Genetics of Kidney Cancer (Renal Cell Cancer) – Health Professional Version

This executive summary reviews the topics covered in this PDQ summary on the genetics of kidney cancer (renal cell cancer), with hyperlinks to detailed sections below that describe the evidence on each topic.

[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.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2018, about 65,340 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to an estimated 14,970 deaths.[1] This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1.[2] 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). Non-RCCs of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary. Genetic pathogenic variants have been identified as the cause of inherited cancer risk in some RCC–prone families; these pathogenic variants are estimated to account for only 5% to 8% of RCC cases overall.[3,4] It is likely that other undiscovered genes and background genetic factors contribute to the development of familialRCC in conjunction with nongenetic risk factors.

RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inheritedRCC syndromes have been identified:

These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on Renal Cell Cancer Treatment and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatmentfor more information about sporadic kidney cancer.)

Natural History

The natural history of each syndrome is distinct and influenced by several factors, including histologic features and underlying genetic alterations. 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.[5–7]

Family History as a Risk Factor for RCC

RCC accounts for about 4% of all adult malignancies in the United States.[8] Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,9,10] 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 relative risk (RR) in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[9] 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 had either a first-degree relative or a second-degree relative with RCC, with an estimated RR of 2.5 for a sibling of an RCC-affected patient.[4] A study that evaluated 80,309 monozygotic twin individuals and 123,382 same-sex dizygotic twin individuals in Denmark, Finland, Norway, and Sweden found an excess cancer risk in twins whose co-twin was diagnosed with cancer.[10] The estimated cumulative risks were an absolute 5% higher (95% confidence interval [CI], 4%–6%) in dizygotic twins (37%; 95% CI, 36%–38%) and an absolute 14% higher (95% CI, 12%–16%) in monozygotic twins (46%; 95% CI, 44%–48%)—for twins whose co-twin also developed cancer—than that in the overall cohort (32%). Overall heritability of cancer, calculated by assessing the relative contribution of heredity versus shared environment, was estimated to be 33%. Heritability of kidney cancer was estimated to be 38% (95% CI, 21%–55%), with shared environmental factors not showing a significant contribution to overall risk.

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,[3] compared with a median age at diagnosis of 64 years in the overall population.[11]. Bilaterality and multifocality are common in most heritable RCC. A retrospective analysis of 1,235 patients with RCC who underwent genetic testing revealed that 6.1% of this population had positive genetic test results, 75.5% had negative test results, and 18.4% had a variant of unknown significance. The only variable associated with a positive test result was younger age at diagnosis of RCC.[12]

There is no consensus regarding whom to refer for genetic consultation for a possible hereditary kidney cancer syndrome, although the following organizations have offered guidance:

• American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[13]
• VHL AllianceExit Disclaimer.
• Kidney Cancer Research Network of Canada.[14]

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.[15] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to somatic variants in the VHL gene.[16] 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.[17]

References

1. American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available onlineExit Disclaimer. Last accessed January 5, 2018.
2. DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
3. 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]
4. 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]
5. 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]
6. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
7. 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]
8. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2016. CA Cancer J Clin 66 (1): 7-30, 2016 Jan-Feb. [PUBMED Abstract]
9. 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]
10. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
11. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute. Available online. Last accessed November 2, 2017.
12. Nguyen KA, Syed JS, Espenschied CR, et al.: Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test. Cancer 123 (22): 4363-4371, 2017. [PUBMED Abstract]
13. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
14. Reaume MN, Graham GE, Tomiak E, et al.: Canadian guideline on genetic screening for hereditary renal cell cancers. Can Urol Assoc J 7 (9-10): 319-23, 2013 Sep-Oct. [PUBMED Abstract]
15. McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [PUBMED Abstract]
16. 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]
17. Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct. [PUBMED Abstract]

Four major heritable renal cell cancer (RCC) syndromes (von Hippel-Lindau disease [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé syndrome [BHD], and hereditary papillary renal carcinoma [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following sections of this summary.

Syndrome (Inheritance Pattern)	Gene Locus, Gene Type (Protein)	Renal Tumor Pathology (Cumulative Cancer Risk)	Nonrenal Tumors and Associated Abnormalities
AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.
von Hippel-Lindau disease (VHL) (AD) [1,2]	VHL 3p26, tumor suppressor(pVHL)	ccRCC (multifocal) (24%–45%)	CNS hemangioblastoma, retinal angiomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of the pancreas, the epididymis, and the broad ligament
Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD) [3–6]	FH 1q42.1, tumor suppressor (fumarate hydratase)	‘HLRCC-type RCC’ may be new entity (formerly called papillary type 2) (up to 32%)	Cutaneous leiomyomas, uterine leiomyomas (fibroids)
Birt-Hogg-Dubé syndrome (BHD) (AD) [7–10]	FLCN 17p11.2, tumor suppressor (folliculin)	Chromophobe oncocytic hybrid, papillary clear cell oncocytoma (15%–30%)	Cutaneous: fibrofolliculomas/ trichodiscomas
			Pulmonary: lung cysts, spontaneous pneumothoraces
Hereditary papillary renal carcinoma (HPRC) (AD) [11,12]	MET 7q34, proto-oncogene (hepatocyte growth factor receptor)	Papillary type 1 (approaching 100%)	None known

Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affectedby these major RCC syndromes. Autosomal dominant means that it is sufficient for the altered gene to be present in one of the parents and that the chances of transmitting this gene and the disease to the offspring is 50% for each pregnancy. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for the genes associated with 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.)

References

1. Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995. [PUBMED Abstract]
2. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003. [PUBMED Abstract]
3. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PUBMED Abstract]
4. Alam NA, Olpin S, Leigh IM: Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 153 (1): 11-7, 2005. [PUBMED Abstract]
5. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PUBMED Abstract]
6. Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PUBMED Abstract]
7. Toro JR, Wei MH, Glenn GM, et al.: BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet 45 (6): 321-31, 2008. [PUBMED Abstract]
8. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999. [PUBMED Abstract]
9. Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11 (4): 393-400, 2002. [PUBMED Abstract]
10. Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002. [PUBMED Abstract]
11. Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997. [PUBMED Abstract]
12. Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [PUBMED Abstract]

Introduction

Von Hippel-Lindau disease (VHL) (OMIM) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germline pathogenic variants 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 renal cell cancers (ccRCCs) and renal cysts; pheochromocytomas, cysts, cystadenomas, and neuroendocrine tumors (NETs) of the pancreas; endolymphatic sac tumors (ELSTs); and cystadenomas of the epididymis (males) and of the broad ligament (females).[1–4] 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.[5]VHL pathogenic variants occur in all three exons of this gene. Most affected individuals inherit a germline pathogenic variant of VHL from an affected parent and a normal (wild-type) VHL copy from their unaffectedparent. VHL-associated tumors conform to Knudson’s “two-hit” hypothesis,[6,7] 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 pathogenic variant in VHL represents the first “hit,” which is present in every cell in the body. The second “hit” is a somatic pathogenic variant, 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 may proliferate 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.[8,9] 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 pathogenic variants in this small three-exon gene indicates that most family clusters have not arisen from a single founder.

Penetrance of pathogenic variants

VHL pathogenic variants are highly penetrant, with manifestations found in more than 90% by age 65 years.[8] 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 VHL pathogenic variant allele from their affected parent. (Refer to the Genetic diagnosis section of this summary for more information.)

Genotype-phenotype correlations

Specific pathogenic variant types leading to VHL clinical manifestations include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variants of VHL. The specific alteration may influence clinical manifestations. Two major clinical phenotypes of VHL have been described. Type I, commonly associated with large gene deletions, is characterized by the development of all VHL-associated lesions except pheochromocytoma. Type II, more commonly associated with missense variants, is characterized by the development of all clinical manifestations including pheochromocytoma. Type II clinical phenotype is subdivided into Type IIA (low risk of RCC), Type IIB (high risk of renal cell cancer [RCC]), and Type IIC (no RCC development, where the predominant clinical picture is characterized by CNS hemangioblastoma and pheochromocytoma development). Overall, the risk of RCC correlates with the loss of hypoxia-inducible factor (HIF)2-alpha regulation by the specific VHL germline variant.[10–13] Specific alterations can be useful in segregating risks; however, significant overlap exists, and surveillance tailored according to phenotype is not generally advised.

De novo pathogenic variants 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 pathogenic variant 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.[14] A new variant is by definition a postzygotic event, because it is not transmitted from a parent.

Depending on the embryogenesis stage at which the new variant occurs, there may be different somatic cell lineages carrying the variant; 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.[15] If the postzygotic de novo variant affects the gonadal cell line, there is a risk of transmitting a germline variant to offspring.[14]

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 pathogenic variants in VHL in which affected individuals develop abnormally high numbers of red blood cells (polycythemia). The affected individuals have biallelic pathogenic variants in the VHL gene. It had been originally thought that the typical VHL syndromic tumors do not occur in these affected individuals.[16–18]

Other genetic alterations

In sporadic RCC, mutational inactivation of the VHL gene is the most frequent molecular event. In addition to VHL inactivation, sporadic ccRCC tumors harbor frequent variants in other genes, including PBRM1, SETD2, and BAP1.[19,20] Mutational inactivation of PBRM1, SETD2, and BAP1 are “second hit” events occurring after VHLalterations in sporadic ccRCC, and they contribute to development and growth of ccRCC.[21,20] Germline pathogenic variants in PBRM1 and BAP1 result in the development of hereditary forms of ccRCC.[22] The role of PBRM1, BAP1, and SETD2 in VHL-related ccRCC growth and progression is under investigation.

