[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]
Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2015, about 61,560 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 14,080 deaths. This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1. RCC is distinct from kidney cancer that involves the renal pelvis or renal medulla, and it only applies to cancer that forms in the lining of the kidney bed (i.e., in the renal tubules). Genetic mutations have been identified as the cause of inherited cancer risk in some RCC cancer–prone families; these mutations are estimated to account for only 1% to 2% of RCC cases overall. It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors. About 80% of sporadic RCC is of clear cell histopathology. Non–renal cell cancers of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary.
RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inherited RCC syndromes have been identified:
- von Hippel-Lindau syndrome (VHL).
- Hereditary leiomyomatosis and renal cell cancer (HLRCC).
- Hereditary papillary renal cancer (HPRC).
- Birt-Hogg-Dubé syndrome (BHD).
These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on Renal Cell Cancer Treatment for more information and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)
Natural History Varies by Histopathology
The natural history of each of the RCCs varies according to the characteristic histopathology of the renal tumors that arise in the specific syndrome. Although it is useful to follow the predominant reported natural history of each syndrome, each individual affected will need to be evaluated and monitored for occasional individual variations. The individual prognosis will depend upon the characteristics of the renal tumor at the time of detection and intervention and will differ for each syndrome (VHL, HPRC, BHD, and HLRCC). Prognostic determinants at diagnosis include the stage of the RCC, whether the tumor is confined to the kidney, primary tumor size, Fuhrman nuclear grade, and multifocality.[4-6]
Family History as a Risk Factor for RCC
Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease. The relative risk (RR) is estimated to be 2.5 for a sibling of an RCC-affected patient. This observation was reproducible in a number of studies.[7,8] Analysis of renal carcinomas up to the year 2000 in the Sweden Family-Cancer Database, which includes all Swedes born since 1931 and their biological parents, led to the observation that risk of RCC was particularly high in the siblings of those affected with RCC. The higher RR in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma. Investigators in Iceland studied all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). In addition, they used an extensive computerized database to perform a unique genealogic study that included more than 600,000 Icelandic individuals. The results revealed that nearly 60% of RCC patients in Iceland during this time period had either a first-degree relative or a second-degree relative with RCC.
Because RCC accounts for only about 4% of all adult malignancies in the United States,[2,9] the presence of two or more family members with RCC may suggest a hereditary etiology. Having a relative affected with kidney cancer is one of the known epidemiologic risk factors for this disease. There is a 2.5 times greater chance of RCC arising in a sibling of an affected individual than in someone in the general population.[7,8,10] Young age at onset is also a clue to possible hereditary etiology. In contrast with sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of kidney cancer are generally diagnosed at an earlier age. In a review from the National Cancer Institute of over 600 cases of hereditary kidney cancer, the median age at diagnosis was 37 years, with 70% of the cases being diagnosed at age 46 years or younger, compared with a median age at diagnosis of 64 years in the overall population.. Bilaterality and multifocality are common in most heritable RCC, except in HLRCC.
Other Risk Factors for RCC
Studies of environmental and lifestyle factors contributing to the risk of RCC focus almost exclusively on sporadic (i.e., nonhereditary) RCC. Smoking, hypertension, and obesity are the major environmental and lifestyle risk factors associated with RCC. In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to somatic mutations in the VHL gene. Dietary intake of vegetables and fruits has been inversely associated with RCC. Greater intake of red meat and milk products have been associated with increased RCC risk, although not consistently.
- American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed April 1, 2015.
- DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
- Hung RJ, Moore L, Boffetta P, et al.: Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev 16 (6): 1287-90, 2007. [PUBMED Abstract]
- Vira MA, Novakovic KR, Pinto PA, et al.: Genetic basis of kidney cancer: a model for developing molecular-targeted therapies. BJU Int 99 (5 Pt B): 1223-9, 2007. [PUBMED Abstract]
- Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
- Zbar B, Glenn G, Merino M, et al.: Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol 177 (2): 461-5; discussion 465, 2007. [PUBMED Abstract]
- Hemminki K, Li X: Familial risks of cancer as a guide to gene identification and mode of inheritance. Int J Cancer 110 (2): 291-4, 2004. [PUBMED Abstract]
- Gudbjartsson T, Jónasdóttir TJ, Thoroddsen A, et al.: A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas. Int J Cancer 100 (4): 476-9, 2002. [PUBMED Abstract]
- McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [PUBMED Abstract]
- Teh BT, Giraud S, Sari NF, et al.: Familial non-VHL non-papillary clear-cell renal cancer. Lancet 349 (9055): 848-9, 1997. [PUBMED Abstract]
- Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014. [PUBMED Abstract]
- National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute, 2014. Available online. Last accessed December 5, 2014.
