Four major heritable renal cell cancer syndromes (von Hippel-Lindau syndrome [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé syndrome [BHD], and hereditary papillary renal cancer [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following sections of this summary.
Table 1. Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes
Syndrome (Inheritance Pattern)
Gene Locus, Gene Type (Protein)
Renal Tumor Pathology (Cumulative Cancer Risk)
Non-renal Tumors and Associated Abnormalities
AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.
Hereditary papillary renal cancer (HPRC) (AD) [11,12]
MET 7q34, proto-oncogene (hepatocyte growth factor receptor)
Papillary type 1 (approaching 100%)
Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major renal cell cancer (RCC) syndromes. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for VHL, BHD, HLRCC, and HPRC. Genetic counseling is a prerequisite for genetic testing. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Von Hippel-Lindau Syndrome
Von Hippel-Lindau syndrome (VHL) (OMIM) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germlinemutations in the VHL gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system (CNS) hemangioblastomas, retinal angiomas, clear cell RCCs (ccRCCs) and cysts, pheochromocytomas, cysts and neuroendocrine tumors (NETs) of the pancreas, endolymphatic sac tumors (ELSTs), and cystadenomas of the epididymis (males) and of the broad ligament (females).[1,2,13,14] A multidisciplinary approach is required for the evaluation, and in some cases the management, of individuals with VHL. Specialists involved in the care of individuals with VHL may include urologic oncology surgeons, neurosurgeons, general surgeons, ophthalmologists, endocrinologists, neurologists, medical oncologists, genetic counselors, and medical geneticists.
The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26. VHL disease-causing mutations occur in all three exons of this gene. Most affected individuals inherit a germline mutation of VHL from an affected parent and a normal ("wild-type") VHL from their unaffected parent. VHL-associated tumors conform with Knudson’s “two-hit” hypothesis,[16,17] in which the clonal origin or first transformed cell of the tumor occurs only after both VHLalleles in a cell are inactivated. The inherited germline mutation in VHL represents the first "hit," which is present in every cell in the body. The second “hit” is a somatic mutation, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, VHL allele, creating a clonal neoplastic cell of origin, which then proliferates into a tumor mass.
Prevalence and rare founder effects
The prevalence of VHL has been estimated to be 1 per 35,000 and 1 per 40,000 persons in the general population.[18,19] Thus, the number of VHL-affected individuals in the United States is estimated at between 6,000 and 7,000. Precise quantification of this number is a challenge because it requires comprehensive screening of potentially at-risk blood relatives of individuals diagnosed with VHL. Within this population, the large number of unique mutations in this small three-exon gene indicates that most family clusters have not arisen from a single founder. A founder effect was reported when a large U.S. family was compared with a family in Germany, both of whom had pheochromocytoma-predominant VHL.
Penetrance of mutations
VHL mutations are highly penetrant and overall penetrance is greater than 90% by age 65 years. Almost all carriers develop one or more types of syndrome-related neoplasms.
Risk factors for VHL
Each offspring of an individual with VHL has a 50% chance of inheriting the mutated VHLallele from their affected parent. The primary factors affecting the chances of developing VHL are: 1) a relative with VHL; 2) a germline mutation in the VHL gene; 3) a family member with one of the manifestations of VHL (e.g., CNS hemangioblastomas). (Refer to theGenetic diagnosis section of this summary for more information.)
For example, pheochromocytoma without RCCs is the VHL pattern found in a large family with a single nucleotide change at position 505.[14,21,23] A similar family outside the United States was identified and found to have a common ancestor (i.e., a founder mutation). However, no common ancestor was identified for several other mutations that occurred in multiple families. In general, founder mutations do not comprise a significant fraction of all VHL mutations. Single nucleotide changes at position 712 and 713 are “hot spots” for mutations leading to pheochromocytomas. Mutation types leading to clinical VHL include missense, nonsense, frameshifts, insertions, partial and completedeletions, and splice-site mutations of VHL.
De novo mutations and mosaicism
When a VHL diagnosis is made in an individual whose ancestors (biological parents and their kindred) do not have VHL, this may result from a de novo (new) VHL mutation in the affected individual. Patients diagnosed with VHL, who have no family history of VHL, have been estimated to comprise about 23% of VHL kindreds. A new mutation is by definition a postzygotic event, because it is not transmitted from a parent.
Depending on the embryogenesis stage at which the new mutation occurs, there may be different somatic cell lineages carrying the mutation; this influences the extent ofmosaicism. Mosaicism is the presence in an individual of two or more cell lines that differ in genotype but which arise from a single zygote. If the postzygotic de novo mutation affects the gonadal cell line, there is a risk of transmitting a germline mutation to offspring.
VHL-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or compound heterozygous mutations in VHL in which affected individuals develop abnormally high numbers of red blood cells. The affected individuals have biallelic mutations in the VHL gene. The typical VHL syndromic tumors do not occur in these affected individuals.[26-28]
Other genetic lesions
In sporadic RCC, other genetic lesions have been found. These include PBRM1, SETD2, andBAP1 and may have relevance in RCC arising in VHL patients. Future studies will define their significance in the hereditary patient population.
The VHL gene product, pVHL, is a 213 amino acid protein that regulates hypoxia-inducible factors (HIFs), maintains a normal extracellular matrix, is involved in microtubule and centrosome regulation, and regulates the cell cycle.[30-32] These functions are described in more detail in the following paragraphs.
HIF1-alpha and HIF2-alpha
pVHL regulates protein levels of HIF1-alpha and HIF2-alpha in the cell by acting as an E3 ubiquitin ligase for HIF. In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome.
Under hypoxic conditions, hydroxylation does not occur; HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex and are not ubiquitinated. The resulting high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of proteins. Loss of functional pVHL creates a pseudohypoxic state, with uncontrolled HIF1-alpha and HIF2-alpha protein levels, and resultant inappropriate transcription of HIF-dependent genes.
HIF1-alpha and HIF2-alpha possess distinct functional characteristics, and a shift towards a HIF2-alpha–dominant phenotype occurs in RCC. HIF1-alpha and HIF2-alpha may preferentially upregulate Myc activity. Hypoxia activated factor has been shown to increase HIF2-alpha transactivation  and HIF1-alpha instability. Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha.
Microtubule regulation and cilia centrosome control
Emerging data point to the importance of pVHL-mediated control of the primary cilium and the cilia centrosome cycle. The nonmotile primary cilium acts as a mechanosensor, is a regulator of cell signaling, and controls cellular entry into mitosis. Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation. Loss of pVHL results in loss of the primary cilium. pVHL binds to and stabilizes microtubules  in a glycogen synthase 3–dependent fashion. Loss of pVHL or expression of mutated pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.
Cell cycle control
pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines. Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage. Nuclear localization and intensity of p27 is inversely associated with tumor grade. pVHL binds to, stabilizes, and transactivates p53  in a phosphorylation-dependent fashion. The importance of these findings is underscored by the findings that p53 is an important regulator of mitotic checkpoints, and loss of p53 permits aneuploid cells to survive.
Extracellular matrix control
Functional pVHL is needed to form an extracellular fibronectin matrix. Additionally, pVHL directly binds to, phosphorylates, and regulates fibronectin. Collagen IV homeostasis is also regulated by pVHL. pVHL isoforms that are collagen IV binding–incompetent demonstrated a malignant phenotype.
Animal models of VHL
No representative VHL animal models are currently available. Vhlh gene knockout in mice did not produce RCC or hemangioblastomas. Murine homologues of the R200W-induced polycythemia in mice, phenocopying Chuvash polycythemia. A R167Q homologue did not generate RCC. Coordinate inactivation of Vhlh and Pten resulted in a higher rate of cyst formation, but, once again, no obvious RCC was observed. The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1, SETD2, and BAP1  provide new avenues for developing relevant animal models of at least some VHL disease manifestations.
Age ranges and cumulative risk of different syndrome-related neoplasms
The age at onset of VHL varies both from family to family and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. The youngest age at onset of specific VHL syndrome components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. Examples of reported mean ages and age ranges of the following manifestations are summarized in Table 2.
Table 2. Neoplasms in von Hippel-Lindau Syndrome: Mean Age at Diagnosis and Cumulative Risk in Patients Affected
Mean Age (Range) in y
Cumulative Risk (%)
Adapted from Choyke et al. and Lonser et al.
Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC). More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC. These specific VHL phenotypes are summarized below.
Table 3. Genotype-Phenotype Classification of Families With von Hippel-Lindau Syndromea
More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass. Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2 or 4) and minimally invasive, and their rate of growth varies widely. An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a cyst to a solid lesion was rare. Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.
Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[59,60] RCCs often remain asymptomatic for long intervals.
Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs. Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas). A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.
Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients. Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 35.9 years. These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children younger than 10 years.[64,65]
Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas. The median number of lesions per affected eye is approximately six. Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.
Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients  having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration. Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[66,69]
Cerebellar and spinal hemangioblastomas
Hemangioblastomas are the most common disease manifestation in patients with VHL, potentially affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas. After a mean follow-up of 7 years, 75% of the 225 patients studied developed new lesions. Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P < .01). Partial germline deletions had more tumors per patient than did missense mutations (P < .01). Younger patients developed more tumors per year. Hemangioblastoma growth rate was higher in men than in women (P < .01). Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.
Pheochromocytomas and paragangliomas
The rate of pheochromocytoma formation in the VHL patient population is approximately 25%, with bilaterality occurring in some patients. Of patients with VHL pheochromocytomas, 44% developed disease in both adrenal glands. One study reported a mean age at onset for pheochromocytoma in VHL patients of 30 years. Rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL disease, and approximately two-thirds will experience physical manifestations. Missense VHL gene mutations correlated with the risk of pheochromocytoma in patients with VHL, with a low incidence of pheochromocytoma in patients with complete deletion of the VHL gene. The rate of VHLgermline mutation in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL disease.
Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen. A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.
The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas in one series was 31 years, and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions (19 vs. 34 years; P < .001).
Endolymphatic sac tumors (ELSTs)
ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone. ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[77,78] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[77,79]
ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[77,78] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage. Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.
Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[80,81] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[78,80]
Broad/round ligament papillary cystadenomas
Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature. Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL. One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically. Therefore, any female with a broad ligament papillary cystadenoma should be referred for genetic counseling. These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.
More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL disease. Among symptomatic patients, the most common presentation is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.
One group of investigators observed that epididymal tumorigenesis in VHL disease occurred in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells caused by developmental arrest of progenitor cells, followed by neoplastic papillary proliferation with activation/up-regulation of HIF and VEGF, associated with continuous reactive fibrovascular proliferation. In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. CAIX was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.
Risk assessment for Von Hippel-Lindau syndrome
The primary risk factor for VHL (or any of the hereditary forms of renal cancer under consideration) is the presence of a family member affected with the disease. Risk assessment should also consider gender and age for some specific VHL-related neoplasms. For example, pheochromocytomas may have onset in early childhood, as early as 8 years of age. Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%–26%), which are virtually pathognomonic for VHL, especially when bilateral, and are rare in the general male population. Epididymal cysts are also common in VHL, but they are reported in 23% of the general male population, making them a poor diagnostic discriminator. Females have histologically similar lesions to cystadenomas that occur in the broad ligament.
Each offspring of an individual with VHL has a 50% chance of inheriting the mutated VHLallele from their affected parent. Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, then a patient with one or more specific VHL-type tumors (e.g., hemangioblastoma of the CNS or retina, pheochromocytoma, or ccRCC) may be diagnosed with VHL.
At-risk family members should be informed that genetic testing for VHL is available. A family member with a clinical diagnosis of VHL or who is showing signs and symptoms of VHL is offered genetic testing initially. Germline mutations in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point mutations in the VHL gene (~72% of all mutations). Using Southern blot analysis and/or quantitative polymerase chain reaction to detect partial or complete gene deletions will detect deleterious mutations in the remaining 28% of VHL families.[89,90] The technique has a detection rate approaching 100%. Newer techniques such as array comparative genomic hybridization (array CGH) are powerful tools for identifying genomic imbalances. Anecdotal evidence exists for the utility of next-generation sequencing in cases of suspected mosaicism with a negative VHL genetic test.
Genetic counseling is first provided, including discussion of the medical, economic, and psychosocial implications for the patient and their bloodline relatives. After counseling, the patient may choose to voluntarily undergo testing, after providing informed consent. Additional counseling is given at the time results are reported to the patient. When a VHLmutation is identified in a family member, their biologic relatives who then test negative for the same mutation are not carriers of the trait (i.e., they are true negatives) and are notpredisposed to developing any VHL manifestations. Equally important, the children of true-negative family members are not as risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.
A germline mutation in the VHL gene is considered a genetic diagnosis. It is expected to carry a predisposition to clinical VHL and confers a 50% risk among offspring to inherit theVHL mutation. Approximately 400 unique mutations in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the mutation. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL mutation is identified, that specific mutation becomes the DNA marker for which other biological relatives may be tested. In cases where there is a clear VHL clinical diagnosis without a VHL mutation by usual testing of peripheral blood lymphocytes and without a history of VHL in the biological parents or in the parents’ kindreds, then either a de novo mutation or mosaicism may be the cause. The latter may be detected by performing genetic testing on other bodily tissues, such as skin fibroblasts or exfoliated buccal cells.
Diagnosis of VHL is frequently based on clinical criteria (see Table 4). If there is family history of VHL, then a previously unevaluated family member may be diagnosed clinically if they present with one or more specific VHL-related tumors (e.g., CNS or retinal hemangioblastoma, pheochromocytoma, ccRCC, or endolymphatic sac tumor). If there is no family history of VHL, then a clinical diagnosis requires that the patient have two or more CNS hemangioblastomas or one CNS hemangioblastoma and a visceral tumor or endolymphatic sac tumor. See Table 4 for more diagnostic details.[2,13,14]
Since 1998, when a cohort of 93 VHL families in whom all germline mutations were identified was reported, diagnoses have included a combined approach of clinical and genetic testing within families. The diagnostic strategy differs among individual family members. Table 4 summarizes a combined approach of genetic testing and clinical diagnosis.
Table 4. Diagnostic Approaches to von Hippel-Lindau Syndrome (VHL) in Individuals With and Without a Family History
Family History of VHL
Requirements for Clinical Diagnosis
CNS = central nervous system; ccRCC = clear cell renal cell cancer; VHL = von Hippel-Lindau syndrome.
Adapted and updated from Glenn et al.  and Pithukpakorn and Glenn.
With a family history of VHL
Test DNA for the same VHL gene mutation as previously identified in affected biologic relative(s)
When VHL gene mutation is unknown for a biologic relative
One or more of the following is required for a clinical diagnosis:
- Epididymal or broad ligament cystadenomas
- CNS hemangioblastoma
- ccRCC, multifocal
- Retinal angiomas
- Pancreatic neuroendocrine tumor
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
Without a family history of VHL
May be negative if the VHL mutation occurred postzygotically (e.g., VHLmosaicism)
When VHLmutation is unknown or germline negative, but there are clinical signs compatible for VHL
Either or both of the following are required for a clinical diagnosis:
- CNS hemangioblastoma
- Retinal angiomas
If only one of the above is present, then also one of the following:
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
- Epididymal or broad ligament cystadenomas
Surveillance guidelines that have been suggested for various manifestations of VHL are summarized in Table 5. In general, these recommendations are based on expert opinion and consensus; most are not evidence-based. These modalities may be used for the initial clinical diagnostic testing and also for periodic surveillance of at-risk individuals for early detection of developing neoplasm. Periodic presymptomatic screening is advised for at-risk individuals. At-risk individuals are those testing positive for a VHL mutation and those individuals who choose not to be tested for a VHL mutation but have biologic relatives affected by VHL. The risk of inheriting the VHL predisposition in such persons may be as high as 50%.
Table 5. Practice Guidelines for Surveillance of von Hippel-Lindau Syndrome (VHL)
Condition Screened For
CNS = central nervous system; CT = computerized tomography; IACs = internal auditory canals; MRI = magnetic resonance imaging.
aFrequencies of exams or tests may be increased at organ sites of VHL lesions being monitored.
bBrain MRIs may be used to examine areas of the IACs for signs of endolymphatic sac tumors (ELSTs). If signs or symptoms of ELSTs are present, examine IACs by CT and MRI.
Adapted from Pithukpakorn and Glenn ; Choyke et al. ; and Lonser et al.
From infancy; every 6 to 12 mo
If needed (not routinely performed)
Plasma or 24-hour urinary catecholamines and metanephrines
From age 2 y; yearly and as clinically indicated when blood pressure is elevated
Enhanced MRI of brain/spineb
CNS and peripheral hemangioblastoma
From age 11 y; every 1 to 2 y and if symptoms appear
CT of abdomen with and without contrast (substitute MRI every other year)
Renal, pancreatic, and adrenal neoplasms and cysts
From age 18 y, earlier if indicated; yearly; alternate CT and MRI (reduces radiation)
Ultrasound of abdomen
Renal, pancreatic, and adrenal neoplasms and cysts
Yearly from age 8 to 18 y, earlier if indicated; MRI as clinically indicated
The management of VHL has changed significantly as clinicians have learned how to best balance the risk of cancer dissemination while minimizing renal morbidity. Some of the initial surgical series focused on performing a bilateral radical nephrectomy for renal tumors followed by a renal transplantation.[92,93] Nephron-sparing surgery (NSS) for VHL was introduced in the 1980s after several groups demonstrated a low risk of cancer dissemination with a less-radical surgical approach.[94,95] In 1995, a large, multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC. Because of multiple reports of excellent outcomes, when feasible, NSS is now considered the surgical standard of care. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. To avoid the taking of a wide margin, enucleative resection was developed and allows the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.
Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. To minimize the morbidity of multiple surgical procedures, loss of kidney function, and the risk of distant progression, a specific timing for intervention was questioned. The National Cancer Institute evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated before the largest lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months. Later series reinforced that this was an important threshold because 0 of 108 patients with tumors managed at 3 cm or smaller had evidence of distant spread. For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence. This threshold is now widely used to trigger surgical intervention for VHL-associated ccRCC. When surgery is performed on a patient with VHL, resection of more than a dozen renal tumors may be necessary. The use of intraoperative ultrasound to identify and then remove smaller lesions may delay the need for further surgical interventions.
Many patients with VHL develop new RCCs on an ongoing basis and may require further intervention. Adhesions and perinephric scarring make subsequent surgical procedures more challenging. While a radical nephrectomy could be considered, NSS is still the preferred approach, when feasible. While there may be a higher incidence of complications, repeat and salvage NSS can enable patients to maintain excellent renal functional outcomes and provide promising oncologic outcomes at intermediate follow-up.[101,102] These surgeries may be best handled at a specialized center with significant experience with this surgical approach.
Radiofrequency ablation (RFA) and cryoablation (CA)
Thermal ablative techniques utilize either heating or cooling of a mass in an effort to destroy the tumor. Cryoablation (CA) and radiofrequency ablation (RFA) were introduced into the management of small renal masses in the late 1990s.[104,105] For sporadic renal masses, both thermal ablative techniques have a nearly 90% recurrence-free survival rate, leading the American Urologic Association to consider this as a recommendation in high-risk patients with a small renal mass. For patients with VHL, the clinical applications of ablative techniques are still not clearly defined, and surgery is still the most-studied intervention. Ablative techniques were first introduced into the management of VHL-associated RCC in a phase II trial investigating the effects of ablation at the time of lesion resection. In this study, 11 tumors were treated, and an intra-operative ultrasound showed complete elimination of blood flow to the tumors; on final pathology, there was evidence of treatment effect on all tumors. Since this time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success. Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function. Despite limited long-term data, these techniques have been increasingly utilized in the treatment of RCC in patients with VHL. A single-institution study evaluated treatment trends in RCC in 113 patients with VHL. Between 2004 and 2009, 43% of cases were managed with RFA at this center.
Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. Cryoablation as salvage therapy was evaluated in a series of 14 patients to avoid the morbidity of repeat NSS. There was minimal change in renal function; at a median follow-up of 37 months, there was suspicion for lesion recurrence in only 4 of 33 tumors treated. However, it must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications due to adhesions and scarring, especially along the tract of the ablative probes.[112-114] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[103,115]
The clinical applications of ablative techniques in VHL are still not clearly defined, and surgery is still the most-studied intervention. The available clinical evidence suggests that ablative approaches be reserved for small (≤3 cm), solid-enhancing renal masses in older patients with high operative risk, especially in patients facing salvage renal surgery because of a higher complication rate. Young age, tumor size larger than 4 cm, hilar tumors, and cystic lesions can be regarded as relative contraindications. Irreversible coagulopathy is widely accepted as an absolute contraindication.[116,117]
A 2011 study prospectively evaluated the safety and efficacy of sunitinib in VHL patients. Fifteen patients with VHL were given 50 mg of sunitinib daily for 28 days, followed by 14 days off for up to four cycles, with a primary endpoint of toxicity. Grade 3 toxicity included fatigue in five patients (33%); dose reductions were made in ten patients (75%). A significant response was observed in RCC but not in hemangioblastoma. Eighteen RCCs and 21 hemangioblastoma lesions were evaluable. Of these, six RCCs (33%) responded partially, versus none of the hemangioblastomas (P = .014). The expression of pFRS2 in hemangioblastoma tissue was also observed to be higher than in RCC, thus raising the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with hemangioblastoma. A retrospective study of 14 patients with VHL, 10 of whom had metastatic disease, demonstrated significant response in metastatic and primary RCC lesions. Eleven patients had cerebellar hemangioblastomas, and eight had spinal hemangioblastomas. No response was seen in hemangioblastomas.
Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[120-122] Modest improvement was observed in patients with retinal hemangioblastomas.[120,121] In a series of six VHL patients treated with SU5416, stabilization in CNS hemangioblastomas was observed in two patients. A study of intravitreally administered anti–vascular endothelial growth factor therapy for a patient with retinal hemangioma yielded mixed results. SU5416 is not licensed for human use.
Two studies suggest that pregnancy is associated with hemangioblastoma progression in patients with VHL.[124,125] One study retrospectively examined the records of 29 patients with VHL from the Netherlands who became pregnant 48 times (49 newborns) between 1966 and 2010 (40% became pregnant before 1990); imaging records were available for 31% of the pregnancies. Researchers reported that 17% of all pregnancies had VHL-related complications, including three patients who had craniospinal hemangioblastoma that significantly (P = .049) changed in progression score before and after pregnancy. This study's findings are in contrast with a small, prospective investigation. Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.
Morbidity and mortality in VHL vary and are influenced by the individual and the family’s VHL phenotype (e.g., Type 1, 2A, 2B, or 2C). (Refer to the VHL familial phenotypes section of this summary for more information.)
In the past, metastatic RCC has caused about one-third of deaths in patients with VHL, and in some reports, it was the leading cause of death.[88,126-128] With increased surveillance of mutation-positive individuals, the RCC mortality rate is thought to have diminished.
Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem. Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[126,129] Hearing and vision may also be decreased or lost as a result of VHL tumors. Periodic screening allows early detection and may prevent advanced disease.
Currently, the renal manifestations of VHL are still generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies. These will include defining the molecular biology and genetics of kidney cancer development, which may result in the development of effective prevention or early intervention therapies. In addition, the evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHL function, identifying new targets, or discovering synthetic lethal strategies that can effectively eradicate RCC.
Hereditary Leiomyomatosis and Renal Cell Cancer
Hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and RCC. Germline mutations in the fumarate hydratase (FH) gene are responsible for the susceptibility to HLRCC. FH codes for fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle).
Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern. That report also described a woman aged 20 years with uterine leiomyosarcoma and metastatic RCC. Subsequently, the association of cutaneous and uterine leiomyomas became known as Reed syndrome. However, the clear association of cutaneous leiomyomas and RCC was not described until 2001, when a study reported two Finnish families in whom cutaneous and uterine leiomyomas and papillary type 2 RCC co-segregated. The name hereditary leiomyomatosis and renal cell cancer was then assigned. The term HLRCC is preferred because it is impossible to distinguish between individuals with cutaneous leiomyomas who do or do not have an increased risk of renal cancer.
The FH gene consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. The human FH gene is located on chromosome 1q42.3-43.
HLRCC is an autosomal dominant syndrome; a single mutated FH allele is sufficient to cause the disease. Inherited biallelic mutations cause fumarate hydratase deficiency (FHD), a disorder characterized by rapidly progressive neonatal neurologic impairment including hypotonia, seizures, and cerebral atrophy. (Refer to the Genetically related disorders section of this summary for more information.)
Germline mutations in FH, plus somatic mutations and loss of heterozygosity (LOH) in RCC, suggest that loss of function in the fumarate hydratase protein is the basis of tumor formation in HLRCC and, further, that FH functions as a tumor suppressor gene.[3,132]
Various mutations in FH have been identified in families with HLRCC. Most are missense mutations, but nonsense, frameshift, and splice-site mutations have been described.[5,6,132,133] Recently, whole-gene or partial deletions have been identified.
The prevalence of HLRCC is unknown. It is estimated that more than 100 families with HLRCC have been seen at the National Institutes of Health, but it is likely that HLRCC remains an underrecognized entity (R. Srinivasan, MD, PhD, oral communication, April 2014).
Penetrance of mutations
Considering the three major clinical manifestations combined, the penetrance of HLRCC is considered to be very high. However, the estimated cumulative incidence of RCC varies widely, from between 2% and 7% to 15%, and perhaps as high as 32%, in families with germline FH mutations, depending on ascertainment method and the imaging modalities used.[3-6,134]
No genotype-phenotype correlations have been described. Thus, no correlation has been observed between specific FH mutations and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.
Although smaller studies have suggested the presence of different mutational spectra in FHD and HLRCC,[5,132] a study that included a larger cohort of patients indicated that the mutational distribution is fairly similar in these two entities. The predisposition to HLRCC versus FHD likely results from a difference in gene dosage, rather than the location of the FH mutation as originally suggested.
Between 80% and 100% of individuals with HLRCC have identifiable, deleterious sequence alterations in FH.[5,6,135]
FHD, resulting from inherited biallelic mutations in FH, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline mutations in FH are found in individuals with FHD.[136,137] To date, RCC has not been reported in FHD-affected individuals. Most individuals with FHD survive only a few months; very few survive to early adulthood. However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.
LOH around the FH locus has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumor characteristics of the heritable disease.[139,140] All three tumors displayed biallelic inactivation of FH. In sporadic forms of kidney cancer, there have been no somatic mutations identified in FH to date.
