Patterns of intervention for renal lesions in von Hippel-Lindau disease

Authors


Surena F. Matin, 1515 Holcombe Blvd, Unit 1373, Houston, TX 77030, USA.
e-mail: surmatin@mdanderson.org

Abstract

OBJECTIVE

To review the records of patients at our centre with von Hippel-Lindau (VHL) disease, to determine the incidence of renal cell carcinoma (RCC) and patterns of intervention using minimally invasive therapies.

PATIENTS AND METHODS

Patients with genetically confirmed VHL were evaluated in a multidisciplinary clinical care centre established in 2003. Patients were preferentially offered percutaneous radiofrequency ablation (RFA). Cystic tumours were considered contraindications to RFA, as were larger tumours or extensive multifocality with tumours of >3 cm. These patients had either open partial nephrectomy (OPN) or, in unsalvageable cases, radical nephrectomy.

RESULTS

Of 38 patients with VHL, 16 (42%) were found to have RCC; two with small tumours are under observation. Fourteen of the 16 have had a total of 25 renal interventions, none of whom has progressed to end-stage renal disease. OPN was performed in 15 (60%) cases, including those who had had multiple bilateral procedures; RFA was used in five (20%) cases. After median follow-up of 41 months, local recurrence was detected in 33%; the metastasis-free survival rate was 93.3% and overall survival 87.5%.

CONCLUSIONS

Of patients with VHL, 88% with renal involvement require interventions for their kidneys. OPN is the primary method used, and was successful both as a primary and secondary procedure in 60% of cases. In only 20% was RFA possible due to limitations of current technology. The introduction of protocol-based targeted therapies holds the promise of reducing the number of interventions required for treating VHL.

Abbreviations
VHL

von Hippel-Lindau

RFA

radiofrequency ablation

(O)(P)(L) (R)

(open) (laparoscopic) (partial) (radical) nephrectomy

NSS

nephron-sparing surgery.

INTRODUCTION

von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome occurring in ≈1 in 35 000 births [1,2]. VHL is primarily characterized by the development of retinal and CNS haemangioblastomas, phaeochromocytomas, pancreatic neuroendocrine tumours [3], and clear-cell RCC [4,5]. Additional features include endolymphatic sac tumours [6], pancreatic cysts [3], renal cysts, epididymal cystadenomas in men, and adnexal cystadenomas in women [7]. There is a clear genotype-phenotype correlation in patients with VHL [8]. Clinical manifestations of the disease often begin in childhood and often accelerate into adulthood [4,5]. The median duration of survival for individuals with VHL is ≈50 years [9]. The primary cause of morbidity and mortality for these patients arises from neurological compromise caused by haemangioblastomas, blindness from retinal tumours, and progression of RCC or end-stage renal disease as a result of treatment [4]. Improvement in the ability to manage RCC and CNS complications will clearly affect the morbidity and mortality of VHL.

Of patients with VHL ≈40% have multifocal, bilateral RCC; the lesions may be cystic, solid, or both [10]. On the basis of studies published by the National Cancer Institute, lesions of <3 cm appear to have very low metastatic potential, thus interventions are usually reserved for lesions approaching 3 cm to balance prevention of metastatic progression with the number of interventions [11]. Before the popularity of nephron-sparing surgery (NSS), the primary treatment option was total nephrectomy, which ultimately rendered patients dialysis-dependent [12]. In the past 10 years, NSS with open partial nephrectomy (OPN) has become a standard of care for patients whose renal function is threatened, including patients with VHL [13]. Several published series of patients with sporadic RCC have shown excellent outcomes, with acceptable morbidity and low rates of disease recurrence [14–17]. OPN has also resulted in the preservation of renal function in patients with VHL [12]. In a multicentre study published in 1995, Steinbach et al.[12] evaluated the treatment of patients with VHL and RCC, showing that NSS provided effective initial treatment, with 75% of patients undergoing NSS, and 50% developing local recurrence over time. In a more recent study, Ploussard et al.[18] evaluated 21 patients with VHL to evaluate recurrence-free survival and the interval to repeat surgery. All of these patients had had open NSS or open radical nephrectomy (RN). The advent of ablative therapy has allowed many of these tumours to be approached percutaneously [19]. Probe-based ablation, including cryoablation and radiofrequency ablation (RFA), have recently been shown to be feasible nephron-sparing therapies, with several series showing excellent safety and variable local relapse rates, including in patients with VHL, and have been proposed as first-line treatments for patients with VHL [20–24]. We evaluated the applicability and feasibility of diverse nephron-sparing and minimally invasive therapies for VHL in a contemporary, consecutive series of patients at one institution.

