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Renal cancer in von Hippel–Lindau disease and related syndromes
Birke Bausch, Cordula Jilg, Sven Gläsker, Alexander Vortmeyer, Niklas Lützen, Alexandra Anton, Charis Eng and Hartmut P. H. Neumann
Abstract | Sporadic and hereditary forms of renal cell carcinoma (RCC), von Hippel–Lindau (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 2–4%. 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. et al. Nat. Rev. Nephrol. 9, 529–538 (2013); published online 30 July 2013; doi:10.1038/nrneph.2013.144

Sporadic and hereditary forms of renal cell carcinoma (RCC), von Hippel–Lindau (VHL) disease and the familial paraganglioma syndromes are closely related in their clinical and molecular genetic aspects. The majority of RCCs occur sporadically and only 2–4% 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 frequently 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 sporadic 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 germline mutations, they all involve a final common pathway, namely, the hypoxia-inducible factor–vascular endothelial growth factor (HIF–VEGF) 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 practicing clinician, these syndromes together comprise the genetic differential diagnosis of hereditary RCC.

Renal cell carcinoma
Renal cancer is one of the 10 most common types of cancer in both men and women, and accounts for 2–3% 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 2‑year survival rate of only 18%.3 Approximately onethird of patients with RCC present with metastases at the time of first diagnosis but an additional 20–40% of

Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases (B. Bausch), Department of Diagnostic Radiology (N. Lützen), and Department of Ophthalmology (A. Anton), University Hospital; Department of Urology (C. Jilg), Department of Neurosurgery, (S. Gläsker), and Department of Nephrology and General Medicine (H. P. H. Neumann), Medical University Center, Albert-LudwigsUniversity; Hugstetter Strasse 55, D‑79106 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@

© 2013 Macmillan Publishers Limited. All rights reserved

VOLUME 9  |  SEPTEMBER 2013  |  529

ataxia.26.35 Retinal haemangioblastomas are often the initial lesion of VHL disease.36 Clinical symptoms of central nervous system haem­ angioblastomas depend on the site of the tumour. 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. papillary RCC (10% of cases). The majority of RCCs are sporadic.25 Although the fraction of hereditary RCCs is small. pancreatic cysts. sensory and occasional motor loss are the most common symptoms experienced by patients with VHL. At least 50% of sporadic clear-cell RCCs are associated with somatic inactivation of the VHL gene. paraganglioma syndromes types 1. VHL disease is the oldest known and most common RCC susceptibility syndrome. www. VHL disease and the paraganglioma syndromes differ in their molecular background but involve a common final pathway.000 births 29. Molecular genetic analysis performed when the particular clinical characteristics are present may lead to the diagnosis of the underlying syndrome. Almost all carriers of VHL mutations express disease-related symptoms by the time they reach 65 years of age.6. In general. the phenotypic variability of the disease is large (Table 2). phaeochromocytomas. are heritable.21 The syndrome-specific lesions differ in mean age of onset. Oncocytomas are another common renal epithelial tumour. PGL3 and PGL4). 35 At least 60–70% of VHL-affected patients develop retinal lesions. hereditary leiomyomatosis and RCC (HLRCC). Renal tumours occurring in VHL disease are exclusively clear-cell carcinomas known for their disease-specific biology. frequency and in the underlying type of germline mutation. chromo­phobe RCC (5% of cases) and collecting duct carcinoma (<1% of cases).34. Birt– Hogg–Dubé syndrome. familial non-syndromic clear-cell RCC. the HIF–VEGF pathway ■■ Improved knowledge of the molecular genetic basis. the familial paraganglioma syndromes are 530  |  SEPTEMBER 2013  |  VOLUME 9 associated with a variety of histological RCC types such as clear-cell RCCs. approximately 2–4%.