- Brauch H, Weirich G, Hornauer MA, et al.: Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst 91 (10): 854-61, 1999. [PUBMED Abstract]
- Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct. [PUBMED Abstract]
Major Heritable Renal Cell Cancer Syndromes
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.
|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.|
|Merck Manual 18th edition.|
|Lindor et al.; Rennebeck et al.|
|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|
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
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.
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,[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.
Penetrance of mutations
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.)
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). 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 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. 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. 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.[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.
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 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.
|Neoplasm||Mean Age (Range) in y||Cumulative Risk (%)|
|Adapted from Choyke et al. and Lonser et al.|
|Renal cell cancer||37 (16–67)||24–45|
|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 (12–46)||10–25|
|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). 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.
|CNS = central nervous system.|
|aAdapted from Lonser et al.|
|Renal cell cancers|
|Pancreatic neoplasms and cysts|
|Renal cell cancers|
|Pancreatic neoplasms and cysts|
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.
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.
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 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.
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.[57,58] 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 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.
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.
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.
|Family History of VHL||Genetic Testing||Clinical Diagnosis||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., VHL mosaicism)||When VHL mutation 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%.
|Examination/Test||Condition Screened For||Starting Age/Frequencya|
|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.|
|Ophthalmoscopy||Retinal hemangioblastoma||From infancy; every 6 to 12 mo|
|Fluorescein angioscopy||Retinal hemangioblastoma||If needed (not routinely performed)|
|Plasma or 24-hour urinary catecholamines and metanephrines||Pheochromocytoma||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|
|MRI and CT of IACs, audiology, neurology||Endolymphatic sac tumor||Any age for hearing loss, tinnitus, or vertigo|
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.[60,61] 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.[62,63] 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.[69,70] 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.[72,73] 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.[80-82] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[71,83]
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.[84,85]
A 2011 study 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.
Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[87-89] Modest improvement was observed in patients with retinal hemangioblastomas.[87,88] 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.
VHL in pregnancy
Two studies suggest that pregnancy is associated with hemangioblastoma progression in patients with VHL.[91,92] 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.[56,93-95] 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.[93,96] 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.[98,100]
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.[100-103] 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.[98,101,102,104,105]
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,[100,101] 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.
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.[107,108] 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.[110,111] 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.[98,101,102]
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 years) than do women in the general population (median age, 45 years).[101,106,115,116]
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.[101,106] 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,[119,120] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.
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.[121,122] 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.[106,121,124]
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.[102,127] 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.[127,128] A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.[127,128]
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 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. 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.[134,136,137]
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.[98,101,116]
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.[119,120]
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.[105,119,120]
Treatment of manifestations
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.[101,116]
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.[105,119,120]
Therapies under investigation
Recent studies suggest that HIF overexpression is involved in HLRCC tumorigenesis.[139,140] 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  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),  a heat-shock protein inhibitor, resulting in greatly improved anti-tumor activity. It is expected that HLRCC kidney tumors will be especially sensitive to 17-AAG. Animal xenograft studies are in progress to test this hypothesis.
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.[144,145] 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.
General information about clinical trials is also available from the NCI Web site.
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 [98,101,106,117] 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.
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Changes to This Summary (01/29/2015)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added level of evidence 5.
The Surgical interventions subsection was comprehensively reviewed and extensively revised.
Added level of evidence 3di.
The Radiofrequency ablation and cryoablation subsection was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of kidney cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Kidney Cancer (Renal Cell Cancer) are:
- Eric Jonasch, MD (University of Texas, M.D. Anderson Cancer Center)
- Brian Matthew Shuch, MD (Yale University School of Medicine)
- Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)
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Levels of Evidence
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National Cancer Institute: PDQ® Genetics of Kidney Cancer (Renal Cell Cancer). Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/genetics/kidney/HealthProfessional. Accessed <MM/DD/YYYY>.
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