow-up period is still too short. Future studies with longer postoperative follow-up is necessary to assess the clinical significance of perioperative CTCs detection in the diagnosis and treatment of RCC.