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Renal cancer in von HippelLindau disease and related syndromes

Birke Bausch, Cordula Jilg, Sven Glsker, Alexander Vortmeyer, Niklas Ltzen, Alexandra Anton, CharisEng and Hartmut P.H. Neumann
Abstract | Sporadic and hereditary forms of renal cell carcinoma (RCC), von HippelLindau (VHL) disease and the familial paraganglioma syndromes are closely related in terms of their clinical, molecular, and genetic aspects. Most RCCs occur sporadically and the heritable fraction of RCC is estimated to be just 24%. An understanding of the molecular genetic basis, the disease-specific and gene-specific biology and the clinical characteristics of these cancer syndromes is of utmost importance for effective genetic diagnosis and appropriate treatment. In addition, such insight will improve our understanding of sporadic RCCs. To date, 10 different heritable RCC syndromes have been described. VHL syndrome is the oldest known hereditary RCC syndrome. Similar to VHL disease, phaeochromocytoma is a major manifestation of the paraganglioma syndromes types 1, 3 and 4 in which RCCs have been reported. These syndromes are therefore regarded as VHL-related disorders and are included in this Review. Multifocal tumours, bilateral occurrence, a young age at diagnosis and/or family history are clinical red flags suggestive of hereditary disease and should trigger referral for genetic and molecular analysis. The identification of an underlying genetic alteration enables gene-specific risk assessment and opens up the possibility of a tailored follow-up strategy and specific surveillance protocols as the basis of effective preventive medicine. The important goals of preventive medicine are to increase the life expectancy of affected patients and to improve their quality of life. The study of seemingly rare hereditary syndromes and their susceptibility genes has consistently revealed clues regarding the aetiology and pathogenesis of these diseases, and can aid diagnosis and the development of therapeutics for patients affected by much more common sporadic counterparts.
Bausch, B. etal. Nat. Rev. Nephrol. 9, 529538 (2013); published online 30 July 2013; doi:10.1038/nrneph.2013.144

Introduction
Sporadic and hereditary forms of renal cell carcinoma (RCC), von HippelLindau (VHL) disease and the familial paraganglioma syndromes are closely related in their clini cal and molecular genetic aspects. The majority of RCCs occur sporadically and only 24% of all RCCs are known to have a heritable basis. We suspect, however, that other genes that predispose patients to these diseases are yet to be identified. Importantly, the somatic inactivation of tumour suppressor genes associated with hereditary RCCs is fre quently identified in sporadic renal tumours. Most of our current understanding of tumourigenesis and appropriate treatment strategies for renal cancer comes from the careful investigation of heritable types of RCC. VHL disease is the oldest known, best defined and most common hereditary RCC syndrome. Most sporadic RCCs have been identified to involve somatic inactivation of the VHL gene, which shows how information garnered from the study of rare, inherited disease can improve understanding of their spor adic counterparts. The paraganglioma syndromes have only been recently identified as important syndromes in which RCCs occur. Although VHL disease and the familial
Competing interests The authors declare no competing interests.

paraganglioma syndromes are caused by different germ line mutations, they all involve a final common pathway, namely, the hypoxia-inducible factorvascular endothelial growth factor (HIFVEGF) pathway. An understanding of the molecular genetic background, gene-specific biology and clinical characteristics of these diseases is essential to the development of effective preventive medicine and new treatment options for both hereditary and sporadic tumours. This Review will focus on VHL disease, VHLdisease-specific renal lesions, and related cancer syndromes such as familial paraganglioma syndromes. For the prac ticing clinician, these syndromes together comprise the genetic differential diagnosis of hereditaryRCC.

Renal cell carcinoma

Renal cancer is one of the 10 most common types of cancer in both men and women, and accounts for 23% of all malignant disease in adults.1 The incidence of renal cancer is rising at a rate of approximately 2.5% per year in the USA.2 Only localized disease is associated with long-term survival, with advanced renal cancer having a 2year survival rate of only 18%.3 Approximately onethird of patients with RCC present with metastases at the time offirst diagnosis but an additional 2040% of

Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases (B.Bausch), Department of Diagnostic Radiology (N. Ltzen), and Department of Ophthalmology (A.Anton), University Hospital; Department of Urology (C.Jilg), Department of Neurosurgery, (S.Glsker), and Department of Nephrology and General Medicine (H.P.H.Neumann), Medical University Center, Albert-LudwigsUniversity; Hugstetter Strasse 55, D79106 Freiburg, Germany. Division of Neuropathology, Yale University, New Haven, CT, USA (A. Vortmeyer). Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA (C. Eng). Correspondence to: H.P.H. Neumann hartmut.neumann@ uniklinik-freiburg.de

