Renal Neoplasia: Diagnostic Problems and Recently Recognized Entities
Case 1 -
VHL-Associated Clear Cell Renal Cell Carcinoma as an Example for Familial Renal Cell Carcinoma
John N Eble, M.D.
Holger Moch, M.D.
37 year old man with detection of left renal tumor by
computerized tomography (CT). In addition, multiple smaller renal tumors in the same and contralateral
kidney were observed. Some tumors were cystic. In addition, imaging revealed a few cysts. The largest
tumor was removed by organ-sparing surgery. Macroscopic findings: The
tumor measured 5 x 5 x 1.5 cm. The cut-surface of the tumor was yellow.
VHL-associated clear cell renal cell carcinoma as an example for familial renal cell carcinoma
A surprising number of hereditary syndromes predispose to the development of renal cell carcinoma.
Within the last few years 7 renal cancer syndromes have been characterized. Five of the predisposing
genes have meanwhile been identified: VHL, MET, FH, BHD, and HRPT2 (Table 1).
VHL disease is the most frequent familial renal cancer syndrome and is associated with clear cell
renal carcinoma and multi-organ neoplasia, associated with mutations in the VHL gene and loss of the wild-type VHL-allele.
Patients with hereditary papillary renal carcinoma syndrome (HPRC) have a germline activating mutation in
the MET-proto-oncogene which can cause renal cancers with papillary type 1
histology. Papillary type 2 renal carcinomas and uterine smooth-muscle tumors are associated with the
hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), which is caused by germline
loss-of-function mutations in the Fumarate-Hydratase (FH) gene. The hyperparathyreoidism-jaw tumor (HPT-JT) syndrome is associated with
parathyroid adenomas, fibro-myalgious tumors of the jaw and renal tumors. This syndrome is caused by
germline mutations in HRPT2. The Birt-Hogg-Dubé syndrome (BHD) is
associated with an increased risk for renal cancers of various histological types, such as chromophobe
RCC and oncocytic hybrid tumors.
Von Hippel-Lindau (VHL) disease is inherited through an autosomal dominant trait and characterized by
the development of capillary hemangioblastomas of the central nervous system and retina, clear cell renal
carcinoma, pheochromocytoma, pancreatic and inner ear tumors The syndrome is caused by germ line
mutations of the VHL tumor suppressor gene, located on chromosome 3p25-26.
The VHL-protein is involved in cell cycle regulation and angiogenesis (figure1). Inactivation of the
VHL gene affects VHL protein function. The VHL protein negatively regulates
hypoxia-inducible factor, which activates genes involved in cell proliferation, neo-vascularization, and
extracellular matrix formation. The hypoxic response, as a result of dysregulation of HIF subunits,
results in transcriptional activation of hypoxia-inducible genes. These genes encode growth and
angiogenic factors such as vascular-endothelial growth factor, erythropoietin and platelet-derived growth
factor-β that enhance neovascularization of these proliferating renal tumors. Transforming growth
factor-a (TGF- a), another HIF target gene, might function in the development of renal tumors, as TGF-a
and its receptor, epidermal growth factor receptor, are commonly over expressed in renal carcinoma.
The von Hippel-Lindau syndrome is estimated to occur at rates of 1:36,000 to 1:45,500 population.
The typical renal manifestations of VHL are kidney cysts and clear cell carcinomas. Multiple kidney
tumors of other histological types rule out the diagnosis of VHL syndrome. Histological examination of
renal tissue from VHL patients may reveal several hundred independent tumors and cysts. The mean age of
manifestation is 37 years versus 61 years for sporadic clear cell renal carcinomas, with an onset age of
16 to 67 years. Metastatic RCC is the leading cause of death from VHL. The median life expectancy of
VHL-patients is 49 years. In order to detect VHL-associated tumors in time, analysis of germ line
mutations of the VHL gene have been recommended in every patient with
retinal or CNS hemangioblastoma, particularly those of younger age and with multiple lesions. Germ line
mutations of the VHL-gene are spread all over the 3 exons.
Missense-mutations are most common, but nonsense-mutations microdeletions/insertions, splice mutations
and large deletions also occur. The spectrum of clinical manifestations of VHL reflects the type of germ
line mutations. Phenotypes are based on the absence (type 1) or presence (type 2) of pheochromocytoma.
