Descriptive report of complex cystic renal mass fluid cytology: a cross-sectional analysis
Highlight box
Key findings
• Most complex renal cysts contain benign fluid.
• Bosniak 4 lesions were more likely to contain cyst cytology that was suspicious or positive for malignancy.
What is known and what is new?
• There are no guidelines that address the oncologic implications of complex renal cyst rupture.
• Using contemporary cytology analysis methods, we found that, among the 18 histologically confirmed malignant lesions, cytology was either suspicious or positive in only three (17%).
What is the implication, and what should change now?
• Understanding the cytologic composition of complex cystic renal masses could inform the risk of tumor seeding in the event of intraoperative cyst rupture.
• More sophisticated testing, such as cell-free DNA, may provide insight into the malignant potential of renal cyst fluid.
• For now, standard surgical principles of safe dissection, minimal tumor manipulation, and avoidance of cyst rupture should continue to be the standard of care.
Introduction
Background
Cystic renal masses require surgical extirpation when the risk of malignancy outweighs the morbidity of surgical intervention; this is generally the case in patients with a Bosniak III or IV lesion and in younger and healthier patients who prefer upfront definitive management (1,2). During surgical extirpation of cystic renal masses, surgeons universally attempt to avoid inadvertent cyst rupture due to the theoretical risk of tumor seeding. Attempting to avoid cyst rupture can greatly increase the difficulty of the surgery, particularly for large cystic masses. Despite intraoperative precautions, accidental cyst rupture during partial nephrectomy occurs at a rate of approximately 15–19% (3,4). Whether or not the concern regarding tumor seeding is warranted is debatable, as oncologic outcomes in the setting of cyst rupture have been mixed. Furthermore, there are no guidelines that address the oncologic implications of cyst rupture or that indicate any alteration to the postoperative surveillance of patients who experience intraoperative cyst rupture.
Rationale and knowledge gap
Several prior studies have attempted to characterize the cytologic contents of renal cysts, but have fallen short of providing clinically relevant information, as many of these studies are outdated, do not use clinically available cytologic testing, and/or include largely Bosniak < III lesions (5-8). Characterization of the malignant potential of complex cystic renal masses concerning malignancy would prove useful in understanding whether cyst rupture compromises oncologic outcomes.
Objective
To that end, we investigated cystic fluid cytology in a cohort of patients undergoing open or minimally invasive radical or partial nephrectomy of a clinically localized cystic renal mass. Our goal was to characterize the presence of malignant cells in the fluid of complex renal cysts. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-464/rc).
Methods
This was a cross-sectional analysis of consecutive patients undergoing surgical resection of complex cystic renal masses. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of Mayo Clinic (No. 21-011986) and was approved with “exempt” status due to its minimal risk nature and because no additional interventions beyond usual clinical practice were implemented. Given that this study was classified as institutional review board-exempt, by definition, no informed consent was required from study subjects. Patients undergoing a partial or radical nephrectomy by open or robotic approach for a clinically localized (< cT2N0M0) cystic renal mass were identified prior to their surgery. Every patient had a preoperative evaluation with computed tomography (CT) imaging and standard baseline labs. Based on the preoperative imaging, the renal masses were characterized by a single board-certified radiologist (T.A.P.). Cystic lesions with <25% solid component were described by Bosniak classification. Lesions with a significant cystic component but >25% solid component were also included and will be referred to as renal neoplasms with cystic features. Postoperatively, patients were followed with CT imaging surveillance every 3 months. Exclusion criteria were previous chemotherapy/immunotherapy, cyst rupture prior to controlled aspiration, and incomplete data.
Outcomes
Baseline patient and tumor characteristics including sex, age, tumor diameter tumor laterality, and radiologic tumor classification were recorded. Postoperative outcomes of interest included the presence or absence of cyst rupture intraoperatively, final pathologic staging and tumor histology, cytologic analysis of the cystic fluid, and cancer recurrence.