Molecular Biology

The VHL tumor suppressor gene encodes two proteins: a 213 amino acid protein (pVHL30) and a 154 amino acid protein, which is the product of internal translation.[23] The best-studied function of pVHL, linked to its ability to suppress tumor formation, is the regulation of HIF activity. Other reported functions of pVHL include regulation of extracellular matrix formation, microtubule and centrosome maturation, and inactivation of p53.[24–27] 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 a substrate recognition site for HIF as part of an E3 ubiquitin ligase complex.[27] In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated by intracellular prolyl hydroxylases. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome.[28,29]

Hypoxia inactivates prolyl hydroxylases, leading to lack of HIF hydroxylation. Nonhydroxylated HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex for ubiquitination, and, therefore, accumulate. The resulting constitutively high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of genes, including growth and angiogenic factors, enzymes of the intermediary metabolism, and genes promoting stemness-like cellular phenotypes.[30]

HIF1-alpha and HIF2-alpha possess distinct and partially contrasting functional characteristics. In the context of RCC, it appears that HIF2-alpha acts as an oncogene, and HIF1-alpha acts as a tumor suppressor gene. HIF2-alpha may preferentially upregulate Myc activity, whereas HIF1-alpha may inhibit Myc activity.[31] Hypoxia-associated factor has been shown to increase HIF2-alpha transactivation [32] and HIF1-alpha instability.[33] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha protein.[34]

Numerous studies using xenografted or transgenic animal models have shown that inactivation of HIF2-alpha by pVHL is necessary and sufficient for tumor suppression by the pVHL proteins. HIF2-alpha is now an established therapeutic target for VHL-related malignancies.[35–37] Specific HIF2-alpha inhibitors are in preclinical and clinical testing.[38–40]

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.[41] Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation.[42] Loss of pVHL results in loss of the primary cilium.[43] pVHL binds to and stabilizes microtubules [44] in a glycogen synthase 3–dependent fashion.[45] Loss of pVHL or expression of variant pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.[26]

Cell cycle control

pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[24] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[46] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[47] pVHL binds to [48] and facilitates phosphorylation of p53 in an ATM-dependent fashion.[49]

Extracellular matrix control

Functional pVHL is needed for appropriate assembly of an extracellular fibronectin matrix.[50] Additionally, phosphorylation of pVHL regulates binding of fibronectin and secretion into the extracellular space.[51]

Regulation of oncogenic autophagy

In ccRCC, oncogenic autophagy dependent on microtubule-associated protein 1 light chain 3 alpha and beta (LC3A and LC3B) is stimulated by activity of the transient receptor potential melastatin 3 (TRPM3) channel through multiple complementary mechanisms. The VHL tumor suppressor represses this oncogenic autophagy in a coordinated manner through the activity of miR-204, which is expressed from intron 6 of the gene encoding TRPM3. TRPM3 represents an actionable target for ccRCC treatment.[52,53]

Animal models of VHL

VHL knockout mice die in utero. Heterozygous VHL mice develop vascular liver lesions reminiscent of hemangioblastomas.[54] Conditional targeted inactivation of the Vhlh gene in the mouse kidney results in the generation of VHL-resembling cysts but not RCC. Coordinate inactivation of Vhlh and Pten results in a higher rate of cyst formation, but no obvious RCC.[55] Murine homologues of the VHL R200W pathogenic variant induced polycythemia in mice, phenocopying Chuvash polycythemia.[56] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[57] SETD2,[58] and BAP1[59] provide new avenues for developing relevant animal models of at least some VHL 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 components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. At least one study has demonstrated that the incidence of new lesions varies depending on patient age, the underlying pathogenic variant, and the organ involved.[60] Examples of reported mean ages and age ranges of VHL clinical manifestations are summarized in Table 2.

Neoplasm	Mean Age (Range) in y	Cumulative Risk (%)
Adapted from Choyke et al.[1] and Lonser et al.[2]
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 (12–46)	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).[9] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[61] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[62] These specific VHL phenotypes are summarized in Table 3.

Type	Defining Characteristics
RCC = renal cell cancer.
aEach of the VHL subtypes can include other manifestations, such as central nervous system hemangioblastomas; retinal angiomas; renal cysts; cysts, cystadenomas, and neuroendocrine tumors of the pancreas; endolymphatic sac tumors; and cystadenomas of the epididymis (males) and of the broad ligament (females).
1	Absence of pheochromocytomas
	RCC
2A	Pheochromocytomas
	Low risk of RCC
2B	Pheochromocytomas
	High risk of RCC
2C	Pheochromocytomas
	Absence of RCC

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.[63] 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) and minimally invasive,[64] and their rate of growth varies widely.[65] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a simple cyst to a solid lesion was infrequent.[63] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.

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Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[65,66] RCCs often remain asymptomatic for long intervals.

Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[2] 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).[67] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[68]

Retinal hemangioblastomas

Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[69] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 35.9 years.[70] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children as young as 1 year.[2,70,71]

Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[69] The median number of lesions per affected eye is approximately six.[72] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[73]

Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [69] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[74] Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[72,75]

Cerebellar and spinal hemangioblastomas

Hemangioblastomas are the most common disease manifestation in patients with VHL, affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[76] After a mean follow-up of 7 years, 72% of the 225 patients studied developed new lesions.[77] Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P < .01). Partial germline deletions were associated with more tumors per patient than were missense variants (P < .01). Younger patients developed more tumors per year. Hemangioblastoma growth rate was higher in men than in women (P < .01). Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.

ENLARGE

ENLARGE

Pheochromocytomas and paragangliomas

The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%.[78,79] Of patients with VHL-associated pheochromocytomas, 44% developed disease in both adrenal glands.[80] One study reported a mean age at onset for pheochromocytoma in VHL patients of 30 years.[2] The rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL,[81] and approximately two-thirds will experience physical manifestations such as hypertension, tachycardia, and palpitations.[78] Patients with a partial loss of VHL function (Type 2 disease) are at higher risk of pheochromocytoma than are VHL patients with a complete loss of VHL function (Type 1 disease); the latter develop pheochromocytoma very rarely.[10,11,78,82] The rate of VHL germline pathogenic variants in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL.[83]

Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[84] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[80]

The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[79,85] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 years; P < .001).[85] Diagnosis of pheochromocytoma was made in patients as young as 5 years in one cohort,[79] providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.[79]

Pancreatic manifestations

VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts.[1] VHL patients do not have an increased risk of pancreatic adenocarcinoma. Serous cystadenomas are benign tumors and warrant no intervention. Simple pancreatic cysts can be numerous and rarely cause symptomatic biliary duct obstruction. Endocrine function is nearly always maintained; occasionally, however, patients with extensive cystic disease requiring pancreatic surgery may ultimately require pancreatic exocrine supplementation.

Pancreatic NETs are usually nonfunctional but can metastasize (to lymph nodes and liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients.[86] The risk of metastasis was lower in patients with small primary lesions (≤3 cm), in patients without an exon 3 pathogenic variant, and in patients whose tumor had a slow doubling time (>500 days). Nonfunctional pancreatic NETs can be followed by imaging surveillance with intervention when tumors reach 3 cm. Lesions in the head of the pancreas can be considered for surgery at a smaller size to limit operative complexity.

Endolymphatic sac tumors (ELSTs)

ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[87] ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[87,88] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[87,89]

ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[87,88] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[88] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[87]

Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[90,91] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[88,90]

Broad/round ligament papillary cystadenomas

Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[92] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[93] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[94] These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.