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Key points
Von HippelLindau (VHL) disease is the oldest known, most common hereditary renal cell carcinoma (RCC) syndrome; it is an autosomal dominant disorder caused by germline mutations in the VHL tumour suppressor gene RCCs are the major neoplasm and leading cause of death in patients with VHLdisease A substantial amount of our knowledge regarding the tumourigenesis and treatment strategies for sporadic renal cancer results from the investigation of heritable types of RCC, particularly VHL-associated RCC At least 50% of sporadic RCCs are associated with somatic inactivation of the VHL gene Sporadic RCCs and the hereditary RCC syndromes, VHL disease and the paraganglioma syndromes differ in their molecular background but involve a common final pathway, the HIFVEGF pathway Improved knowledge of the molecular genetic basis, gene-specific biology and clinical characteristics of VHL disease are contributing to the improved assessment of neoplasia risk and the development of effective preventive strategies and treatment options

patients with initially localized disease develop meta stases. 4,5 Inmore than 90% of cases, tumours show epithelial features and are referred to as RCC. RCC is a hetero geneous disorder, histopathologically subdivided into clear cell RCC (75% of cases), papillary RCC (10% of cases), chromophobe RCC (5% of cases) and collecting duct carcinoma (<1% of cases). Oncocytomas are another common renal epithelial tumour, with an estimated prevalence of 5%, but they are benign neoplasms. The majority of RCCs are sporadic. They occur pre dominantly in the sixth to seventh decade of life, with a mean age at onset of about 64years. Patients with RCC present with local symptoms such as haematuria and flank pain or with systemic signs due to distant meta stases and paraneoplastic events. In general, symptomatic disease is a negative prognostic sign. Fortunately, the diagnosis of the majority of RCCs is incidental and occurs as a result of thewidespread use of abdominalimaging. Only a small proportion of RCCs, approximately 24%, are heritable.6,7 Hereditary tumours are characterized by a younger age at onset and multifocal, bilateral tumour growth. At least 12 different inherited renal cancer syn dromes have been described: VHL disease, paraganglioma syndromes types 1, 3 and 4 (PGL1, PGL3 and PGL4), hereditary leiomyomatosis and RCC (HLRCC), Birt HoggDub syndrome, familial non-syndromic clear-cell RCC, hereditary papillary renal carcinoma type1 (HPRC1) syndrome, hyperparathyroidismjaw tumour syndrome, chromosome 3 translocation, Lynch syndrome and tuber ous sclerosis (Table1).819 These syndromes are character ized by their underlying genetic alteration, the presence of extrarenal syndrome-specific features and the histopatho logical type of RCC. Molecular genetic analysis performed when the particular clinical characteristics are present may lead to the diagnosis of the underlying syndrome. VHL disease is the oldest known and most common RCC susceptibility syndrome. Renal tumours occurring in VHL disease are exclusively clear-cell carcinomas known for their disease-specific biology.2023 The familial para ganglioma syndromes are a group of recently described important heritable RCC syndromes. In contrast to VHL disease, the familial paraganglioma syndromes are
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associated with a variety of histological RCC types such as clear-cell RCCs, chromophobe RCCs and benign onco cytomas.19,24 About 5% of patients with familial RCCs harbour a germline mutation in the SDHB gene without PGL4-associated features.14 RCCs in hereditary disease have an important effect on long-term survival as they are the major component that induces metastases among the spectrum of other neoplasias occurring in VHL disease. Screening guidelines have significantly increased the life expectancy of affected patients with hereditary RCCs.25 Although the fraction of hereditary RCCs is small, insights into their pathogenesisparticularly at a molec ular levelis of utmost importance to the understanding of renal cancer in general. Most of what is known today about the tumourigenesis of renal cancer comes from the careful investigation of hereditary types of RCC, espe cially of the VHL tumour suppressor gene. Some famil ial cancer genes are frequently somatically inactivated in sporadic tumours. At least 50% of sporadic clear-cell RCCs are associated with somatic inactivation of the VHLgene.26,27

VHL disease
VHL disease is the first described, best defined and most common hereditary renal cancer syndrome. It is an autosomal dominant inherited disorder caused by germline mutations in the VHL tumour suppressor gene.28 The incidence of VHL disease is thought to be approximately one in 36,000 births 29,30 and the pen etrance is high. Almost all carriers of VHL mutations express disease-related symptoms by the time they reach 65years of age.31 The mean age at initial diagno sis is about 26years but onset of the disease can occur from early childhood until late adulthood.31 VHL disease is characterized by haem angioblastomas of the retina, brain and spinal cord, phaeochromocytomas, pancreatic cysts, pancreatic neuro endocrine tumours, renal cysts and RCCs, endolymphatic sac tumours of the inner ear, and cyst adenomas of the epididymis and broad ligament (Figures1 and2).21 The syndrome-specific lesions differ in mean age of onset, frequency and in the underlying type of germline mutation. Even within one family, the phenotypic variability of the disease is large (Table2).21,3133 The prototypic lesions of VHL disease include haemangioblastomas of the retina and the central nervous system (Figure2ad).34,35 Retinal haemangio blastomas are often the initial lesion of VHL disease, occurring during early childhood. 35 At least 6070% of VHL-affected patients develop retinal lesions. The majority of central nervous system haemangioblastomas develop in the cerebellum and spinal cord. These haem angioblastomas usually occur in adolescence and patients develop multiple tumours throughout their lifetime. Retinal haem angioblastomas lead to visual field defects or vision loss and the likelihood of these defects increases with age.36 Clinical symptoms of central nervous system haem angioblastomas depend on the site of the tumour. Pain, gait disturbances, ataxia, sensory and occasional motor loss are the most common symptoms experienced by patients with VHL.
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Table 1 | Inherited renal cancer syndromes Disease
VHL disease

