Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)—Health Professional Version - National Cancer Institute

Hereditary Leiomyomatosis and Renal Cell Cancer

In This Section

• Introduction
  • Nomenclature
• Genetics
  • FH gene
  • Prevalence
  • Penetrance of FH pathogenic variants
  • Genotype-phenotype correlations
  • Sequence analysis
  • Genetically related disorders
• Molecular Biology
• Clinical Manifestations
  • Cutaneous leiomyomas
  • Uterine leiomyomas
  • RCCs
  • Uterine leiomyosarcomas
  • Other manifestations
• Histopathology
  • Cutaneous leiomyomas
  • Uterine leiomyomas
  • RCCs
• Management
  • Diagnosis and testing
  • Surveillance
  • Treatment of manifestations
• Prognosis
• Future Directions

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 allelepredisposes the individual to develop manifestations of the disease.[3] Inherited biallelicpathogenic variants cause autosomal recessive fumarate 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 FHtypically 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 FHvariants 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 FHvariant 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 FHpathogenic 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 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 y) 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 y). 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 y) than do women in the general population (median age, 45 y).[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%).[5,6,27] 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,[28] although some cases have been reported to occur as early as age 10 years.[29] In contrast to other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[11,30] 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

Figure 4. Hereditary leiomyomatosis and renal cell cancer–associated renal tumors are commonly unilateral and solitary; in a few individuals, they are multifocal. Red arrow indicates a retroperitoneal lymph node. White arrow indicates a left renal mass.

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.[31,32] It seems that most FHpathogenic 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.[33] It remains to be determined whether these manifestations are truly part of the HLRCC phenotype.[12,31,34]

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.[35]

Uterine leiomyomas

A review of NCI's experience with HLRCC-associated uterine leiomyomas reported that most 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.[36]

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.[6,37] 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.[37,38] A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.[37,38]

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. Most 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 significance result 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.[39]

Some experts suggest that a clinical dermatologic diagnosis of HLRCC requires one of the following:[40]

• 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:[41]

• 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.[42] 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.[43]
• 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.[44] Individuals with BHD can present with cutaneous fibrofolliculomas /trichodiscomas and/or with multiple lung cysts and spontaneous pneumothorax. Inheritance is autosomal dominant.[30,45]

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.[46] Laboratories offering genetic testing for use in clinical decision making must be certified under CLIA laws.[47]

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 diagnosissection of this summary, or individuals who have renal tumors with histologic characteristics consistent with HLRCC.[37,48,49] (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 FH testing.
• 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.[50]

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.[47,51,52]

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 [41] 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.[53] 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.[2,5,26,54]
• 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.[39] 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.[11,30]
  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.[10,11,30]

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.[55] A small, randomized clinical trial (09-C-0072[NCT00971620]) showed that intralesional injection of botulinum toxin A (Botox) may improve quality of life.[56]

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.[53] Radical nephrectomy or partial nephrectomy with a wide margin should be considered in individuals with a detectable renal mass, including small, subcentimetric tumors.[10,11,30]

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.[57,58] 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.[59]

Other investigations [60] 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.[61] 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 [2,5,12,28] 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.[62]

