Cystic RCC represents about 5–10% of all renal cell carcinomas [1–3]. Tumor violation and cancer cell spillage used to be one of concern during surgery, particularly when cystic renal tumors are operated. Urologists may face vague 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 . 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 . 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 comparable to open or those for solid renal masses [12–15].
Safety of cystic wall puncture for cytology and biopsy during tumor ablation also has been reported in the literature [11–14]. So far, only few reported cases are available of needle tract seeding after percutaneous needle aspiration of renal tumors [16, 17]. However, fine needle aspiration cytology (FNAC) of cystic renal tumor is of limited usefulness, probably due to inadequate sampling and false positive results with low accuracy [18, 19]. Hayakawa and colleagues studied FNAC of renal tumors associated cysts. Positive cytology was identified in only 14% of 37 subsequently proved cystic RCC patients . 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 .
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 . 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 cancer 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 cytology and 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 28 (59.5%) of 47 patients including various cell subtypes of RCC, with clear cell type most common. To the best of our knowledge, this is the highest incidence of positive cystic RCC cytology among the previous published in literatures. It may be attributed to the prospective analysis associated with accurate sampling from the specimen in the surgical field, and meticulous handling without 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. Futhermore, risk factors of positive cystic fluid cytology have been evaluated through unruptured retrieved specimens.
Of the 28 positive cytology cases, definite malignant cells were identified in 24 patients while the other four 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 age (> 60years), Bosniak grade, tumor size (> 4cm 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. Twenty-five cases (92%) of positive cytology tumors were less than 7 cm in size (clinical stage T1 disease). Clear cell carcinoma was most common histological subtype and found in 18 patients (64.2%). Both of papillary type 2 variant histology cases were positive for malignant cells. More than two third of these positive cytology tumors were of low Fuhrman Grade 1–2. These parameters’ results of positive cytology patients were almost similar to those of the 42 patients included in the study.
The results of our data showed that old age and higher Bosniak grade remained as the significant risk factor of positive cytology in cystic RCC. On the other hand, small tumors of Bosniak class III can 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 aged patient (> 60years) 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, interlukines, 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 worth detailed evaluation.
Chen et al. compared prognosis of patients with intraoperative cyst ruptures group and the group without cyst ruptures among total of 174 patients, through the evaluation of risk factors of intraoperative cystic rupture . 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.
Main limitations of this study are median-term follow up period and small sample size. Studying the cystic fluid cytology of benign cysts would be helpful to assess the false positive cytology rate to predict the value of FNAC of these tumors. Also, most common histology of our enrolled cases were clear cell type, but a few of other histomorphotypes 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. Also, 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.