Gene
VHL

Chromosome
3p25

Mode of inheritance
AD

RCC subtype
Clear cell RCC

Associated extrarenal lesions

Haemangioblastoma of the brain, spinal cord and retina, pancreatic cysts, pancreatic neuroendocrine tumours, renal cysts Head and neck paraganglioma, phaeochromocytoma, extra-adrenal paraganglioma, gastrointestinal stromal tumours Head and neck paraganglioma, rarely phaeochromocytoma and gastrointestinal stromal tumours Head and neck paraganglioma, phaeochromocytoma and extra-adrenal paraganglioma, gastrointestinal stromal tumours, thyroid carcinoma

Paraganglioma syndromes 1, 3 and 4

SDHD

11q23

AD; penetrant only in children of affected fathers AD

Clear cell RCC

SDHC

1q21

Clear cell RCC Papillary RCC Clear cell RCC Chromophobe RCC Oncocytoma Unique histology with cuboidal cells, eosinophilic cytoplasm, and pleomorphic and sarcomatoid features Papillary RCC type2 Clear cell RCC Chromophobe RCC Hybrid oncocytoma Oncocytoma Clear cell RCC Papillary RCC type1 Papillary RCC Wilms tumour Renal hamartomas Clear cell RCC Transitional cell carcinoma of the renal pelvis and ureter

SDHB

1p35p36

AD

HLRCC BirtHoggDub syndrome

FH BHD/ FCLN

1q2532 17p11.2

AD AD

Cutaneous and uterine leiomyoma, leiomyosarcoma Fibrofolliculomas, lung cysts and pneumothorax, colorectal polyps

Familial non-syndromic clear cell RCC HPRC1 Hyperparathyroidismjaw tumour Chromosome 3 translocation Lynch syndrome

Not known MET 7 CDC73/ HRPT2 Various genes MSH2 MLH1 PMS2 PMS1 MSH6 TSC1 TSC2

Not known 7q31 1q25

Not known AD AD

Not known Not known Parathyroid tumours, fibro-osseous mandibular and maxillary tumours, renal cysts Not known Colorectal cancer, endometrial cancer

Not known 2p22p21 3p21.3 7p22.2 2q31.1 2p16 9q34 16p13.3

AD AD

Tuberous sclerosis

AD

Angiomylipoma Oncocytoma

Hamartoma, angiofibroma and fibroma, rhabdomyoma, angiomyolipoma, epilepsy

Information obtained from references 819. Abbreviations: AD, autosomal dominant; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; HPRC1, hereditary papillary renal carcinoma type1; RCC, renal cell carcinoma; VHL, von HippelLindau.

Renal manifestations of VHL disease

Multiple renal cysts and RCC are common in VHL disease, affecting approximately two-thirds of patients (Table2, Figures1 and 3).21,31 Patients with VHL disease can develop up to several hundred cysts and tumours.37 The cystic lesions are defined as being simple or complex by the Bosniak classification system (Figures1 and 3).20 In general, renal function is not compromised by the development of multiple renal cysts. Although renal cysts are considered benign, their occurrence is associ ated with an increased risk of RCC. Complex renal cysts almost always show dysplastic features in their lining epithelium or show carcinoma insitu.20,38,39 In patients with VHL disease, RCC occurs with an age-dependent frequency ranging from 25% up to 70%. Approximately 70% of VHL-affected patients who survive to the age of 60years develop an RCC.31 Some characteristics of VHL-associated tumours are different to those of sporadic RCCs. The mean age at
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diagnosis of VHL-associated tumours is about 40years, which is 25years earlier than the age at diagnosis for sporadic tumours. 22 VHL-associated tumours dem onstrate exclusively clear cell histology (Figure3c,d); their growth rate varies widely and is a controversial issue. 20,21,23,40,41 Some researchers have reported that the growth rate of VHL-associated tumours is slower thanthat of sporadic tumours whereas others have reported that the growth rates are similar to those in VHL-associated RCCs and that VHL-associated tumours are often multilocular and bilateral. Dysplastic microfoci and carcinoma insitu are typically wide spread in the renal parenchyma of patients with VHLassociated RCCs, which means that the recurrence rate throughout an individuals lifetime is high.42 RCCs are the major neoplasm and leading cause of death in patients with VHL disease. Life expectancy in a patient with VHL disease is low, with an average survival of 50years. The most important risk factors for
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a b