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.24 About 5% of patients with familial RCCs harbour a germline mutation in the SDHB gene without PGL4-associated features. chromosome 3 translocation. histopathologically subdivided into clear cell RCC (75% of cases). with a mean age at onset of about 64 years. Only a small proportion of RCCs. endolymphatic sac tumours of the inner ear.7 Hereditary tumours are characterized by a younger age at onset and multifocal. The majority of central nervous system haem­angioblastomas develop in the cerebellum and spinal cord.nature. RCC is a hetero­ geneous disorder. Fortunately. occurring during early childhood.31 VHL disease is characterized by haem­ angioblastomas of the retina. and cyst­ adenomas of the epididymis and broad ligament (Figures 1 and 2). These haemangioblastomas usually occur in adolescence and patients develop multiple tumours throughout their lifetime.31 The mean age at initial diagnosis is about 26 years but onset of the disease can occur from early childhood until late adulthood. gait disturbances.5 In more than 90% of cases. best defined and most common hereditary renal cancer syndrome.31–33 The prototypic lesions of VHL disease include haemangioblastomas of the retina and the central nervous system (Figure 2a–d). but they are benign neoplasms. 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.20–23 The familial paraganglioma syndromes are a group of recently described important heritable RCC syndromes. hereditary papillary renal carcinoma type 1 (HPRC1) syndrome. Pain. Retinal haem­ angioblastomas lead to visual field defects or vision loss and the likelihood of these defects increases with age.8–19 These syndromes are characterized by their underlying genetic alteration. Lynch syndrome and tuberous sclerosis (Table 1). bilateral tumour growth. brain and spinal cord. the presence of extrarenal syndrome-specific features and the histopathological type of RCC. It is an autosomal dominant inherited disorder caused by germline mutations in the VHL tumour suppressor gene. 4. They occur predominantly in the sixth to seventh decade of life.30 and the penetrance is high. most common hereditary renal cell carcinoma (RCC) syndrome. Some familial cancer genes are frequently somatically inactivated in sporadic tumours. All rights reserved .21.19. Even within one family. In contrast to VHL disease. 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 metastases. 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 VHL disease ■■ 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. tumours show epithelial features and are referred to as RCC. Screening guidelines have significantly increased the life expectancy of affected patients with hereditary RCCs. 3 and 4 (PGL1. the diagnosis of the majority of RCCs is incidental and occurs as a result of the widespread use of abdominal  © 2013 Macmillan Publishers Limited. with an estimated prevalence of 5%. chromophobe RCCs and benign oncocytomas. hyperparathyroidism–jaw tumour syndrome. renal cysts and RCCs. especially of the VHL tumour suppressor gene. At least 12 different inherited renal cancer syndromes have been described: VHL disease.REVIEWS Key points ■■ Von Hippel–Lindau (VHL) disease is the oldest known. pancreatic neuro­ endocrine tumours.27 VHL disease VHL disease is the first described. Most of what is known today about the tumourigenesis of renal cancer comes from the careful investigation of hereditary types of RCC. insights into their pathogenesis—particularly at a molecular level—is of utmost importance to the understanding of renal cancer in general. symptomatic disease is a negative prognostic sign.28 The incidence of VHL disease is thought to be approximately one in 36.