Epididymal cysts

More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL.[95] Among symptomatic patients, the most common presentation is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[96]

In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX (CAIX) was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[93]

Management

Risk assessment for VHL

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,[1] as early as 8 years of age.[97] 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.[1] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[1]

Each offspring of an individual with VHL has a 50% chance of inheriting the VHL variant 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 initially offered genetic testing. Germline pathogenic variants in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point variants in the VHL gene (~72% of all pathogenic variants).[98] Using Southern blot analysis and/or quantitative polymerase chain reaction to detect partial or complete gene deletions will detect pathogenic variants in the remaining 28% of VHL families.[98,99] The technique has a detection rate approaching 100%.[98] 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.[100]

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 pathogenic variant is identified in a family member, their biologic relatives who then test negative for the same pathogenic variant 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.[3]

Genetic diagnosis

A germline pathogenic variant 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 pathogenic variant. Approximately 400 unique pathogenic variants in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the variant. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL pathogenic variant is identified, that specific pathogenic variant 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 pathogenic variant 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 pathogenic variant 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 (refer to 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. Refer to Table 4 for more diagnostic details.[2–4]

Since 1998, when a cohort of 93 VHL families in whom all germline pathogenic variants 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.
Adapted and updated from Glenn et al. [4] and Pithukpakorn and Glenn.[3]
With a family history of VHL	Test DNA for the same VHL gene pathogenic variant as previously identified in affected biologic relative(s)	When VHL gene pathogenic variant 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
			– 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 pathogenic variant occurred postzygotically (e.g., VHL mosaicism)	When VHL pathogenic variant 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:
			– ccRCC
			– Pheochromocytoma
			– Pancreatic cysts and/or cystadenomas
			– Endolymphatic sac tumor
			– Epididymal or broad ligament cystadenomas

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 pathogenic variant and those individuals who choose not to be tested for a VHL pathogenic variant 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 = computed 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 VHL Alliance.[101]
Ophthalmoscopy	Retinal hemangioblastoma	Annually from age 1 y
Plasma or 24-hour urinary catecholamines and metanephrines	Pheochromocytoma	From age 5 y; annually and as clinically indicated when blood pressure is elevated
Enhanced MRI of brain/spineb	CNS and peripheral hemangioblastoma	From age 16 y; every 2 y and if symptoms appear
MRI of abdomen with and without contrast	Renal, pancreatic, and adrenal neoplasms and cysts	From age 16 y; annually alternating with ultrasound
Ultrasound of abdomen	Renal, pancreatic, and adrenal neoplasms and cysts	From age 16 y; annually alternating with MRI
Audiology; MRI and CT of IACs; neurology	Endolymphatic sac tumor	Audiology from age 5 y; every 2–3 y or annually if hearing loss, tinnitus, or vertigo. Imaging as needed at any age for hearing loss, tinnitus, vertigo. Annual neurological assessment from age 5 y

Level of evidence: 5

Surgical interventions

The management of VHL has changed significantly as clinicians have learned how to 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.[102,103] 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.[104,105] In 1995, a large, multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC.[106] Because of multiple reports of excellent outcomes, NSS is now considered the surgical standard of care when technically feasible. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. Instead of taking a wide margin traditionally described for NSS, enucleation was developed to allow the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.[107]

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 method to balance over- and under-treatment was sought. The National Cancer Institute evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated when the largest solid lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[65] Later retrospective 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.[108] For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence.[108] 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 as many renal tumors as is clinically feasible may delay the need for further surgical interventions.[109] The use of intraoperative ultrasound is helpful to identify and then remove smaller lesions.[110]

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.[111,112] These surgeries may be best handled at a specialized center with significant experience with the management of hereditary forms of kidney cancer.[113]

Level of evidence: 3di

Ablative techniques

Radiofrequency ablation (RFA) and cryoablation (CA)

Thermal ablative techniques utilize either extreme heating or cooling of a mass in an effort to destroy the tumor. CA and RFA were introduced into the management of small renal masses in the late 1990s.[114,115] 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 (≤4 cm).[116] 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.[117] Since this time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success.[118] Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function.[119] 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.[120]

Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. CA 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 (12.1%).[121] 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.[122–124] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[113,125]

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.[126,127]

Level of evidence: 3di

Chemotherapy

Much of the preclinical data that forms the basis for current systemic treatment strategies stem from the study of VHL alteration. All the large randomized phase III trials investigating aldesleukin, vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, mTOR inhibitors, and checkpoint inhibitors are based on data from the treatment of sporadic clear cell kidney cancer. Despite limited studies investigating these agents in the VHL population with metastatic kidney cancer, they are believed to be efficacious and are available as treatment options. Systemic therapy to limit the development or progression of VHL manifestations has been of interest to many groups.

A 2011 study prospectively evaluated the safety and efficacy of sunitinib in patients.[128] Fifteen patients 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%) had partial responses, versus none of the hemangioblastomas (P = .014). Archival VHL-related tumor specimens were evaluated to determine expression of relevant sunitinib targets. The expression of pFRS2 in hemangioblastoma tissue was 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.[128] A retrospective study of 14 VHL patients with RCC, 10 of whom had metastatic disease, demonstrated significant response in metastatic and primary RCC lesions. Eleven patients had cerebellar hemangioblastomas, and eight had spinal hemangioblastomas. No response was seen in patients with hemangioblastomas.[129]

A study of intravitreally administered pegaptanib, an anti-VEGF therapy, was evaluated in five patients with VHL-associated retinal hemangioblastomas.[130] Only two patients were able to complete the intended therapy, and no responses were seen in the primary tumors. Two patients had decreased retinal thickening and reduced hard exudates. Although the agent is approved by the U.S. Food and Drug Administration for macular degeneration, it is not approved for the treatment of VHL retinal lesions.

Level of evidence: 2

VHL in pregnancy

Two studies have examined the effect of pregnancy on hemangioblastoma progression in patients with VHL.[131,132] 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.[131] This study’s findings are in contrast with a small, prospective investigation.[132] 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.[97,133–135] With increased surveillance of pathogenic variant–positive individuals, the RCC mortality rate is thought to have diminished significantly because of adherence to RCC treatment recommendations including the 3 cm rule.

Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem.[2] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[133,136] 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 generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies and development of targeted systemic therapy. 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.

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89. Megerian CA, Haynes DS, Poe DS, et al.: Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome. Otol Neurotol 23 (3): 378-87, 2002. [PUBMED Abstract]
90. Kim HJ, Butman JA, Brewer C, et al.: Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J Neurosurg 102 (3): 503-12, 2005. [PUBMED Abstract]
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92. Nogales FF, Goyenaga P, Preda O, et al.: An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel-Lindau disease and one aggressive sporadic type. Histopathology 60 (5): 748-57, 2012. [PUBMED Abstract]
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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 renal cell cancer (RCC). Germline pathogenic variants in the fumarate hydratase (FH) gene are responsible for the susceptibility to HLRCC. FH encodes 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.[1] 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 [2] and the name hereditary leiomyomatosis and renal cell cancer (HLRCC) was introduced.

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; inheritance of a single variant FH allele predisposes the individual to develop manifestations of the disease.[3] Inherited biallelic pathogenic variants cause autosomal recessivefumarate hydratase deficiency (FHD), a disorder characterized by rapidly progressive neonatal neurologic impairment including hypotonia, seizures, and cerebral atrophy. (Refer to the Genetically related disorderssection of this summary for more information.)

Renal tumors that develop in individuals who inherit a germline pathogenic variant in FH typically display a loss of heterozygosity because of a second somatic FH pathogenic variant. This finding suggests that loss of function of the fumarate hydratase protein is the basis for tumor formation in HLRCC and supports a tumor suppressor function for FH.[2,4]

Various pathogenic variants in FH have been identified in families with HLRCC. Most are missense pathogenic variants, but nonsense, frameshift, and splice-site variants have been described.[4–7] Recently, whole-gene or partial deletions have been identified.[8]

Prevalence

The prevalence of HLRCC is unknown. It is estimated that several hundred families with HLRCC have been seen at the National Institutes of Health and other centers around the world, but it is likely that HLRCC remains an underrecognized entity.

Penetrance of FH pathogenic variants

On the basis of the observation that most patients with HLRCC have at least one of the three major clinical manifestations, the penetrance of HLRCC in carriers of pathogenic FH variants appears to be very high. However, the estimated cumulative lifetime incidence of RCC varies widely, with most estimates ranging from 15% to 30% in families with germline FH pathogenic variants, depending on ascertainment method and the imaging modalities used.[2,5,6,9–11]

Genotype-phenotype correlations

No genotype –phenotype correlations have been described. Thus, no correlation has been observed between specific FH variants and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.[6]

Although smaller studies have suggested the presence of different variant spectra in FHD and HLRCC,[4,5] a study that included a larger cohort of patients indicated that the variant distribution is fairly similar in these two entities.[3] The predisposition to HLRCC versus FHD likely results from a difference in gene dosage, rather than the location of the FH variant as originally suggested.[4]

Sequence analysis

Using bidirectional DNA sequencing methodology, pathogenic variants in FH have been detected in more than 85% of individuals with HLRCC.[5,6,12]

Genetically related disorders

Fumarate hydratase deficiency (fumaric aciduria, FHD)

FHD, resulting from the inheritance of biallelic pathogenic variants 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 pathogenic variants in FH are found in individuals with FHD.[13,14] To date, RCC has not been reported in FHD-affected individuals, possibly because most individuals with FHD survive only a few months with very few surviving to early adulthood.[15] However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.[4]

Somatic FH pathogenic variants

Biallelic somatic loss of FH 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.[16,17] Only a very low frequency of somatic FH pathogenic variants have been identified in sporadic forms of kidney cancer.[16,18]

Molecular Biology

The mechanisms by which alterations in FH lead to HLRCC are currently under investigation. Biallelic inactivation of FH has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Interruption of the Krebs cycle because of reduced or absent fumarate hydratase activity results in increased levels of intracellular fumarate, which inhibit the activity of hypoxia-inducible factor (HIF) prolyl hydroxylases, resulting in the accumulation of HIF-alpha.[19,20] Inactivating variants of FH also appear to result in the generation of reactive oxygen species, further contributing to the stabilization of HIF-alpha.[21] Activation of the HIF pathway leads to a pseudohypoxic state and upregulation of a transcriptional program contributing to aggressive tumor growth.[22] In addition, accumulated fumarate can activate the antioxidant response pathway which enables cancer cells to survive in an environment of oxidative stress. Fumarate, an electrophile, is able to posttranslationally modify KEAP1 by succination on cysteine sulfhydryls,[23] thereby releasing KEAP1 inhibition of NRF2. The resultant stabilization of NRF2 leads to transcriptional upregulation of antioxidant response element–controlled genes such as aldo-keto reductase family 1 member, B10 (AKR1B10), possibly contributing to the neoplastic process.[24]

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. HLRCC is phenotypically variable; disease severity shows significant intrafamilial and interfamilial variation.[2,5,6]

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 can be painful. Pain is correlated with severity of cutaneous involvement.[5] 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).[5,12,25,26]

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. The exact incidence of RCC in affected individuals remains to be determined, and widely varying estimates have been provided by different groups (1%–60%). The incidence appears to vary on the basis of where the study was performed, the referral patterns of individual groups, and the extent to which individuals were screened for RCC. In studies from the National Cancer Institute (NCI), RCC was identified in approximately 32% of families evaluated.[5,6] The median age at detection of RCC was 37 years,[27] although some cases have been reported to occur as early as age 10 years.[28] In contrast to other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[11,29] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.[5] Figure 4 depicts RCCs in a patient with HLRCC.