The mechanisms by which alterations in FH lead to HLRCC are still being elucidated. Biallelic inactivation of FH has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Blockage of the Krebs cycle at FH results in increased levels of intracellular fumarate, inhibiting HIF prolyl hydroxylases. Inactivating mutations of FH also appear to result in the generation of reactive oxygen species, further contributing to the stabilization of HIF. This upregulation of the HIF pathway leads to a pseudohypoxic state and upregulation of a transcriptional program contributing to aggressive tumor biology. Others have demonstrated upregulation of the antioxidant response pathway due to posttranslational modification of KEAP1. The resultant NRF-2 dysregulation leads to upregulation of antioxidant response element–controlled genes such as aldo-keto reductase family 1 member, B10 (AKR1B10), possibly contributing to the neoplastic process.
The clinical characteristics of HLRCC include cutaneous leiomyomas, uterine leiomyomas (fibroids), and RCC. Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; an RCC that is typically solitary, or no renal tumors; and/or uterine leiomyomas. Disease severity shows significant intrafamilial and interfamilial variation.[3,5,6]
Cutaneous leiomyomas present as firm pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 years) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful. Pain is correlated with severity of cutaneous involvement. The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup; a solitary leiomyoma requires careful analysis of family history. (Refer to the Clinical diagnosis and Differential diagnosis sections below for more information.)
The onset of uterine leiomyomas in women with HLRCC occurs at a younger age than in women in the general population. The age at diagnosis ranges from 18 to 52 years (mean age, 30 years). Uterine leiomyomas are usually large and numerous. Most women experience symptoms including irregular or heavy menstruation and pelvic pain, thus requiring treatment at a younger age than females with leiomyomas in the general population. Women with HLRCC and uterine leiomyomas undergo hysterectomy or myomectomy for symptomatic uterine leiomyomas at a younger age (<30 45="" a="" age="" do="" general="" href="http://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#cit/section_2.5" in="" median="" population="" style="border: 0px; box-sizing: border-box; color: #2b7bba; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" than="" the="" women="" years="">530>
The symptoms of RCC may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with RCC are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop RCC. Most RCCs are unilateral and solitary; in a few individuals, they are multifocal. Approximately 10% to 32% of individuals with HLRCC who presented with multiple cutaneous leiomyomas had RCC at the time that renal imaging was performed.[5,135] The median age at detection of RCC was 37 years, although some cases have been reported to occur as early as age 10 years. In contrast with other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[148,149] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis. Figure 4 depicts RCCs in a patient with HLRCC.
Whether all women with HLRCC have a higher risk of developing uterine leiomyosarcomas than expected among women of similar age in the general population is unclear. In the original description of HLRCC, it was reported that 2 of 11 women with uterine leiomyomas also had uterine leiomyosarcoma, a cancer that may be clinically aggressive if not detected and treated at an early stage. To date, germline mutations in FH have been reported in six women with uterine leiomyosarcoma.[150,151] It seems that most FH mutation–positive families are not highly predisposed to uterine cancer, but a few individuals and families appear to be at high risk. In North American studies, no uterine leiomyosarcomas in HLRCC individuals or families have been reported. Therefore, the risk of uterine leiomyosarcoma in women with HLRCC is uncertain. This is a question in urgent need of a definitive answer.
Four FH-positive individuals with breast cancer, one case of bladder cancer, and one case of bilateral macronodular adrenocortical disease with Cushing syndrome have been reported. A series from the National Cancer Institute (NCI) found that 20 of 255 patients (7.8%) with HLRCC had adrenal nodules, some of which did not appear to be adenomas on the basis of imaging characteristics. Because many of these lesions were fluorodeoxyglucose avid, resections were performed and all showed evidence of both micronodular and macronodular adrenal hyperplasia, suggesting that adrenal nodules could be an additional manifestation of HLRCC. It remains to be determined whether these manifestations are truly part of the HLRCC phenotype.[135,150,153]
Cutaneous leiomyomas are believed to arise from the arrectores pilorum muscles attached to the hair follicles. Histologically, these are dermal tumors that spare the epidermis. Morphologically, these tumors have interlacing smooth muscle fibers interspersed with collagen fibers.
A review of NCI's experience with HLRCC-associated uterine leiomyomas reported that the majority of these cases were well-circumscribed fascicular tumors with occasional cases showing increased cellularity and atypia. The hallmark features of these cases were similar to those observed in HLRCC kidney cancer: the presence of orangiophilic, prominent nucleoli that are surrounded by a perinuclear halo. While some cases had atypical features, no cases had tumor necrosis or atypical mitosis suggestive of malignancy or leiomyosarcoma.
The RCCs associated with HLRCC have unique histologic features, including the presence of cells with abundant amphophilic cytoplasm and large nuclei with large inclusion-like eosinophilic nucleoli. These cytologic features were attributed to type 2 papillary tumors in the original description. However, early studies reported that HLRCC is associated with a spectrum of renal tumors ranging from type 2 papillary to tubulopapillary to collecting-duct carcinoma.[6,156] RCC associated with HLRCC may constitute a new renal pathologic entity or a unique HLRCC type. Two studies reported the morphologic spectrum of RCC in HLRCC syndrome after histologic examinations of 40 RCCs from 38 patients with germlineFH mutations and HLRCC family histories.[156,157] A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.[156,157]
Diagnosis and testing
Molecular genetic testing for the FH gene is clinically available and performed by CLIA-certified laboratories. FH currently is the only gene known to be associated with HLRCC. The majority of patients with HLRCC have a germline mutation in FH.
Because the genetic analysis of HLRCC is complex, any interpretation of a variant of unknown significance results needs to be performed with consultation by clinical cancer geneticists, ideally in a center that has significant experience with this disease.
There is no current consensus on the diagnostic criteria for HLRCC.
Some experts suggest that a clinical dermatologic diagnosis of HLRCC requires one of the following:
Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma.
A single leiomyoma in the presence of a positive family history of HLRCC.
More recent comprehensive criteria for diagnosis have been suggested and are often used by experts in the field. Suggested criteria include dermatologic manifestations or a combination of two of the following manifestations: surgical treatment for symptomatic uterine leiomyomas before age 40 years, type 2 papillary RCC before age 40 years, or a first-degree relative who meets one of these criteria. Collecting duct RCC before age 40 years has been suggested as an additional criterion.
Cutaneous leiomyomas are rare. The detection of multiple lesions is specific for HLRCC. Because leiomyomas are clinically similar to various cutaneous lesions, histologic diagnosis is required to objectively prove the nature of the lesion.
Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. The majority of uterine leiomyomas are sporadic and nonsyndromic.
Diagnostic clues of the syndrome may rely on the presence of several phenotypic features in different organs (cutaneous, uterine, and renal). One or more of these characteristic features of the syndrome may be present in the patient or in one or more of their affected biologic relatives.
Although familial RCCs are associated with rather specific renal pathology, the rarity of these syndromes results in few pathologists gaining sufficient experience to recognize their histologic features.
The differential diagnoses may include other rare familial RCC syndromes with specific renal pathology, including:
Hereditary papillary renal cancer (HPRC). Predisposition to type 1 papillary renal cancer occurs. Inheritance is autosomal dominant.
Birt-Hogg-Dubé syndrome (BHD). A spectrum of renal tumors including renal oncocytoma (benign), chromophobe renal cell cancer (malignant), and a combination of both cell types, so-called oncocytic hybrid tumor. Individuals with BHD can present with cutaneous fibrofolliculomas and/or with multiple lung cysts and spontaneous pneumothorax. Inheritance is autosomal dominant.
Molecular genetic testing is used clinically for confirmation of diagnoses or for predictive testing. It is recommended that both pretest and posttest genetic counseling be offered to persons contemplating germline mutation testing. Laboratories offering genetic testing for use in clinical decision making must be certified under CLIA laws.
Molecular genetic testing for a germline FH mutation is indicated in all individuals known to have or who are suspected of having HLRCC, with or without a family history of HLRCC, including individuals with cutaneous leiomyomas, as described in the Clinical diagnosissection of this summary, or individuals who have renal tumors with histologic characteristics consistent with HLRCC. (Refer to the Histopathology section of this summary for more information.)
Risk to family members
HLRCC is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a disease-causing mutation, the siblings of the proband have a 50% chance of inheriting the mutation. Each child of an individual with HLRCC has a 50% chance of inheriting the mutation. The degree of clinical severity is not predictable. Prenatal molecular genetic testing may be available in laboratories offering custom prenatal testing for families in which the disease-causing mutation has been identified in an affected family member.
Parents of a proband
Some individuals diagnosed with HLRCC have an affected parent, while others have unaffected parents, suggesting that some individuals have HLRCC as the result of a de novo gene mutation.
The proportion of cases caused by de novo mutations is unknown as subtle manifestations in parents have not been systematically evaluated; not all unaffected parents have undergone FH mutation testing.
Evaluation of parents of a proband with a suspected de novo mutation may include molecular genetic testing if the FH disease-causing mutation in the proband has been identified.
Although some individuals diagnosed with HLRCC have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the affected parent before the onset of syndrome-related symptoms, or late onset of the disease in the affected parent.
Siblings of a proband
The risk to the siblings of the proband depends upon the genetic status of the proband's parents.