gastrointestinal stromal tumours Head and neck paraganglioma.20 In general. renal function is not compromised by the development of multiple renal cysts. RCC. 3 and 4 SDHD 11q23 AD. RCC occurs with an age-dependent frequency ranging from 25% up to 70%.23. 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.39 In patients with VHL disease. renal cell carcinoma. with an average survival of 50 years. angiofibroma and fibroma. fibro-osseous mandibular and maxillary tumours. eosinophilic cytoplasm. epilepsy Information obtained from references 8–19.42 RCCs are the major neoplasm and leading cause of death in patients with VHL disease. rarely phaeochromocytoma and gastrointestinal stromal tumours Head and neck paraganglioma.1 2p16 9q34 16p13. phaeochromocytoma.REVIEWS 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. Life expectancy in a patient with VHL disease is low. Abbreviations: AD.20.2 2q31.2 AD AD Cutaneous and uterine leiomyoma. The mean age at NATURE REVIEWS | NEPHROLOGY diagnosis of VHL-associated tumours is about 40 years. Renal manifestations of VHL disease Multiple renal cysts and RCC are common in VHL disease. gastrointestinal stromal tumours. All rights reserved . which is 25 years earlier than the age at diagnosis for sporadic tumours. hereditary leiomyomatosis and renal cell carcinoma. renal cysts Head and neck paraganglioma. extra-adrenal paraganglioma. 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.21. renal cysts Not known Colorectal cancer.37 The cystic lesions are defined as being simple or complex by the Bosniak classification system (Figures 1 and 3).31 Some characteristics of VHL-associated tumours are different to those of sporadic RCCs. and pleomorphic and sarcomatoid features Papillary RCC type 2 Clear cell RCC Chromophobe RCC Hybrid oncocytoma Oncocytoma Clear cell RCC Papillary RCC type 1 Papillary RCC Wilms tumour Renal hamartomas Clear cell RCC Transitional cell carcinoma of the renal pelvis and ureter SDHB 1p35–p36 AD HLRCC Birt–Hogg–Dubé syndrome FH BHD/ FCLN 1q25–32 17p11.3 7p22. their occurrence is associated with an increased risk of RCC. HPRC1. leiomyosarcoma Fibrofolliculomas. von Hippel–Lindau. autosomal dominant. Approximately 70% of VHL-affected patients who survive to the age of 60 years develop an RCC.21. spinal cord and retina. Figures 1 and 3).41 Some researchers have reported that the growth rate of VHL-associated tumours is slower than that 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. angiomyolipoma. endometrial cancer Not known 2p22–p21 3p21. Although renal cysts are considered benign. pancreatic neuroendocrine tumours. 20. 22 VHL-associated tumours demonstrate exclusively clear cell histology (Figure 3c. thyroid carcinoma Paraganglioma syndromes 1. VHL. their growth rate varies widely and is a controversial issue. pancreatic cysts.40.38. which means that the recurrence rate throughout an individual’s lifetime is high. Dysplastic microfoci and carcinoma in situ are typically widespread in the renal parenchyma of patients with VHLassociated RCCs. hereditary papillary renal carcinoma type 1.d). affecting approximately two-thirds of patients (Table 2.3 AD AD Tuberous sclerosis AD Angiomylipoma Oncocytoma Hamartoma.31 Patients with VHL disease can develop up to several hundred cysts and tumours. The most important risk factors for VOLUME 9  |  SEPTEMBER 2013  |  531 © 2013 Macmillan Publishers Limited. Complex renal cysts almost always show dysplastic features in their lining epithelium or show carcinoma in situ. lung cysts and pneumothorax. rhabdomyoma. phaeochromocytoma and extra-adrenal paraganglioma. HLRCC.