ENLARGE

Uterine leiomyosarcomas

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.[2] To date, germline pathogenic variants in FH have been reported in six women with uterine leiomyosarcoma.[30,31] It seems that most FH pathogenic variant–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.[5] Therefore, the risk of uterine leiomyosarcoma in women with HLRCC is uncertain. This is a question in urgent need of a definitive answer.

Other manifestations

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 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.[32] It remains to be determined whether these manifestations are truly part of the HLRCC phenotype.[12,30,33]

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.[34]

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 orangeophilic, 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.[35]

RCCs

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.[2] However, early studies reported that HLRCC is associated with a spectrum of renal tumors ranging from type 2 papillary to tubulopapillary to collecting-duct carcinoma.[6,36] 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 pathogenic variants and HLRCC family histories.[36,37] A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.[36,37]

Management

Diagnosis and testing

Genetic testing for the FH gene is clinically available and performed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. FH currently is the only gene known to be associated with HLRCC. The majority of patients with HLRCC have a germline pathogenic variant in FH.

Because the genetic analysis of HLRCC is complex, any interpretation of a variant of unknown significanceresult 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.[38]

Some experts suggest that a clinical dermatologic diagnosis of HLRCC requires one of the following:[39]

• 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 as above or a combination of two of the following manifestations:[40]

• Surgical treatment for symptomatic uterine leiomyomas before age 40 years.
• Type 2 papillary RCC before age 40 years.
• A first-degree relative who meets one of these criteria.

Collecting duct RCC before age 40 years has been suggested as an additional criterion.[41] Patients with seemingly sporadic tumors who have a negative family history and a single, histologically confirmed cutaneous leiomyoma may test positive for the presence of a germline FH pathogenic variant. Although the percentage of germline pathogenic variants in these patient populations is not known, many centers may refer for genetic counseling and testing any patient with even a single cutaneous leiomyoma, independent of family history.[5]

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. Most uterine leiomyomas are sporadic and nonsyndromic.[26]

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 carcinoma (HPRC). Predisposition to type 1 papillary renal cancer occurs. Inheritance is autosomal dominant.[42]
• 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.[43] Individuals with BHD can present with cutaneous fibrofolliculomas /trichodiscomas and/or with multiple lung cysts and spontaneous pneumothorax. Inheritance is autosomal dominant.[29,44]

Genetic testing

Genetic testing is used clinically for diagnostic confirmation of at-risk individuals. It is recommended that both pretest and posttest genetic counseling be offered to persons contemplating germline pathogenic variant testing.[45] Laboratories offering genetic testing for use in clinical decision making must be certified under CLIA laws.[46]

Testing strategy

Genetic testing for a germline FH pathogenic variant 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.[36,47,48] (Refer to the Histopathology section of this summary for more information.)

Risk to family members

HLRCC is inherited in an autosomal dominant manner.[2] If a parent of a proband is clinically affected or has a disease-causing variant, the siblings of the proband have a 50% chance of inheriting the pathogenic variant. Each child of an individual with HLRCC has a 50% chance of inheriting the pathogenic variant. The degree of clinical severity is not predictable. Prenatal genetic testing may be available in laboratories offering custom prenatal testing for families in which a pathogenic variant 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 pathogenic variant or parental mosaicism.
• The proportion of cases caused by de novo pathogenic variants is unknown as subtle manifestations in parents have not been systematically evaluated; similarly, not all unaffected parents have undergone FHtesting.
• Evaluation of parents of a proband with a suspected de novo pathogenic variant may include genetic testing if the FH disease-causing variant 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 limited family history, 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.[49]

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 variant, each sibling of the proband is at a 50% risk of inheriting the variant.
• If the disease-causing variant 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 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 variant.[46,50,51]

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 pathogenic variant

It is not possible to predict whether HLRCC-related symptoms will occur or, if they do, what the age at onset, type, severity, or clinical characteristics will be in individuals who have a pathogenic variant. 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.[6]

When neither parent of a proband with an autosomal dominant condition has the disease-causing variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, nonmedical explanations include the possibility of alternate paternity or undisclosed adoption. Genetic testing of at-risk family members is appropriate in order to identify the need for continued, lifelong, clinical surveillance. Interpretation of the pathogenic variant test result is most accurate when a disease-causing variant has been identified in an affected family member. Those who have a disease-causing variant are recommended to undergo lifelong, periodic surveillance. Meanwhile, family members who have not inherited the pathogenic variant and their offspring are thought to have RCC risks similar to those in the general population and no special management of these individuals is recommended.

Early detection of at-risk individuals affects medical management

Screening for early disease manifestations in HLRCC is an important aspect of clinical care of affected individuals. Although there are no prospective studies comparing specific renal cancer screening practices, the aggressive nature of HLRCC [40] justifies efforts directed at early identification of cancer before the dissemination of tumor cells. When tumors are small and localized, partial nephrectomy may be a feasible option; however, the infiltrative nature of these tumors has led some groups to suggest a wide margin must be taken to achieve complete resection.[52] Uterine fibroids often cause significant symptoms related to bleeding and a mass effect, but small fibroids may be asymptomatic. As HLRCC fibroids can lead to hysterectomies and loss of the ability to bear children in affected young women, the goal of screening in women interested in preserving fertility is to limit some of these irreversible complications. Although there are no specific management recommendations related to HLRCC-associated fibroids, various management strategies have proven effective in the treatment of sporadic fibroids. These strategies include use of hormonal therapies, pain medications, percutaneous and endovascular procedures, and surgical options. Early referral to a fertility specialist may be useful to assist with family planning.

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 pathogenic variants in FH regardless of clinical manifestations, and at-risk family members who have not undergone 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 periodic imaging including magnetic resonance imaging (MRI) of the pelvis or ultrasound to assess severity of uterine leiomyomas and to search for changes suggestive of developing leiomyosarcoma.[2,5,26,53]
• Renal. In view of the aggressive nature of this disease, annual imaging with either computed tomography (CT) scan with contrast or MRI with gadolinium is warranted even if the initial (baseline) evaluation reveals normal kidneys. Special attention to imaging is warranted in this population because subtle findings, such as a complex cyst, may sometimes represent an aggressive malignancy. The age to initiate renal screening is uncertain, however, because HLRCC has been described in children as young as 10 years. The HLRCC Family AllianceExit Disclaimer recommends annual imaging beginning at age 8 years in children at risk of HLRCC and those with HLRCC.[38] MRI has the advantage of sparing the patient radiation exposure and for this reason it may be preferred over CT for lifetime surveillance of HLRCC patients.

  Any suspicious renal lesion (indeterminate, questionable, or complex cysts) at a previous examination should be closely followed with periodic imaging, preferably using the same modality to allow for comparisons. The use of renal ultrasound examination may be helpful in the characterization of cystic lesions identified on cross-sectional imaging. It should be cautioned that ultrasound examination alone is never sufficient. Renal tumors should be evaluated by a clinician familiar with HLRCC-related renal cancer.[11,29]

  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.[10,11,29]

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. Generally, asymptomatic cutaneous leiomyomas require no treatment. Treatment of symptomatic cutaneous leiomyomas may be difficult if a patient has diffuse disease in a wide distribution. 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.[54] A small, randomized clinical trial (09-C-0072 [NCT00971620]) showed that intralesional injection of botulinum toxin A (Botox) may improve quality of life.[55]

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 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 women desire preservation of fertility, myomectomy to remove leiomyomas while preserving the uterus is the treatment of choice. Hysterectomy should be performed only when necessary.[5,26]

Level of evidence: 4

RCCs

Because of their biological aggressiveness, efforts aimed at early detection of HLRCC-related RCC are 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 at the first sign of disease is recommended, unlike management of other hereditary cancer syndromes. The propensity for lymph node involvement even with small renal tumors may necessitate a lymph node dissection for more appropriate staging.[52] Radical nephrectomy or partial nephrectomy with a wide margin should be considered in individuals with a detectable renal mass, including small, subcentimetric tumors.[10,11,29]

Level of evidence: 4

Therapies under investigation

It has been suggested that HIF1-alpha overexpression is involved in HLRCC tumorigenesis.[19,20] Therefore, potential targeted therapies for HLRCC-associated tumors may include HIF1-alpha targeting agents, when such agents become clinically available.

