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Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)

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Last Modified: 09/26/2014

Major Heritable Renal Cell Cancer Syndromes

Von Hippel-Lindau Syndrome
        Introduction
        Genetics
        Molecular biology
        Clinical manifestations
        Tissue manifestations
        Management
        Prognosis
        Future directions
Hereditary Leiomyomatosis and Renal Cell Cancer
        Introduction
        Genetics
        Molecular biology
        Clinical manifestations
        Histopathology
        Management
        Prognosis
        Future directions

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. VHL and HLRCC are summarized in detail in the following sections of this summary. Sections describing the other major syndromes are in progress.

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 
von Hippel-Lindau syndrome (VHL) (AD)VHL 3p26, tumor suppressor (pVHL)ccRCC (multifocal) (28%–45%)CNS hemangioblastoma, retinal angiomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of epididymis and broad ligament
Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD)FH 1q42.1, tumor suppressor (fumarase)‘HLRCC-type RCC’ may be new entity (formerly called papillary type 2) (unknown frequency)Cutaneous leiomyomas, uterine leiomyomas (fibroids)
Birt-Hogg-Dubé syndrome (BHD) (AD)FLCN 17p11.2, tumor suppressor (folliculin)Chromophobe oncolytic hybrid, papillary clear cell oncocytoma (8%–15%)Cutaneous: fibrofolliculomas, trichodiscomas, acrochordons
Pulmonary: lung cysts, spontaneous pneumothoraces
Hereditary papillary renal cancer (HPRC) (AD)MET 7q34, proto-oncogene (hepatocyte growth factor receptor)Papillary type 1 (19%)None known

AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.
Merck Manual 18th edition, 2006.[1].
Lindor et al.[2]; Rennebeck et al.[3]

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

Introduction

VHL (OMIM) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germline mutations 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, and cystadenomas of the epididymis (males) and of the broad ligament (females).[4-7] 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.

Genetics

VHL gene

The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.[8] 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,[9,10] in which the clonal origin or first transformed cell of the tumor occurs only after both VHL alleles 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.[11,12] 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.[13]

Penetrance of mutations

VHL mutations are highly penetrant and overall penetrance is greater than 90% by age 65 years.[11] 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 VHL allele 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 the Genetic diagnosis section of this summary for more information.)

Genotype-phenotype correlations

There are a few highly predictive, direct genotype -phenotype correlations.[14,15]

For example, pheochromocytoma without RCCs is the VHL pattern found in a large family with a single nucleotide change at position 505.[7,14,16] A similar family outside the United States was identified and found to have a common ancestor (i.e., a founder mutation).[16] 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.[16] Mutation types leading to clinical VHL include missense, nonsense, frameshifts, insertions, partial and complete deletions, 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.[17] 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 of mosaicism. Mosaicism is the presence in an individual of two or more cell lines that differ in genotype but which arise from a single zygote.[18] If the postzygotic de novo mutation affects the gonadal cell line, there is a risk of transmitting a germline mutation to offspring.[17]

Allelic disorder

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.[19-21]

Other genetic lesions

In sporadic RCC, other genetic lesions have been found. These include PBRM1, SETD2, and BAP1 and may have relevance in RCC arising in VHL patients. Future studies will define their significance in the hereditary patient population.[22]

Molecular biology

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.[23-25] 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 ubiquinated. 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.[26] Hypoxia activated factor has been shown to increase HIF2-alpha transactivation [27] and HIF1-alpha instability.[28] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha.[29]

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.[30] Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation.[31] Loss of pVHL results in loss of the primary cilium.[32] pVHL binds to and stabilizes microtubules [33] in a glycogen synthase 3–dependent fashion.[34] 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.[25]

Cell cycle control

pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[23] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[35] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[36] pVHL binds to, stabilizes, and transactivates p53 [37] in a phosphorylation-dependent fashion.[38] 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.[39]

Extracellular matrix control

Functional pVHL is needed to form an extracellular fibronectin matrix.[40] Additionally, pVHL directly binds to, phosphorylates, and regulates fibronectin.[41] Collagen IV homeostasis is also regulated by pVHL. pVHL isoforms that are collagen IV binding–incompetent demonstrated a malignant phenotype.[24]

Animal models of VHL

No representative VHL animal models are currently available. Vhlh gene knockout in mice did not produce RCC or hemangioblastomas.[42] Murine homologues of the R200W-induced polycythemia in mice, phenocopying Chuvash polycythemia.[43] A R167Q homologue did not generate RCC.[44] Coordinate inactivation of Vhlh and Pten resulted in a higher rate of cyst formation, but, once again, no obvious RCC was observed.[45] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[46] SETD2,[47] and BAP1 [48] provide new avenues for developing relevant animal models of at least some VHL disease manifestations.

