Percutaneous microwave ablation on management of hereditary renal cell carcinoma in Von Hippel–Lindau disease

Abstract

Background

The effect of microwave ablation (MWA) for the renal cell carcinoma (RCC) in Von Hippel-Lindau (VHL) disease is unclear.

Objective

To assess the safety, Technique efficacy, renal function and oncological outcome of MWA for RCC in VHL patients.

Methods

Consecutive patients with RCCs in VHL disease treated by MWA were retrospectively collected from November 2009 to October 2020. The technical efficacy rate and complications were assessed. The outcomes of pre- and post-ablative eGFR were compared. The local recurrent-free survival (LRFS), renal-cancer-free survival (RCFS), cancer-specific survival (CSS), overall survival (OS) and complications were presented.

Results

A total of 10 patients (mean age, 39.0 years ± 10.7 [SD]; 3 women) with 28 RCCs (mean tumor size, 3.0 cm ± 0.34; mean tumor volume, 20.7 mL ± 43.3) treated with MWA were included. Th median follow-up time was 52 months(IQR:27-80). The overall technical efficacy rate was 100% with no major complications occurred. No significant statistical difference between pre-ablative and postablative creatinine level (102.0 µmol/L ± 30.4 vs 112.3 µmol/L ± 38.7, p = 0.06), but the pre-ablative eGFR level was significantly higher than the post-ablative eGFR (78.0 mL/(min*1.73m²) ± 28.6 vs 72 mL/(min*1.73m²) ± 31.4, p = 0.04), with the mean decrease of 5.86 ml/(min*1.73m²). The local recurrent-free survival(LRFS) and renal-cancer-free survival (RCFS) were 100% and 60%, respectively. The cancer specifical survival (CSS) and overall survival (OS) were 95.5% and 100%, respectively.

Conclusion

Microwave ablation is a safe and feasible method for the treatment of RCC in VHL disease, preserving renal function and yielding satisfactory oncological outcomes.

Keywords:

• Microwave ablation
• renal cell carcinoma
• overall survival
• von Hippel–Lindau (VHL) disease

Introduction

Von Hippel–Lindau (VHL) disease, an inherited syndrome with a prevalence of 1 in every 36,000 newborns, is a rare condition that follows an autosomal dominant pattern. The syndrome is identified by a significant occurrence of noncancerous or cancerous highly vascular growths and fluid-filled sacs in different body organs, including multiple, recurring renal cell cancers (RCCs), pancreatic neuroendocrine tumors, central nervous system and retina hemangioblastomas, phaeochromocytomas, and additional malignancies [1–3]. Renal cell cancer was observed to have an incidence ranging from 25% to 38%, and it frequently presented in the bilateral kidneys, at young age, and with multifocal foci. Around 70% of patients with VHL usually exhibit bilateral and multifocal RCCs [4], which is the primary factor impacting their estimated lifespan by up to 50% with clear cell RCC [2,4]. Renal function failure and metastatic RCC are the primary factors leading to death in individuals with VHL [5,6]. Meeting the delicate balance between tumor control and maintaining renal function is a difficult task for the reasons aforementioned.

The excellent oncological outcome makes nephron sparing surgery (NSS) the preferred treatment for T1a RCC, being considered the standard. However, in order to attain a negative margin of resection, it is necessary to eliminate the healthy renal tissue surrounding the tumor. Given the possibility of multifocal and recurring RCC in VHL, performing repeated NSS in this situation can be quite difficult from a technical standpoint and may lead to increased complications, including post-operative fibrosis. Therefore, several studies have indicated that thermal ablation techniques like radiofrequency ablation (RFA), cryoablation (CRYO), and irreversible electroporation (IRE) show potential in the treatment of RCCs in VHL syndrome [7–10]. Due to its benefits, microwave ablation (MWA) has gained extensive acceptance in various types of tumors, such as liver, thyroid, kidney, and others. Microwave ablation exhibits elevated intratumoral temperatures (e.g. less affected by the renal rich blood supply), greater ablation volumes, and reduced ablation times in comparison to alternative ablative methods [11,12]. Previous research has shown that percutaneous ablation therapy holds great potential for treating RCCs in individuals with VHL disease [7–10]. However, there has been a lack of investigation into the use of MWA for managing RCCs in VHL patients. In this study, we conducted a retrospective assessment of the technical effectiveness and complications of MWA. We also examined the impact of ablation on renal function before and after the procedure, as well as the oncological outcomes in individuals with VHL disease who underwent treatment for RCCs. As far as we know, this is the initial collection that only employed MWA for the treatment of RCCs in patients with VHL.