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, targeting aerobic glycolysis is being explored as a therapeutic strategy.[56,57] 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.[58]

Other investigations [59] evaluating the known consequences of FH inactivation in HLRCC kidney cancer have confirmed very high expression of NAD(P)H dehydrogenase quinine 1 (NQO1) in HLRCC kidney tumors, compared with that seen in two other types of hereditary RCC, including ccRCC from VHL and type 1 papillary RCC from HPRC families. The activation of an oxidative stress response pathway mediated by NRF2, a transcription factor that regulates the transcription of NQO1, could explain NQO1 overexpression in these tumors. Vandetanib, an oral VEGFR2 and EGFR inhibitor with additional activity against Abl-1 kinase, has potent activity against FH-deficient cells in vitro and induces regression of HLRCC-derived xenografts in mice. The activity of vandetanib in this model is mediated, at least in part, by its ability to disrupt the NRF2-mediated cytoprotective oxidative stress response pathway in an Abl-dependent fashion. Furthermore, metformin, an activator of 5’–AMP activated protein kinase (AMPK), was synergistic with vandetanib both in vitro and in mouse xenografts derived from FH-deficient human renal cancer.[60] These data provide the basis for a newly instituted clinical trial (NCT02495103) that will evaluate the efficacy of this combination in HLRCC patients with advanced kidney cancer.

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

Prognosis

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. 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 15% to 30% of HLRCC patients who develop RCC [2,5,12,27] are at high risk of developing metastatic disease.[11] Metastatic RCC associated with HLRCC is characterized by an aggressive clinical course and is uniformly fatal. We do not currently have sufficiently large patient cohorts or databases to provide a precise estimate of survival in this population; however, retrospective cohorts demonstrate that these cancers have worse outcomes than other conventional forms of kidney cancer.[61]

Future Directions

There are two major unmet needs, other than the availability of effective medical therapy for metastatic disease, in the management of patients with HLRCC. The first is the ability to predict who will develop RCC to allow detection 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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55. Naik HB, Steinberg SM, Middelton LA, et al.: Efficacy of Intralesional Botulinum Toxin A for Treatment of Painful Cutaneous Leiomyomas: A Randomized Clinical Trial. JAMA Dermatol 151 (10): 1096-102, 2015. [PUBMED Abstract]
56. Xie H, Valera VA, Merino MJ, et al.: LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther 8 (3): 626-35, 2009. [PUBMED Abstract]
57. Yamasaki T, Tran TA, Oz OK, et al.: Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. Nat Rev Urol 8 (3): 165-71, 2011. [PUBMED Abstract]
58. Linehan WM, Srinivasan R, Garcia JA: Non-clear cell renal cancer: disease-based management and opportunities for targeted therapeutic approaches. Semin Oncol 40 (4): 511-20, 2013. [PUBMED Abstract]
59. Linehan WM, Pinto PA, Srinivasan R, et al.: Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics. Clin Cancer Res 13 (2 Pt 2): 671s-679s, 2007. [PUBMED Abstract]
60. Sourbier C, Ricketts CJ, Matsumoto S, et al.: Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell 26 (6): 840-50, 2014. [PUBMED Abstract]
61. Chen F, Zhang Y, Şenbabaoğlu Y, et al.: Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma. Cell Rep 14 (10): 2476-89, 2016. [PUBMED Abstract]

Introduction

Birt-Hogg-Dubé syndrome (BHD) (OMIM) is an autosomal dominant inherited hamartomatous disorder caused by germline pathogenic variants in the folliculin (FLCN) gene.[1,2] First described by Birt in 1977, BHD is characterized by cutaneous hamartomas known as fibrofolliculomas /trichodiscomas.[3] The clinical characteristics of BHD include not only cutaneous manifestations (fibrofolliculomas/trichodiscomas), but also pulmonary cysts/history of spontaneous pneumothorax, and various histologic types of renal tumors.[4] Acrochordons can be found in BHD but are a common finding in the general population and are not diagnostic.[5–7] Disease severity can vary significantly. Skin lesions typically appear during the third or fourth decade of life and increase in size and number with age. Lung cysts are usually bilateral and multifocal; most individuals are asymptomatic but have a high risk of developing spontaneous pneumothorax. Approximately 15% to 30% of individuals with BHD develop renal tumors, which are typically bilateral, multifocal, and slow growing; the median age at tumor diagnosis is 46 to 50 years.[8–10] The most common tumors are hybrid oncocytic tumors (with features of oncocytoma and chromophobe histologic cell types) (50%), chromophobe renal cell cancer (RCC) (34%), and oncocytomas (9%). Clear cell and papillary tumors have been described but make up less than 10% of BHD renal tumors.[8] Some families present with renal tumors and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.[9,11,12]

Natural history

The clinical characteristics of BHD include specific cutaneous hamartomas of the skin, called fibrofolliculomas/trichodiscomas, pulmonary cysts/history of pneumothorax, and various histologic types of renal tumors. BHD is characterized by phenotypic heterogeneity and disease severity can vary significantly among family members and between families. To date, there is no evidence of increased risk of skin cancer or malignant transformation of these hamartomatous lesions. In 2001, a family-based study showed that patients with the clinical diagnosis of BHD were seven times more likely than clinically unaffected family members to develop renal tumors.[13] It also demonstrated that patients with the clinical diagnosis of BHD were 50 times more likely than clinically-unaffected family members to develop a spontaneous pneumothorax. That study confirmed that renal tumors and spontaneous pneumothorax are both major manifestations of BHD. Renal tumors associated with BHD can be aggressive, but generally are fairly indolent. Most appropriately managed patients will require no more than one partial nephrectomy on each kidney during their lifetimes.[14] Metastatic disease, although described, is rare.[14]

Genetics

FLCN gene

FLCN, a novel tumor suppressor gene, comprises 14 exons located at chromosome 17p11.2.[2] In BHD patients, FLCN pathogenic variants have been identified in all translated exons,[1,15–17] and pathogenic intronic variants have also been described.[18] FLCN encodes a 64-kDa phosphoprotein, folliculin (FLCN), which is highly conserved among species.

Prevalence

More than 200 families affected with BHD from various populations have been described in various countries, including the United States, United Kingdom, Japan, Denmark, Spain, Italy, Australia, Canada, and the Netherlands.[1,9,15,16,19–22]

Genotype-phenotype correlations

No correlation has been established between specific FLCN variants and renal, pulmonary, and cutaneous manifestations. However, it was reported that individuals who have a deletion in the polycytosine tract of exon 11 may have a lower risk of developing renal cancers than individuals with other variants,[15] but the sample size was small and this observation was not replicated in a subsequent study from the same institution.[1] On the basis of the three major clinical manifestations (fibrofolliculomas/trichodiscomas, lung cysts/pneumothorax, and renal tumors), penetrance of BHD is considered to be very high. Anticipation is not known to occur in BHD.

Molecular Biology

The identification of a somatic “second hit” in most BHD-associated renal tumors strongly suggests that FLCNfunctions as a tumor suppressor. Both somatic point mutations (variants) in the wild-type FLCN allele and loss of heterozygosity at chromosome 17p have been identified, although the former appears to be the more common mechanism of inactivation of the second FLCN allele.[23] The precise mechanisms by which inactivation of FLCN leads to tumorigenesis remain to be elucidated. However, folliculin, the protein product of FLCN, has been implicated as a component of the cellular energy–sensing system. Folliculin in association with either of two novel folliculin interacting proteins, FNIP1 and FNIP2, interacts with AMPK.[24,25] AMPK is a major cellular energy and nutrient sensor that regulates the activity of mTOR in response to these stimuli.[26] Additionally, both folliculin and FNIP1 are phosphorylated by AMPK, although the significance of this posttranslational modification is not clearly understood. The C-terminal domain of FLCN is required for its interaction with FNIP1 and FNIP2. Most, but not all, tumor-associated FLCN variants predict for a truncated protein missing this C-terminal domain or they appear to destabilize the FLCN protein.[24,27]

The effects of folliculin loss on mTOR activity have been studied by several groups. Tissue-specific activation of mTORC1 was demonstrated in a kidney-specific FLCN knockout mouse model,[28] in which both mTORC1 and mTORC2 were activated in renal tumors that developed in FLCN heterozygous knockout mice subsequent to loss of the wild-type allele,[29] suggesting that mTOR may play a role in the development of BHD-related tumors. More recent work suggests that aerobic glycolysis is upregulated as a consequence of FLCNinactivation. This glycolytic shift, although moderate, appears to be a consequence of constitutive AMPK activation in FLCN-null cells. AMPK activation has been shown to upregulate hypoxia-inducible factor 1 (HIF1) and is well studied as a transcriptional activator of several genes necessary for aerobic glycolysis.[30] More research on the mechanism(s) of tumor suppressor function of FLCN is required.