If a parent of a proband is clinically affected or has a disease-causing mutation, each sibling of the proband is at a 50% risk of inheriting the mutation.
If the disease-causing mutation cannot be detected in the DNA of either parent, the risk to siblings is low but greater than that of the general population because of the possibility of germline mosaicism.
Testing of at-risk family members
Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces costly and stressful screening procedures in at-risk members who have not inherited their family's disease-causing mutation.[162,164,165]
Early recognition of clinical manifestations may allow timely intervention, which could, in theory, improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early RCC detection is reasonable, but additional objective data regarding the impact of screening on syndrome-related mortality are needed.
Related genetic counseling issues
Predicting the phenotype in individuals who have inherited a disease-causing mutation
It is not possible to predict whether HLRCC-related symptoms will occur or, if they do, what the age at onset, type, severity, or rate of disease progression will be in individuals who have a disease-causing mutation. In an in-depth characterization of clinical and genetic features analyzed within 21 new families, the phenotypes displayed a wide range of clinical presentations and no apparent genotype-phenotype correlations were found.
When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or undisclosed adoption could also be explored. Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued, lifelong, clinical surveillance. Interpretation of the mutation test result is most accurate when a disease-causing mutation has been identified in an affected family member. Those who have a disease-causing mutation are recommended to undergo lifelong, periodic surveillance. Meanwhile, family members who have not inherited the mutation and their offspring are thought to have RCC risks similar to those in the general population. No special management is recommended for mutation-negative members of mutation-positive families.
Early detection of at-risk individuals affects medical management
More information is needed on the childhood incidence of RCC in HLRCC-affected individuals. One study reported a 17-year-old male who presented with cervical adenopathy and a palpable left flank mass. His father had died of metastatic RCC at age 40 years, and others in the family had skin and uterine leiomyomas. The patient agreed to DNA banking until a genetic test for HLRCC became available, and subsequently gene sequencing revealed a novel mutation (1164delA) in FH, permitting surviving family members to be tested. Because of the early onset of disease manifestations, earlier genetic testing could provide valuable guidance for these families.
There is no consensus on what comprises appropriate clinical surveillance.
It has been suggested that individuals with the clinical diagnosis of HLRCC, individuals with heterozygous mutations in FH without clinical manifestations, and at-risk family members who have not undergone molecular genetic testing undertake the following regular surveillance, performed by physicians familiar with the clinical manifestations of HLRCC.
Skin. There are some published recommendations to perform skin exams on a regular basis, but there is no consensus regarding frequency of skin exams, and recommendations have not been prospectively validated.
Uterus. For women with an intact uterus, annual gynecologic consultation is recommended, accompanied by magnetic resonance imaging (MRI) of the pelvis to assess severity of uterine leiomyomas and to search for changes suggestive of developing leiomyosarcoma.[3,5,145]
Renal. In view of the aggressive nature of this disease, annual imaging with either computerized tomography (CT) scan with contrast or MRI with gadolinium is warranted even if the initial (baseline) evaluation reveals normal kidneys. The age to initiate renal screening is uncertain, however, because HLRCC has been described in children as young as 10 years. The HLRCC Family Alliance recommends annual imaging beginning at age 8 years in children at risk of HLRCC and those with HLRCC.
Any suspicious renal lesion (indeterminate, questionable, or complex cysts) at a previous examination should be closely followed with periodic CT scan or MRI. Additional use of renal ultrasound examination is helpful in the characterization of cystic lesions. It should be cautioned that ultrasound examination alone is never sufficient. Renal tumors should be evaluated by a urologic oncology surgeon familiar with the HLRCC-related renal cancer.[148,149]
Because of the aggressive growth of these tumors, patients warrant regular surveillance with a low threshold for early surgical intervention for solid renal lesions. This strategy differs from that described for several other hereditary kidney cancer syndromes, in which the tumor behavior is more indolent, and for which observation may be a viable option.[134,148,149]
Cutaneous leiomyomas are most appropriately examined by a dermatologist. Treatment of cutaneous leiomyomas is difficult. Surgical excision may be performed for a solitary painful lesion. Lesions can be treated by cryoablation and/or lasers. Several medications, including calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and antiepileptic drugs, reportedly reduce leiomyoma-related pain. Results are pending from a randomized clinical trial (09-C-0072 [NCT00971620]) that used botulinum toxin A (Botox) for the treatment of pain associated with cutaneous leiomyomas.
Uterine leiomyomas are best evaluated by a gynecologist. The uterine leiomyomas of HLRCC are treated in the same manner as sporadic leiomyomas. However, because of the multiplicity, size, and potential rapid growth observed in HLRCC-related uterine leiomyomas, most such women may require medical and/or surgical intervention earlier and more often than would be expected in the general population. Medical therapy (currently including gonadotropin-releasing hormone agonists, anti-hormonal medications, and pain relievers) may be used to initially treat uterine leiomyomas, both to decrease their size in preparation for surgical removal and to provide temporary relief from leiomyoma-related pain. When possible, myomectomy to remove leiomyomas while preserving the uterus is the treatment of choice. Hysterectomy should be performed only when necessary.[5,145]
Because of their biological aggressiveness, efforts aimed at early detection of HLRCC-related RCC is prudent, although it must be acknowledged that there currently is no proof that early detection in this context is clearly associated with improved survival. Surgical excision of these malignancies appears to require earlier and more extensive surgery than that required for other hereditary kidney cancers. Further studies may demonstrate that even small tumors are of a high histologic grade upon pathologic review. Total nephrectomy or partial nephrectomy with a wide margin should be considered in individuals with a detectable renal mass, including small, subcentimetric tumors.[134,148,149]
Recent studies suggest that HIF overexpression is involved in HLRCC tumorigenesis.[167,168] Therefore, potential targeted therapies for HLRCC-associated tumors may include, for example, anti-HIF therapies, such as R59949, that regulate prolyl hydroxylase activity, thus preventing HIF accumulation.
Loss of oxidative phosphorylation resulting from biallelic inactivation of FH renders HLRCC tumors almost entirely reliant on aerobic glycolysis for meeting cellular adenosine triphosphate and other bioenergetics requirements. Consequently, aerobic glycolysis is being explored as a therapeutic strategy.[169,170] A phase II study (10-C-0114[NCT01130519]) examining the combination of bevacizumab and erlotinib for the treatment of advanced HLRCC is ongoing and is based partly on the premise that this combination might inhibit effective glucose delivery to tumor cells.
Other investigations  evaluating the known consequences of FH inactivation in HLRCC kidney cancer have confirmed very high expression of NAD(P)H dehydrogenase quinine 1 (NQO1) in HLRCC kidney tumors, compared with that seen in two other types of hereditary RCC, including ccRCC from VHL disease and type 1 papillary RCC from HPRC families. The activation of an oxidative stress response pathway mediated by NRF2, a transcription factor that regulates the transcription of NQO1, could explain NQO1 overexpression in these tumors. Vandetanib, an oral VEGFR2 and EGFR inhibitor with additional activity against abl-1 kinase, has potent activity against FH-deficient cells in vitro and induces regression of HLRCC-derived xenografts in mice. The activity of vandetanib in this model is mediated, at least in part, by its ability to disrupt the NRF2-mediated cytoprotective oxidative stress response pathway in an Abl-dependent fashion. Furthermore, metformin, an inhibitor of 5’–AMP activated protein kinase (AMPK), was synergistic with vandetanib both in vitro and in mouse xenografts derived from FH-deficient human renal cancer. These data provide the basis for a newly instituted clinical trial (NCT02495103) that will evaluate the efficacy of this combination in HLRCC patients with advanced kidney cancer.
General information about clinical trials is also available from the NCI website.
Prognosis is quite good for cutaneous and uterine manifestations of HLRCC. Local management of cutaneous manifestations, when required, and hysterectomy, where indicated, will address these sites fairly effectively and with minimal long-term consequences or sequelae. The incidence of uterine leiomyosarcomas is likely quite low and is unlikely to substantively affect median survival at a cohort level. RCC in the context of HLRCC is a considerably more ominous manifestation, and the 10% to 32% of HLRCC patients who develop RCC [3,5,135,146] are at high risk of developing metastatic disease. Metastatic RCC associated with HLRCC is characterized by an aggressive clinical course and is uniformly fatal in the absence of effective intervention. We do not currently have sufficiently large patient cohorts or databases to provide a precise estimate of survival in this patient subgroup.
There are two major unmet needs in the management of patients with HLRCC. The first is the ability to detect RCC earlier and with a higher degree of precision. Development of blood-based or imaging tools that permit cost-effective surveillance of the kidneys of patients with HLRCC will have a major positive effect on the outcomes of these individuals. The second major unmet need is a more accurate determination of the genotype-phenotype correlations with the various genetic lesions found in the FH gene. New polymorphisms in the FH gene are frequently of uncertain significance, and considerable effort needs to be expended to determine their clinical significance. Devising in silico prediction tools and linking these to robust patient databases and registries will assist in expanding our understanding of the consequences of specific FH gene variants.
