Hereditary kidney cancer syndromes

INTRODUCTION — Hereditary kidney cancer syndromes were initially described based on clinical observations that defined the disease phenotype. Family studies and advances in molecular genetics have provided important insights into the molecular pathways underlying the pathogenesis of these syndromes, as well as new insights into sporadic renal cell carcinoma (RCC) [1,2]. Each of these syndromes has its own molecular alteration, and these are often reflected in distinctive histologic features and clinical course.

The inherited kidney cancer syndromes are presented here (table 1). Other topics related to the diagnosis and management RCC are discussed separately.

●(See "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)

●(See "Prognostic factors in patients with renal cell carcinoma".)

●(See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)

●(See "Overview of the treatment of renal cell carcinoma".)

ESTABLISHING THE DIAGNOSIS — Among all cases of renal cell carcinoma (RCC), approximately five percent or less are due to a hereditary syndrome [3,4]. Observational studies of patients with RCC undergoing tumor sequencing have confirmed the low incidence of highly penetrant pathogenic variants that cause kidney cancer [5]. By contrast, individuals with high-risk clinical features or a family history suggestive of a hereditary kidney cancer syndrome may have a higher incidence of a germline pathogenic variant.

As such, the most important step in establishing the diagnosis of a hereditary kidney cancer syndrome is recognizing the associated clinical features, as described in this topic. These initial clinical features, along with the patient's family history, are effective means for identifying affected individuals who should undergo further evaluation for hereditary kidney cancer syndromes [6].

The identification of an inherited genetic predisposition for renal cell carcinoma in a patient or family member may be an indication for screening for cancer or dictate a treatment strategy that can minimize or prevent disease-related morbidity [6]. Discussions about the risks and benefits of genetic screening for a hereditary kidney cancer syndrome should involve a trained genetic counselor who can review any issues with patients prior to proceeding with genetic testing. (See "Genetic testing".)

Further details on genetic counseling for patients with a suspected hereditary kidney cancer syndrome are discussed separately (table 2). (See "Diagnostic approach, differential diagnosis, and management of a small renal mass", section on 'Genetic counseling'.)

POLYCYSTIC KIDNEY DISEASE — Autosomal dominant polycystic kidney disease is a common disorder, occurring in approximately 1 in every 400 to 1000 live births. It is estimated that fewer than one-half of these cases are diagnosed during an individual's lifetime, since the disease is often clinically silent. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth" and "Autosomal dominant polycystic kidney disease (ADPKD): Treatment" and "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Renal cancer'.)

The incidence of renal cell carcinoma (RCC) in patients with polycystic kidney disease does not appear to be increased compared with the general population [7,8]. However, compared to patients with sporadic RCC in the general population, patients with polycystic kidney disease who develop RCC have tumors that are more often bilateral (12 versus 1 to 4 percent), multicentric (28 versus 6 percent), and of sarcomatoid histology (33 versus 1 to 5 percent).

A subset of patients with autosomal dominant polycystic kidney disease may also have features of tuberous sclerosis complex (TSC). This condition is known as TSC2/PKD1 contiguous gene syndrome, since the polycystic kidney disease 1 (PKD1) gene is located adjacent to the TSC2 gene [9] It is unknown whether patients with this condition are at higher risk of kidney cancer. TSC2/PKD1 contiguous gene syndrome is discussed separately. (See "Renal manifestations of tuberous sclerosis complex", section on 'TSC2/PKD1 contiguous gene syndrome'.)

HEREDITARY PAPILLARY RENAL CARCINOMA — Hereditary papillary renal carcinoma (HPRC) is a familial cancer syndrome in which affected individuals are at risk for the development of papillary renal cell carcinomas [10]. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Papillary carcinomas'.)

HPRC is a highly penetrant, autosomal dominant condition. Both early and late-onset forms of HPRC have been described [11,12]. HPRC is manifested primarily by the development of papillary renal tumors, which are often multifocal and bilateral. On imaging studies, the lesions are relatively hypovascular and grow slowly [13].

Genetic linkage analyses found that the HPRC gene (the c-MET protooncogene) is located on the long arm of chromosome 7 [14]. This gene codes for a membrane-bound receptor for hepatocyte growth factor (HGF) and has an intracellular tyrosine kinase domain. Pathogenic variants in MET constitutively activate the tyrosine kinase domain of this protein in patients with HPRC [15].