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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15. Badeloe S, Frank J: Clinical and molecular genetic aspects of hereditary multiple cutaneous leiomyomatosis. Eur J Dermatol 19 (6): 545-51, 2009 Nov-Dec. [PUBMED Abstract]
16. Kiuru M, Lehtonen R, Arola J, et al.: Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res 62 (16): 4554-7, 2002. [PUBMED Abstract]
17. Lehtonen R, Kiuru M, Vanharanta S, et al.: Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol 164 (1): 17-22, 2004. [PUBMED Abstract]
18. Linehan WM, Spellman PT, Ricketts CJ, et al.: Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 374 (2): 135-45, 2016. [PUBMED Abstract]
19. Isaacs JS, Jung YJ, Mole DR, et al.: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8 (2): 143-53, 2005. [PUBMED Abstract]
20. Pollard PJ, Brière JJ, Alam NA, et al.: Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14 (15): 2231-9, 2005. [PUBMED Abstract]
21. Sudarshan S, Sourbier C, Kong HS, et al.: Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol 29 (15): 4080-90, 2009. [PUBMED Abstract]
22. Pollard P, Wortham N, Barclay E, et al.: Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 205 (1): 41-9, 2005. [PUBMED Abstract]
23. Alderson NL, Wang Y, Blatnik M, et al.: S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Arch Biochem Biophys 450 (1): 1-8, 2006. [PUBMED Abstract]
24. Ooi A, Wong JC, Petillo D, et al.: An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20 (4): 511-23, 2011. [PUBMED Abstract]
25. Farquhar CM, Steiner CA: Hysterectomy rates in the United States 1990-1997. Obstet Gynecol 99 (2): 229-34, 2002. [PUBMED Abstract]
26. Stewart L, Glenn GM, Stratton P, et al.: Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch Dermatol 144 (12): 1584-92, 2008. [PUBMED Abstract]
27. Muller M, Ferlicot S, Guillaud-Bataille M, et al.: Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin Genet 92 (6): 606-615, 2017. [PUBMED Abstract]
28. 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]
29. Wong MH, Tan CS, Lee SC, et al.: Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC). Fam Cancer 13 (2): 281-9, 2014. [PUBMED Abstract]
30. Linehan WM, Bratslavsky G, Pinto PA, et al.: Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 61: 329-43, 2010. [PUBMED Abstract]
31. Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, et al.: Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet 43 (6): 523-6, 2006. [PUBMED Abstract]
32. Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, et al.: Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer 119 (2): 283-7, 2006. [PUBMED Abstract]
33. Shuch B, Ricketts CJ, Vocke CD, et al.: Adrenal nodular hyperplasia in hereditary leiomyomatosis and renal cell cancer. J Urol 189 (2): 430-5, 2013. [PUBMED Abstract]
34. Matyakhina L, Freedman RJ, Bourdeau I, et al.: Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab 90 (6): 3773-9, 2005. [PUBMED Abstract]
35. Fearfield LA, Smith JR, Bunker CB, et al.: Association of multiple familial cutaneous leiomyoma with a uterine symplastic leiomyoma. Clin Exp Dermatol 25 (1): 44-7, 2000. [PUBMED Abstract]
36. Sanz-Ortega J, Vocke C, Stratton P, et al.: Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol 37 (1): 74-80, 2013. [PUBMED Abstract]
37. Merino MJ, Torres-Cabala C, Pinto P, et al.: The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 31 (10): 1578-85, 2007. [PUBMED Abstract]
38. Merino MJ, Torres-Cabala CA, Zbar B, et al.: Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC): Clinical histopathological and molecular features of the first American families described. [Abstract] Mod Pathol 16 (Suppl): A-739, 162A, 2003.
39. HLRCC Family Alliance: The HLRCC Handbook. Version 2.0. Boston, MA: HLRCC Family Alliance, 2013. Available onlineExit Disclaimer. Last accessed December 14, 2018.
40. Schmidt LS, Linehan WM: Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis 7: 253-60, 2014. [PUBMED Abstract]
41. Smit DL, Mensenkamp AR, Badeloe S, et al.: Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 79 (1): 49-59, 2011. [PUBMED Abstract]
42. Lehtonen HJ: Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer 10 (2): 397-411, 2011. [PUBMED Abstract]
43. Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PUBMED Abstract]
44. 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]
45. Schmidt LS, Linehan WM: Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12 (10): 558-69, 2015. [PUBMED Abstract]
46. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
47. Update: information about obtaining a CLIA certificate. Jt Comm Perspect 26 (12): 6-7, 2006. [PUBMED Abstract]
48. Kopp RP, Stratton KL, Glogowski E, et al.: Utility of prospective pathologic evaluation to inform clinical genetic testing for hereditary leiomyomatosis and renal cell carcinoma. Cancer 123 (13): 2452-2458, 2017. [PUBMED Abstract]
49. Menko FH, Maher ER, Schmidt LS, et al.: Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer 13 (4): 637-44, 2014. [PUBMED Abstract]
50. Refae MA, Wong N, Patenaude F, et al.: Hereditary leiomyomatosis and renal cell cancer: an unusual and aggressive form of hereditary renal carcinoma. Nat Clin Pract Oncol 4 (4): 256-61, 2007. [PUBMED Abstract]
51. American Society of Clinical Oncology: American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21 (12): 2397-406, 2003. [PUBMED Abstract]
52. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
53. Shuch B, Singer EA, Bratslavsky G: The surgical approach to multifocal renal cancers: hereditary syndromes, ipsilateral multifocality, and bilateral tumors. Urol Clin North Am 39 (2): 133-48, v, 2012. [PUBMED Abstract]
54. Patel VM, Handler MZ, Schwartz RA, et al.: Hereditary leiomyomatosis and renal cell cancer syndrome: An update and review. J Am Acad Dermatol 77 (1): 149-158, 2017. [PUBMED Abstract]
55. Ritzmann S, Hanneken S, Neumann NJ, et al.: Type 2 segmental manifestation of cutaneous leiomyomatosis in four unrelated women with additional uterine leiomyomas (Reed's Syndrome). Dermatology 212 (1): 84-7, 2006. [PUBMED Abstract]
56. 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]
57. 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]
58. 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]
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Birt-Hogg-Dubé Syndrome