Figure 1 | MRI of renal lesions in von HippelLindau disease. a | Bilateral multiple renal cysts and two renal carcinomas of the left kidney (arrows). b | Left kidney with complicated renal cysts (Bozniak class 3; arrow). a b

identificationof the VHL tumour suppressor gene, the establishment of a cancer registry and the implementa tion of targeted surveillance recommendations. Patients with single candidate tumours such as haemangio blastomas of the central nervous system can be identified early as carriers of VHL mutations and then adequately screened and treated in time.25,28 In contrast to RCCs, haemangioblastomas of the retina and central nervous system develop indepen dently of the underlying germline mutation and are present in almost all VHL-affected patients. The life time risk of RCCs is, however, associated with a specific type of germline mutation. Knowledge of the particular genetic alteration involved can be used to estimate the risk of RCC, and regular screening procedures are avail able even for asymptomatic carriers of mutations. Four VHL disease phenotypes have been defined according to the likelihood of phaeochromocytoma or RCC and charac terized by distinct types of germline VHL muta tions (Table3).4446 VHL disease type1 is characterized by a low risk of phaeochromo cytoma and a high risk of RCC and is commonly associated with truncating muta tions and missense mutations that disrupt the folding of the VHL protein. VHL disease type2 is charac terized by a high risk of phaeochromo c ytoma and is commonly caused by missense mutations in the VHL gene. Depending on the effect of the missense muta tion on the encoded VHL protein, the risk of RCC is high in patients with type2B disease, low in patients with type2A disease and extremely low in those with type2C disease. Large deletions of the VHL gene seem to be associated with a considerable reduction in the risk of RCC.47,48

Paraganglioma syndromes
The familial paraganglioma syndromes types 1 to 4 (PGL14) belong to the group of inherited renal cancer syndromes and to the group of syndromes associated with phaeochromocytoma or paraganglioma.4954 Todate, the underlying molecular genetic alterations of 10dif ferent heritable phaeochromocytoma-associated syn dromes have been identified: neurofibromatosis type1 (NF1), VHL disease, multiple endocrine neoplasia type2 (MEN2), PGL14, and three familial phaeochromocytoma syndromes (TMEM127-gene-associated, MAX-geneassociated and SDHA-gene-associated). The underlying molecular genetic characteristics of PGL types14 were defined in the early 21st century. In addition to being characterized by their molecular genetic basis, these syn dromes are now characterized by the high frequency of associated head and neck paragangliomas, their associa tion with adrenal and extra-adrenal phaeochromocytomas and paragangliomas, their malignant potential and their extra-adrenal manifestations, such as RCC, thyroid carcin oma and gastrointestinal stromal tumours (Figure4). Susceptibility genes for PGL14 encode subunits of succi nate dehydrogenase (SDHB, SDHC, SDHD and SDHAF2), a key respiratory enzyme linking the Krebs cycle with the electron transport chain. Little is known about succinate-dehydrogenase-associated RCCs.
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Figure 2 | Extrarenal and extra-adrenal lesions in von HippelLindau disease. a|Haemangioblastoma of the retina (arrow) and a pair of tortuous feeding vessels. b | Solid cystic cerebellar haemangioblastoma (arrow). c | Spinal haemangioblastoma (arrow) without cysts. d | Spinal haemangioblastoma (thick arrow) with a longitudinal tumour cysts (thin arrows). e | Endolymphatic sac tumour of the inner ear (arrow). f|Multiple pancreatic cysts. g | Pancreatic neuroendocrine tumour (arrow).