Most patients have bilateral, multifocal tumors. As such, nephron-sparing procedures such as partial nephrectomy are preferred to maintain renal function while minimizing the risk of distant metastases [16]. Patients with smaller kidney tumors are generally managed with active surveillance. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy' and "Diagnostic approach, differential diagnosis, and management of a small renal mass", section on 'Active surveillance'.)

The treatment of patients with distant metastases or unresectable disease, including agents targeting the MET pathway, is being discussed separately. (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Papillary renal cell carcinoma'.)

Analysis of germline MET pathogenic variants is recommended for patients with clinical features that raise suspicion for a diagnosis of HPRC, such as bilateral, multifocal, or familial papillary renal cell carcinoma.

KIDNEY CANCER ASSOCIATED WITH GERMLINE PATHOGENIC VARIANTS OF THE TRICARBOXYLIC ACID CYCLE — Inherited pathogenic variants involving enzymes of the tricarboxylic acid (Krebs) cycle are associated with aggressive forms of renal cell carcinoma (RCC) that have a propensity to metastasize even at a small size. Therefore, early surgical intervention is warranted, even for very small tumors.

Enzymes with alterations contributing to RCC include fumarate hydratase, which causes hereditary leiomyomatosis and RCC, and succinate dehydrogenase, which is associated with hereditary paraganglioma and pheochromocytoma, gastrointestinal stomal tumors (GIST), and rarely, RCC. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Pheochromocytoma and paraganglioma in children" and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'SDH-deficient tumors'.)

Hereditary leiomyomatosis and renal cell cancer syndrome

Molecular pathogenesis — Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome in which affected family members have cutaneous and uterine leiomyomas, and/or RCCs that resemble high-grade papillary RCC (also known as fumarate-hydratase deficient renal cell carcinoma). This syndrome was previously known as multiple cutaneous and uterine leiomyomatosis syndrome (MCUL1) or Reed's syndrome. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Fumarate hydratase-deficient RCC and hereditary leiomyomatosis and renal cell cancer associated RCC' and "Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential", section on 'Fumarate hydratase deficiency'.)

Family studies have linked HLRCC to molecular alterations in the fumarate hydratase (FH) gene, which is located on the long arm of chromosome 1 [17]. FH is part of the mitochondrial Krebs or tricarboxylic acid cycle. There are several mechanisms by which alterations in FH leads to tumorigenesis, including increased cellular dependence on glycolysis and pseudohypoxia and fumarate serving as an oncometabolite to damage various repair subcellular processes like DNA repair [18-20]. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Hypoxia-inducible factor 1 and 2'.)

HLRCC is transmitted in an autosomal dominant fashion, and the FH gene is thought to act as a tumor suppressor gene. Germline alterations that have been identified include missense, nonsense, insertion, deletion, and splice-site mutations [21].

Clinical presentation — One clinical feature of the disease is the occurrence of severely symptomatic uterine fibroids among affected women, often requiring hysterectomy at a young age due to uterine bleeding or discomfort [22]. Leiomyomas to leiomyosarcomas have been reported in individuals with HLRCC [23], but it is unclear whether this is due to atypical pathologic features or occurred spontaneously.

Cutaneous leiomyomas are common among individuals with HLRCC. These leiomyomas typically develop on the trunk and extremities and are quite apparent and symptomatic. Often patients found incidentally may have only subtle skin findings [22,24]. (See "Hereditary leiomyomatosis and renal cell cancer (HLRCC)", section on 'Cutaneous leiomyomas'.)

Among patients with HLRCC, although the incidence of renal cell carcinoma is between 20 to 30 percent [17,24], the lifetime penetrance is estimated at less than 10 percent [25,26]. Renal tumors tend to be aggressive, with rapid nodal and distant dissemination, even if the primary kidney tumor is relatively small and contained. As an example, in a French series of 182 patients with HLRCC, the median age at diagnosis was 40 years old, and 82 percent had metastatic disease at diagnosis [27]. Due to the limited treatment options at the time, the median survival in those with metastatic disease was 18 months.