Clinical 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
Neoplasm Mean Age (Range) in y  Cumulative Risk (%)  
Adapted from Choyke et al.[4] and Lonser et al.[5]
Renal cell cancer 37 (16–67)24–45
Pheochromocytoma 30 (5–58)10–20
Pancreatic tumor or cyst 36 (5–70)35–70
Retinal hemangioblastoma 25 (1–67)25–60
Cerebellar hemangioblastoma 33 (9–78)44–72
Brainstem hemangioblastoma 32 (12–4610–25
Spinal cord hemangioblastoma 33 (12–66)13–50
Endolymphatic sac tumor 22 (12–50)10

(Refer to the Clinical diagnosis section of this summary for more information.)

VHL familial phenotypes

Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[12] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[13] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[49] These specific VHL phenotypes are summarized below.

Table 3. Genotype-Phenotype Classification of Families With von Hippel-Lindau Syndromea
Type  Clinical Characteristics 
1Retinal hemangioblastomas
CNS hemangioblastomas
Renal cell cancers
Pancreatic neoplasms and cysts
2APheochromocytomas
Retinal hemangioblastomas
CNS hemangioblastomas
2BPheochromocytomas
Retinal hemangioblastomas
CNS hemangioblastomas
Renal cell cancers
Pancreatic neoplasms and cysts
2CPheochromocytomas only

CNS = central nervous system.
aAdapted from Lonser et al.[5]

Tissue manifestations

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.[50] 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,[51] and their rate of growth varies widely.[52] 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.[50] 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.

Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[52,53] RCCs often remain asymptomatic for long intervals.

Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[5] 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).[54] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[55]

Management

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,[4] as early as 8 years of age.[56] 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.[4] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[4]

Each offspring of an individual with VHL has a 50% chance of inheriting the mutated VHL allele 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.

Genetic testing

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).[57] 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.[57,58] The technique has a detection rate approaching 100%.[57] Newer techniques such as array comparative genomic hybridization (array CGH) are powerful tools for identifying genomic imbalances.

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 VHL mutation 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 not predisposed 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.[6]

Genetic diagnosis

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 the VHL 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.

Clinical diagnosis

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.[5-7]

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  Genetic Testing  Clinical Diagnosis Requirements for Clinical Diagnosis 
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 relativeOne or more of the following is required for a clinical diagnosis:
- Epididymal or broad ligament cystadenomas
- CNS hemangioblastoma
- ccRCC, multifocal
- Pheochromocytoma
- 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., VHL mosaicism)When VHL mutation is unknown or germline negative, but there are clinical signs compatible for VHLEither 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:
- ccRCC
- Pheochromocytoma
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
- Epididymal or broad ligament cystadenomas

CNS = central nervous system; ccRCC = clear cell renal cell cancer; VHL = von Hippel-Lindau syndrome.
Adapted and updated from Glenn et al., 1991 [7] and Pithukpakorn & Glenn, 2004.[6]

Surveillance

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)
Examination/Test  Condition Screened For Starting Age/Frequencya 
OphthalmoscopyRetinal hemangioblastomaFrom infancy; every 6 to 12 mo
Fluorescein angioscopyRetinal hemangioblastomaIf needed (not routinely performed)
Plasma or 24-hour urinary catecholamines and metanephrinesPheochromocytomaFrom age 2 y; yearly and as clinically indicated when blood pressure is elevated
Enhanced MRI of brain/spinebCNS and peripheral hemangioblastomaFrom 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 cystsFrom age 18 y, earlier if indicated; yearly; alternate CT and MRI (reduces radiation)
Ultrasound of abdomenRenal, pancreatic, and adrenal neoplasms and cystsYearly from age 8 to 18 y, earlier if indicated; MRI as clinically indicated
MRI and CT of IACs, audiology, neurologyEndolymphatic sac tumorAny age for hearing loss, tinnitus, or vertigo

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, 2004 [6]; Choyke et al, 1995 [4]; and Lonser et al, 2003.[5]