Materials and methods

Patients selection

Our hospital’s institutional review board approved this retrospective study(NCT03094949). Prior to ablation, all patients were admitted to our hospital and provided informed consent for MWA. The committees waived the need for informed consent for data publication since no personal information would be disclosed.

From November 2009 to October 2020, information on individuals diagnosed with RCC in VHL was collected in a retrospective manner. The study included individuals who met the following criteria: (1) A clinical diagnosis of VHL with either a family history of VHL and one hemangioblastoma or visceral lesion, or two or more hemangioblastomas or one hemangioblastoma and one type of visceral lesion; (2) All cases of RCC in VHL were treated using MWA [3]. Patients who lost follow-up and those for whom suffered from the other kinds of malignant tumor option were excluded from the study.

Data collection

We gathered demographic and clinical data of patients, encompassing age, gender, body mass index (BMI), tumor complexity, histologic characteristics of the tumor, pre- and post-renal function (creatinine and eGFR levels), duration of ablation, and estimated amount of blood loss.

The calculation of the Charlson Comorbidity Index (CCI) occurred prior to the commencement of treatment [13]. The MWA eligibility criteria included age, presence of other medical conditions, total tumor volume per resection, and assessment of tumor complexity using the R.E.N.A.L score. The RENAL score is determined by various factors, such as the tumor’s dimensions, endophytic or exophytic tumors, the proximity of the tumor to the renal sinus, whether it is described as anterior or posterior, and its position in relation to the polar lines. According to the R.E.N.A.L score system, tumor complexity is classified as low when the RENAL score is between 4 and 6, moderate when it is between 7 and 9, and high when it is between 10 and 12 [14].

Prior to ablation, renal cell carcinomas (RCCs) in the MWA cohort were diagnosed through needle biopsy of the lesion, relying on pathologic findings. Experienced operators assessed the echogenic features, margins, and internal vascularity of each tumor, as well as its maximum diameter (a) and two perpendicular diameters (b and c), using ultrasound. The tumor volume (V) was calculated using the ellipsoid formula V = πabc/6. Also, eGFR was determined using the MDRD equation.

The MWA was performed under ultrasound guidance by three imaging specialists. General anesthesia is recommended to the patient without contraindication. After the anesthesia, the antenna is placed into the tumor. The shortest path between the skin and the target is chosen while avoiding puncture of other organs or vessels. If more than one needle was needed, two antennae directly inserted into the tumor in parallel 1–2.5 cm apart. At each insertion, the tip of the needle is placed in the deepest part of the tumor. Multiple thermal zones are created along the major axis of the needle antenna by simply withdrawing the antenna from the preceding thermal lesion. Due to tumor size, multiple overlapping ablations are usually needed to cover the entire tumor with a safety margin. In general, the microwave energy application is suggested to set at 50–60 W for 5–10 min in a session [15].

Technique success was determined by complete eradication of visible tumors immediately after ablation using three-phase contrast-enhanced ultrasound, computed tomography, or magnetic resonance imaging, as confirmed by subsequent imaging without nodular or crescentic enhancement within the ablated lesion. Patients need be observed on an outpatient basis at 3 months post MWA as the initial follow-up. For the size ≤4cm, we recommended every six months intervals for surveillance. The size ≥4cm, we recommended every three months intervals for monitoring. At the first visit, technique efficacy was determined by the absence of residual tumor.