Clinical Manifestations

The three major features of BHD include fibrofolliculomas/trichodiscomas, pulmonary cysts and spontaneous pneumothorax, and renal tumors.[1,4,15]

Cutaneous lesions

Individuals with BHD usually present with multiple, small, skin-colored, dome-shaped papules distributed over the face, neck, and upper trunk. The characteristic dermatologic manifestation is termed a fibrofolliculoma or trichodiscoma (hamartoma of the hair follicle).[31] The age at diagnosis of cutaneous lesions ranges from 20 to 72 years (median age, 54 years). Only a small percentage of carriers of FLCN pathogenic variants lack cutaneous manifestations,[1,11,12] suggesting that this syndromic phenotype is highly penetrant in affected individuals. In two large BHD family studies, 73% and 84% of affected patients in whom skin lesions were biopsied were found to have fibrofolliculomas/trichodiscomas.[1,15] Histologically, fibrofolliculomas/trichodiscomas are characterized by multiple anastomosing epithelial strands emanating from a central follicle. Mucin-rich or thick connective tissue stroma may encapsulate the epithelial component.[32] Some describe these as lesions that emanate from the sebaceous mantle of the hair follicle. The underlying molecular mechanism, which stems from FLCN loss and drives the development of fibrofolliculomas/trichodiscomas, is unclear but one report suggests that increased WNT signaling may play a role.[32] Fibrofolliculomas and trichodiscomas are different stages of a single pathologic process.

Pulmonary cysts and spontaneous pneumothorax

Lung cysts are present in 85% to 87% of BHD patients when computed tomography (CT) imaging is performed.[1,15] These cysts are often bilateral and multifocal and are located predominantly within the lower lobes of the lung. Most BHD-related lung cysts are asymptomatic; however, individuals affected with BHD have an increased risk of developing spontaneous pneumothorax. Patients with a pathogenic variant in FLCN and a family history of spontaneous pneumothorax had a statistically significant increased risk of spontaneous pneumothorax compared with BHD patients without a family history of spontaneous pneumothorax (P = .011).[33]

In a study of 198 BHD-affected patients, the occurrence of spontaneous pneumothorax was comparable between men (20%) and women (29%). The age range for initial pneumothorax was 22 to 75 years, but the median age for first occurrence was 38 years [33] and is typically before the fifth decade. The probability of having the first spontaneous pneumothorax by age 30 years was 6% (95% CI, 3%–10%), and by age 50 years was 75% (95% CI, 19%–32%).[33]

The clinical presentation of spontaneous pneumothorax ranges from asymptomatic to dyspnea and chest pain. Clinical findings include tachypnea or decreased to absent breath sounds. Radiographic investigation may require a high-resolution chest CT to confirm the diagnosis because a chest x-ray may not be sensitive enough to detect a loculated pneumothorax. Up to 75% of patients with a history of spontaneous pneumothorax experience a second one. Differences in reported spontaneous pneumothorax recurrence may reflect the efficacy of different treatment modalities.

Histologic findings of pleuro-pulmonary lesions associated with BHD patients include thin-walled pleural and subpleural cysts and bullae, intra-parenchymal air cysts, pleural blebs and changes consistent with spontaneous pneumothorax, and underlying emphysematous changes in lung tissue parenchyma adjacent to the bullae.[11]

Renal tumors

Approximately 25% to 35% of individuals with BHD develop renal tumors,[1,8,13,31] which are multifocal in 65% of cases and often bilateral. The frequency of renal tumors among patients with BHD whose medical records were reviewed was 20%, and the frequency of renal tumors among BHD patients evaluated by CT scan was 29%. Most renal tumors associated with BHD are slow growing. Median age at diagnosis is 48 to 50 years (range, 31–71 years).[10,15,34] Men developed renal tumors more often than did women (27 males; 11 females). Renal tumors associated with BHD seem to occur at a younger age than do sporadic forms of RCC, in which the median age at diagnosis is 64 years.[35] Figure 5 depicts bilateral renal tumors in a patient with BHD.

ENLARGE

The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumors, chromophobe renal cell cancer, and renal oncocytoma. Only renal oncocytoma is considered a benign tumor.[34] Other histologic renal tumor subtypes, including clear cell renal cell cancer (ccRCC) and papillary renal carcinoma, occur uncommonly in BHD patients.[8]

Among 70 BHD patients with renal tumors and an FLCN pathogenic variant seen at the National Institutes of Health and identified through a literature review, five (7%) reportedly died from metastatic RCC.[1] The tumor histology in these five patients included clear cell, tubulo-papillary, and/or papillary histologic features, which are known to have a more biologically aggressive natural history. Death related to BHD-related oncocytoma and chromophobe neoplasms is exceedingly uncommon. Similar to VHL and HPRC, the renal parenchyma of BHD patients commonly shows microscopic renal tumors adjacent to renal cell cancers. The presence of microscopic oncocytosis provides histologic evidence that BHD patients have a lifetime risk of developing renal tumors. The high frequency of FLCN somatic second hits (70%) in BHD-associated renal tumors supports the hypothesis that FLCN functions as a tumor suppressor gene.[23] Acquired somatic FLCN variants have been only rarely identified in sporadic ccRCC.[36,37]

Other manifestations

Bilateral multifocal parotid oncocytomas [38] have been reported in eight BHD patients.[1,15,38,39,16] The bilateral, multifocal presentation of these rare tumors, in combination with recent molecular investigations, have led to the speculation that parotid oncocytomas might be part of the BHD phenotypic spectrum.

It should be noted that germline FLCN variants were also found in patients suspected of having BHD because of their specific renal and pulmonary manifestations, in the absence of cutaneous findings.[16]

Lipomas, angiolipomas,[40] collagenomas,[31] cutaneous neurothekeomas, meningiomas,[41] multinodular goiters of thyroid,[42,43] ovarian cysts,[43] parathyroid adenomas,[40] pulmonary histiocytomas,[44] and chorioretinal lesions [43,45] have all been reported in BHD patients. Whether these manifestations are truly associated with BHD remains to be determined.

Although initial epidemiologic observations linked BHD with an increased risk of colonic polyps, subsequent epidemiologic studies did not appear to confirm this association.[13,37,46]

Management

Risk assessment for Birt-Hogg-Dubé syndrome

Genetic testing

FLCN (BHD) is the only gene known to be associated with BHD. It is located on chromosome 17p11.2.[47] Molecular testing is available for clinical applications such as diagnostic testing and prenatal diagnosis. Fifty-three percent (27 of 51) of families with BHD were found to have an insertion or deletion in the polycytosine tract in exon 11 (a variant hot spot).[15] Bidirectional DNA sequencing of all FLCN coding exons (exon 4–14) resulted in a pathogenic variant detection rate of 84%,[1,15], which has been improved by the development of real time-quantitative polymerase chain reaction and multiplex ligation-dependent probe amplification assays to detect intragenic deletions and duplications [48] and is available on a clinical basis.

Genetic testing performed in a CLIA-certified laboratory is indicated for all individuals known to have or suspected of having BHD, including individuals with the following:

1. Five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma [31] with or without family history of BHD.
2. A family history of BHD with a single fibrofolliculoma or a single renal tumor or history of spontaneous pneumothorax.
3. Multiple and bilateral chromophobe, and/or oncocytic hybrid renal tumors.
4. A single chromophobe, or oncocytic hybrid tumor and a family history of renal cancer with any of above renal cell tumor types.
5. A family history of autosomal dominant primary spontaneous pneumothorax without a history of lung cyst.

Genetic counseling

Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a pathogenic variant, the siblings of the proband are at 50% risk of inheriting the variant. The degree of clinical severity is not predictable. Prenatal diagnosis for pregnancies at 50% risk is possible if the disease-causing allele of an affected family member has been identified. (Refer to the Cancer Genetics Risk Assessment and Counseling PDQ summary for more information.)

Clinical diagnosis

The three major features of BHD include cutaneous lesions, lung cysts and spontaneous pneumothorax, and renal tumors.[1,15] (Refer to the Clinical Manifestations section for more detailed descriptions of these manifestations.)

The dermatologic diagnosis of BHD is made in individuals who have five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma.[31] An adequate biopsy (typically a punch biopsy) is required to make a diagnosis of fibrofolliculoma. An expert panel has developed the following diagnostic criteria for BHD (patients must fulfill one major or two minor criteria for diagnosis):[49]

• Major criteria:
  • At least five fibrofolliculomas/trichodiscomas, at least one histologically confirmed, of adult onset.
  • Germline FLCN pathogenic variant.
• Minor criteria:
  • Multiple lung cysts: bilateral, basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax.
  • Renal cancer: early-onset (age <50 y) or multifocal or bilateral renal cancer, or renal cancer of mixed chromophobe and oncocytic histology.
  • A first-degree relative with BHD.