decreased life expectancy is a high prevalence of RCC and a high recurrence rate.25,31,32,43 Before improved imaging modalities such as CT scanning were widely available, 1342% of patients with VHL disease died of metastatic RCC.41 A reduc tion in the number of patients with VHL disease dying from metastatic RCC has been achieved following the
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The number of paraganglioma syndrome cases pub lished in the literature is still small. PGL1 is the oldest known and most common familial paraganglioma syn drome. SDHD germline mutations, causative for PGL1, are predominantly associated with the development of head and neck paraganglioma and phaeochromo cytoma (Figure4). Mean age at diagnosis of PGL1associated phaeochromocytoma and paraganglioma is about 25years.52,53,55 Only a single case of PGL1 has been described to be affected by RCC.15,16 This patient pre sented initially with a bilateral carotid body tumour at the age of 17years (left side) and 21years (right side). At 28years he presented with a retroperitoneal extraadrenal paraganglioma and at 31years he presented with a recurrent extra-adrenal paraganglioma. At the age of 45years, a unifocal, clear cell RCC was identi fied. In general, the malignancy rate of PGL1-associated tumours, especially of head and neck paraganglioma and phaeochromocytoma, is low. But the RCC identified in the single patient with PGL1, who carried an SDHD mutation, seemed to be an aggressive form.16 Staging of this patient revealed retroperitoneal, pulmonary and osseous metastases. SDHC -mutation-associated disease, PGL3, is rare and is associated with the development of head and neck para ganglioma (Figure4c). Phaeochromocytomas are rarely identified in patients with PGL3. Biallelic inactivation of the SDHC gene was identified in a clearcell RCC and in a papillary RCC in one PGL3-affected patient with a carotid body tumour. 12 An additional family with a total of six siblings with RCCs, exclusively clear-cell RCCs, harbours a germline SDHC mutation.16 Mean age at RCC diagnosis in these siblings was 47years. Metastatic disease was observed in two family members. Germline mutations in the SDHB gene, resulting in PGL4, predispose patients to the development of extraadrenal phaeochromocytomas with high malignant potential (Figure4b,d,e). The lifetime risk of RCC is approximately 15% in patients with SDHB mutations and is thus the highest among the entity of familial para ganglioma syndromes but considerably lower than the risk in VHL-affected individuals.15 Mean age at RCC diagnosis in carriers of SDHB mutations was 33years and thus close to the mean age at RCC diagnosis for car riers of VHL mutations. PGL4-associated RCCs occur not only in the context of PGL4 syndrome. Up to 5% of inherited RCCs are caused by germline mutations in the SDHB gene without further syndrome-specific lesions.14 In contrast to VHL-associated tumours, tumours asso ciated with mutations in SDH genes have different histo logical subtypes. Clear-cell RCC, chromophobe RCC and benign oncocytoma have been described.19,24 In addi tion to the classic histological subtypes, tumours with a unique, atypical morphology composed of cuboidal cells with eosinophilic cytoplasm and RCCs with pleomorphic and sarcomatoid features have been described.24,56,57 RCCs associated with SDH mutations occur at a younger age than sporadic RCCs, and bilateral tumours are often observed. These RCCs seem to have a more aggressive nature than that of VHL-associated RCCs and have the
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Table 2 | Age-dependent, characteristic lesions of von HippelLindau disease Tumour type and/or location
Haemangioblastoma of the retina Cerebellum Brainstem Spinal cord Endolymphatic sac tumours Renal cysts and renal cell carcinoma Phaeochromocytomas Pancreatic cysts or neuroendocrine tumours

Age range (years)

167 978 1236 1266 1246 1667 458 570

Usual age at diagnosis (years)

1225 1825 2435 2435 2435 2550 1225 2435

Frequency (%)
2560 4472 1025 1350 1025 2560 1020 3570

Information obtained from references 21 and 3133.

tendency to spread when the tumours are still small. The mortality rate of patients with SDH-mutation-associated RCCs seems to be high, with some patients dying of meta static cancer.16 Even for small tumours, surgical resection with a wide margin should be performed.16 The growth kinetics and aggressiveness of SDH associated renal tumours are similar to those observed in HLRCC,16 a disease caused by mutations in the gene encoding fumarate hydratase, another respiratory enzyme that has an important role in the Krebs cycle and the electron transport chain. HLRCC is inherited in an autosomal dominant manner. The characteristic clinical features of HLRCC are multiple cutaneous and uterine leiomyomas and renal tumours. HLRCC seems to be associated with an aggressive form of renal cancer, with metastatic spread occurring in an early stage of the disease; mortality rate is therefore high and death occurs
a b

Figure 3 | Histopathological characteristics of simple and complex renal cysts and renal cell carcinoma in von HippelLindau disease. Haematoxylin and eosin stain. a|Simple renal cyst with proteinaceous fluid. Original magnification 50. b|Complex cystic epithelium. Original magnification 200.c | Clear cell carcinoma with peritumoural fibrosis and inflammation. Original magnification 200.d | Renal cell carcinoma. Original magnification 200.

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Table 3 | The classic VHL phenotypes VHL type
1

Mutation type
Truncating mutations Missense mutations disrupting the folding of the VHL protein Large deletions of the VHL gene

Classic associated lesions

Retinal haemangioblastoma, haemangioblastoma of the brain and spinal cord Pancreatic cysts and neuroendocrine tumours Retinal haemangioblastoma, haemangioblastoma of the brain and spinal cord Pancreatic cysts and neuroendocrine tumours Phaeochromocytoma Retinal haemangioblastoma, haemangioblastoma of the brain and spinal cord Pancreatic cysts and neuroendocrine tumours Retinal haemangioblastoma, haemangioblastoma of the brain and spinal cord Pancreatic cysts and neuroendocrine tumours No associated tumours

Risk of RCC and/or pheochromocytoma

High risk of RCC Low risk of phaeochromocytoma

1B

Low risk of RCC and phaeochromocytoma

2A

Missense mutations

High risk of phaeochromocytoma Low risk of RCC High risk of RCC and phaeochromocytoma

2B

Missense mutations

2C

Missense mutations

High risk of phaeochromocytoma only

Information obtained from references 4446. Abbreviations: RCC, renal cell carcinoma; VHL, von HippelLindau.

at a young age. Renal tumours are frequently of papillary typeII or collecting duct histology.18,58

Genetic background and pathogenesis

Although hereditary RCC, VHL disease and the famil ial paraganglioma syndromes are caused by different germline mutations occurring in different genes, they have a related pathogenic pathway. Most hereditary RCC syndromes are thought to involve the HIFVEGF pathway. Tumours caused by VHL and SDH, for example, are charac terized by a hypoxic transcriptional signature
a b