In This Section

• Introduction
  • Natural history
• Genetics
  • FLCN gene
  • Prevalence
  • Genotype-phenotype correlations
• Molecular Biology
• Clinical Manifestations
  • Cutaneous lesions
  • Pulmonary cysts and spontaneous pneumothorax
  • Renal tumors
  • Other manifestations
• Management
  • Risk assessment for Birt-Hogg-Dubé syndrome
  • Surveillance
  • Treatment
• Prognosis
• Future Directions

Introduction

Birt-Hogg-Dubé syndrome (BHD) (OMIM) is an autosomal dominantly inheritedhamartomatous 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 FLCN functions 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 FLCNvariants 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 y). 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 y).[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 5depicts bilateral renal tumors in a patient with BHD.

ENLARGE

Figure 5. Birt-Hogg-Dubé syndrome–associated renal tumors are commonly multifocal and bilateral. Arrows indicate the locations of the tumors.

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 FLCNsomatic 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 FLCNvariants). 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.

References

1. 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]
2. Nickerson ML, Warren MB, Toro JR, et al.: Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2 (2): 157-64, 2002. [PUBMED Abstract]
3. Birt AR, Hogg GR, Dubé WJ: Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113 (12): 1674-7, 1977. [PUBMED Abstract]
4. Schmidt LS, Linehan WM: Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12 (10): 558-69, 2015. [PUBMED Abstract]
5. Boza JC, Trindade EN, Peruzzo J, et al.: Skin manifestations of obesity: a comparative study. J Eur Acad Dermatol Venereol 26 (10): 1220-3, 2012. [PUBMED Abstract]
6. Sanfilippo AM, Barrio V, Kulp-Shorten C, et al.: Common pediatric and adolescent skin conditions. J Pediatr Adolesc Gynecol 16 (5): 269-83, 2003. [PUBMED Abstract]
7. Yosipovitch G, DeVore A, Dawn A: Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol 56 (6): 901-16; quiz 917-20, 2007. [PUBMED Abstract]
8. 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]
9. Benusiglio PR, Giraud S, Deveaux S, et al.: Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis 9: 163, 2014. [PUBMED Abstract]
10. 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]
11. Graham RB, Nolasco M, Peterlin B, et al.: Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med 172 (1): 39-44, 2005. [PUBMED Abstract]
12. Painter JN, Tapanainen H, Somer M, et al.: A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet 76 (3): 522-7, 2005. [PUBMED Abstract]
13. 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]
14. Stamatakis L, Metwalli AR, Middelton LA, et al.: Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 12 (3): 397-402, 2013. [PUBMED Abstract]
15. Schmidt LS, Nickerson ML, Warren MB, et al.: Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet 76 (6): 1023-33, 2005. [PUBMED Abstract]
16. Maffé A, Toschi B, Circo G, et al.: Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations. Clin Genet 79 (4): 345-54, 2011. [PUBMED Abstract]
17. Kunogi M, Kurihara M, Ikegami TS, et al.: Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet 47 (4): 281-7, 2010. [PUBMED Abstract]
18. Rossing M, Albrechtsen A, Skytte AB, et al.: Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation. J Hum Genet 62 (2): 151-157, 2017. [PUBMED Abstract]
19. Gunji Y, Akiyoshi T, Sato T, et al.: Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet 44 (9): 588-93, 2007. [PUBMED Abstract]
20. Leter EM, Koopmans AK, Gille JJ, et al.: Birt-Hogg-Dubé syndrome: clinical and genetic studies of 20 families. J Invest Dermatol 128 (1): 45-9, 2008. [PUBMED Abstract]
21. Kluger N, Giraud S, Coupier I, et al.: Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol 162 (3): 527-37, 2010. [PUBMED Abstract]