Birt-Hogg-Dubé syndrome (BHD) (OMIM) is an autosomal dominant inherited hamartomatous disorder caused by germline mutations in the folliculin (FLCN) gene. First described by Birt in 1977, BHD often causes cutaneous hamartomas such as fibrofolliculomas and trichodiscomas. The clinical characteristics of BHD include not only cutaneous manifestations (fibrofolliculomas, trichodiscomas), but also pulmonary cysts/history of spontaneous pneumothorax, and various histology types of renal tumors. Acrochordons can be found in BHD but are a common finding in the general population and are not specific.[174-176] Disease severity can vary significantly. Skin lesions typically appear during the third or fourth decade of life and increase in size and number with age. Lung cysts are mainly bilateral and multifocal; most individuals are asymptomatic but have a high risk of spontaneous pneumothorax. Approximately 15% to 30% of individuals with BHD develop renal tumors, which are typically bilateral, multifocal, and slow growing; the median age at tumor diagnosis is 46 to 48 years.[10,177] The most common tumors are hybrid oncocytic tumors (a mixture of oncocytoma and chromophobe histologic cell types) (50%), chromophobe RCC (30%), and oncocytomas (9%). Clear cell and papillary tumors have been described but make up less than 10% of BHD renal tumors. Some families present with renal tumors and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.[178,179]
The clinical characteristics of BHD include cutaneous hamartomas of the skin, including fibrofolliculomas (specific cutaneous lesions), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly among family members and between families. To date, there is no evidence of increased risk of skin cancer or malignant transformation of these hamartomatous lesions. In 2001, a family-based study showed that patients with the clinical diagnosis of BHD were seven times more likely than clinically unaffected family members to develop renal tumors. It also demonstrated that patients with the clinical diagnosis of BHD were 50 times more likely than clinically-unaffected family members to develop a spontaneous pneumothorax. That study confirmed that renal tumors and spontaneous pneumothorax are both major manifestations of BHD. To date, there is no evidence of increased overall mortality or decreased pulmonary function in BHD patients. Renal tumors associated with BHD are relatively indolent. Most appropriately managed patients will require no more than one partial nephrectomy during their lifetimes. Metastatic disease, although described, is rare.
FLCN encodes a transcript of 5.5 kb containing 14 exons. In BHD patients, FLCN mutations have been identified in all translated exons, except for exons 8 and 10.[7,181] FLCN encodes a 64-kDa protein, folliculin (FLCN), which is highly conserved among species.
More than 100 affected families from various populations have been described in various countries, including the United States, United Kingdom, Japan, Denmark, Spain, Italy, Australia, Canada, and the Netherlands.[7,182,183]
No correlation has been established between specific FLCN mutations and renal, pulmonary, and cutaneous manifestations. However, it was reported that individuals who have a deletion in the polycytosine tract of exon 11 may have a lower risk of developing renal cancers than individuals with other mutations, but the sample size was small and this observation was not replicated in a subsequent study. On the basis of three major clinical manifestations, penetrance of BHD is considered to be very high. Anticipation is not known to occur in BHD.
The identification of a somatic "second hit" in most BHD-associated tumors strongly suggests that FLCN functions as a tumor suppressor. Both somatic point mutations in the wild-type FLCN allele and loss of heterozygosity have been identified, although the former appears to be the more common mechanism of inactivation of the second allele. The precise mechanisms by which inactivation of FLCN leads to tumorigenesis remain to be elucidated. However, folliculin, the protein product of FLCN, has been implicated as a component of the cellular energy–sensing system. Both folliculin and two recently identified folliculin interacting proteins, FNIP1 and FNIP2, appear to interact with AMPK.[182,185] AMPK is a major cellular energy and nutrient sensor and regulates activity of mTOR in response to these stimuli. Additionally, both folliculin and FNIP1 are phosphorylated by AMPK, although the significance of this posttranslational modification is not clearly understood.
The effects of folliculin loss on mTOR activity have been studied by several groups. Tissue-specific activation of both mTORC1 and mTORC2 was demonstrated in two independently generated kidney-specific FLCN knockout mouse models, suggesting that mTOR may play a role in the development of BHD-related tumors.[187,188] More recent work suggests that aerobic glycolysis is upregulated as a consequence of FLCN inactivation. This glycolytic shift appears to be a consequence of constitutive AMPK activation in FLCN-null cells. AMPK activation has been shown to upregulate HIF1 and is well studied as a transcriptional activator of several genes necessary for aerobic glycolysis.
The three major features of BHD include cutaneous lesions, pulmonary cysts and spontaneous pneumothorax, and renal tumors.[7,181]
Individuals with BHD usually present with multiple, small, skin-colored, dome-shaped papules distributed over the face, neck, and upper trunk. The characteristic dermatologic manifestations include fibrofolliculomas (hamartomas of the hair follicle) and trichodiscomas.[8,190] The age at diagnosis of cutaneous lesions ranges from 20 to 72 years (median age, 54 years). Only a very small percentage of FLCN mutation carriers lack cutaneous manifestations,[7,178,179] suggesting that FLCN is highly penetrant for this syndromic phenotype. Approximately 84% of patients in whom skin lesions are biopsied are found to have fibrofolliculomas, which are suggestive of BHD. Histologically, fibrofolliculomas are characterized by multiple anastomosing epithelial strands emanating from a central follicle. Mucin-rich or thick connective tissue stroma may encapsulate the epithelial component. The molecular biology of fibrofolliculoma is being elucidated. Some describe these as lesions that emanate from the sebaceous mantle of the hair follicle. The underlying molecular mechanism, which stems from FLCN loss and drives the development of fibrofolliculomas, is unclear but is possibly the result of increased WNT signaling. Fibrofolliculomas and trichodiscomas are different stages of a single pathologic process. Trichodiscomas consist of a round or elliptical well-demarcated proliferation of thick fibrous and vascular stroma in the reticular dermis. Trichodiscomas are also associated with BHD, but they are not specific to this disorder.
Pulmonary cysts and spontaneous pneumothorax
Lung cysts are present in 89% of BHD patients when CT imaging is performed. These cysts are often bilateral and multifocal and are located predominantly within the lower lobes of the lung. Most BHD-related lung cysts are asymptomatic; however, they have an increased risk of developing spontaneous pneumothorax. Patients with a mutation in FLCN and a family history of spontaneous pneumothorax had a statistically significant increased risk of spontaneous pneumothorax compared with BHD patients without a family history of spontaneous pneumothorax (P = .011).
The occurrence of spontaneous pneumothorax is similar among men (20%) and women (29%). Patients with BHD who suffer spontaneous pneumothorax do so at an early age, typically before the fifth decade. Although spontaneous pneumothorax typically occurs before age 22 years, the oldest reported age at occurrence is 71 years. The probability of having the first spontaneous pneumothorax by age 30 years is 6% (95% CI, 3–10%), and by age 50 years is 75% (95% CI, 19–32%).
The clinical presentation of spontaneous pneumothorax ranges from asymptomatic to dyspnea and chest pain. Clinical findings include tachypnea or decreased to absent breath sounds. Radiographic investigation may require a high-resolution chest CT to confirm the diagnosis because a chest x-ray may not be sensitive enough to detect a loculated pneumothorax. Up to 75% of patients with a history of spontaneous pneumothorax experience a second one. Differences in reported spontaneous pneumothorax recurrence may reflect the efficacy of different treatment modalities.
Histologic findings of pleuro-pulmonary lesions associated with BHD patients include thin-walled pleural and subpleural cysts and bullae, intra-parenchymal air cysts, pleural blebs and changes consistent with spontaneous pneumothorax, and underlying emphysematous changes in lung tissue parenchyma adjacent to the bullae.
Approximately 25% to 35% of individuals with BHD develop renal tumors,[7-10] which are multifocal in 65% of cases and often bilateral. The frequency of renal tumors among patients with BHD whose medical records were reviewed was 20%, and the frequency of renal tumors among BHD patients evaluated by CT scan was 29%. Most renal tumors associated with BHD are slow growing. Median age at diagnosis is 48 to 50 years (range, 31–71 years).[146,193] Men developed renal tumors more often than did women (27 males; 11 females). Renal tumors associated with BHD seem to occur at a younger age than do sporadic forms of RCC, in which the median age at diagnosis is 64 years. Figure 5 depicts bilateral renal tumors in a patient with BHD.
The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumors (67%), chromophobe renal cell cancer (23%), and renal oncocytoma (3%). Only renal oncocytoma is considered a benign tumor. Other histologic renal tumor subtypes, including clear cell renal cell cancer and papillary renal carcinoma, occur uncommonly in BHD patients.