Figure 4 | Paraganglial tumours. a | Phaeochromocytoma of the right adrenal gland (arrow). b | Interaortocaval extra-adrenal phaeochromocytoma (paraganglioma; arrow). c | Paraganglioma of the right glomus caroticus (carotid body tumour; arrow). d | Thoracic paraganglioma (arrow). e | Paraganglioma of the urinary bladder (arrow). In von HippelLindau disease, most tumours are like those shown in panel a; tumours such as those shown as in panel b occur less frequently. In paraganglioma syndrome type1 (PGL1), adrenal and extra-adrenal tumours (such as those shown in panels b, c, d and e) are most common. In PGL2 and PGL3, paragangliomas of the skull base and neck (as shown in panel c) occur and in PGL4, single extra-adrenal tumours most often occur (mostly of the types shown in panels b, d and e).

indicating reduced oxidoreductase activity and increased hypoxia and angio genesis. RCCs are generally highly vascu larized tumours. The VHL gene is a tumour sup pressor gene. Its gene product, pVHL, has multiple func tions but its most important ability in this context is its regulation of hypoxia response genes. pVHL is part of an important protein complex that regulates the activ ity of hypoxia-induced factors, particularly HIF1 and HIF2. When pVHL is non-functional, HIF is stabilized and under normoxic conditions it accumulates, resulting in high levels of VEGF, which in turn leads to hypervascu larization and angiogenesis. HIF2 is thought to have an additional direct oncogenic effect and can even override the tumour suppressor activity of pVHL.59,60 As mentioned earlier, SDH is an enzyme with a key role in the Krebs cycle and the electron transport chain. Impairment or loss of SDH function results in energy deficits and the production of free oxygen radicals. These hypoxic effects lead to the activation of HIF and thus to hypervascularization, angiogenesis and cell pro liferation.61,62 The same mechanism is responsible for RCC carcinogenesis caused by mutations in the fumarate hydratase (FH) gene in HLRCC. HIF deregulation as a result of VHL, SDH and FH inacti vation is an important feature of tumourigenesis in RCCs,63 but tumourigenesis is a complex process that involves many different pathways. Detailed insights into RCC carcino genesis offer great promise for the development of effective targeted therapies. Drugs such as the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsiroli mus have been shown to indirectly influence HIF levels and seem to have a beneficial effect in RCC.64,65 The VEGF inhibitors sunitinib, sorafenib and pazopanib have also shown success in the treatment of RCCs.6668

Diagnosis of RCC in VHL disease

The incidence of RCC has increased considerably over the past 50years, but so has the 5year survival rate. Both observations are thought to be the result of an increas ing number of localized tumours incidentally detected by ultrasound and abdominal imaging by CT scanning and
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magnetic resonance imaging (MRI). MRI is currently the standard tool for diagnosis and staging of renal lesions in VHL disease. who are not suitable for large surgical intervention. Although some reports on the use of radio-frequency ablation in VHL disease demonstrated some technical limitations, other researchers have shown promising results of this therapy.7981 However, larger clinical trials of radiofrequency ablation in the setting of VHL disease have not yet been performed and this technique therefore needs further evaluation. Renal transplantation has been successfully performed in patients with VHL disease. 81 The risk of recurrent RCCs seems to be low in patients with VHL disease who have undergone renal transplantation, despite the need for immunosuppression, which has the potential to predispose patients to recurrence.82 The long-term prognosis of patients with advanced RCC is poor. These patients often have a limited response to chemotherapy and radiotherapy, but respond better to immunotherapy, biologic or targeted therapy. Immunotherapy with interleukin 2 (IL2) and interferon has been the standard of care for patients with metastatic RCC for years. It is a viable treatment option for patients who have a good Karnofsky performance status, a small number of comorbidities and preserved organ function. Targeted therapies are a potentially effective possibility for patients who are not candidates for IL2 immuno therapy. Based on the improved understanding of HIF VEGF-associated pathogenesis, two different targeted therapy approaches have been developed. One approach is blockade of the intracellular domain of the VEGF recep tor by small molecule tyrosine kinase inhibitors such as sunitinib, sorafenib and pazopanib. The second approach is the binding of circulating VEGF by the monoclonal antibody bevacizumab.66,67,8385 Tailored treatment strat egies are recommended on the basis of the underlying renal cancer, previous treatments, concomitant diseases and the patients health status. The development of tar geted systemic therapies is important not only for treat ment of advanced disease but also for decreasing the size of neoplastic lesions and minimizing the frequency of surgical intervention. Clinical trials investigating the efficacy of sunitinib and pazopanib are ongoing or have demonstrated at least partial tumour response.6668