d | Spinal haemangioblastoma (thick arrow) with a longitudinal tumour cysts (thin arrows). haemangioblastomas of the retina and central nervous system develop independently of the underlying germline mutation and are present in almost all VHL-affected patients. SDHC. SDHD and SDHAF2). Large deletions of the VHL gene seem to be associated with a considerable reduction in the risk of RCC.47. Four VHL disease phenotypes have been defined according to the likelihood of phaeochromocytoma or RCC and charac­ terized by distinct types of germline VHL mutations (Table 3). such as RCC. associated with a specific type of germline mutation. f | Multiple pancreatic cysts. Patients with single candidate tumours such as haemangioblastomas of the central nervous system can be identified early as carriers of VHL mutations and then adequately screened and treated in time. g | Pancreatic neuroendocrine tumour (arrow).44–46 VHL disease type 1 is characterized by a low risk of phaeochromo­ cytoma and a high risk of RCC and is commonly associated with truncating mutations and missense mutations that disrupt the folding of the VHL protein. c | Spinal haemangioblastoma (arrow) without cysts.31.25. their association with adrenal and extra-adrenal phaeochromocytomas and paragangliomas.43 Before improved imaging modalities such as CT scanning were widely available. these syndromes are now characterized by the high frequency of associated head and neck paragangliomas. b | Left kidney with ‘complicated’ renal cysts (Bozniak class 3.REVIEWS a b Figure 1 | MRI of renal lesions in von Hippel–Lindau disease.49–54 To date. VHL disease. The underlying molecular genetic characteristics of PGL types 1–4 were defined in the early 21st century. thyroid carcinoma and gastrointestinal stromal tumours (Figure 4).25.48 Paraganglioma syndromes The familial paraganglioma syndromes types 1 to 4 (PGL1–4) belong to the group of inherited renal cancer syndromes and to the group of syndromes associated with phaeochromocytoma or © 2013 Macmillan Publishers Limited. Susceptibility genes for PGL1–4 encode subunits of succinate dehydrogenase (SDHB. multiple endocrine neoplasia type 2 (MEN2). e | Endolymphatic sac tumour of the inner ear (arrow). however. PGL1–4. Little is known about succinate-dehydrogenase-associated RCCs. the underlying molecular genetic alterations of 10 different heritable phaeochromocytoma-associated syndromes have been identified: neurofibromatosis type 1 (NF1). VHL disease type 2 is characterized by a high risk of phaeochromo­ c ytoma and is commonly caused by missense mutations in the VHL gene. low in patients with type 2A disease and extremely low in those with type 2C disease. a key respiratory enzyme linking the Krebs cycle with the electron transport chain.28 In contrast to RCCs. Knowledge of the particular genetic alteration involved can be used to estimate the risk of RCC. the establishment of a cancer registry and the implementation of targeted surveillance recommendations. the risk of RCC is high in patients with type 2B disease. b | Solid cystic cerebellar haemangioblastoma (arrow). MAX-geneassociated and SDHA-gene-associated). and three familial phaeochromo­cytoma syndromes (TMEM127-gene-associated.32. decreased life expectancy is a high prevalence of RCC and a high recurrence rate.41 A reduction in the number of patients with VHL disease dying from metastatic RCC has been achieved following the 532  |  SEPTEMBER 2013  |  VOLUME 9  . Depending on the effect of the missense mutation on the encoded VHL protein. 13–42% of patients with VHL disease died of metastatic RCC.nature. a | Haemangioblastoma of the retina (arrow) and a pair of tortuous feeding vessels. All rights reserved f g Figure 2 | Extrarenal and extra-adrenal lesions in von Hippel–Lindau disease. The lifetime risk of RCCs is. a | Bilateral multiple renal cysts and two renal carcinomas of the left kidney (arrows). a b c d e identification of the VHL tumour suppressor gene. and regular screening procedures are available even for asymptomatic carriers of mutations. their malignant potential and their extra-adrenal manifestations. In addition to being characterized by their molecular genetic basis. www. arrow).

56. Haematoxylin and eosin stain. These RCCs seem to have a more aggressive nature than that of VHL-associated RCCs and have the NATURE REVIEWS | NEPHROLOGY © 2013 Macmillan Publishers Limited.14 In contrast to VHL-associated tumours. 