Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®) 5/6 –Health Professional Version - National Cancer Institute

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

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

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

Natural history

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

Genetics

FLCN gene

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

Prevalence

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

Genotype-phenotype correlations

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

Molecular Biology

The identification of a somatic "second hit" in most BHD-associated renal tumors strongly suggests that 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 FLCN variants predict for a truncated protein missing this C-terminal domain or they appear to destabilize the FLCN protein.[24,27]

The effects of folliculin loss on mTOR activity have been studied by several groups. Tissue-specific activation of mTORC1 was demonstrated in a kidney-specific FLCN knockout mouse model,[28] in which both mTORC1 and mTORC2 were activated in renal tumors that developed in FLCN heterozygous knockout mice subsequent to loss of the wild-type allele,[29] suggesting that mTOR may play a role in the development of BHD-related tumors. More recent work suggests that aerobic glycolysis is upregulated as a consequence of FLCN inactivation. 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 5 depicts 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 FLCN somatic second hits (70%) in BHD-associated renal tumors supports the hypothesis that FLCN functions as a tumor suppressor gene.[23] Acquired somatic FLCN mutations have been only rarely identified in sporadic ccRCC.[36,37]

Other manifestations

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

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

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

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

Management

Risk assessment for Birt-Hogg-Dubé syndrome

Genetic testing

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

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

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

Genetic counseling

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

Clinical diagnosis

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

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

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

Differential diagnosis

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

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

Surveillance

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

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

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

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

Level of evidence: 5

Treatment

Skin

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

Level of evidence: 5

Renal

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

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

Level of evidence: 4

Spontaneous pneumothorax

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

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

Level of evidence: 4

Prognosis

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

Future Directions

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

References

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