Local tumor recurrence (LTR) was defined as signs of enhancement within the ablation zone in the imaging examination. New renal cancer (NRC) was defined as signs of enhancement beyond the ablation zone in the treated renal. The primary endpoints were the local recurrent-free survival (LRFS), which means no LTR and the renal cancer-free survival (RCFS), which means no LTR or NRC during the follow-up. The secondary outcomes included overall survival (OS), which measures the proportion of patients who succumbed to any cause, including the progression of ablated lesions and the cancer-specific survival (CSS), which represents the proportion of patients who survived without dying due to the advancement of the ablated lesion. Meanwhile, the complications of MWA and the post-ablative renal function were collected too. As per the Clavien-Dindo classification, significant complications were categorized as grades III and IV occurring within a 30-day period of treatment [16].

Statistical analysis

SPSS statistical software (IBM SPSS, Inc., Chicago, IL, USA, version 25) was conducted to perform the analyses. Frequencies and proportions were computed for categorical variables, whereas medians and interquartile ranges were computed for continuous variables. For continuous variables, either the Wilcoxon rank sum test or t-test was employed. Categorical variables were displayed as total numbers (percentage), and the χ² test or Fisher exact test was employed for analyzing categorical variables. All tests were two-sided, with p < 0.05 indicating a statistically significant difference. The LRFS, RCFS, CSS and OS are presented using Kaplan-Meier curves.

Results

Patients

Ten patients VHL with 28 tumors underwent percutaneous MWA were included after exclusion of two patients (Figure 1). Patients’ clinicopathological characteristics are summarized in Table 1. Three patients underwent unilateral radical nephrectomy and two patients underwent bilateral partial nephrectomy. In our study, 70% (7/10) had an eGFR level below 90 ml/(min*1.73m²) before the operation.

Figure 1. Research flowchart. RCC: renal cell carcinoma; MWA: microwave ablation; VHL: Von Hippel-Lindau disease.

Table 1. General information of patients (n = 10) and tumors (n = 28) included.

Variable	Result
Age at surgery, yr
Mean (range)	39.5 (20–57)
Male/female, n(%)	3(30)/7(70)
Tumor dia, cm
Mean (range)	3.0 (1.7–7.1)
Tumor vol. per session, ml
Mean (range)	20.7 (1.9–174.3)
CCI, n(%)
2	5(50)
3	4(40)
≥4	1(10)
Single kidney, n(%)
No	7(70)
Yes	3(30)
BMI, kg/m^2
Mean (range)	23.8 (18.7–26.3)
R.E.N.A.L score, n(%)
Low complexity	10(35.7)
Intermediate complexity	14(50.0)
High complexity	4 (14.3)
Histology, n(%)
Clear cell	28(100)
eGRF, n(%)
<90 ml/(min*1.73m^2)	3(30)
>90 ml/(min*1.73m^2)	7(70)
Intraprocedure time, h
Mean(range)	1.3(0.8–2.0)
Follow-up time, mon
Median(range)	52(8-97)

CCI: Charlson Comorbidity Index; BMI: Body Mass Index;.

eGFR: estimated Glomerular Filtration Rate.

Treatment outcomes and complications

In the cohort, 28 tumors of 10 patients received 15 ablation sessions, with an average of 1.5 ablation treatment per patient. All the treatments were performed by the ultrasound guidance. The mean tumor diameter was 3.0 cm ± 0.34. The average size of the tumor was 20.7 ml ± 43.3, with median R.E.N.A.L score of 8 (IQR, 7–10). The mean intraprocedural time was 1.3h± 0.43. The technical success and the technical efficacy rates were both 100%.

Table 2 displays the renal functions prior to and following the ablation procedure. There was no significant distinction between pre- and postablative creatinine concentration (102.0 µmol/L ± 30.4 vs 112.3 µmol/L ± 38.7, p = 0.06). However, the pre-ablative eGFR level surpassed the post-ablative level (78.0 ml/(min*1.73m²) ± 28.6 vs 72 ml/(min*1.73m²) ± 31.4, p = 0.04), with an average reduction of 3.50 ml/(min*1.73m²) following each MWA session. Out of all the patients with a single kidney, only one (10%) underwent two sessions of ablation and experienced a reduction of more than 25% in eGFR during the immediate post-MWA laboratory test and we counted as minor complication (10%). As a result, this patient needed a longer hospital stay for renal function monitoring and received medication for treatment. No patient needed temporary dialysis and no major complications occurred because of the treatment. Three patient suffering from fever and another 2 patients were with pain, considered as minor complications (Clavien–Dindo classification I).