Treatment of RCC in VHL disease

Treatment of a particular VHL-associated RCC is adjusted to the specific biological features of the tumour in ques tion. Such features include multiple neoplastic foci, young age at diagnosis, and a high tumour recurrence rate with subsequent need for repeated interventions in one kidney. Treatment also depends on the stage of RCC. In VHL disease, however, the decision on when to excise RCCs is mainly made on the basis of the tumour size and the growth kinetics of the corresponding lesion, because both of these parameters determine the risk of metastatic disease.69 Furthermore, the number of malignant renal lesions must be considered in the decision of when to perform renal surgery. Nephron-sparing surgery is cur rently the standard treatment for VHL-associated RCC, although the average VHL kidney is predicted to harbour a large number of microscopic clear cell RCCs and abun dant cysts37 and the number of interventions that are pos sible in one kidney is limited.70 The need for surgery should therefore be considered carefully and the total number of operations kept to a minimum. The therapeutic challenge is to determine the appropriate time at which to intervene. The goals are twofold: to avoid metastatic spread and to delay dialysis for as long as possible. Although meta static potential is present for any size of RCC, in principle, awatch and wait strategy is recommended for lesions smaller than 34cm in diameter because of their low metastatic potential. Several authors have demonstrated the correlation between increasing tumour size and risk of metastases in patients with VHL disease, leading to a general recommendation to use a cut-off diameter of 3cm for surgical resection.7175 As such a therapeutic strategy achieves a recurrence-free survival rate of 76% at 5years and 20% at 8years, it is clear that many patients will face repeat surgery and dialysis. Using a diameter of 4cm as a cut-off level for surgical resection has been shown to result in a probability for second surgery of 21% at 5years and 42% at 10years, with median time to second nephronsparing surgery of 6years.76,77 Gupta etal. have also shown the feasibility of removing RCCs with a diameter larger than 4cm in patients with VHL disease.78 Although the cut-off limit for the decision on when best to remove an RCC is under debate, organ-preserving strategies such as nephron-sparing surgery or partial nephrectomy should be performed whenever technically feasible; the success of such strategies depends highly on the skills of the surgeon. Radical nephrectomy should only be performed in cases of functional organ loss or in cases where the parenchyma remnants are not considered worth preserving. CT-guided cryoablation of VHL-related RCC seems to be becoming an increasingly important therapeutic strategy.79 In principle, cryoablation and radio frequency therapy should be considered for tumours measuring 23cm in diameter that are not close to vessels and bowel structures. Cryoablation is a minimally invasive pro cedure for tumour therapy, particularly for patients
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General aspects of preventive care

The major goals of an effective preventive medicine strategy include an increase in life expectancy and an improvement in quality of life. As mentioned, the average life expectancy of patients with VHL disease is less than 50years,31,32,43 with RCCs being the major cause of death. Quality of life has been shown to correlate inversely with the number of operations a patient has undergone on the central nervous system and the kidneys.86 Hereditary diseases offer the possibility that asympto matic mutation carriers are detected early, which means that syndrome-specific lesions could be detected early by regular screening. For VHL disease, a rare hereditary cancer syndrome that is characterized by a variety of dif ferent lesions affecting multiple organs, such a screening program is complex. To guarantee effective preventive medicine, patients should be screened, diagnosed and
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Table 4 | Age-dependent surveillance protocol for VHL disease Age group
14years

Investigations performed annually

Eye and retinal investigation by ophthalmoscopy Careful clinical investigation with focus on neurological abnormalities: nystagmus, strabismus, white pupil, vision or hearing abnormalities, blood pressure abnormalities

Investigations performed every 2years

None

abdomen and central nervous system are the cornerstones of an interdisciplinary diagnostic protocol. Abdominal ultrasound is recommended annually for patients aged 512years, in order to detect intra-abdominal lesions. As the risk of phaeochromo cytoma, pancreatic cysts and pancreatic neuroendocrine tumours, renal cysts and RCC increases with age, annual abdominal ultrasounds and an MRI scan of the abdomen at least every other year are rec ommended for patients from the age of 12years onwards.

512years

Eye/retinal investigation by ophthalmoscopy Careful clinical investigation with focus on neurological abnormalities: nystagmus, strabismus, white pupil, vision or hearing abnormalities, blood pressure abnormalities Laboratory values, particularly urinary catecholamines and metanephrines Abdominal ultrasound

Complete audiology assessment MRI in case of recurrent ear infections

>12years

Eye/retinal investigation by ophthalmoscopy Careful clinical investigation with focus on neurological abnormalities (nystagmus, strabismus, white pupil, vision or hearing abnormalities, blood pressure abnormalities) Laboratory values, particularly urinary catecholamines and metanephrines Abdominal ultrasound

Complete audiology assessment MRI with contrast of brain and cervical spine with attention to the inner ear and petrous fossa to rule out endolymphatic sac tumours and haemangioblastomas MRI of the abdomen

Abbreviation: VHL, von HippelLindau.

treated at specialized medical centres. Patients with VHL disease undergo an age-related surveillance protocol throughout their life (Table4). A thorough physical exami nation, the measurement of 24h urinary meta nephrines or plasma metanephrines, a regular retinal investigation by ophthalmoscopy and the performance of an MRI of the
Box 1 | Screening day for patients with VHL disease Below is an example of best practice for an interdisciplinary, patient-oriented screening-day schedule 0800h First appointment and interview with the medical expert and coordinator; evaluation of clinical history, physical examination, measurement of the required laboratory values 0900h Contrast-enhanced MRI of the abdomen 1100h Contrast-enhanced MRI of the central nervous system 1400h Ophthalmologic examination with eye and retinal investigation by ophthalmoscopy 1500h Final appointment with the medical expert and coordinator 1600h If necessary, appointment and interview with different specialists (urologist, neurosurgeon, visceral and endocrine surgeon, geneticist)
Abbreviation: VHL, von HippelLindau.