PATIENTS AND METHODS

An Institutional Review Board-approved retrospective chart review protocol was used to evaluate patients with genetically confirmed VHL and RCC treated at our institution from 2003 to 2007. Patient demographics, e.g. age and sex, were recorded, as were the type of genetic defect and the organs affected by VHL. The number and type of interventions were recorded. With little exception, patients were seen by a medical oncologist who directs the VHL Clinical Care Center (E.J.), one of two urological oncologists (S.F.M. and C.G.W.), one interventional radiologist (K.A.) and a clinical genetic counsellor (M.D.).

Patients were considered eligible for treatment of RCC if a dominant renal tumour approached 3 cm, based on the criteria established by the National Cancer Institute [11]. Since 2003, all patients with VHL have been preferentially offered percutaneous RFA as primary therapy unless there was a contraindication to this procedure. Percutaneous cryoablation was not available at our institution during the study period. Contraindications for percutaneous RFA include primarily cystic tumours, tumours adjacent to critical structures (such as the ureter or bowel), and extensive multifocality with multiple large tumours that could not all be managed with percutaneous RFA alone. In such cases, alternative therapies were used. During RFA, the presence of multifocal small tumours was managed depending on the anatomy, such that any other lesions near the index lesion were treated if no additional morbidity or renal parenchymal loss was expected. During OPN, the goal was to remove all visible disease that could be resected safely. Descriptive statistics and percentages are provided; central tendencies are reported as medians.

RESULTS

Thirty-eight patients with genetic or clinical findings of VHL were identified; their median (range) age at diagnosis of VHL was 27 (4–59) years, and there were 20 women (53%) and 18 men (47%). Most of these patients had had more than two procedures for any organ-system involvement by 30 years of age. Of the 38 patients, 16 (42%) were found to have RCC; the demographic and disease status of these 16 patients are listed in Table 1. Two patients (13%) have small lesions, and they are under observation. Among the remaining 14 of 16 patients with RCC, there were 25 interventions on 19 separate renal units over a 17-year period; five (20%) RFA, 15 (60%) OPN, two (in one patient, 8%) laparoscopic PN (LPN), and three (12%) unilateral RN, for a mean (range) of 1.7 (1–5) renal interventions per patient. The interventions used in these 14 patients are shown in Table 2.Figures 1–5 illustrate representative lesions for patients described in Table 2. Patients ineligible for RFA had lesions that exceeded size thresholds, had numerous large tumours, tumours with primarily cystic features, or tumours in areas inaccessible for percutaneous RFA (Figs 1,3,5).

Table 1.  The demographic and clinical characteristics of 16 patients with VHL and RCC
CharacteristicN
Gender
 Men8
 Women8
Age at diagnosis, year31
Other VHL organ manifestations11
 CNS11
 Retinal9
 Adrenal2
 Pancreatic2
 Epididymis1
Table 2.  Renal interventions for 16 patients with VHL and RCC
PatientType, side (L vs R), year and (size of lesion, cm)Reason for most recent renal procedure
ObservationRFALPNOPNRN
  1. L, left; R, right; N/A, information not available; *see Figures; †Patient had nephrectomy for a large symptomatic kidney tumour in the context of metastatic kidney cancer, with a functioning contralateral kidney. She had significant symptomatic relief after nephrectomy and maintained good renal function.

1L (1.3)*    Lesion <3 cm
2L (0.9)    Lesion <3 cm
3 L 2004 (2.2)   Amenable to RFA
4 L 2004 (N/A)   Amenable to RFA
5 L 2005 (3.0)   Amenable to RFA
6   R + L 1993
R + L 2001
R 2003 (N/A)
 Other methods not available (all outside centre)
7   L 2002 (2.8) Not amenable to RFA
8   L 1996 (4.0) Other methods not available
9   R + L 2001 (0.3, 0.3, 0.9, 1.8) Cystic tumours
10   R 2005* (3.5) Location, cystic tumours
11   L 2004 (2.0) Cystic tumours
12    R 1994 (N/A)Outside centre
13   L 1991 (N/A)L 2005 (8.5)*Large tumour
14 L 2002 (4.0)  R 2003 (13.0)Large tumour
15  R +  L 2006*(4.0, 2.8)R 2007 (4.0, 3.5, 1.8) Multiple larger tumours
16 R 2007 (2.8) R 1990 (N/A)
L 1999 (2.4)
 Amenable to RFA
Figure 1.