12 An additional family with a total of six siblings with RCCs.55 Only a single case of PGL1 has been described to be affected by RCC. another respiratory enzyme that has an important role in the Krebs cycle and the electron transport chain. PGL3. causative for PGL1. HLRCC is inherited in an autosomal dominant manner. with some patients dying of metastatic cancer. atypical morphology composed of cuboidal cells with eosinophilic cytoplasm and RCCs with pleo­morphic and sarcomatoid features have been described. b | Complex cystic epithelium. All rights reserved Table 2 | Age-dependent. are predominantly associated with the development of head and neck paraganglioma and phaeochromocytoma (Figure 4).16 This patient presented initially with a bilateral carotid body tumour at the age of 17 years (left side) and 21 years (right side). HLRCC seems to be associated with an aggressive form of renal cancer. PGL1 is the oldest known and most common familial paraganglioma syndrome. Original magnification ×200. c | Clear cell carcinoma with peritumoural fibrosis and inflammation. resulting in PGL4. At 28 years he presented with a retroperitoneal extraadrenal paraganglioma and at 31 years he presented with a recurrent extra-adrenal paraganglioma. tumours with a unique. Mean age at diagnosis of PGL1associated phaeochromocytoma and paraganglioma is about 25 years. The lifetime risk of RCC is approximately 15% in patients with SDHB mutations and is thus the highest among the entity of familial paraganglioma syndromes but considerably lower than the risk in VHL-affected individuals. tendency to spread when the tumours are still small. In general. clear cell RCC was identified.52.57 RCCs associated with SDH mutations occur at a younger age than sporadic RCCs. seemed to be an aggressive form. Original magnification ×200. is low. Clear-cell RCC. a | Simple renal cyst with proteinaceous fluid. and bilateral tumours are often observed.16 The growth kinetics and aggressiveness of SDH associated renal tumours are similar to those observed in HLRCC.15 Mean age at RCC diagnosis in carriers of SDHB mutations was 33 years and thus close to the mean age at RCC diagnosis for carriers of VHL mutations. Phaeochromocytomas are rarely identified in patients with PGL3.e). Up to 5% of inherited RCCs are caused by germline mutations in the SDHB gene without further syndrome-specific lesions. a unifocal.24. surgical resection with a wide margin should be performed.16 a disease caused by mutations in the gene encoding fumarate hydratase. with metastatic spread occurring in an early stage of the disease. especially of head and neck paraganglioma and phaeochromocytoma. SDHC -mutation-associated disease.d. Original magnification ×200.16 Mean age at RCC diagnosis in these siblings was 47 years. VOLUME 9  |  SEPTEMBER 2013  |  533 . is rare and is associated with the development of head and neck para­ ganglioma (Figure 4c). At the age of 45 years. tumours associated with mutations in SDH genes have different histological subtypes. SDHD germline mutations. characteristic lesions of von Hippel–Lindau 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) 1–67 9–78 12–36 12–66 12–46 16–67 4–58 5–70 Usual age at diagnosis (years) 12–25 18–25 24–35 24–35 24–35 25–50 12–25 24–35 Frequency (%) 25–60 44–72 10–25 13–50 10–25 25–60 10–20 35–70 Information obtained from references 21 and 31–33.24 In addition to the classic histological subtypes.15.16 Staging of this patient revealed retroperitoneal.19. predispose patients to the development of extraadrenal phaeochromocytomas with high malignant potential (Figure 4b.16 Even for small tumours. Germline mutations in the SDHB gene. who carried an SDHD mutation. Metastatic disease was observed in two family members. But the RCC identified in the single patient with PGL1.REVIEWS The number of paraganglioma syndrome cases published in the literature is still small. pulmonary and osseous metastases. The characteristic clinical features of HLRCC are multiple cutaneous and uterine leiomyomas and renal tumours. the malignancy rate of PGL1-associated tumours. d | Renal cell carcinoma. harbours a germline SDHC mutation. PGL4-associated RCCs occur not only in the context of PGL4 syndrome. 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. The mortality rate of patients with SDH-mutation-associated RCCs seems to be high. mortality rate is therefore high and death occurs a b c d Figure 3 | Histopathological characteristics of simple and complex renal cysts and renal cell carcinoma in von Hippel–Lindau disease. Original magnification ×50. chromophobe RCC and benign oncocytoma have been described.53. exclusively clear-cell RCCs.