22. Houweling AC, Gijezen LM, Jonker MA, et al.: Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer 105 (12): 1912-9, 2011. [PUBMED Abstract]
23. Vocke CD, Yang Y, Pavlovich CP, et al.: High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst 97 (12): 931-5, 2005. [PUBMED Abstract]
24. Baba M, Hong SB, Sharma N, et al.: Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 103 (42): 15552-7, 2006. [PUBMED Abstract]
25. Hasumi H, Baba M, Hong SB, et al.: Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 415 (1-2): 60-7, 2008. [PUBMED Abstract]
26. Shaw RJ: LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 196 (1): 65-80, 2009. [PUBMED Abstract]
27. Nahorski MS, Reiman A, Lim DH, et al.: Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat 32 (8): 921-9, 2011. [PUBMED Abstract]
28. Baba M, Furihata M, Hong SB, et al.: Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst 100 (2): 140-54, 2008. [PUBMED Abstract]
29. Hasumi Y, Baba M, Ajima R, et al.: Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 106 (44): 18722-7, 2009. [PUBMED Abstract]
30. Yan M, Gingras MC, Dunlop EA, et al.: The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest 124 (6): 2640-50, 2014. [PUBMED Abstract]
31. 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]
32. Vernooij M, Claessens T, Luijten M, et al.: Birt-Hogg-Dubé syndrome and the skin. Fam Cancer 12 (3): 381-5, 2013. [PUBMED Abstract]
33. Toro JR, Pautler SE, Stewart L, et al.: Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 175 (10): 1044-53, 2007. [PUBMED Abstract]
34. Pavlovich CP, Grubb RL 3rd, Hurley K, et al.: Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol 173 (5): 1482-6, 2005. [PUBMED Abstract]
35. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2011. Bethesda, Md: National Cancer Institute, 2014. Also available online. Last accessed February 22, 2019.
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]
48. Benhammou JN, Vocke CD, Santani A, et al.: Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes Chromosomes Cancer 50 (6): 466-77, 2011. [PUBMED Abstract]
49. Menko FH, van Steensel MA, Giraud S, et al.: Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 10 (12): 1199-206, 2009. [PUBMED Abstract]
50. Gupta N, Seyama K, McCormack FX: Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer 12 (3): 387-96, 2013. [PUBMED Abstract]
51. Jacob CI, Dover JS: Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol 137 (1): 98-9, 2001. [PUBMED Abstract]
52. Gambichler T, Wolter M, Altmeyer P, et al.: Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol 43 (5 Pt 1): 856-8, 2000. [PUBMED Abstract]
53. Kahle B, Hellwig S, Schulz T: [Multiple mantleomas in Birt-Hogg-Dubé syndrome: successful therapy with CO2 laser] Hautarzt 52 (1): 43-6, 2001. [PUBMED Abstract]

Hereditary Papillary Renal Carcinoma

In This Section

• Introduction
• Genetics
  • MET gene
  • Prevalence and founder effects
  • Penetrance of MET pathogenic variants
  • Genotype-phenotype correlations
• Molecular Biology
• Clinical Manifestations
  • Kidney cancer
• Histopathology
• Management
  • Surveillance
  • Genetic testing
  • Treatment
• Prognosis
• Future Directions

Introduction

Hereditary papillary renal carcinoma (HPRC) (OMIM) is an autosomal dominant 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 haplotypewithin and immediately distal to the MET gene, suggesting a common ancestor (founder effect).[8] However, families with identical germline MET pathogenic 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 y), 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 METvariants 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 Treatment subsection 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 METpathogenic 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 sequencingtechnology 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.