Cystic fluid analysis
Following excision, fluid from the mass was aspirated and sent for cytologic analysis. Cyst fluid was prepared by splitting the collected fluid in half and processing up to 50 mL (minimum of 0.5 mL required) into a PreservCyt® Vial on a ThinPrep® 2000 or ThinPrep® 5000 processor using standard protocols resulting in a pap-stained ThinPrep glass slide (Figure 1). The second half of the fluid was processed into a cellblock using a plasma/thrombin process resulting in a Formalin-Fixed Paraffin-Embedded (FFPE) block cut to produce a hematoxylin and eosin (H&E)-stained slide. Both the pap-stained and H&E slides were evaluated for malignant cells by a cytotechnologist and pathologist.
Statistical analysis
Continuous variables were reported as median [interquartile range (IQR)], and categorical variables were reported as n (%). Microsoft® Excel® version 2401 was used for data management and basic descriptive statistics including frequency, percentage, median, and IQR.
Results
Twenty-three patients underwent resection of 24 cystic tumors, including 17 (73.9%) males and 6 (26.1%) females (Table 1). The median patient age was 58 years (IQR, 43–68 years). The median tumor diameter was 3.7 cm (IQR, 3.2–6.1 cm). On preoperative cross-sectional imaging, tumors were most often characterized as Bosniak 4 (n=11/24, 45.8%), Bosniak 3 (n=5/24, 20.8%), renal neoplasm with cystic features (n=4/24, 16.7%), Bosniak 2F (n=3/24, 12.5%), or Bosniak 1 (n=1/24, 4.2%). The Bosniak 1 lesion was removed incidentally during a robotic partial nephrectomy done for a solid renal mass. Most patients underwent robotic partial or radical nephrectomy (n=20/23, 87.0%), and 3/23 (13.0%) patients underwent an open resection. There were no cases of intraoperative cyst rupture. Final histology was most often clear cell renal cell carcinoma (ccRCC) (n=17/24, 70.8%), followed by benign cyst (n=2/24, 8.3%), and oncocytoma (n=1/24, 4.2%). Other final histologies are included in Table 1. At a median follow-up of 12.5 months, there were no instances of cancer recurrence.
Table 1
| Characteristic | Values |
|---|---|
| Gender | |
| Male | 17 (73.9) |
| Female | 6 (26.1) |
| Age (years) | 58 [43–68] |
| Tumor diameter (cm) | 3.7 [3.2–6.1] |
| Preoperative imaging | |
| Bosniak 1 | 1 (4.2) |
| Bosniak 2F | 3 (12.5) |
| Bosniak 3 | 5 (20.8) |
| Bosniak 4 | 11 (45.8) |
| Renal neoplasm with cystic features | 4 (16.7) |
| Surgical approach | |
| Robotic partial nephrectomy | 19 (82.6) |
| Robotic radical nephrectomy | 1 (4.3) |
| Open partial nephrectomy | 2 (8.7) |
| Open radical nephrectomy | 1 (4.3) |
| Final histology | |
| Clear cell RCC | 17 (70.8) |
| Oncocytoma | 1 (4.2) |
| Benign cyst | 2 (8.3) |
| Other† | 4 (16.7) |
Data are presented as n (%) or median [IQR]. †, angiomyolipoma, metanephric adenoma, RCC with fibro-myomatous stroma, clear cell papillary RCC. RCC, renal cell carcinoma; IQR, interquartile range.
Renal cyst cytology was benign in 46% (11/24) of tumors, atypical in 29% (7/24), suspicious in 8% (2/24), positive for neoplasm in 4% (1/24), and positive for malignancy in 4% (1/24) (Table 2). Among 18 histologically confirmed malignancies, 17% (3/18) corresponded to either positive (n=1) or suspicious (n=2) cytologies. The cytologic specimen that was positive for neoplasm correlated with a final histology metanephric adenoma, while the cytologic specimen positive for malignancy correlated with a final histology of ccRCC; preoperatively, these masses had both been radiographically characterized as Bosniak 4 lesions. Notably, two cytologic specimens were “suspicious” for malignancy; the final histology for these lesions was ccRCC in each case, and the corresponding preoperative imaging was read as a Bosniak 4 lesion in both cases. The cytology for Bosniak 1, 2F and 3 lesions as well as renal neoplasms with cystic features, was benign or atypical in all cases. There were two cases of nondiagnostic cytology, one in a Bosniak 4 lesion (ccRCC, pT2a) and the other in a renal neoplasm with cystic features (ccRCC, pT1a).
