Nonneoplastic Renal Parenchymal Changes in Renal Cell Carcinoma With Tumor Thrombus

Introduction: Renal cell carcinoma may extend into the inferior vena cava (IVC) by the tumour thrombus (TT). Renal cell carcinoma with tumour thrombus (RCC/TT) could be associated with multiple collaterals making the surgery in cases of venous involvement very complex and challenging. The pathologic findings of non-neoplastic parenchymal changes in radical nephrectomy specimens of RCC/TT have not been well described. Methods: We conducted a retrospective study of 200 nephrectomies for RCC/TT during eight years. We only included 22 patients who had a full histopathological examination of the resected nephrectomies, including the non-neoplastic parenchymal tissues. Results: Median tumour thrombus level was III (range: II-IV), and median tumour diameter was 9.3 (range: 4-17) cm. Clear cell RCC was the most common tumour diagnosis in this cohort. Non-neoplastic renal pathologies included: (1) Global Glomerulosclerosis (GGS) in 90.9% (1-9% GGS in 15, 10-30% GGS in 4, >30% GGS in 1); (2) Interstitial fibrosis in 90.9% (mild in nine, moderate in nine, severe in 2); (3) Acute tubular injury in 14 (63.6%) patients; (4) Chronic inflammation in 77.3% (5-25% in 10, 26-50% in 7); (5) Arteriolosclerosis in all patients (mild, moderate and severe in 12, 9 and 1 patients, respectively); (6) Arteriolosclerosis: as none in 12, mild in six, moderate in four patients; (7) Focal Segmental Glomerulosclerosis in one patient. Our findings suggest that non-neoplastic parenchymal changes occur in the presence of RCC/TT. Neither tumour extension (via T-stage) nor tumour thrombus level were associated with the degree of any of these non-neoplastic parenchymal changes. Conclusions: Knowledge of the existence of these non-neoplastic parenchymal changes in addition to determining the tumour margin(s) will be important in caring for and early determining whether any specific medical intervention(s) to help preserve renal function in the remaining contralateral kidney becomes warranted.


Introduction
Renal cell carcinoma (RCC) is the most common malignant tumour of the kidney. Over 73,750 new cases were diagnosed in 2020 [1]. RCC has a myriad of presentations, and although infrequently encountered, it may extend by a tumour thrombus into the inferior vena cava (IVC) [2,3]. Chronic obstruction of the IVC by the tumour thrombus (TT) may occur. Such obstruction is often associated with the development of multiple collaterals, making the surgery in cases of venous involvement very complex and challenging [2][3][4][5].
The TT, which originates in the renal parenchyma due to its venous tropism, may extend into the renal vein, the IVC, and ultimately reach the right atrium. Once the TT reaches the IVC, the renal vein will be completely obstructed by the tumour thrombus [6,7]. Chronic obstruction of the renal vein could instigate pathologic non-neoplastic changes in the renal parenchyma. Initial interest in studying the non-neoplastic changes seen in nephrectomies performed for RCC began in 2006 by Bijol et al. [8]. Since then, multiple studies demonstrated a significant correlation between the non-neoplastic pathological findings and postoperative renal function in the contralateral kidney [9,10]. However, non-neoplastic parenchymal changes occurring in RCC/TT have not previously reported. Herein, we report the non-neoplastic pathologic findings in the renal parenchyma of patients with RCC complicated by TT.

Statistics
Descriptive statistical analysis was performed using SPSS 26 (Statistical Package for the Social Sciences), whereby distributions of categorical variables were reported in the form of percentages, and distributions of continuous variables were reported as medians along with corresponding ranges (as measures of dispersion), respectively. Tests of associations of the TT level and degree of tumour extension (via T-stage) with each non-neoplastic parenchymal changes were performed using Pearson (uncorrected) chi-squared tests, using a type I error of 0.05.

Patient Demographics
Over eight years between 2012 and 2020, 22 patients who had a full histopathological examination of the resected nephrectomies to involve the non-neoplastic parenchymal tissues were included in the study. The median age at the time of resection was 57 years (range: 33-79 years). There were five females (22.7%). The comorbidity prevalence was 77.3%, including hypertension in 15 patients (68.2%), diabetes mellitus type II in eight patients (36.4%), coronary artery disease in four patients (18.2%) and smoking history in six patients (27.3%). Table 1 shows the distributions of selected demographic and tumour characteristics.

Pathological Examination
Histological examination revealed RCC clear cell type in 17 patients (77.3%) and papillary type in one patient (4.6%), sarcomatoid type in one patient (4.6%), and unspecified in 3 patients (13.6%). Global Glomerulosclerosis was present in all but two patients (90.9% of patients  Preoperative creatinine had a median of 1.0 (range: 0.47-1.8) mg/dl, and immediate postoperative creatinine median was 1.25mg/dl (range; 0.73-2.26mg/dl). Overall median EBL for all 22 patients was 675mL (range: 50 -5000mL). Intra-operative blood transfusion was required in 11 patients; the median transfusion requirement was five units of packed red blood cells (range: 1-18 units). One patient required cardiopulmonary bypass during the surgery. EBL for the patient who required cardiopulmonary bypass was 850mL (n=1). An analysis of the 22 patients found no significant statistical associations of TT level and degree of tumour extension (via T-stage) with any of the non-neoplastic parenchymal changes (p>.10).