b | Interaortocaval extra-adrenal phaeochromocytoma (paraganglioma. d and e) are most common. e | Paraganglioma of the urinary bladder (arrow). arrow). adrenal and extra-adrenal tumours (such as those shown in panels b. Detailed insights into RCC carcinogenesis offer great promise for the development of effective targeted therapies. they have a related pathogenic pathway. These hypoxic effects lead to the activation of HIF and thus to hypervascularization.61. SDH is an enzyme with a key role in the Krebs cycle and the electron transport chain. single extra-adrenal tumours most often occur (mostly of the types shown in panels b. In PGL2 and PGL3. 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 Retinal haemangioblastoma. The VHL gene is a tumour suppressor gene. a | Phaeochromocytoma of the right adrenal gland (arrow).59. von Hippel–Lindau. particularly HIF‑1α and HIF‑2α. Both observations are thought to be the result of an increasing number of localized tumours incidentally detected by ultrasound and abdominal imaging by CT scanning and www.nature. VHL disease and the familial paraganglioma syndromes are caused by different germline mutations occurring in different genes. In von Hippel–Lindau disease. which in turn leads to hypervascularization and angio­genesis. Its gene product.REVIEWS 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 534  |  SEPTEMBER 2013  |  VOLUME 9  © 2013 Macmillan Publishers Limited. paragangliomas of the skull base and neck (as shown in panel c) occur and in PGL4. are charac­ terized by a hypoxic transcriptional signature a b c d e Figure 4 | Paraganglial tumours. arrow). d and e).63 but tumourigenesis is a complex process that involves many different pathways. Tumours caused by VHL and SDH. tumours such as those shown as in panel b occur less frequently. resulting in high levels of VEGF. All rights reserved . sorafenib and pazopanib have also shown success in the treatment of RCCs. RCCs are generally highly vascu­ larized tumours. When pVHL is non-functional.58 Genetic background and pathogenesis Although hereditary RCC. HIF is stabilized and under normoxic conditions it accumulates. SDH and FH inactivation is an important feature of tumourigenesis in RCCs. most tumours are like those shown in panel a.66–68 Diagnosis of RCC in VHL disease The incidence of RCC has increased considerably over the past 50 years. 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 44–46. HIF‑2α is thought to have an additional direct oncogenic effect and can even override the tumour suppressor activity of pVHL. c. pVHL. HIF deregulation as a result of VHL. but so has the 5‑year survival rate. Renal tumours are frequently of papillary type II or collecting duct histology. Most hereditary RCC syndromes are thought to involve the HIF–VEGF pathway. pVHL is part of an important protein complex that regulates the activity of hypoxia-induced factors. Drugs such as the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus have been shown to indirectly influence HIF levels and seem to have a beneficial effect in RCC. renal cell carcinoma.65 The VEGF inhibitors sunitinib. indicating reduced oxidoreductase activity and increased hypoxia and angio­ genesis. at a young age. In paraganglioma syndrome type 1 (PGL1).64. Abbreviations: RCC. angiogenesis and cell proliferation. d | Thoracic paraganglioma (arrow). Impairment or loss of SDH function results in energy deficits and the production of free oxygen radicals. for example.60 As mentioned earlier. has multiple functions but its most important ability in this context is its regulation of hypoxia response genes. haemangioblastoma of the brain and spinal cord Pancreatic cysts and neuroendocrine tumours Phaeochromocytoma Retinal haemangioblastoma. c | Paraganglioma of the right glomus caroticus (carotid body tumour.62 The same mechanism is responsible for RCC carcinogenesis caused by mutations in the fumarate hydratase (FH) gene in HLRCC.18. VHL.

For VHL disease. however. CT-guided cryoablation of VHL-related RCC seems to be becoming an increasingly important therapeutic strategy.71–75 As such a therapeutic strategy achieves a recurrence-free survival rate of 76% at 5 years and 20% at 8 years. a rare hereditary cancer syndrome that is characterized by a variety of different lesions affecting multiple organs. cryoablation and radio frequency therapy should be considered for tumours measuring 2–3 cm in diameter that are not close to vessels and bowel structures.31. patients should be screened. despite the need for immunosuppression. previous treatments.86 Hereditary diseases offer the possibility that asymptomatic mutation carriers are detected early.70 The need for surgery should therefore be considered carefully and the total number of operations kept to a minimum. Immunotherapy with interleukin 2 (IL‑2) and interferon has been the standard of care for patients with metastatic RCC for years. the number of malignant renal lesions must be considered in the decision of when to perform renal surgery. with median time to second nephronsparing surgery of 6 years. two different targeted therapy approaches have been developed. Several authors have demonstrated the correlation between increasing tumour size and risk of metastases in patients with VHL disease. The second approach is the binding of circulating VEGF by the monoclonal antibody bevacizumab. 