Cystic RCC represents about 5–10% of all renal cell carcinomas [1,2,3]. Tumor violation and cancer cell spillage are the major concerns during surgery, particularly when cystic renal tumors are operated. Urologists may face anxiety if intraoperative cystic RCC rupture is encountered. The stress due to possible tumor cell seeding can adversely affect the surgical and oncological outcomes. However, Pradere et al. reported no local recurrence or distant metastasis on long-term follow up in intraoperative cyst rupture of cystic RCC in 18.7% of 268 patients [8]. Tumorous effect of cystic fluid rupture in cystic RCC has been still on debate, according to previous published reports.
Laparoscopic evaluation with cystic wall biopsy and fluid sampling of 57 indeterminate renal cysts was performed by Limb et al. [10]. Eleven patients were diagnosed to have RCC, out of which only one (9%) had positive cystic fluid cytology. There was no peritoneal or port site recurrence on follow up period. Nephron sparing surgery by laparoscopic or robotic approaches for complex renal cysts is safe, feasible and not inferior to open surgery for solid renal masses [12,13,14,15].
Safety of cystic wall puncture for cytology and biopsy during tumor ablation also has been reported in the literature [11,12,13,14]. So far, only few cases of needle tract seeding after percutaneous needle aspiration of renal tumors are reported [16, 17]. However, fine needle aspiration cytology (FNAC) of cystic renal tumor is of limited usefulness, probably due to inadequate sampling and false negative results with low accuracy [18, 19]. Hayakawa and colleagues studied FNAC of renal cystic tumors. Positive cytology was identified in only 14% among total of 37 subsequently proved cystic RCC patients [11]. Meanwhile, the risk of cyst rupture associated with intraoperative manipulations should not be neglected because cyst rupture and subsequent fluid spillage might increase risk of local recurrence [13].
Li et al. have reported 10 positive percutaneous FNAC (48%) of 21 documented RCC after surgery. Among those 11 positive cytology cases, there were 4 cases of suspected malignant and 7 cases of clearly malignant cells [20]. One patient had false positive result of histology proven benign cyst.
However, these previous studies have limitations because they were based on preoperative FNA study. FNAC of cystic renal tumor has limitations due to its inadequate sampling and high false negative rates. Consequentially, risk of cystic rupture and the least possible consequential tumor cell seeding could be underestimated. Up to now, detailed evaluation about the actual presence of malignant cell in cystic fluid and the associated risk factor is lacking. Therefore, we prospectively investigated the cystic fluid cytology of histologically confirmed cystic RCC by performing direct cystic fluid aspiration from the retrieved specimen in the surgical field, to figure out the incidence and associated risk factors of malignant cells in the cystic fluid of RCC.
In our data, cystic fluid cytology was positive in nearly half (48.6%) of among total of 70 cystic RCC patients including various histologic subtypes, with clear cell type most common. To the best of our knowledge, this is the highest incidence of positive cystic RCC cytology compared with the previous published literatures. It may be attributed to the prospective analysis associated with accurate sampling from the specimen in the surgical field, and meticulous handling without intraoperative cyst rupture. Also, study of cystic fluid cytology in our study revealed definite existence of cancer cells in cystic fluid using light microscope, which warrants meticulous dissection during surgery of cystic RCC to avoid tumor cell seeding caused by cystic rupture. To overcome the hurdles and limitations of inadequate sampling in CT or ultrasonography guided FNAC, we conducted direct cystic fluid aspiration from the delivered specimen in the surgical field. Furthermore, risk factors of positive cystic fluid cytology have been evaluated through retrieved specimens without cystic rupture.
FNAC may be helpful in diagnosis of RCC in preoperative imaging study. However, the diagnostic accuracy of FNAC in cystic RCC is low and the risk of cystic rupture or fluid leakage exist. According to the results of our study, the presence of tumor cells in the cystic fluid was confirmed in about half of the cases. Hence, preoperative FNAC would better be performed limitedly to selected patients.
Of the 34 positive cytology cases, definite malignant cells were identified in 28 patients while the other six cases showed highly suspicious atypical cells. We included atypical cells in the same group of positive malignant cells because they were assumed to exhibit similar tumorous characteristics with malignant cells, due to speculation of their cell components showing dysmorphic nucleus and high nucleus to cytoplasmic ratio. However, actual evaluation of behavior of these cells was limited due to absence of cystic rupture cases.
We presumed that positive cystic cytology would be associated with patient's old age (> 55 years), Bosniak grade, tumor size (> 4 cm in diameter, cT1a between cT1b) or histological grade of the tumor. Among those variables, patients’ age and Bosniak grade were found to be the significant risk factors of positive cytology. Thirty-one cases (91%) of positive cytology tumors were less than 7 cm in size (clinical stage T1). Clear cell carcinoma was most common histological subtype (24 patients; 70.8%). Both of papillary type 2 variant histology cases were positive of malignant cells. More than two third of these positive cytology tumors were of low Fuhrman Grade 1 or 2. These parameters of positive cytology patients were almost similar to the total patients included in the study.
The results of our data showed that old age and higher Bosniak grade remained as the significant risk factors of positive cytology in cystic RCC. On the other hand, small tumors of Bosniak class III could still harbor malignant or atypical cells in their cystic fluid.
Although tumor cell seeding of ruptured cystic renal cancer is known to be uncommon in previous published studies, our results still warrant that the necessity of meticulous manipulation of cystic renal tumor should not be underemphasized to avoid cystic rupture in older age patients (> 55 years) and higher Bosniak grade (III, IV). The presence of malignant cells in cystic fluid of RCC could be the evidence that warrants the least possible tumor cell implantation in case of cystic rupture.
Obviously, rupture of cystic component of RCC may lead to spillage of tumor cells in the surgical field. However, the evidence regarding ability of these cells to implant and grow is uncertain yet. This definitely necessitates further studies to understand the biology of this type of tumor cells. Detailed analysis of cystic fluid of renal tumors to understand the biological nature and behavior of the tumor cells is important. Different molecular biomarkers like proteins, interleukines, tumor necrosis and growth factors were observed in the cystic fluid [21, 22]. However, clinical significance of the molecular assay particularly when the malignant cells are absent in the cystic fluid, may needs to be evaluated in detail.
Chen et al. compared prognosis of patients with intraoperative cystic ruptures group and the group without cyst ruptures among total of 174 patients, through the evaluation of risk factors of intraoperative cystic rupture [23]. There were 27 (15.5%) intraoperative cyst ruptures. The median follow-up time was 60 months. They reported that 5-year recurrence free survival and cancer free survival in patients with cyst rupture were worse than those without cyst rupture. However, there was no significant difference in overall survival between the two groups. This could be another evidence of tumorous effect of positive cystic fluid cytology when cystic rupture occurred during surgery of cystic RCC.
Several limitations are present in our study. First, follow up period is median-term and numbers of enrolled cases were small. Second, we did not evaluate the cytology of benign renal cysts. It would be helpful to assess the false positive cytology rate to predict the value of FNAC of cystic renal tumors. Also, most common histology of our enrolled cases were clear cell type, but a few of other histologic types including papillary type and other cell types are included. As these tumors have different clinical, pathological and genetic features, further studies regarding correlation between cytology findings and each histologic types will be required. In addition, due to surgeon’s effort and carefulness of not trying to rupture the cystic component of tumor, there was no case of cystic rupture. Paradoxically, actual evaluation of behavior and aggressiveness of these cystic fluid tumor cells was limited due to absence of cystic rupture case. Studying the cystic fluid cytology of simple renal cysts and clarified evaluation of each histologic types of cystic RCC cytology would be required with larger numbers of cases.