Table 2
| Case No. | Preoperative imaging | Cytology | Final histology |
|---|---|---|---|
| 1 | Bosniak 1 | Benign | Benign cyst |
| 2 | Bosniak 2F | Benign | Clear cell RCC |
| 3 | Bosniak 2F | Benign | Benign cyst |
| 4 | Bosniak 2F | Atypical | Clear cell RCC |
| 5 | Bosniak 3 | Benign | Clear cell RCC |
| 6 | Bosniak 3 | Benign | Clear cell RCC |
| 7 | Bosniak 3 | Benign | RCC with fibro-myomatous stroma |
| 8 | Bosniak 3 | Atypical | Clear cell RCC |
| 9 | Bosniak 3 | Atypical | Clear cell RCC |
| 10 | Bosniak 4 | Benign | Clear cell RCC |
| 11 | Bosniak 4 | Benign | Clear cell RCC |
| 12 | Bosniak 4 | Benign | Clear cell RCC |
| 13 | Bosniak 4 | Benign | Clear cell RCC |
| 14 | Bosniak 4 | Atypical | Clear cell papillary RCC |
| 15 | Bosniak 4 | Atypical | AML, incidental papillary adenoma with oncocytic features |
| 16 | Bosniak 4 | Suspicious | Clear cell RCC |
| 17 | Bosniak 4 | Suspicious | Clear cell RCC |
| 18 | Bosniak 4 | Positive for neoplasm | Metanephric adenoma |
| 19 | Bosniak 4 | Positive for malignancy | Clear cell RCC |
| 20 | Bosniak 4 | Nondiagnostic | Clear cell RCC |
| 21 | Renal neoplasm with cystic features | Benign | Oncocytoma |
| 22 | Renal neoplasm with cystic features | Atypical | Clear cell RCC |
| 23 | Renal neoplasm with cystic features | Atypical | Clear cell RCC |
| 24 | Renal neoplasm with cystic features | Nondiagnostic | Clear cell RCC |
RCC, renal cell carcinoma; AML, angiomyolipoma.
Discussion
Key findings
In this descriptive report, we used contemporary cytologic analysis methods to characterize the cytologic composition of cyst fluid in complex renal cysts that were radiographically suspicious for malignancy, with one exception of an incidentally excised Bosniak 1 lesion. This is clinically relevant, as an understanding of the cytologic composition of complex cystic renal masses could inform the risk of tumor seeding in the event of intraoperative cyst rupture. Such knowledge may change the intraoperative approach (e.g., intraoperative aspiration of large cystic masses to decrease the complexity of the dissection) in addition to the postoperative surveillance plan in the event of cyst rupture. Overall, there is a paucity of data in this area, and the current study provides a contemporary update regarding the malignant potential of renal cyst cytology with findings that are translatable to North American centers that generally operate under a shared set of guidelines in regard to complex cystic renal mass management.
Comparison with similar research
In 1976 prior to the conception of the Bosniak classification schema, Stewart et al. evaluated the aspirate of cyst fluid in 84 consecutive surgically excised renal cysts in which aspiration of cysts was performed either preoperatively or intraoperatively (5). Final pathology showed one case of renal cell carcinoma, and normal cytology was seen in all cases. In a subsequent manuscript, Todd et al. reported on five cases of Bosniak III or IV lesions that were excised and found to be cystic RCC; three of these were cytologically benign on preoperative fine needle aspiration, and two showed typical cytologic findings of ccRCC (6). Hayakawa et al. collected information via a survey of institutions in Japan regarding cyst cytology and the correlating final pathology from 37 cystic renal masses, 16 (43%) and 12 (32%) of which were simple and multilocular cysts, respectively (7). Cytology was positive (defined as Papanicolaou class IV and V) in 5/37 (14%) samples, including in 2 of the 12 (17%) cases of cystic RCC and in 2 of the 16 (13%) simple cysts. A more recent analysis of cystic fluid in Bosniak III and IV lesions in 70 patients undergoing surgical resection, was performed by Hur and colleagues (8). They identified definitive malignant cytology in 28 specimens and atypical cytology in six specimens, while the rest were negative.