Preventive medicine in VHL disease The cornerstone of preventive medicine for patients with VHL disease is a multidisciplinary approach involving various specialties including genetics, urology, ophthal mology, neuroradiology, neurosurgery, visceral radiology, endocrinology and visceral surgery. When evaluating a patient with VHL in a specialist centre, all relevant prior records, including the actual CTs and MRIs of the central nervous system and CTs and MRIs of the visceral organs, must be reviewed prior to the visit. Best quality imaging is required, and to ensure high fidelity, MRIs must be performed within 1min of injection of intra venous contrast medium. Newly detected tumours may be retrospectively identifiable in earlier images, although they may not be clearly visible in these images because of insuf ficient contrast. All investigations, including eye investi gations, MRI of the central nervous system and MRI of the abdomen as well as ultrasound of the testes should be performed on a single day. Before and after these investiga tions, the patient should have a personal meeting with the principal care provider. Although a face-to-face discussion is preferable, a telephone appointment is an option, in order to keep the invested time for the patient to a minimum. If an operation is deemed to be necessary, a second visit is mandatory, and confirmation of phaeochromocytomas or paragangliomas by nuclear medicine modalities may need to be performed. An example of a well-organized inter disciplinary, patient-oriented screening day for patients with VHL disease is shown (Box1). The surveillance of patients with VHL disease must be performed at regular intervals. Regular screening is essential for the prevention of blindness due to retinal angiomas, as vision reduction occurs without preced ing pain, and once retinal detachment occurs, com plete recovery of vision is rarely achieved. Diagnosed lesions grow slowly, and yearly surveillance is sufficient. Organs free of lesions need to be re-investigated only every23years. Preventive medicine in SDH-associated RCCs A specific protocol for the surveillance of familial para ganglioma syndromes still needs to be established. Although regular follow-up of the paraganglial system is necessary, protocols and the intervals between visits vary from centre to centre. Initial programs should include MRIs of the entire paraganglial systemincluding para ganglia in the skull base and neck area, thorax, abdomen and pelvis. Individuals who have hereditary RCCs but do not show PGL4-associated clinical features should be offered
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molecular genetic screening for germline mutations of the SDHB gene. Because of the relatively high inci dence of RCCs in patients with SDHB mutations and the aggressive nature of these tumours, we feel that an annual routine screening program should be performed so that RCCs are detected at an early stage when they are stilltreatable. the VHL tumour suppressor gene. RCCs are the major neoplasm occurring in patients with VHL disease and the leading cause of death in VHL disease. A detailed understanding of the clinical characteristics, pathology and tumourigenesis of VHL disease and the associated RCCs are the cornerstone of an effective surveillance protocol. Excellent preventive care strategies signifi cantly increase the life expectancy and improve the quality of life of patients with VHL disease. This knowl edge is also of utmost importance for improved under standing of sporadic RCCs and opens up possibilities for new treatment strategies.
Review criteria
MEDLINE and the Cochrane Collaboration Library were searched for the most relevant original articles and review articles on renal cell carcinoma and von HippelLindau disease using the following terms: phaeochromocytoma, paraganglioma, hereditary phaeochromocytoma, hereditary paraganglioma, von HippelLindau disease, paraganglioma syndromes, SDHB, SDHD, SDHC, SDHAF2 germline mutations, renal cell carcinoma, hereditary renal cell carcinoma, renal cell carcinoma in von HippelLindau disease, renal cell carcinoma in paraganglioma syndromes, therapeutic strategies in renal cell carcinoma, and surgery in renal cell carcinoma, and targeted therapies in renal cell carcinoma. No date limits were placed on the search.

Molecular genetic testing

As a guideline, patients with RCC who are younger than 40years, have multifocal RCC within one kidney or bilateral renal tumours, or have a family history of RCC, are candidates for referral to genetics specialists for the consideration of molecular genetic investigation, which should only be performed in association with genetic counselling. The hereditary syndromes discussed in this Review are inherited in an autosomal dominant manner, meaning that the children of mutation carriers have a 50% likelihood of inheriting the mutation. However, it is important to remember that PGL1 caused by germline SDHD mutations will result in disease manifestation only if the mutation is inherited from the father, owing to material imprinting (the parent-of-origin effect).87

Conclusions
VHL disease is the oldest known, most common heredi tary renal cancer syndrome. It is an autosomal domi nant inherited disorder caused by germline mutations in
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