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.43 with RCCs being the major cause of death. 81 The risk of recurrent RCCs seems to be low in patients with VHL disease who have undergone renal transplantation. in principle. young age at diagnosis. such a screening program is complex.77 Gupta et al. All rights reserved . the average life expectancy of patients with VHL disease is less than 50 years. The therapeutic challenge is to determine the appropriate time at which to intervene. As mentioned.REVIEWS magnetic resonance imaging (MRI). These patients often have a limited response to chemotherapy and radiotherapy. because both of these parameters determine the risk of metastatic disease. concomitant diseases and the patient’s health status. a ‘watch and wait’ strategy is recommended for lesions smaller than 3–4 cm in diameter because of their low metastatic potential.78 Although the cut-off limit for the decision on when best to remove an RCC is under debate. the success of such strategies depends highly on the skills of the surgeon. It is a viable treatment option for patients who have a good Karnofsky performance status. Treatment also depends on the stage of RCC. Although metastatic potential is present for any size of RCC. particularly for patients NATURE REVIEWS | NEPHROLOGY 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. Based on the improved understanding of HIF– VEGF-associated pathogenesis. it is clear that many patients will face repeat surgery and dialysis.76. diagnosed and VOLUME 9  |  SEPTEMBER 2013  |  535 © 2013 Macmillan Publishers Limited. Although some reports on the use of radio-frequency ablation in VHL disease demonstrated some technical limitations. To guarantee effective preventive medicine. which means that syndrome-specific lesions could be detected early by regular screening. have also shown the feasibility of removing RCCs with a diameter larger than 4 cm in patients with VHL disease. although the average VHL kidney is predicted to harbour a large number of microscopic clear cell RCCs and abundant cysts37 and the number of interventions that are possible in one kidney is limited.69 Furthermore.82 The long-term prognosis of patients with advanced RCC is poor. One approach is blockade of the intracellular domain of the VEGF receptor by small molecule tyrosine kinase inhibitors such as sunitinib.32.66.79–81 However. Clinical trials investigating the efficacy of sunitinib and pazopanib are ongoing or have demonstrated at least partial tumour response. Using a diameter of 4 cm as a cut-off level for surgical resection has been shown to result in a probability for second surgery of 21% at 5 years and 42% at 10 years. The development of targeted systemic therapies is important not only for treatment of advanced disease but also for decreasing the size of neoplastic lesions and minimizing the frequency of surgical intervention. In VHL disease. but respond better to immunotherapy. Targeted therapies are a potentially effective possibility for patients who are not candidates for IL‑2 immunotherapy. sorafenib and pazopanib. which has the potential to predispose patients to recurrence.67. The goals are twofold: to avoid metastatic spread and to delay dialysis for as long as possible. who are not suitable for large surgical intervention. larger clinical trials of radio­frequency ablation in the setting of VHL disease have not yet been performed and this technique therefore needs further evaluation. 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. MRI is currently the standard tool for diagnosis and staging of renal lesions in VHL disease. a small number of comorbidities and preserved organ function. leading to a general recommendation to use a cut-off diameter of 3 cm for surgical resection. Radical nephrectomy should only be performed in cases of functional organ loss or in cases where the parenchyma remnants are not considered worth preserving. Renal transplantation has been successfully performed in patients with VHL disease. Nephron-sparing surgery is currently the standard treatment for VHL-associated RCC. organ-preserving strategies such as nephron-sparing surgery or partial nephrectomy should be performed whenever technically feasible. and a high tumour recurrence rate with subsequent need for repeated interventions in one kidney. biologic or targeted therapy. other researchers have shown promising results of this therapy.79 In principle. Such features include multiple neoplastic foci. Cryoablation is a minimally invasive pro­ cedure for tumour therapy.66–68 Treatment of RCC in VHL disease Treatment of a particular VHL-associated RCC is adjusted to the specific biological features of the tumour in question.83–85 Tailored treatment strategies are recommended on the basis of the underlying renal cancer.