Patient no. 13 presented with a history of previous left OPN (note the surgical metal clips near the renal hilum) with multiple large left-side renal masses up to 8 cm in an unsalvageable kidney. He had a RN and is awaiting further therapy for his right renal mass.

Figure 2.

Panel (A): patient no. 5 had left percutaneous RFA for two tumours measuring 3.5 (arrowhead) and 3.1 cm (arrow). A 2.5-cm tumour is also seen arising from the right kidney in addition to multiple smaller lesions. Panel B shows the CT results 14 months after percutaneous RFA, showing no enhancement, and shrinkage of the treated lesions. The right renal lesion is under observation and the patient is currently in a phase 2 trial using sunitinib for treating VHL-related lesions.

Figure 3.

Panel A shows the CT from patient no. 10, who presented with a large right cyst and a 4-cm intrarenal medial lower-pole tumour in close apposition to the ureter (arrow). On the left side, multiple smaller solid tumours and cysts were present. The patient had right OPN with resection of all visible disease. Panel B shows the CT 18 months after surgery, with a satisfactory nephron-sparing and oncological outcome on the right side, with interval development of a cyst with a solid nodule on the left (arrowhead). This patient enrolled in a phase 2 trial using sunitinib for treating VHL-related lesions due to haemangioblastomas in the brain and spine.

Figure 4.

(A) Patient no. 1 presented with a 1-cm renal mass in 2001 which has been under observation. (B) 4 years later, repeat CT showed the lesion to be only slightly larger. The patient continues on observation.

Figure 5.

Patient no. 15 had a staged bilateral LPN elsewhere. Top panel: CT 10 months after surgery shows residual tumours bilaterally, the largest on the right, of 5 cm (arrowheads) and 3.5 cm (arrow). The patient had right OPN with resection of all visible disease (four total tumours) and preservation of about half of the kidney. Bottom panel: CT 3 months after surgery, showing no residual index lesions.

The median (mean, range) follow-up of the 15 patients was 41 (58.7, 6–166) months; recurrence data were available for all but one. There was local recurrence in a treated kidney in five patients and distant disease in one. The patients with new renal lesions in previously treated kidneys are detailed in Table 3. In each case, the patient had had surgery as their primary method. There were no cases of in-field treatment failure. The time to developing new lesions was 1–17 years. For patient no. 15, with a 1-year interval between surgery, the additional lesions were apparently not identified at the time of the initial LPN, but we have no information from the outside centre for this initial operation. For patient no. 9, a small lesion was noticed several years after undergoing bilateral PN. This also appears to be a de novo lesion, and is in keeping with the multifocal nature of the disease.

Table 3.  Patients who developed new lesions in a treated kidney
PatientPrimary methodType of recurrenceSecondary procedureInterval to new lesion, yearsReason for method
  1. N/A, information not available.

6OPNBilateral massesOPN 8N/A
9OPNSolitary massObservation 3Small stable lesion
13OPNSolitary massRN14Large tumour
15LPNMultifocal massesOPN 1Multiple lesions
16OPNSolitary massRFA17Small accessible tumours

At the last follow-up, two patients had died, one from metastatic disease and the other of unknown causes; 12 were alive, two of whom have no evidence of RCC recurrence. No patient has progressed to end-stage renal disease.

DISCUSSION

In this study, 88% of patients with VHL and renal involvement required a mean of 1.7 renal interventions during the period studied. Even with the availability of percutaneous ablative therapy, this was possible in only five cases (20%). However, most patients successfully had primary and secondary OPN, with satisfactory preservation of renal function.

At the 2006 International Symposium on VHL, Shuin et al.[25] presented data showing that a patient’s quality of life is inversely related to the number of surgical treatments undergone for the disease. These patients have many lifelong interventions on the brain, spine, eyes, kidneys, pancreas, adrenal glands, and other organs. Each subsequent intervention becomes more complicated due to postoperative scarring. Minimally invasive therapies hold the promise of maintaining quality of life by decreasing surgical trauma and scarring. Percutaneous RFA has been used at our centre since 2001 and has been offered routinely to eligible candidates since 2003 [26]. RFA is ideally suited to patients with solitary, solid, peripheral lesions of <4 cm. For some patients with larger tumours, RFA can also offer favourable results, particularly those with medical indications and patients with exophytic lesions [27,28]. In the present consecutive series of patients, many were not candidates for RFA due to largely cystic renal tumours. Probe-ablation of cystic tumours is generally considered a contraindication because of the risk of tumour seeding. Therefore, until improvements in technology are developed, tumours with primarily cystic components that require intervention continue to be approached via OPN.