References

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2. 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]
3. Zbar B, Glenn G, Lubensky I, et al.: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153 (3 Pt 2): 907-12, 1995. [PUBMED Abstract]
4. Park M, Dean M, Kaul K, et al.: Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci U S A 84 (18): 6379-83, 1987. [PUBMED Abstract]
5. Komada M, Hatsuzawa K, Shibamoto S, et al.: Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett 328 (1-2): 25-9, 1993. [PUBMED Abstract]
6. Bottaro DP, Rubin JS, Faletto DL, et al.: Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251 (4995): 802-4, 1991. [PUBMED Abstract]
7. Gherardi E, Birchmeier W, Birchmeier C, et al.: Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12 (2): 89-103, 2012. [PUBMED Abstract]
8. Schmidt L, Junker K, Weirich G, et al.: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 58 (8): 1719-22, 1998. [PUBMED Abstract]
9. 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]
10. 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]
11. Schmidt L, Junker K, Nakaigawa N, et al.: Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18 (14): 2343-50, 1999. [PUBMED Abstract]
12. Miller M, Ginalski K, Lesyng B, et al.: Structural basis of oncogenic activation caused by point mutations in the kinase domain of the MET proto-oncogene: modeling studies. Proteins 44 (1): 32-43, 2001. [PUBMED Abstract]
13. Zhuang Z, Park WS, Pack S, et al.: Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20 (1): 66-9, 1998. [PUBMED Abstract]
14. Linehan WM, Spellman PT, Ricketts CJ, et al.: Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 374 (2): 135-45, 2016. [PUBMED Abstract]
15. Pal SK, Ali SM, Yakirevich E, et al.: Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling. Eur Urol 73 (1): 71-78, 2018. [PUBMED Abstract]
16. Lubensky IA, Schmidt L, Zhuang Z, et al.: Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 155 (2): 517-26, 1999. [PUBMED Abstract]
17. Delahunt B, Eble JN: Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10 (6): 537-44, 1997. [PUBMED Abstract]
18. Störkel S, Eble JN, Adlakha K, et al.: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80 (5): 987-9, 1997. [PUBMED Abstract]
19. Ornstein DK, Lubensky IA, Venzon D, et al.: Prevalence of microscopic tumors in normal appearing renal parenchyma of patients with hereditary papillary renal cancer. J Urol 163 (2): 431-3, 2000. [PUBMED Abstract]
20. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
21. Vikram R, Ng CS, Tamboli P, et al.: Papillary renal cell carcinoma: radiologic-pathologic correlation and spectrum of disease. Radiographics 29 (3): 741-54; discussion 755-7, 2009 May-Jun. [PUBMED Abstract]
22. Choyke PL, Walther MM, Glenn GM, et al.: Imaging features of hereditary papillary renal cancers. J Comput Assist Tomogr 21 (5): 737-41, 1997 Sep-Oct. [PUBMED Abstract]
23. Walther MM, Choyke PL, Glenn G, et al.: Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 161 (5): 1475-9, 1999. [PUBMED Abstract]
24. Duh FM, Scherer SW, Tsui LC, et al.: Gene structure of the human MET proto-oncogene. Oncogene 15 (13): 1583-6, 1997. [PUBMED Abstract]
25. Choueiri TK, Vaishampayan U, Rosenberg JE, et al.: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 31 (2): 181-6, 2013. [PUBMED Abstract]
26. Kiuru M, Kujala M, Aittomäki K: Inherited forms of renal cell carcinoma. Scand J Surg 93 (2): 103-11, 2004. [PUBMED Abstract]

Changes to This Summary (02/28/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Introduction

Updated statistics with estimated new kidney cancer and renal pelvis cancer cases and deaths for 2019 (cited American Cancer Society as reference 1).

Von Hippel-Lindau Disease

Added Treatment of pheochromocytomas as a new subsection.

Hereditary Leiomyomatosis and Renal Cell Cancer

Added Muller et al. as reference 27.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of kidney cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Kidney Cancer (Renal Cell Cancer) are:

• Thai H. Ho, MD, PhD (Mayo Clinic)
• Brian Matthew Shuch, MD (UCLA Health)
• Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Kidney Cancer (Renal Cell Cancer). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389510]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

• Updated: February 28, 2019