Table 2. Renal functions and complications outcomes before and after microwave ablation.

	Pre-ablation	Post-ablation	р value
Creatinine, µmol/L mean (range)	102.0 (47.6-161.0)	112.3 (47.6-196.0)	0.06
eGFR, mL/(min*1.73m2) Mean (range)	78.0 (43.0-153.5)	72.1 (34.0-153.5)	0.04
Major complications, n(%)	0 (0)	0 (0)

Throughout the median 52-month(IQR:27-80)duration of the study, no patient experienced local tumors recurrence. In 4 patients, 5 new renal cancer lesions were observed, with a median duration of 21 months from ablation, the RCFS rate was 60% (Figure 2). All the new lesions were ablated by MWA successfully. 3 individuals experienced the development of cerebellar hemangioblastoma during their subsequent examination, however, none of the patients exhibited metastatic RCC. Patients who received MWA had OS and CSS rates were both 100%, respectively.

Figure 2. Kaplan–Meier survival analysis.

Discussion

Performing surgery to remove RCC in patients with VHL disease who have previously undergone renal surgery is difficult because of various technical and clinical factors. Several prior investigations have indicated that the rate of local recurrence remains high, ranging from 29% to 46% after five years and 84% to 85% after ten years, even following NSS or nephrectomy in individuals with VHL disease [17–19]. The urologists were afraid to postoperative fibrosis after NSS and multifocal and recurrent RCCs of VHL patients. Thus, even after receiving NSS treatment for RCC, patients may experience future renal failure and deterioration of life quality. Due to the aforementioned factors, percutaneous ablations are regarded as the optimal therapy option to circumvent the constraints of surgery [20]. Until 2012, RFA was the initial thermal technology widely employed before the advent of CRYO’s application [21]. After that, the CRYO system, introduced in 2008, has become a more commonly used thermal ablation technique for all T1 cancers, due to its improved ice-ball visibility and higher confidence in the R0 margin [22]. Recently, IRE has been used to treat RCCs near the ureter, collecting system, or adjacent bowels without using heat [10].

Previous research has documented the treatment of RCC with VHL using RFA, CRYO, and IRE [7–10]. However, there is a scarcity of published data on the use of MWA for managing RCCs in VHL. Over the last ten years, there has been the development of MWA devices equipped with internally cooled mechanisms and improved thermal efficiencies, offering superior potential benefits [23]. Many high-quality studies of the MWA used in managing RCCs have been reported, but most of them focused on sporadic, not hereditary RCCs. Here, we presented the series comprising 10 VHL disease patients’ RCCs treated with MWA in our department.

Compared to the earlier studies on the management of RCCs in VHL, our study had similar results with a longer follow-up. Allasia et al. reported that 20 RCCs were successfully treated using RFA in 9 patients with a median follow-up of 102 months. Chan VW et al. reported that fifty-four RCCs were successfully treated in 9 patients using various techniques such as RFA, CRYO, and IRE with a median follow-up of 79 months. All the other writings had a median follow-up of less than 5 years reported similar results. In our series. the oncological durability for LRFS, NRCS overall survival (OS), cancer-specific survival (CSS) over a period of 5 years was 95.5%, 100%, and 100% respectively. This is in line with literature for VHL's long-term oncological durability.