VHL type 2 is usually associated with missense-mutations and subdivided on the presence (type 2a) or
absence (2b) of renal cell carcinoma. In contrast to loss of functions variance in VHL type 1, mutations
predisposing to pheochromocytoma (VHL type 1) are mainly of the missense type predicted to give rise to
conformational change of pVHL. In addition, VHL type 2c has been used for patients with only
pheochromocytoma; however several years later some of these cases developed other VHL manifestations.
Figure 1: Dysregulation of HIF-1a by VHL inactivation leads to clear cell renal tumors in patients with von Hippel-Lindau disease
Under normoxic conditions, hypoxia-inducible factor-1α (HIF-1α) is hydroxylated (-OH) on two conserved
proline residues (for simplicity, only one is shown) by a family of prolyl hydroxylases at its
oxygen-dependent degradation domain. This hydroxylation provides a substrate-recognition site for the
von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, which contains elongins C and B, cullin-2 (CUL2) and
RBX1. Polyubiquitylation of HIF-1α by the VHL complex leads to its proteasomal degradation by the 26S
proteasome. HIF-1α is also hydroxylated at an asparagine residue in its carboxy-terminal transactivation
domain by FIH-1, an asparaginyl hydroxylase. This blocks binding of the transcriptional coactivators
CREB-binding protein (CBP) and p300 to HIF-1α, thereby inhibiting transcription of HIF-target genes.
Hypoxic conditions block both types of hydroxylation, allowing HIF-1α subunits to accumulate and activate
transcription of hypoxia-responsive genes. VHL inactivation - as occurs in renal cells from patients
with a germline VHL mutation and loss of the wild-type allele - mimics the
hypoxic response by preventing degradation of HIF-1α subunits. Loss of VHL function causes accumulation
of HIF-1α subunits in the cytoplasm and their translocation to the nucleus. HIF-1 a dimerizes with HIF-1
b and is coactivated by CBP/p300. HIF-1 a/b binds to hypoxia response elements (HRE) in gene promoters,
thereby activating transcription of genes upregulated in clear-cell renal tumors, including vascular
endothelial growth factors, erythropoietin and platelet-derived growth factor- b. (HIF-1α is shown, but
HIF-2a is also recognized as a VHL substrate.). from: Nature 4, 2004, 381-393
Table 1: Hereditary causes of renal cell carcinoma and angiomyolipomas
|Syndrome ||Gene Protein ||Chromosome ||Kidney ||Skin ||Other Tissue|
|von Hippel-Lindau ||VHL|
|3p25 ||Multiple, bilateral clear-cell renal cell carcinoma (CCRCC), renal cysts ||- ||Retinal and CNS haemangioblastomas, phaechromocytoma, pancreatic cysts|
|Hereditary papillary renal cancer ||c-MET|
|7q31 ||Multiple, bilateral papillary renal cell carcinomas (PRCC), Type 1 ||- |
|Hereditary leiomyomatosis and RCC ||FH|
|1q42-43 ||Papillary renal cell carcinoma (PRCC), non-Type 1 ||Nodules (leiomyomas) ||Uterine leiomyomas and leiomyosarcomas|
|17p11.2 ||Multiple chromophobe RCC, conventional RCC, hybrid oncocytoma, papillary RCC, oncocytic tumors ||Facial fibrofolliculomas ||Lung cysts, spontaneous pneumothorax|
|Constitutional chromosome 3 translocation ||unknown || ||Multiple, bilateral clear-cell renal cell carcinomas (CCRCC) ||- ||-|
|Hyperparathyreoidism-jaw tumor (HP-JT) ||HRTP2 ||1q25-32 ||Mixed epithelial and stromal tumors, papillary RCC: cysts ||- ||Parathyroid tumors, fibro-osseous mandibular and maxillary tumors|
|Familial papillary thyroid cancer (FPTC) ||Unknown gene ||1q21 ||Papillary RCC, oncocytoma ||- ||Papillary thyroid cancer, nodular thyroid disease|
|Tuberous sclerosis ||TSC1|
|Multiple, bilateral angio-myolipomas, lymph-angioleiomyomatosis ||Cutaneous angiofibroma ('adenoma sebaceum') peau chagrin, subungual fibromas ||Cardiac rhabdomyomas, adenomatous polyps of the duodenum and the small intestine, lung and kidney cysts, cortical tubers and subependymal giant cell astrocytomas (SEGA)|
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- Schmidt L, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 16: 68-73, 1997
- Tomlinson IP, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30: 406-10, 2002.
- Carpten JD, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 32: 676-80, 2002.
- Nickerson, M.L., et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2: 157-64, 2002.
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- Maxwell PH, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271-5, 1999.
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