Explanations of findings
Regarding the current study, of the 24 cytologic specimens, one was definitively positive for malignancy, which did indeed correlate with a final histology of a malignant neoplasm (i.e., ccRCC). One cytologic specimen was positive for neoplasm but not for malignancy; this sample correlated with the final histology of metanephric adenoma, which is a benign lesion with only rare case reports of metastatic potential (9,10). Out of the Bosniak 3 and 4 lesions (n=16), 12 (75%) had a final histological diagnosis of RCC. Out of these 12, only one had a positive cytology. Moreover, among the 18 histologically confirmed malignant lesions, cytology was either suspicious or positive in only 3 (17%). These three lesions with suspicious or positive cytology each corresponded to a Bosniak 4 lesion on preoperative imaging. While renal cyst cytology had a high positive predictive value (100%) for malignant lesions, we argue that the high false-negative rate (negative predictive value 29%) likely precludes renal cyst cytology from being an effective tool for determining the malignant potential of complex cystic masses. Interestingly, the cytologic fluid of most malignant cystic lesions did not contain malignant cells detectable in our cytologic analyses. This calls into question whether intraoperative cyst rupture should be considered harmful from an oncologic outcomes perspective. All Bosniak 1–3 lesions in this study did not contain malignant cells in the cyst fluid, though it is possible that the cyst fluid of malignant lesions does have malignant potential that is not detectable on cytologic analysis.
There are overall limited data regarding the oncologic implications of intraoperative renal cyst rupture. In a cohort of patients who experienced intraoperative cyst rupture while undergoing excision of Bosniak 2F–4 cystic renal masses, 75% of the masses were malignant, and there was no difference in 5-year recurrence-free survival, cancer-specific survival, nor overall survival between patients with and without intraoperative cyst spillage (3). Notably, the median follow-up for cyst rupture patients was only 40 months. Conversely, a more recent study found a significantly lower cancer-specific survival and recurrence-free survival in patients who experienced intraoperative cyst rupture (4). These studies were retrospective and represent the best available data regarding oncologic outcomes following intraoperative cyst rupture. Given the consternation associated with intraoperative cyst rupture and the incongruence in the reported outcomes of such an event, there is a need for further investigation of the oncologic implications of inadvertent cyst rupture. At this time, we do not have definitive data regarding the malignant potential of complex renal cyst fluid, and intraoperative cyst rupture should continue to be avoided.
Strengths and limitations
The current study benefits from its clinical practicality. We used a contemporary cytologic analysis that is replicable in most centers and easy to interpret. Limitations include a small sample size and a lack of more sophisticated cytogenetic testing, which may be more sensitive than cytology in determining the malignant potential of renal cyst fluid.
Implications and actions needed
Future direction will include cystic fluid analysis for the presence of cell-free DNA. Cell-free DNA is circulating tumor DNA released from cancer cells into the blood stream or other body fluids and has been previously used for genomic analysis of multiple tumor types. Previous fluid types analyzed for cell-free DNA include urine, pleural fluid, and ascitic fluid (11). Adapting cell-free DNA studies to renal cyst fluid may more accurately predict lesions that have potential for malignant seeding.
Conclusions
Based on routine cytologic analysis, the majority of complex renal cysts contain benign fluid. Bosniak 4 lesions were more likely to have cyst cytology that was suspicious or positive for malignancy. These findings are of interest, as currently the implications of intraoperative cyst rupture are poorly understood, and there are no specific recommendations for postoperative management in the event of cyst rupture. More sophisticated testing, such as cell-free DNA, may provide insight into the malignant potential of renal cyst fluid. Due to the theoretical risk of tumor seeding, standard surgical principles of safe dissection, minimal tumor manipulation, and avoidance of cyst rupture should continue to be the standard of care.
Acknowledgments
A prior abstract version of this study was published in The Journal of Urology as part of the American Urological Association annual meeting supplement (https://www.auajournals.org/doi/10.1097/01.JU.0001008940.44711.d4.18).
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-464/rc
Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-464/dss
Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-464/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-464/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of Mayo Clinic (No. 21-011986) and was approved with “exempt” status due to its minimal risk nature and because no additional interventions beyond usual clinical practice were implemented. Given that this study was classified as institutional review board-exempt, by definition, no informed consent was required from study subjects.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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