Of 70 BHD patients with renal tumors and FLCN mutation, five (7%) have reportedly died from metastatic RCC. The tumor histology in these five patients included clear cell, tubulo-papillary, and/or papillary histologic features, which are known to have a more biologically aggressive natural history. Death related to BHD-related oncocytoma and chromophobe neoplasms is exceedingly uncommon. Similar to VHL and HPRC, the renal parenchyma of BHD patients commonly shows microscopic renal tumors adjacent to renal cell cancers. The presence of microscopic oncocytosis provides histologic evidence that BHD patients are at lifetime risk of developing clinical renal tumors. It has been shown that 70% of BHD-related renal tumors had either a BHD somatic mutation or an LOH involving the second wild-type FLCN allele. The high frequency of FLCN somatic second hits supports the hypothesis that FLCN functions as a tumor suppressor gene. Acquired somaticFLCN mutations have been only rarely identified in sporadic clear cell renal cell cancer.[195,196]
Bilateral multifocal parotid oncocytomas  have been reported in eight BHD patients.[7,181,197-199] The bilateral, multifocal presentation of these rare tumors, in combination with recent molecular investigations, suggests they are part of the BHD phenotype.
It should be noted that germline FLCN mutations were also found in patients suspected of having BHD because of their specific renal and pulmonary manifestations, in the absence of cutaneous findings.
Lipomas, angiolipomas, collagenomas, cutaneous neurothekeomas, meningiomas, multinodular goiters of thyroid,[202,203] ovarian cysts, parathyroid adenomas, pulmonary histiocytomas, and chorioretinal lesions [203,205] have all been reported in BHD patients. Whether these manifestations are truly associated with BHD remains to be determined.
The evidence associating colonic polyps and neoplasms and BHD is conflicting.[9,196]
Risk assessment for Birt-Hogg-Dubé syndrome
FLCN (BHD) is the only gene known to be associated with BHD. It is located on chromosome 17p11.2. Molecular testing is available for clinical applications such as diagnostic testing and prenatal diagnosis. Fifty-three percent (27 of 51) families with BHD were found to have an insertion or deletion in the polycytosine tract in exon 11 (a mutational "hot spot"). Sequence analysis of all FLCN coding exons (exon 4–14) increases the mutation detection in probands to 84% (51 of 61) and is available on a clinical basis.
Molecular genetic testing performed in a CLIA-certified laboratory is indicated for all individuals known to have or suspected of having BHD, including individuals with the following:
Five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma  with or without family history of BHD.
A family history of BHD with a single fibrofolliculoma or a single renal tumor or history of spontaneous pneumothorax.
Multiple and bilateral chromophobe, oncocytic, and/or oncocytic hybrid renal tumors.
A single oncocytic, chromophobe, or oncocytic-hybrid tumor and a family history of renal cancer with any of above renal cell tumor types.
A family history of autosomal dominant primary spontaneous pneumothorax without a history of lung cyst.
Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a disease-causing mutation, the siblings of the proband are at 50% risk of inheriting the mutation. The degree of clinical severity is not predictable. Prenatal diagnosis for pregnancies at 50% risk is possible if the disease-causing allele of an affected family member has been identified. (Refer to the Cancer Genetics Risk Assessment and Counseling PDQ summary for more information.)
The three major features of BHD include cutaneous lesions, lung cysts and spontaneous pneumothorax, and renal tumors.[7,181] (Refer to the Clinical manifestations section for more detailed descriptions of these manifestations.)
The dermatologic diagnosis of BHD is made in individuals who have five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma. An adequate biopsy (typically a punch biopsy) is required to make a diagnosis of fibrofolliculoma. An expert panel has developed the following diagnostic criteria for BHD (patients must fulfill one major or two minor criteria for diagnosis):
At least five fibrofolliculomas or trichodiscomas, at least one histologically confirmed, of adult onset.
Pathogenic FLCN germline mutation.
Multiple lung cysts: bilateral, basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax.
It is important to distinguish between BHD-associated renal cancer and sporadic RCC because this may have implications for management. Genetic testing for a mutation inFLCN, a family history of BHD, or the presence of extra-renal manifestations associated with BHD are helpful in establishing a diagnosis of this condition. Because a variety of histologic variants of kidney cancer can be seen in association with BHD, it is often necessary to make a histologic diagnosis to help differentiate between the benign tumors (oncocytomas) and those with a malignant potential (chromophobe, clear cell, and papillary RCC).
The differential diagnosis of pulmonary cysts includes lymphangioleiomyomatosis (LAM); distinguishing this from BHD can be clinically challenging. One study proposed a set of findings that permit differentiation between BHD and LAM. These include bibasilar, peripheral, and subpleural distribution for BHD versus diffuse distribution for LAM; elliptical or lentiform shape for BHD-related cysts versus round shape for LAM; and HMB-45 negativity on immunohistochemical staining for BHD versus HMB-45 positivity for LAM. This approach has not been validated; further study is warranted.
BHD patients display two main clinical presentations. Most commonly, individuals present with a documented family history of BHD. Other presentations include individuals without a BHD family history or one that is unknown. In the former clinical scenario, if the patient's biological relative has a genetic diagnosis with an identified FLCN mutation, the patient may choose to begin evaluation with genetic counseling and mutation testing.
Clinical surveillance for individuals at risk of BHD includes dermatologic, radiological, and histological examinations to identify characteristic cutaneous lesions, renal tumors, and lung cysts, with or without a history of spontaneous pneumothorax. Not all features are present in each at-risk individual, and some BHD family members may have no discernible phenotypic findings (i.e., they are clinically unaffected carriers of deleterious FLCNmutations). This clinical scenario is being encountered with increasing frequency as the number of syndrome-associated genes for which mutation testing can be offered clinically expands. In most disorders, the natural history of genetically abnormal/clinically normal individuals has not yet been well characterized. These major features of BHD are described in the Clinical diagnosis section.
Decisions regarding the use of lifelong surveillance for hereditary RCC syndromes must consider both risks and benefits. Approximately 15% to 29% of individuals with BHD have renal tumors,[9,181] which are commonly bilateral and multifocal and include a number of specific histologies within an individual or family. For at-risk individuals who will undergo periodic imaging for many years even when no tumor is present, a surveillance schedule that minimizes the lifetime dose of radiation is advised.
Contrast-enhanced CT or MRI are both useful modalities for the detection of BHD renal tumors. Ultrasounds (sonograms) alone may not be sufficient for detecting renal tumors because some tumors are isoechoic with the renal parenchyma, but they may help identify renal cysts. If a renal tumor is detected, the patient is referred to a urologic oncology surgeon for management, which may include continued monitoring or surgery, depending mainly on tumor size. If no renal tumor is detected on initial imaging, experts recommend lifelong surveillance at least once every 36 months because of the risk of developing RCC.
Cryotherapy, electrodessication, surgery, and laser therapy have been used with good cosmetic results, but relapse usually occurs because the cutaneous lesions are a manifestation of an inherited skin condition.[209-211] Therefore, patients may require continuous cosmetic care. Some BHD patients are emotionally affected by their dermatologic condition, regardless of the number or extent of cutaneous lesions. Therefore, the psychological state of BHD patients warrants consideration, with skin care recommendations appropriately tailored to individual needs.
Partial nephrectomy is the treatment of choice in the management of BHD-related kidney neoplasms, to preserve optimal long-term kidney function in patients at risk of multiple primary renal tumors. However, this renal-sparing surgery depends on the size and location of the tumors found during surgery. It is important to incorporate knowledge of the high cumulative risk of multifocal and bilateral kidney tumors in this syndrome, as surgical management is planned. In general, renal tumors smaller than 3 cm in diameter may be monitored radiologically under close supervision of the urologic oncology surgeon; immediate surgery may not be required. These are general recommendations, and each case should be evaluated carefully and managed individually. Total nephrectomy may be necessary in some cases.
Surveillance of at-risk individuals and relatives includes abdominal/pelvic CT scans and evaluation of renal tumors by urologic surgeons and radiologists experienced in the management of these complicated patients. Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and eliminates costly and stressful screening procedures in at-risk relatives who have not inherited their family's disease-causing mutation.
The management of spontaneous pneumothorax in BHD patients is similar to that employed in the general population.
The clinical presentation of spontaneous pneumothorax in patients with BHD is variable. Therapy is dictated by the underlying lung condition and general health of the patient. One study reported that of 101 spontaneous pneumothoraces, 78 required medical intervention, and 23 were managed by observation alone. Thirty-five percent of pneumothoraces were treated with tube thoracostomy (chest tube) only; 14% were treated by open thoracotomy and a second treatment, including mechanical or chemical pleurodesis and lung resection; and approximately 13% were treated with combined tube thoracostomy, thoracotomy, and a third treatment, including mechanical or chemical pleurodesis or lung resection. Patients with BHD—especially those with multiple lung cysts—should be advised to avoid or be cautious with scuba diving, air travel, and mechanical ventilation because each exposure increases the risk of spontaneous pneumothorax.
The major cause of morbidity and mortality in BHD is related to renal lesions. Because of the rarity of BHD, it is difficult to generate robust overall survival data on populations of patients with the syndrome; however, when patients are managed with an appropriate surveillance and intervention strategy, their life expectancy should not be significantly different from that of matched individuals in the general population.