Surgical interventions

Nephron-sparing surgery (NSS) for VHL was introduced in about 1989 and continues to be widely used for the treatment of VHL-associated ccRCC that is 3 cm or smaller in diameter. One group reported that patients with tumors 3 cm or smaller who underwent NSS had no evidence of metastases and did not need dialysis or kidney transplantation at a median follow-up of 60 months (n = 52).[52]

The same group has since published details about the specific surgical techniques applied and the surveillance guidelines used for VHL ccRCCs that are 3 cm or smaller. In 2011, associated issues including repeat partial nephrectomy and routine removal of 20 or more tumors from a single unit in one setting in VHL ccRCC were also addressed. Of the 30 patients who underwent 34 partial nephrectomies, there were no mortalities during the median follow-up of 52 months (range, 4–187 months); more than 80% of the starting renal function was preserved in this cohort, with the exception of one patient.[59]

Although associated with increased complications, repeat and salvage partial nephrectomy can enable patients to maintain excellent renal functional outcomes and promising oncologic outcomes at intermediate follow-up.This challenging approach is generally executed at centers with significant experience in minimally invasive surgical and nonsurgical techniques.[60]

Ablative techniques

Radiofrequency ablation (RFA)

RCC treatment, which must prevent metastatic disease and spare nephrons, has changed in the last two decades with the emergence of ablative techniques, including RFA and cryoablation (CA).[61] A single-institution study evaluated RCC treatment between 1988 and 2009 in 113 patients with VHL. Renal anatomical survival was analyzed for the following three time periods: 1988 to 1994 (the learning phase of NSS); 1995 to 2003 (routine NSS); and 2004 to 2009 (the emergence of RFA). During a median follow-up of 7.2 years, 251 therapeutic procedures were performed in a total of 176 kidneys. A shift in first-line RCC treatment was observed over time. Between 1988 and 1994, 52% of cases underwent nephrectomy; 75% of cases underwent tumorectomy between 1995 and 2003; and 43% of cases underwent RFA between 2004 and 2009. The combination of NSS and, more recently, RFA has enabled earlier treatment of smaller tumors. This combination of NSS and RFA is associated with a significantly improved renal prognosis in patients with VHL syndrome.[61] A case series of 14 patients with histories of surgical resection demonstrated effective disease control with minimal decrease in renal function after thermal ablation.[62]

CA combined with NSS

There have been large increases in the detection of small renal masses as a result of advances in imaging techniques (computed tomography [CT] and magnetic resonance imaging [MRI]).[63] Clinicians commonly use minimally invasive ablative techniques for small tumors. There has been rapid development of laparoscopic partial nephrectomy and novel ablative techniques such as RFA and CA. The use of CA for small renal masses in particular has been advanced as it combines NSS with a minimally invasive approach. Five years of follow-up on these techniques have shown survival of 82% with RFA and 100% with CA.[63] Percutaneous cryoablation in kidneys advanced after the development of argon technology and ultrathin probes. Together with CT and open-access interventional MRI, percutaneous cryoablation allows real-time intraprocedural monitoring, providing the technical breakthroughs needed to make this approach safe and reproducible.[64] One study included patients with VHL and tumors 5 cm or smaller in a solitary kidney. The average follow-up was 16 months (range, 3–30 months); 3 of 12 patients (25%) required retreatment because of incomplete initial ablation. No cancer-related deaths were reported.[65]

Although clinical application and indications of cryoablation of small renal masses are still not clearly defined, available clinical evidence suggests that CA be reserved for small (<3 cm), solid-enhancing renal masses in older patients with high operative risk. Young age, tumor size larger than 4 cm, hilar tumors, intrarenal tumors, and cystic lesions can be regarded as relative contraindications. Irreversible coagulopathy is widely accepted as an absolute contraindication.[63,66]

Chemotherapy

A 2011 study evaluated the safety and efficacy of sunitinib in VHL patients.[67] 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.[67]

Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[68-70] Modest improvement was observed in patients with retinal hemangioblastomas.[68,69] In a series of six VHL patients treated with SU5416, stabilization in CNS hemangioblastomas was observed in two patients.[70] A study of intravitreally administered anti–vascular endothelial growth factor therapy for a patient with retinal hemangioma yielded mixed results.[71] SU5416 is not licensed for human use.

Level of evidence: 2

VHL in pregnancy

Two studies suggest that pregnancy is associated with hemangioblastoma progression in patients with VHL.[72,73] 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.[72] This study's findings are in contrast with a small, prospective investigation.[73] Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.

Prognosis

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.[56,74-76] 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.[5] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[74,77] 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.

Future directions

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

Introduction

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).