Management — Patients with HLRCC syndrome should undergo regular surveillance imaging for renal carcinoma with magnetic resonance imaging (MRI), with early intervention upon diagnosis. Details on surveillance are discussed separately. (See "Hereditary leiomyomatosis and renal cell cancer (HLRCC)", section on 'Surveillance for renal cancer'.)

A multidisciplinary approach is required for optimal management of patients with HLRCC, including referrals, when indicated, to gynecology, dermatology, urology, medical oncology, and genetic counseling.

Patients with HLRCC and locally advanced RCC should be offered prompt surgical management with wide surgical margins and consideration of retroperitoneal lymph node dissection, due to the high risk of metastatic disease. (See "Definitive surgical management of renal cell carcinoma" and "Hereditary leiomyomatosis and renal cell cancer (HLRCC)", section on 'Surveillance for renal cancer'.)

For patients with HLRCC and unresectable or metastatic RCC, we suggest bevacizumab and erlotinib rather than other systemic agents. Systemic targeted therapy with bevacizumab and erlotinib has demonstrated particular efficacy in patients with HLRCC [28,29]. In patients with HLRCC, tumorigenesis is driven by genetic alterations to glucose metabolism [17-19,30,31]. The combination of bevacizumab and erlotinib (inhibitors of vascular endothelial growth factor [VEGF] and epidermal growth factor receptor [EGFR], respectively) is hypothesized to inhibit effective glucose delivery to tumor cells, presenting a logical therapeutic approach to this disease [30]. Further studies are needed to confirm the efficacy and toxicity of this approach.

In preliminary results from a nonrandomized phase II trial, among all 83 patients with advanced papillary RCC treated with bevacizumab plus erlotinib, the objective response rate (ORR) was 54 percent [28]. The ORR was higher among the 43 patients with HLRCC compared to the 40 patients with sporadic papillary RCC (72 versus 35 percent, respectively), and was independent of International Metastatic RCC Database Consortium (IMDC) risk group (table 3) or prior therapy. For patients with HLRCC, median progression-free survival (PFS) was approximately 21 months. (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Papillary renal cell carcinoma'.)

Data are limited and have mixed results for the efficacy of checkpoint inhibitor immunotherapy in patients with HLRCC. While one case report showed no responders to checkpoint inhibitor therapy among eight treated patients with metastatic HLRCC [32], another case report demonstrated a complete response to the combination of nivolumab and ipilimumab [33].

Succinate dehydrogenase deficiency — Succinate dehydrogenase (SDH) is comprised of four subunits (SDHA, SDHB, SDHC, and SDHD) and an assembly factor (SDHAF2). Mutations of each component have been associated with cases of RCC [34].

Succinate dehydrogenase-deficient renal cell carcinoma is a rare, aggressive variant of RCC [35]. SDH-associated RCC presents at an early age [34], although the age at diagnosis ranges from 24 to 73 years [36,37]. The histologic type of kidney cancer varies, perhaps by altered subtype, but cases have been observed with clear cell, papillary, chromophobe, and an eosinophilic RCC [36-38]. Studies of metastatic SDH-associated RCC have reported treatment response to sunitinib or pazopanib [39,40]. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Succinate dehydrogenase–deficient renal cell carcinoma'.)

This enzyme deficiency is also associated with an autosomal dominant condition called hereditary paraganglioma and pheochromocytoma. The syndrome is characterized by paragangliomas involving the head and neck region, thorax, abdomen, pelvis, and/or urinary bladder. Paragangliomas typically develop in patients in their thirties. (See "Pheochromocytoma in genetic disorders".)

Testing for pathogenic variants in SDH is advised in patients with early onset kidney cancer (ie, age <45 years), bilateral or multifocal tumors, pathologic or immunohistochemical findings that suggest loss of SDH, or a personal or family history of pheochromocytoma or paraganglioma, gastrointestinal stromal tumors, and/or kidney cancer [6,34]. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Pheochromocytoma and paraganglioma in children" and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'SDH-deficient tumors'.)

BIRT-HOGG-DUBÉ SYNDROME — Birt-Hogg-Dubé (BHD) syndrome is an inherited syndrome in which affected individuals are at risk for the development of bilateral, multifocal kidney cancer, as well as various dermatologic and pulmonary lesions [41]. (See "Birt-Hogg-Dubé syndrome".)