A thorough physical examination. the measurement of 24 h urinary meta­ nephrines or plasma metanephrines. patient-oriented screening day for patients with VHL disease is shown (Box 1). Before and after these investigations. All investigations. As the risk of phaeochromo­ cytoma. although they may not be clearly visible in these images because of insufficient contrast. particularly urinary catecholamines and metanephrines Abdominal ultrasound Complete audiology assessment MRI in case of recurrent ear infections >12 years Eye/retinal investigation by ophthalmoscopy Careful clinical investigation with focus on neurological abnormalities (nystagmus. must be reviewed prior to the visit. Newly detected tumours may be retrospectively identifiable in earlier images. protocols and the intervals between visits vary from centre to centre. and confirmation of phaeochromocytomas or paragangliomas by nuclear medicine modalities may need to be performed. Patients with VHL disease undergo an age-related surveillance protocol throughout their life (Table 4). endocrinology and visceral surgery. annual abdominal ultrasounds and an MRI scan of the abdomen at least every other year are recommended for patients from the age of 12 years onwards. Organs free of lesions need to be re-investigated only every 2–3 years. visceral and endocrine surgeon. Preventive medicine in VHL disease The cornerstone of preventive medicine for patients with VHL disease is a multidisciplinary approach involving various specialties including genetics. a telephone appointment is an option. 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. Although a face-to-face discussion is preferable. thorax. neuroradiology. appointment and interview with different specialists (urologist. and to ensure high fidelity. Although regular follow-up of the paraganglial system is necessary. strabismus. measurement of the required laboratory values 0900 h Contrast-enhanced MRI of the abdomen 1100 h Contrast-enhanced MRI of the central nervous system 1400 h Ophthalmologic examination with eye and retinal investigation by ophthalmoscopy 1500 h Final appointment with the medical expert and coordinator 1600 h If necessary. Preventive medicine in SDH-associated RCCs A specific protocol for the surveillance of familial paraganglioma syndromes still needs to be established. Best quality imaging is required. urology. vision or hearing abnormalities. Initial programs should include MRIs of the entire paraganglial system—including paraganglia in the skull base and neck area. and yearly surveillance is sufficient. renal cysts and RCC increases with age. Abdominal ultrasound is recommended annually for patients aged 5–12 years. An example of a well-organized interdisciplinary. neurosurgery. abdomen and pelvis. all relevant prior records. The surveillance of patients with VHL disease must be performed at regular intervals. Diagnosed lesions grow slowly. physical examination. neurosurgeon. in order to detect intra-abdominal lesions. complete recovery of vision is rarely achieved. white 536  |  SEPTEMBER 2013  |  VOLUME 9  © 2013 Macmillan Publishers Limited. blood pressure abnormalities Laboratory values. blood pressure abnormalities Investigations performed every 2 years None abdomen and central nervous system are the cornerstones of an interdisciplinary diagnostic protocol. von Hippel–Lindau. pancreatic cysts and pancreatic neuroendocrine tumours.nature. vision or hearing abnormalities. 5–12 years Eye/retinal investigation by ophthalmoscopy Careful clinical investigation with focus on neurological abnormalities: nystagmus. the patient should have a personal meeting with the principal care provider. strabismus. treated at specialized medical centres. Individuals who have hereditary RCCs but do not show PGL4-associated clinical features should be offered www. geneticist) Abbreviation: VHL. If an operation is deemed to be necessary. as vision reduction occurs without preceding pain. blood pressure abnormalities) Laboratory values. Regular screening is essential for the prevention of blindness due to retinal angiomas. a second visit is mandatory. in order to keep the invested time for the patient to a minimum. visceral radiology. von Hippel–Lindau. white pupil.REVIEWS Table 4 | Age-dependent surveillance protocol for VHL disease Age group 1–4 years Investigations performed annually Eye and retinal investigation by ophthalmoscopy Careful clinical investigation with focus on neurological abnormalities: nystagmus. evaluation of clinical history. ophthalmology. MRIs must be performed within 1 min of injection of intravenous contrast medium. 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. vision or hearing abnormalities. When evaluating a patient with VHL in a specialist centre. All rights reserved . including the actual CTs and MRIs of the central nervous system and CTs and MRIs of the visceral organs. strabismus. including eye investigations. white pupil. and once retinal detachment occurs. 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. patient-oriented screening-day schedule 0800 h First appointment and interview with the medical expert and coordinator.

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