An overview of the management of renal malignancies in von Hippel-Lindau syndrome

Von Hippel-Lindau [VHL] syndrome is a hereditary multisystem cancer syndrome characterized by a wide range of benign and malignant tumours. Renal neoplasms are the commonest solid organ malignancies associated with VHL seen in 25–45% of patients. Management of renal tumours is determined by multiple tumour related and patient-related factors and decision making is often difficult due to its multifocal nature and bilateral involvement. Its tendency for frequent recurrences further complicates the clinical picture. We review the existing literature on the management of renal malignancies in VHL syndrome focussing on observational strategies, minimally invasive approaches, nephron-sparing surgery and radical surgery. Furthermore, we provide the Sri Lanka perspective in the management of renal malignancies in VHL syndrome. Surgeons that manage such patients should be cognizant of extra-renal manifestations of VHL and the importance of a multidisciplinary team and referral pathways. Proper follow-up and selecting patients for suitable as well as minimal interventions such as minimally invasive techniques and nephron-sparing approaches is crucial in the management to provide acceptable cancer control while preserving renal functions. In Sri Lanka, establishing proper referral pathways to dedicated centres with a multidisciplinary team equipped with facilities to deal with renal as well as extra-renal manifestations would improve expertise, quality of care and reduce patient discomfort and default rate. Introduction Von Hippel-Lindau [VHL] syndrome is a hereditary multisystem cancer syndrome with an incidence of 1:36000 live births [1]. Around 4% of renal cancers are estimated to be associated with hereditary cancer syndromes [2]. Of which, VHL was the first hereditary cancer syndrome to be described in association with renal cancers. Correspondence: Umesh Jayarajah E-mail: umeshe.jaya@gmail.com https://orcid.org/0000-0002-0398-5197 Received: 08-09-2021 Accepted: 27-11-2021 DOI: http://doi.org/10.4038/sljs.v39i3.8889 65 Renal neoplasms are the commonest solid organ malignancies associated with VHL seen in 25–45% of patients [2]. It develops due to a germline mutation of the VHL tumour suppressor gene in the short arm of chromosome 3 [3]. VHL has an autosomal dominant inheritance through familial transmission, however, 20% of the patients may develop due to sporadic mutation [4]. Its wide spectrum of clinical manifestations demands clinical attention through multiple disciplines. VHL syndrome is characterized by a wide range of benign and malignant tumours. These include central nervous system [CNS] tumours commonly cerebellar haemangioblastomas, retinal angiomas, renal tumours, pheochromocytomas, endolymphatic sac tumours, pancreatic cystic lesions and neuroendocrine tumours and cystadenomas in the epididymis and broad ligament. Among these tumours, management of renal tumours is determined by multiple tumour related and patient-related factors and decision making is often difficult due to its multifocal nature and bilateral involvement. Its tendency for frequent recurrences further complicates the clinical picture. We review the existing literature on the management of renal malignancies in VHL syndrome. Furthermore, we provide the Sri Lankan perspective in the management of renal malignancies in VHL syndrome. Genetics and pathogenesis Transcription of the VHL gene results in a protein complex responsible for the degradation of hypoxia-inducible factor [HIF]. HIF is otherwise responsible for the enhanced expression of angiogenic and growth factors such as VEGF [angiogenic], PDGF ß [growth] and TGF α [mitogenic] which promote cellular proliferation. So failed degradation of HIF would result in overexpression of the above proteins which ultimately leads to uncontrolled cellular proliferation resulting in carcinogenesis. HIF independent mechanisms also exist which involve loss of extracellular matrix framework via fibronectin which further contributes to carcinogenesis [Figure 1] [5, 6]. The Sri Lanka Journal of Surgery 2021; 39(3): 65-70 This disease is an excellent example of Knudson's two-hit hypothesis [3]. As the mutated gene is already present in one allele of all the cells, the development of the disease requires a second hit on the remaining allele. Either the somatic mutation, deletion, loss of functional variants or methylation of this gene manifests the disease in vulnerable organs. The type of mutation determines the phenotype of the disease [7]. For example, a missense mutation is mostly associated with pheochromocytoma. VHL is classified into two types according to the presence of phaeochromocytoma [7]. The presence of missense mutation is more likely to cause pheochromocytoma as in type 2 [with either high risk or low risk for concurrent renal cell carcinoma] and mostly, the deletion and loss of functional variants would cause type 1 disease with a very low risk of phaeochromocytoma [Table 1]. 