Identification of FLCN, the gene responsible for BHD, in 2001 has led to a number of studies elucidating its function and possible genotype-phenotype correlations. Although surveillance followed by surgical resection remains the mainstay of disease management, improvements in early detection and in molecularly targeted early intervention may alter the course of this disease in the kidney and decrease the incidence of overt and/or lethal renal manifestations of the disease.
Hereditary Papillary Renal Cancer Syndrome
Hereditary papillary renal cancer (HPRC) (OMIM) is an autosomal dominant inherited predisposition to the development of bilateral and multifocal type 1 papillary RCC. A germline-activating mutation in the MET proto-oncogene is associated with HPRC susceptibility.[11,172]
No specific environmental risk factors have been reported to cause hereditary or sporadic type 1 papillary RCC. The known major risk factors for HPRC are a biologic relative with bilateral multifocal papillary RCC and/or a known activating mutation in the tyrosine kinase domain of the MET proto-oncogene.[11,212]
The MET gene is located on chromosome 7q31.2 and encodes a 1,390 amino-acid protein. The functional MET receptor is a heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa). The primary single-chain precursor protein is posttranslationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor. Two transcript variants encoding different isoforms have been found for this gene.
The beta subunit of MET was identified as the cell-surface receptor for hepatocyte growth factor (HGF)  and possesses tyrosine-kinase activity. MET transduces signals from the extracellular matrix into the cytoplasm by binding to HGF ligand and regulates proliferation, scattering, morphogenesis, and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. After activation by its ligand, MET interacts with the PI3K subunit PIK3R1, PLCG1, SRC, GRB2, or STAT3, or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades, including RAS-ERK, PI3K/AKT, and PLC-gamma/PKC. The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates prosurvival effects.
Prevalence and founder effects
A novel mutation was identified in exon 16 of the MET gene in two large North American HPRC families. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a common ancestor (founder effect). However, families with identical germline MET mutations who do not share this common ancestral haplotype have also been reported.
Penetrance of mutations
HPRC is highly penetrant (approaching 100%).[12,146,172,217]
To date, all cases of HPRC present with type 1 papillary RCC.[212,218] Extra-renal manifestations associated with this condition have not been reported.
Most germline MET mutations are missense lesions in the tyrosine kinase domain, leading to constitutive activation of the MET protein, with subsequent development of papillary RCC.[11,219]
Renal tumors from HPRC-affected patients also commonly show trisomy of chromosome 7 upon cytogenetic analysis. The trisomy 7 in the HPRC renal tumor tissue includes nonrandom duplication of the mutant MET allele and one chromosome bearing the wild-type allele. A subset of sporadic type 1 papillary RCCs also has somatic MET mutations.
To date, the only recognized manifestation of HPRC is kidney cancer. The mean and median age of onset are 42 and 41 years, respectively. The age at onset may vary widely between families (range, 19–66 years), perhaps influenced by specific genotype. Unlike sporadic tumors, which occur more frequently in males, both sexes appear to be similarly affected by HPRC. Renal tumors in HPRC are most commonly bilateral and multifocal.[212,218] In contrast with many other RCC syndromes, renal cysts are less common in HPRC.[212,218] However, the presentation of HPRC is similar to other forms of kidney cancer in that small tumors may present incidentally, while large lesions can cause the classic triad of flank pain, hematuria, and an abdominal mass. When renal tumors become large, they can metastasize, most commonly to the lungs.
The histopathologic classification of type 1 papillary RCC is defined by small basophilic cells with pale cytoplasm, small oval nuclei, and inconspicuous nucleoli organized in single layers in papillae and tubular structures.[222,223] The HPRC phenotype is limited to the type 1 papillary renal tumor histopathology. Adenomas and multiple microscopic papillary lesions are found in the surrounding renal parenchyma.[12,217] Hereditary and sporadic type 1 papillary RCCs with MET mutations have a similar distinctive morphological phenotype, including macrophages and psammoma bodies. In HPRC, type 1 papillary RCC histology is described as well differentiated/low grade. It has been estimated that patients with HPRC may develop up to 3,400 incipient renal tumors per kidney.
Patients with known HPRC undergo regular surveillance. Papillary RCCs possess specific imaging characteristics that differ from ccRCCs. These tumors are generally hypovascular and enhance only 10 to 30 Hounsfield units after intravenous administration of contrast material. Papillary renal tumors can be mistaken for renal cysts, unless evaluated by careful attenuation measurements before and after contrast enhancement. Ultrasonography used as a single imaging modality can be particularly misleading because these small tumors are often isoechoic and may be missed on repeated examinations.
If kidney function is normal and there is no allergy to contrast, cross-sectional imaging with CT or MRI is considered the best initial imaging technique for identifying these hypovascular renal tumors. Renal ultrasonography is often inadequate for detecting papillary tumors, even when the tumor is clearly present on CT or MRI. Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.
At-risk individuals are generally recommended to undergo periodic kidney imaging throughout their lifetimes, even when no tumors are present. Therefore, MRI may be useful to minimize the lifetime dose of radiation. One approach that has been used is to perform initial cross-sectional imaging at baseline. If there are no tumors present, imaging can be performed periodically. If a tumor smaller than 3 cm is found, imaging should be repeated within the first year to assess the growth rate. Depending upon growth characteristics and the current tumor size, imaging frequency can be adapted to prevent the largest tumor from exceeding 3 cm.
Generally, patients with renal tumors associated with HPRC are candidates for radiologic surveillance until one or more tumors reach 3 cm. At that point, surgical intervention is recommended. (Refer to the Treatment subsection of this summary for more information.)
Genetic testing for HPRC is available at CLIA-certified laboratories. A health professional (usually a physician, geneticist, or genetic counselor) intermediary between the patient and the laboratory is chosen. A genetic counselor or geneticist first reviews the individual and family history and then provides education and counseling about various implications of genetic testing, focusing on how health care management might be altered if the patient were found to be a mutation carrier, and the possible psychosocial and economic impact. Informed consent may then be obtained, and the genetic counselor will assist with contacting the laboratory and coordinating the mutation testing process.
Genetic testing for HPRC may be recommended if an individual has one or both of the following:
A family history of HPRC.
A biologically related family member who has had genetic testing that was positive for a mutation in the tyrosine kinase domain of MET.
MET genetic testing
Conformation-sensitive gel electrophoresis (CSGE) of amplified genomic DNA encoding exons 16 through 19 (tyrosine kinase domain) of the MET proto-oncogene is performed. Then, direct sequence analysis of amplified genomic DNA is performed if CSGE identifies an abnormal exon or region.[11,213,229]
Genetic testing enables early definitive diagnosis of the HPRC syndrome, after which at-risk individuals can be guided to regular surveillance for syndrome-associated phenotypes.
Once HPRC renal tumors reach 3 cm in size, a nephron-sparing partial nephrectomy is usually recommended to minimize the risk of metastatic spread. There are no curative options available for patients with unresectable extra-renal spread of disease. However, there has been significant interest in developing MET-directed systemic therapy for patients with HPRC. Foretinib, a dual MET/VEGFR2 kinase inhibitor with additional activity against a variety of other tyrosine kinases, was evaluated in a multicenter phase II trial in patients with metastatic papillary RCC or bilateral multifocal papillary RCC. The overall response rate in patients with papillary RCC was 13.5%. However, a retrospective analysis revealed that patients with germline MET mutations were particularly sensitive to this agent, with 5 of 10 patients demonstrating a Response Evaluation Criteria In Solid Tumors (RECIST) partial response (overall response rate, 50%), compared with only 5 of 57 demonstrating a partial response in the group without germline MET mutations). More-selective MET inhibitors are currently under investigation for the treatment of papillary RCC.
HPRC-related type 1 papillary RCCs, particularly small tumors confined to the kidneys, tend to be indolent. Consequently, patients present later in life or die of other syndrome-unrelated causes before a renal tumor diagnosis. Surveillance and presymptomatic screening of individuals at risk of HPRC is expected to improve prognosis through early diagnosis, and specialized cancer management (tailored to the biology of syndrome-associated kidney cancer) is expected to improve disease outcome.
Development of blood-based early detection assays, as well as effective systemic therapy for either prevention or treatment of overt disease, would provide new options for individuals with HPRC. Since the penetrance of tumors in HPRC is nearly 100%, this patient population would provide an exciting avenue to study chemoprevention strategies of MET-driven tumors. For advanced disease, many of the MET inhibitors available clinically, including cabozantinib and crizotinib, have other targets. Off-target effects of these agents may not provide antitumor effect while contributing to treatment-related toxicity. Newer MET inhibitors with a more-selective target profile may be clinically active while limiting off-target side effects in this patient population. Other methods to potentiate the activity of and limit toxicity related to MET inhibition may include combination strategies, such as that described with the HSP90 inhibitor ganetespib. The use of an HSP90 inhibitor ganetespib in conjunction with crizotinib was shown to act synergistically. In MET-driven tumor models, the current therapy is not curative for patients with metastatic HPRC. Because redundant signaling pathways are often activated with targeted therapy, the mechanisms of resistance to MET inhibition should be further investigated.
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