Differential diagnosis

It is important to distinguish between BHD-associated renal cancer and sporadic RCC because this may have implications for management. Genetic testing for a pathogenic variant in FLCN, a family history of BHD, or the presence of extra-renal manifestations associated with BHD are helpful in establishing a diagnosis of this condition. Because a variety of histologic variants of kidney cancer can be seen in association with BHD, it is often necessary to make a histologic diagnosis to help differentiate between the benign tumors (oncocytomas) and those with a malignant potential (chromophobe, clear cell, and papillary RCC).[34]

The differential diagnosis of pulmonary cysts includes lymphangioleiomyomatosis (LAM); distinguishing this from BHD can be clinically challenging. One study proposed a set of findings that permit differentiation between BHD and LAM.[50] These include bibasilar, peripheral, and subpleural distribution for BHD versus diffuse distribution for LAM; elliptical or lentiform shape for BHD-related cysts versus round shape for LAM; and HMB-45 negativity on immunohistochemical staining for BHD versus HMB-45 positivity for LAM. This approach has not been validated; further study is warranted.

Surveillance

BHD patients display two main clinical presentations. Most commonly, individuals present with a documented family history of BHD. Other presentations include individuals without a BHD family history or one that is unknown. In the former clinical scenario, if the patient’s biological relative has a genetic diagnosis with an identified FLCN pathogenic variant, the patient may choose to begin evaluation with genetic counseling and pathogenic variant testing.

Clinical surveillance for individuals at risk of BHD includes dermatologic, radiological, and histological examinations to identify characteristic cutaneous lesions, renal tumors, and lung cysts, with or without a history of spontaneous pneumothorax. Not all features are present in each at-risk individual, and some BHD family members may have no discernible phenotypic findings (i.e., they are clinically unaffected carriers of deleterious FLCN variants). This clinical scenario is being encountered with increasing frequency as the number of syndrome-associated genes for which pathogenic variant testing can be offered clinically expands. In most disorders, the natural history of genetically abnormal/clinically normal individuals has not yet been well characterized. These major features of BHD are described in the Clinical diagnosis section.

Decisions regarding the use of lifelong surveillance for hereditary RCC syndromes must consider both risks and benefits. Approximately 15% to 29% of individuals with BHD have renal tumors,[13,15] which are commonly bilateral and multifocal and include a number of specific histologies within an individual or family.[34] For at-risk individuals who will undergo periodic imaging for many years even when no tumor is present, a surveillance schedule that minimizes the lifetime dose of radiation is advised.

Contrast-enhanced CT or magnetic resonance imaging (MRI) are both useful modalities for the detection of BHD renal tumors.[34] Ultrasounds (sonograms) alone may not be sufficient for detecting renal tumors because some tumors are isoechoic with the renal parenchyma,[14] but they may help identify renal cysts. If a renal tumor is detected, the patient is referred to a urologic oncology surgeon for management, which may include continued monitoring or surgery, depending mainly on tumor size.[34] If no renal tumor is detected on initial imaging, experts recommend lifelong surveillance at least once every 36 months because of the risk of developing RCC.[14] Because MRI spares the patient of radiation exposure, it is reasonable to assume that it may be the preferred mode of imaging over CT for lifelong surveillance.

Level of evidence: 5

Treatment

Skin

Cryotherapy, electrodessication, surgery, and laser therapy have been used with good cosmetic results, but relapse usually occurs because the cutaneous lesions are a manifestation of an inherited skin condition.[51–53] Therefore, patients may require continuous cosmetic care. Some BHD patients are emotionally affected by their dermatologic condition, regardless of the number or extent of cutaneous lesions. Therefore, the psychological state of BHD patients warrants consideration, with skin care recommendations appropriately tailored to individual needs.

Level of evidence: 5

Renal

Partial nephrectomy is the treatment of choice in the management of BHD-related kidney neoplasms, to preserve optimal long-term kidney function in patients at risk of multiple primary renal tumors. However, this renal-sparing surgery depends on the size and location of the tumors found during surgery. It is important to incorporate knowledge of the high cumulative risk of multifocal and bilateral kidney tumors in this syndrome, as surgical management is planned. In general, renal tumors smaller than 3 cm in diameter may be monitored radiologically under close supervision of the urologic oncology surgeon; immediate surgery may not be required.[34] These are general recommendations, and each case should be evaluated carefully and managed individually. Total nephrectomy may be necessary in some cases.

Surveillance of at-risk individuals and relatives includes abdominal/pelvic MRI or CT scans and evaluation of renal tumors by urologic surgeons and radiologists experienced in the management of these complicated patients. Use of genetic testing for early identification of at-risk family members improves diagnostic certainty and eliminates costly and stressful screening procedures in at-risk relatives who have not inherited their family’s disease-causing variant.

Level of evidence: 4

Spontaneous pneumothorax

The management of spontaneous pneumothorax in BHD patients is similar to that employed in the general population.[33]

The clinical presentation of spontaneous pneumothorax in patients with BHD is variable. Therapy is dictated by the underlying lung condition and general health of the patient. One study reported that of 101 spontaneous pneumothoraces, 78 required medical intervention, and 23 were managed by observation alone.[33] Thirty-five percent of pneumothoraces were treated with tube thoracostomy (chest tube) only; 14% were treated by open thoracotomy and a second treatment, including mechanical or chemical pleurodesis and lung resection; and approximately 13% were treated with combined tube thoracostomy, thoracotomy, and a third treatment, including mechanical or chemical pleurodesis or lung resection. Patients with BHD—especially those with multiple lung cysts—should be advised to avoid or be cautious with scuba diving, air travel, and mechanical ventilation because each exposure increases the risk of spontaneous pneumothorax.[33]

Level of evidence: 4

Prognosis

The major cause of morbidity and mortality in BHD is related to renal lesions. Because of the rarity of BHD, it is difficult to generate robust overall survival data on populations of patients with the syndrome; however, when patients are managed with an appropriate surveillance and intervention strategy, their life expectancy should not be significantly different from that of matched individuals in the general population.

Future Directions

Identification of FLCN, the gene responsible for BHD, in 2001 has led to a number of studies elucidating its function and possible genotype-phenotype correlations. Although surveillance followed by surgical resection remains the mainstay of disease management, improvements in early detection and in molecularly targeted early intervention may alter the course of this disease in the kidney and decrease the incidence of overt and/or lethal renal manifestations of the disease. Better understanding of the biochemical function of the FLCN protein should provide insights in target identification and validation of medical therapy for localized, locally advanced, and metastatic disease.

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36. da Silva NF, Gentle D, Hesson LB, et al.: Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. J Med Genet 40 (11): 820-4, 2003. [PUBMED Abstract]
37. Khoo SK, Kahnoski K, Sugimura J, et al.: Inactivation of BHD in sporadic renal tumors. Cancer Res 63 (15): 4583-7, 2003. [PUBMED Abstract]
38. Liu V, Kwan T, Page EH: Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 43 (6): 1120-2, 2000. [PUBMED Abstract]
39. Vinit J, Friedel J, Bielefeld P, et al.: [Birt-Hogg-Dubé syndrome and multiple recurrent tumors]. Rev Med Interne 32 (3): e40-2, 2011. [PUBMED Abstract]
40. Chung JY, Ramos-Caro FA, Beers B, et al.: Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol 35 (5): 365-7, 1996. [PUBMED Abstract]
41. Vincent A, Farley M, Chan E, et al.: Birt-Hogg-Dubé syndrome: two patients with neural tissue tumors. J Am Acad Dermatol 49 (4): 717-9, 2003. [PUBMED Abstract]
42. Drummond C, Grigoris I, Dutta B: Birt-Hogg-Dubé syndrome and multinodular goitre. Australas J Dermatol 43 (4): 301-4, 2002. [PUBMED Abstract]
43. Welsch MJ, Krunic A, Medenica MM: Birt-Hogg-Dubé Syndrome. Int J Dermatol 44 (8): 668-73, 2005. [PUBMED Abstract]
44. Tomassetti S, Carloni A, Chilosi M, et al.: Pulmonary features of Birt-Hogg-Dubé syndrome: cystic lesions and pulmonary histiocytoma. Respir Med 105 (5): 768-74, 2011. [PUBMED Abstract]
45. Walter P, Kirchhof B, Korge B, et al.: Flecked chorioretinopathy associated with Birt-Hogg-Dubé syndrome. Graefes Arch Clin Exp Ophthalmol 235 (6): 359-61, 1997. [PUBMED Abstract]
46. Nahorski MS, Lim DH, Martin L, et al.: Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet 47 (6): 385-90, 2010. [PUBMED Abstract]
47. Schmidt LS, Warren MB, Nickerson ML, et al.: Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 69 (4): 876-82, 2001. [PUBMED Abstract]
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Introduction

Hereditary papillary renal carcinoma (HPRC) (OMIM) is an autosomal dominant inherited syndrome with a predisposition to the development of bilateral and multifocal type 1 papillary renal cell cancer (RCC).[1] A germline -activating pathogenic variant in the MET proto-oncogene is associated with HPRC susceptibility.[2]

No known specific environmental risk factors have been reported to cause hereditary or sporadic type 1 papillary RCC. The known major risk factors for HPRC are a biologic relative with bilateral multifocal type 1 papillary RCC and/or a known activating pathogenic variant in the tyrosine kinase domain of the MET proto-oncogene.[2,3]

Genetics

MET gene

The MET gene is located on chromosome 7q31.2 and encodes a 1,390 amino-acid protein.[4] The functional MET receptor is a heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa). The primary single-chain precursor protein is posttranslationally cleaved to produce the alpha and beta subunits,[5] which are disulfide linked to form the mature receptor. Two transcript variants encoding different isoforms have been found for this gene.