66 Screening and diagnosis of VHL syndrome and renal tumours During the process of genetic testing, the altered gene will be detected in peripheral leucocytes almost always in familial inherited cases. In cases with de novo mutation, the mutated gene might not be present in all cell types [mosaicism] and therefore may or may not be seen in peripheral leucocytes. The possibility of transmitting the gene to their offspring is also affected by the presence of a mutation in germ tissues [3, 8]. VHL gene analyses are available with 100% accuracy in experienced laboratories but they are expensive [2]. Clinical criteria for VHL syndrome are very useful in the diagnosis in resource-limited settings [9]. The clinical diagnosis criteria vary with the presence of family history. In patients with a positive family history of VHL, one or more of the following lesions including retinal hemangioblastoma, cerebellar or spinal cord haemangioblastoma, phaeochromocytoma, renal clear cell carcinoma or multiple renal or pancreatic cysts would suffice. In the absence of family history, two or more of the following groups of lesions should be present. These include i] ≥2 retinal, spinal cord or brain hemangioblastomas, or a single hemangioblastoma in addition to visceral organ lesions [multiple renal or pancreatic cysts]; ii] renal clear cell carcinoma; iii] adrenal or extra-adrenal pheochromocytoma and iv] rare lesions including internal lymphoma, papillary cystadenoma of the epididymis and broad ligament, and neuroendocrine tumours of the pancreas [9]. VHL genetic test is warranted in those with atypical manifestations without a family history. Genetic testing should be offered following Figure 1. The genetic basis of carcinogenesis/ tumorigenesis in VHL syndrome Table 1. Classification of VHL syndrome into type 1 and 2 The Sri Lanka Journal of Surgery 2021; 39(3): 65-70 detailed genetic counselling. Renal manifestations are typically characterised by multiple renal cysts and renal tumours often as clear cell renal cell carcinomas [RCC]. Development of renal tumours are rare before the age of 20 years and the mean age is 44 years [10]. Although RCC may present with haematuria, the presence of this symptom indicates a late stage of the disease [11]. Before the utility of computed tomography CT scans, 13-42% of the patients died due to metastatic complications of the disease [11]. At present, mostly, these lesions are detected as part of the surveillance process because the initial presentation is usually of non-renal pathology such as CNS tumours. In patients diagnosed with VHL syndrome, contrastenhanced [CT] of the abdomen and pelvis is usually performed to detect visceral lesions starting at the age of 18 and further frequency of follow up imaging is determined by the disease manifestations [Figure 2] [12]. Renal tumours are seen as simple or complex cystic lesions or solid renal masses [12]. Ultrasonography [USS] or abdominal magnetic resonance imaging [MRI] are useful to further characterise indeterminate lesions. Additional investigations include serum metanephrines for pheochromocytoma and MRI of the brain and ophthalmological assessment for CNS and eye manifestations [2]. Management of renal malignancies in VHL syndrome Management strategy should involve a multidisciplinary approach due to the complexity of the disease and concurrent bilateral involvement [Figure 3]. A high chance of recurrence renders the patients more prone to repeated surgical intervention and subsequent loss of renal function. The management approach for malignant renal tumours is more towards nephron-sparing treatment options keeping in mind to optimally preserve renal parenchyma. Strategies to preserve the functional status of remnant renal tissue should also be considered with optimization of patient comorbidities such as diabetes, hypertension .etc. Nephron sparing surgery [NSS] A major difficulty in decision making is when the patient is having bilateral multifocal tumours, especially if one or more of them are exceedingly large. Nephron sparing approaches should be considered first without compromising the oncological outcome to delay the renal replacement therapy due to surgical intervention. Improvements in imaging modalities such as USS, CT and MRI have contributed to the effective surveillance programme and smaller tumours [< 3cm] with low malignant potential can be safely monitored [11]. The consensus cut off for surgical management in VHL is taken as more than 3 cm [11]. Apart from the size of the tumour, age of diagnosis, synchronous tumours and type of mutation was associated with the rate of growth of VHL tumours are considered in the setting of non-surgical management [13]. A multicentre study of RCC in VHL patients showed higher cancer-specific 5-year survival in 67 Figure 2. CT scan images of renal tumours in VHL syndrome showing bilateral solid and cystic lesions indicated by yellow arrows. Pancreatic cystic lesions are indicated by red ar