Discussion
The main purpose of this study was to investigate the non-neoplastic parenchymal changes seen in 22 nephrectomy specimens of patients having RCC with TT and to determine whether the presence of the TT, which is known to cause venous congestion, may be associated with a greater likelihood of occurrence of non-neoplastic parenchymal changes. We analyzed the demographic and pathological findings of these 22 patients who received a radical nephrectomy at our institution over eight years, between 2012 and 2020.
We reported the parenchymal changes that were observed more than 5mm away from the tumour. This approach was taken in order to avoid reporting histological changes in the peritumoral parenchyma (≤5mm from tumor edge) in RCC cases which may be related to the mass compression effect of the tumor on surrounding parenchyma, possibly also resulting in a thickening of the small arterioles, narrowing and occlusion of the lumen. A mass compression effect could result in long-term ischemia and inflammatory responses with cellular infiltration that lead to these histological changes seen in peritumoral parenchyma [10,13].
When reviewing the literature, we did not find studies that evaluated non-neoplastic changes in cases of RCC with TT. Additionally, in those studies of RCC without TT reported, it was not specified whether TT was present with any of the tumours (we assumed their absence). Tumour size was noticeably more significant in our patient population when compared with other studies of RCC without TT [14]. All tumours except for one were ≥7 cm, and the median tumour size was 9.3cm. Clear cell RCC subtype was the most prevalent subtype in our study, which is a repeated finding of prior studies of RCC without TT. However, the proportion having the clear cell subtype was somewhat higher in our study, at 77.3% compared to 61% in the study of Noroozinia et al. [14].
Non-neoplastic pathologic changes were found in all of our patient population. Bijol et al. (2004) found that 38.2% of samples had normal non-neoplastic parenchyma, whereas, in our study, all of the samples had some parenchymal injury (GGS, FIBR or ATI) [8]. Another study performed by Noroozinia et al. of 85 patients with RCC demonstrated that 29.3% of patients had normal non-neoplastic parenchyma [14]. This rather significant difference may suggest a relationship between the presence of TT and the appearance of such non-neoplastic changes. However, it is interesting to note that the parenchymal changes did not appear to worsen with higher TT levels (III & IV) or higher T-stage in our study, suggesting that these changes could be associated with the mere presence of TT (i.e., obstruction of the renal vein) regardless of its cranial level.
FIBR was present in 90.9%, whereas, in a study by Garcia-Roig et al., FIBR was present in 17.8% of partial nephrectomies for RCC without TT [11]. GGS, ASCL and chronic inflammation were significantly more prevalent among our patients (90.9% vs 18%, 100% vs 16.8% and 77.3% vs 12.4%, respectively). However, when we evaluated the incidence of moderate to severe significant pathologic findings (such as glomerular sclerosis, interstitial fibrosis and vascular sclerosis), they were present in 72.7% of patients, which was similar to 69.3% of cases seen in RCC without TT [16].
Our study has some limitations. It is a single-centre experience with a small number of patients. A larger study that compares non-neoplastic parenchymal changes in RCC with and without TT would be more able to confirm whether or not a higher incidence of non-neoplastic pathological changes is caused by the presence of tumour thrombus. Furthermore, longer follow-up of these patients is needed to correlate the initial non-neoplastic parenchymal findings from the nephrectomy tissue with any chronic changes observed in renal function of the remaining contralateral kidney over time. While we believe that our sample of 22 patients having complete histopathological information represents a representative sample of the whole cohort of 200 patients with RCC/TT who received a radical nephrectomy at our institution during 2012-2020, we still cannot rule out the possibility that some type of selection bias existed for these 22 cases. Finally, to our knowledge, this is the first study to address non-neoplastic parenchymal changes seen in patients with RCC/TT, which should help the clinician to become more aware of the likely presence of subclinical renal disease and in potentially designing some type of medical intervention to protect the remaining contralateral kidney.

Conclusions
We performed a retrospective chart review on patients who underwent surgical treatment for RCC/TT. We analyzed the non-neoplastic pathologic changes in nephrectomies' parenchyma more than 5 mm from the tumour edge to avoid the local effects of the tumour on adjacent tissue. RCC/TT demonstrated nonneoplastic parenchymal changes, which were noticeably more prevalent than in RCC without TT cases previously reported. These changes may tend to increase with advanced stages of RCC in which renal vein obstruction occurs. Moreover, knowledge of the existence of these pathological changes, in addition to determining the tumour margin(s), will be necessary for caring for and early determining whether any specific medical intervention to help preserve renal function in the remaining contralateral kidney becomes warranted.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. University of Miami Miller School of Medicine issued approval 20200791. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.