The beta subunit of MET was identified as the cell-surface receptor for hepatocyte growth factor (HGF) [6] and possesses tyrosine-kinase activity. MET transduces signals from the extracellular matrix into the cytoplasm by binding to HGF ligand and regulates proliferation, scattering, morphogenesis, and survival.[7] Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. After activation by its ligand, MET interacts with the PI3K subunit PI3KR1, PLCG1, SRC, GRB2, or STAT3, or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades, including RAS-ERK, PI3K/AKT, and PLC-gamma/PKC.[7] The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities.[7]

Prevalence and founder effects

A novel pathogenic variant was identified in exon 16 of the MET gene in two large North American HPRC families. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a common ancestor (founder effect).[8] However, families with identical germline METpathogenic variants who do not share a common ancestral haplotype have also been reported.[9]

Penetrance of MET pathogenic variants

HPRC is highly penetrant (approaching 100%).[8–10]

Genotype-phenotype correlations

To date, all cases of HPRC present with type 1 papillary RCC.[1–3,8,9] Extra-renal manifestations associated with this condition have not been reported.

Molecular Biology

All germline MET pathogenic variants in HPRC reported to date are missense variants in the tyrosine kinase domain, leading to constitutive activation of the MET kinase and driving the development of papillary RCC.[2,11,12]

Renal tumors from HPRC-affected patients also commonly show polysomy of chromosome 7 upon cytogenetic analysis.[4] Polysomy 7 in the HPRC renal tumor tissue results from nonrandom duplication of the chromosome bearing the wild-type allele.[13] Approximately 15% to 20% of sporadic type 1 papillary RCCs have somatic MET missense variants.[11,14,15]

Clinical Manifestations

Kidney cancer

To date, the only recognized manifestation of HPRC is kidney cancer. The mean and median age of onset are 42 and 41 years, respectively.[10] The age at onset may vary widely between families (range, 19–66 years), perhaps influenced by specific genotype.[9] Unlike sporadic tumors, which occur more frequently in males, both sexes appear to be similarly affected by HPRC. Renal tumors in HPRC are most commonly bilateral and multifocal.[1,3] In contrast with many other RCC syndromes, renal cysts are less common in HPRC.[1,3] However, the presentation of HPRC is similar to other forms of kidney cancer in that small tumors may present incidentally, whereas large lesions can cause the classic triad of flank pain, hematuria, and an abdominal mass. When HPRC renal tumors become large, they can metastasize, most commonly to the lungs.[16]

Histopathology

The histopathologic classification of type 1 papillary RCC is defined by small basophilic cells with pale cytoplasm, small oval nuclei, and inconspicuous nucleoli organized in single layers in papillae and tubular structures.[17,18] The HPRC phenotype is limited to the type 1 papillary renal tumor histopathology. Incipient microscopic lesions, including adenomas and papillary lesions, are commonly found in the adjacent renal parenchyma. It has been estimated that patients with HPRC may develop up to 3,400 renal tumors or incipient lesions per kidney.[19] These pathologic findings should raise suspicion for a germline variant in the MET gene.[8,9] Hereditary and sporadic type 1 papillary RCCs with MET variants have a similar distinctive morphological phenotype, including macrophages and psammoma bodies.[16] In HPRC, type 1 papillary RCC histology is often well differentiated/low grade, but higher-grade tumors can also be observed.[20]

Management

Surveillance

It is recommended that patients with known HPRC undergo regular surveillance. Papillary RCCs, particularly type 1 variants, possess specific imaging characteristics that differ from clear cell RCCs. Type 1 papillary renal tumors are generally hypovascular and enhance only 10 to 30 Hounsfield units after intravenous administration of contrast material. Papillary renal tumors can be mistaken for renal cysts, unless evaluated by careful attenuation measurements before and after contrast enhancement. Ultrasonography used as a single imaging modality can be particularly misleading because these small tumors are often isoechoic and may be missed on repeated examinations.[20]

If kidney function is normal and there is no allergy to contrast, cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is considered the best initial imaging technique for identifying these hypovascular renal tumors. Renal ultrasonography is often inadequate for detecting papillary tumors, even when the tumor is clearly present on CT or MRI.[21] Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.[22]

At-risk individuals are generally recommended to undergo periodic kidney imaging throughout their lifetimes, even when no tumors are present. Therefore, MRI is typically recommended as an imaging modality to minimize the lifetime dose of radiation. One approach that has been used is to perform initial cross-sectional imaging at baseline. If there are no tumors present, imaging can be performed periodically. If a tumor smaller than 3 cm is found, imaging should be repeated within the first year to assess the growth rate.[23] Depending upon growth characteristics and the current tumor size, imaging frequency can be adapted to prevent the largest tumor from exceeding 3 cm.

Generally, patients with renal tumors associated with HPRC are candidates for radiologic surveillance until one or more tumors reach 3 cm. At that point, surgical intervention is recommended. (Refer to the Treatmentsubsection of this summary for more information.)

Genetic testing

Genetic testing for HPRC is available at Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. A health professional (usually a physician, geneticist, or genetic counselor) intermediary between the patient and the laboratory is chosen. A genetic counselor or geneticist first reviews the individual and family history and then provides education and counseling about various implications of genetic testing, focusing on how health care management might be altered if the patient were found to be a carrier of a pathogenic variant, and the possible psychosocial and economic impact. Informed consent may then be obtained, and the genetic counselor will assist with contacting the laboratory and coordinating the pathogenic variant testing process.

Genetic testing for HPRC may be recommended if an individual has one or more of the following:

• A family history of HPRC.
• A biologically related family member who has had genetic testing that was positive for a pathogenic variant in the tyrosine kinase domain of MET.
• More than one papillary type 1 RCC, a papillary type 1 RCC with incipient lesions of the surrounding parenchyma, or a papillary type 1 RCC diagnosed before age 45 years.

MET genetic testing

Bidirectional DNA sequencing of the MET gene using amplified genomic DNA is carried out to identify sequence variants in the coding exons of MET. All HPRC-associated MET pathogenic variants identified to date are located in the four exons encompassing the tyrosine kinase domain. Therefore, initially analyzing only these four exons may identify most sequence variants while reducing the cost and time involved in analyzing the entire gene of 21 exons.[2,4,24] Some CLIA-approved genetic testing laboratories are now offering diagnostic cancer gene panels for analysis by next-generation sequencing technology that include the entire MET gene.

Genetic testing enables early definitive diagnosis of the HPRC syndrome, after which at-risk individuals can be guided to regular surveillance for syndrome-associated phenotypes.

Treatment

Once HPRC renal tumors reach 3 cm in size, a nephron-sparing partial nephrectomy is usually recommended to minimize the risk of metastatic spread. There are no curative options available for patients with unresectable extra-renal spread of disease. However, there has been significant interest in developing MET-directed systemic therapy for patients with HPRC. Foretinib, a dual MET/VEGFR2 kinase inhibitor with additional activity against a variety of other tyrosine kinases, was evaluated in a multicenter phase II trial in patients with metastatic papillary RCC or bilateral multifocal papillary RCC. The overall response rate in patients with papillary RCC was 13.5%.[25] However, patients with germline MET pathogenic variants were particularly sensitive to this agent, with 5 of 10 patients demonstrating a Response Evaluation Criteria In Solid Tumors (RECIST) partial response (overall response rate, 50%), compared with only 5 of 57 demonstrating a partial response in the group without germline MET pathogenic variants. More-selective MET inhibitors are currently under investigation for the treatment of papillary RCC.

Prognosis

HPRC-related type 1 papillary RCCs, particularly small tumors confined to the kidneys, tend to be indolent. Consequently, patients present later in life or die of other syndrome-unrelated causes before a renal tumor diagnosis.[20] Surveillance and presymptomatic screening of individuals at risk of HPRC is expected to improve prognosis through early diagnosis, and specialized cancer management (tailored to the biology of syndrome-associated kidney cancer) is expected to improve disease outcome.[26]

Future Directions

Development of blood-based early detection assays, and effective systemic therapy for either prevention or treatment of overt disease might provide new options for individuals with HPRC. Because the penetrance of tumors in HPRC is nearly 100%, this patient population might provide an exciting avenue to study chemoprevention using MET-directed strategies. There are currently no systemic therapy options approved by the U.S. Food and Drug Administration (FDA) that specifically address the needs of patients with metastatic RCC associated with HPRC. On the basis of limited data from the foretinib study,[25] agents such as cabozantinib (a multitargeted tyrosine kinase inhibitor with activity against MET, which was approved by the FDA for use in patients with metastatic kidney cancer who have progressed on VEGFR-targeted therapy) may be considered. Newer MET inhibitors with a more-selective target profile may be clinically active while limiting off-target side effects in patients with HPRC-associated kidney cancer and are currently under evaluation (NCT02019693). Because redundant signaling pathways are often activated with targeted therapy, the mechanisms of resistance to MET inhibition should be further investigated.

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