Nomenclature

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.[78] 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.[79] 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.

Genetics

FH Gene

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.[80] 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.[79,81]

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.[81-84] Recently, whole-gene or partial deletions have been identified.

Prevalence

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.[79,82,83,85,86]

Genotype-phenotype correlations

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.[83]

Although smaller studies have suggested the presence of different mutational spectra in FHD and HLRCC,[81,82] a study that included a larger cohort of patients indicated that the mutational distribution is fairly similar in these two entities.[80] 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.[81]

Sequence analysis

Between 80% and 100% of individuals with HLRCC have identifiable, deleterious sequence alterations in FH.[82,83,87]

Genetically related disorders

Fumarate hydratase deficiency (fumaric aciduria, FHD)

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.[88,89] 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.[90] However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.[81]

Somatic mutations

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.[91,92] 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.[91]

Molecular biology

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.[93] This upregulation of the HIF pathway leads to a pseudohypoxic state and upregulation of a transcriptional program contributing to aggressive tumor biology.[94] 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.[95]

Clinical manifestations

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.[79,82,83]

Cutaneous leiomyomas

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.[82] 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.)

Uterine leiomyomas

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 years) than do women in the general population (median age, 45 years).[82,87,96,97]

RCCs

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.[82,87] The median age at detection of RCC was 37 years,[98] although some cases have been reported to occur as early as age 10 years.[99] In contrast with other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[100,101] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.[82]

Uterine leiomyosarcoma

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.[79] To date, germline mutations in FH have been reported in six women with uterine leiomyosarcoma.[102,103] 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.[82] Therefore, the risk of uterine leiomyosarcoma in women with HLRCC is uncertain. This is a question in urgent need of a definitive answer.

Other

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.[104] It remains to be determined whether these manifestations are truly part of the HLRCC phenotype.[87,102,105]

Histopathology

Cutaneous leiomyomas

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.[106]

Uterine leiomyomas

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.[107]

RCC

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.[79] 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.[83,108] 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 germline FH mutations and HLRCC family histories.[108,109] A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.[108,109]

Management

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.

Clinical diagnosis

There is no current consensus on the diagnostic criteria for HLRCC.[110]

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.[111] Collecting duct RCC before age 40 years has been suggested as an additional criterion.[112]

Differential diagnosis

Cutaneous lesions

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 leiomyomas

Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. The majority of uterine leiomyomas are sporadic and nonsyndromic.[97]

RCCs

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.[113]

  • 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.[101]

Genetic testing

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.[114] Laboratories offering genetic testing for use in clinical decision making must be certified under CLIA laws.[115]

Testing strategy

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 diagnosis section 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.[79] 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.[116]

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.[115,117,118]

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.[83]

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.[116] Because of the early onset of disease manifestations, earlier genetic testing could provide valuable guidance for these families.

Surveillance

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 MRI of the pelvis to assess severity of uterine leiomyomas and to search for changes suggestive of developing leiomyosarcoma.[79,82,97]

  • Renal. In view of the aggressive nature of this disease, annual imaging with either 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.[110]

    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.[100,101]

    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.[86,100,101]

Level of evidence (skin surveillance): 5

Level of evidence (uterine surveillance): 4

Level of evidence (renal surveillance): 4

Treatment of manifestations

Cutaneous lesions

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.[119] 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.

Level of evidence: 5

Uterine 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.[82,97]

Level of evidence: 4

RCCs

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.[86,100,101]

Level of evidence: 4

Therapies under investigation

Recent studies suggest that HIF overexpression is involved in HLRCC tumorigenesis.[120,121] 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.

Other investigations [122] that targeted the FH pathway in HLRCC kidney cancer have confirmed very high expression of NAD(P)H dehydrogenase quinine 1 (NQO1) in HLRCC kidney tumors, when compared with two other types of hereditary RCC, including ccRCC from VHL disease, and type 1 papillary RCC from HPRC families. High NQO1 expression predicts enhanced sensitivity to 17-allyl-aminodemethoxy-geldanamycin (AAG), [123] a heat-shock protein inhibitor, resulting in greatly improved anti-tumor activity.[124] It is expected that HLRCC kidney tumors will be especially sensitive to 17-AAG. Animal xenograft studies are in progress to test this hypothesis.[122]

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.[125,126] 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.[127].

General information about clinical trials is also available from the NCI Web site.

Prognosis

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 [79,82,87,98] are at high risk of developing metastatic disease.[100] 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.

Future directions

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.

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