In our study, 8 (80%) patients had a previous NSS and 3 (30%) had a contralateral radical nephrectomy. All the patients were successfully treated with MWA. 4 patients developed subsequent new RCCs, 3 of them experienced one session of ablation and 1 of them has two sessions of ablation. Percutaneous MWA just led to a lighter decrease of renal function after treatment that was normal at discharge. The AUA's recommendation for RCC ≤ 3 cm includes both ablation and partial nephrectomy as treatment options, however, the main difficulty with using ablation as a primary treatment is ensuring complete eradication of the local tumor. While certain studies have indicated the utilization of thermal ablation for salvage therapy following NSS or AT of renal cell carcinoma, there is presently a lack of definitive guidelines regarding the decision to undergo retreatment with ablation in cases of renal tumor recurrence or the emergence of multicentricity. Nevertheless, performing multiple Partial nephrectomy (PN) procedures in this context can present technical difficulties and a greater likelihood of major complications, primarily because of the increased chance of multifocal and recurrent RCCs [24]. Hence, taking into account the progressive decline of healthy tissue that occurs as the tumor’s size or volume increases during surgery, leading to a decrease in kidney function, we conducted MWA on six patients with tumors measuring ≥3cm in diameter. We successfully achieved complete ablation as confirmed by subsequent imaging, and verified the restoration of normal renal function upon discharge. Thus, the impact caused by loss of normal parenchyma on the renal function was harmless in the MWA cohort in present study. Furthermore, we assessed the tumor by the estimated volume derived from imaging add to a single diameter that may be a helpful reference for the pre-ablative plan. Because, especially for the patient with solid kidney or bad renal function, given the recurrence of RCCs and number of de novo lesions in VHL, precise assessment of loss of normal parenchyma depends on the three-dimension not one dimension, if the volume of inactivated tissue (tumor and renal parenchyma) lead to deterioration of renal function, we should ablate limited tissue in one session, and even keep activate surveillance until the opportune time of inactivation.

The incidence of complications associated with percutaneous ablation in the treatment of RCC with VHL ranges from 0 to 8%. Possible complications may involve puncture of the intestines, narrowing of the ureters, uncontrollable hemorrhaging, and the presence of remaining or recurring tumor [25]. Our series did not experience any major complications as a result of the hydrodissection and pyeloperfusion, which effectively shielded the vital organs from thermal harm. The sole individual who experienced a reduction of more than 25% in eGFR had a preexisting low value and possessed a 3.7 cm tumor in their solitary kidney [26]. Thus, the loss of renal parenchyma in the ablation procedure may lead to the transient reduction of renal function, and that recovered in discharge. Compared to surgery, the implementation of MWA does not need the assistance of warm ischemia and blood transfusion, which may lead to renal function impairment [27].

Taken together, our findings suggest that MWA can also yield viable and efficient results in managing the RCCs in individuals with VHL disease. Moreover, the MWA is applicable in cases of more severe kidney function impairment compared to NSS and is suitable for patients who are not suitable candidates for surgery.

One limitation of our study is that it is a retrospective analysis with a limited number of patients. It cannot avoid the selection bias of observational study, although VHL disease is a rare syndrome. However, when it comes to managing the uncommon autosomal dominant inherited syndrome, this research offers a fresh alternative ablative choice for multicentric hereditary renal tumors in individuals with inadequate or limited renal capacity or a past nephrectomy.

Conclusion

Minimally invasive therapy, known as MWA, shows promise for treating RCCs in VHL patients who are at a greater risk of recurring treatments. This therapy allows them to achieve their oncological control while preserving renal function. Nevertheless, due to the insufficient strength of the evidence, we cannot make any definitive inferences solely based on this information. To generate more reliable scientific evidence, it is crucial to carry out a prospective randomized study comparing surgery and MWA in individuals with hereditary or multifocal kidney tumors.

Authors’ contributions

Jiye Chen (First Author): Conceptualization, Methodology, Software, Investigation, Formal Analysis, Writing - Original Draft；Lin Zheng(co-author): Data Curation,

Formal Analysis Writing - Original Draft; Zhang Wei: Data Curation, Writing - Original Draft；Zhen Wang: Visualization, Investigation；Jie Yu: Visualization, Investigation；Ping Liang: Resources, Supervision；

Ethical approval

The studies involving human participants were reviewed and approved by Ethics Committee of PLA General Hospital Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

The datasets analyzed in this manuscript are not publicly available. Requests to access the datasets should be directed to [email protected]

Additional information

Funding

Supported by National Natural Science Foundation of China (12126607)；Supported by the R&D project of Pazhou Lab (Huangpu) under Grant 2023K0607；Health Care Special, GRANT Project No.20BJZ42；Health Care Special, GRANT Project No.22BJZ37.