LPN has not been routinely offered to patients with VHL, as most of them usually have multiple contraindications, including multiple tumours or previous surgery of the kidney. When multiple tumours are present the technical demands of LPN do not allow feasible resection of all tumours [29]. The rare patient with a single lesion might benefit from LPN. OPN remains the most commonly used primary treatment at our institution for patients with VHL and RCC lesions. OPN has resulted in satisfactory oncological outcomes and renal preservation; however, this treatment is associated with greater pain, longer recovery, and more visible abdominal scarring than LPN [29]. Although cosmesis is typically one of the last priorities with oncological surgery, this is a relevant issue for a patient anticipating many lifelong abdominal and neurosurgical interventions. Repeat renal intervention is generally unavoidable because of the natural history of this disease. In the studies by Steinbach et al.[12] and Ploussard et al.[18], both with >5 years of follow-up, the overall risk of recurrence was 51% and 50%, respectively.

A repeat intervention can be done with percutaneous ablative therapy, OPN, or RN for unsalvageable kidneys. Percutaneous ablative therapy is the preferred method for amenable lesions, as it can be safely delivered to a previously operated kidney, and it is least likely to affect quality of life. Several institutions have published satisfactory intermediate-term data using both cryoablation and RFA, using either percutaneous or laparoscopic approaches [22,30,31]. Laparoscopy after previous open renal surgery can be quite challenging due to postoperative scarring. Repeat OPN on a previously operated kidney can also be more difficult. In several cases a kidney becomes unsalvageable and requires nephrectomy (Fig. 1).

Patients with VHL are faced with many issues related to the timing of an intervention, the extent of the resection, interventions used to treat other organs affected by VHL, and the certainty of repeated intervention resulting from the chronicity of this germline genetic disease. Thus, looking forward, one should consider the future implications of treatments currently being offered. For example, certain steps can be taken at the time of OPN to facilitate future surgical interventions. The perinephric fat overlying the kidney can be preserved on a pedicle based on the lower or upper pole, to cover the kidney at the end of surgery, which might aid with future intervention by providing an additional surgical plane and layer of insulation with surrounding structures. Routine use of an absorbable adhesion barrier, e.g. Seprafilm® (chemically modified sodium hyaluronate/carboxymethylcellulose; Genzyme Corp., Cambridge, MA, USA), can also facilitate future surgical intervention.

The major shortcoming of the current method is that all the interventions in all the organ systems are in reality a temporary mechanical correction of a germline genetic disorder. Ultimately, therapies aimed at treating the underlying defect hold the real promise for reducing the morbidity of lesions, and their intervention. An ongoing trial is investigating the role of sunitinib, an oral small-molecule inhibitor of vascular endothelial growth factor receptors implicated in the pathogenesis of VHL-related lesions [32]. Whether treatment with this agent will decrease the need for invasive procedures or make more individuals eligible for minimally invasive procedures is an important question that awaits investigation.

The present study is limited by its retrospective design and data analysis. Some patients had treatment elsewhere, usually before the diagnosis of VHL, which introduces some heterogeneity in patient management; however, most of these cases occurred before 2003 and are clearly indicated in the Tables. Learning-curve bias, which is always a concern with any new technology, does not appear to have been a confounding factor. RFA has been used at our centre since 2001, with >120 patients with sporadic RCC treated to date, and has been considered routinely for patients with VHL since 2003. LPN has been used successfully with satisfactory outcomes in >150 patients to date. Thus, we do not think that there are biases associated with experience or slow adaptation to new technology.

In conclusion, at a median follow-up of 41 months, 88% of patients with VHL and RCC required intervention, most with nephron-sparing approaches, and all without the need for renal replacement therapy; 80% had some form of nephron-sparing therapy. Minimally invasive NSS benefited 20% of this group. The metastasis-free survival was 93.3% and overall survival 87.5%. In patients with VHL, several interventions are available for preventing disease progression and maintenance of renal function. OPN remains the mainstay of current treatment, but every effort should be made to use percutaneous ablative therapy as first- or second-line treatment, as it decreases short- and long-term treatment-related morbidity in a population that is subjected to multiple organ interventions. Better options for the treatment of cystic tumours are needed, as these are difficult to treat by minimally invasive means. Future research should also focus on the integration of systemic therapy with minimally invasive procedures.

CONFLICT OF INTEREST

None declared.

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