BHD syndrome is caused by pathogenic variants in the folliculin (FLCN) gene (also known as the BHD gene), which is localized to the short arm of chromosome 17 [42,43]. Pathogenic variants in the germline of affected individuals have been identified in 90 percent of affected families [44]. DNA sequencing of renal tumors from patients with germline FLCN pathogenic variants has identified somatic pathogenic variants in the wild-type copy of the gene, suggesting that FLCN is a loss-of-function tumor suppressor gene [45].

The FLCN gene may be involved in energy, metabolism, and nutrient sensing through the mammalian target of rapamycin (mTOR) pathway. The folliculin-interacting protein (FNIP1) interacts with 5' AMP-activated protein kinase (AMPK), a key molecule for energy sensing to negatively regulate mTOR activity [46].

The penetrance of renal cancer in patients with BHD is up to 30 percent [47,48]. In one series, the risk of renal tumors was 27 percent at a mean age of 50 years [47]. However, the incidence of renal tumors may vary in different families, and BHD may be underdiagnosed in patients with variable skin findings. One series that included 115 FLCN carriers estimated penetrance for renal cancer and pneumothorax to be 16 and 29 percent, respectively, at 70 years of age [48].

The histology of renal tumors is variable in patients with BHD syndrome. Tumors typically contain a hybrid of oncocytic and chromophobe renal tumors, but other histologies such as classic chromophobe, oncocytomas, and papillary RCC may be present [41,47].

Dermatologic manifestations of BHD syndrome include skin lesions called fibrofolliculomas, which are benign hamartomatous tumors of hair follicles [41]. These whitish papules are most common on the nose and cheeks, and typically are first observed around age 20 years.

Approximately 80 percent of patients with BHD have multiple pulmonary cysts that can be identified by computed tomography (CT) of the lungs [41]. Spontaneous pneumothorax may be seen in up to one-fourth of patients [49-51].

The kidney cancers observed in patients with BHD syndrome tend to be bilateral or multifocal in more than one-half of cases and are usually slow growing. Thus, the recommended management approach includes observation of tumors less than 3 cm; when surgery is recommended, all visible tumors should be removed [52]. As with hereditary papillary renal carcinoma, nephron-sparing surgery is preferred to radical nephrectomy [41,53]. Follow-up in patients undergoing nephron-sparing surgery is important given the high risk of disease recurrence in the ipsilateral kidney.

An animal model of BHD has been developed to provide a model for the evaluation of therapeutic approaches to this syndrome [54]. In this model, treatment with the mTOR inhibitor rapamycin led to tumor shrinkage.

TUBEROUS SCLEROSIS COMPLEX — Tuberous sclerosis complex (TSC; also called tuberous sclerosis) is a hereditary condition that is due to pathogenic variants in one of two interacting tumor suppressor gene products, hamartin (TSC1) or tuberin (TSC2). The clinical manifestations include bilateral, multifocal renal lesions, which typically are angiomyolipomas. (See "Tuberous sclerosis complex: Clinical features".)

The predominant management issue for patients with TSC is the risk of growth and bleeding from renal angiomyolipoma. These issues are discussed separately. (See "Renal manifestations of tuberous sclerosis complex", section on 'Angiomyolipomas'.)

Fewer than 5 percent of patients with TSC develop renal cell carcinoma [55]. In one observational series, the TSC-associated RCC tumors occurred at a younger age than sporadic tumors and occurred primarily in women [56].

Tumors can display a wide variety of histologic patterns, such as clear cell, papillary, and chromophobe RCC, as well as those with eosinophilic/oncocytic features (known as low-grade oncocytic [LOT]) [57]. These tumors can present aggressively, especially in patients with clear cell histology [56].

OTHER CLEAR CELL RCC HEREDITARY SYNDROMES

Von Hippel-Lindau disease — Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors, including clear cell carcinoma of the kidney. The pathogenesis of VHL syndrome and the management of patients with VHL are discussed separately. Familial, non-VHL, clear cell renal cell carcinoma (RCC) may also be associated with chromosome 3 translocations [58]. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Molecular biology and pathogenesis of von Hippel-Lindau disease" and "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Von Hippel-Lindau gene'.)

Hereditary BAP-1-associated renal cell carcinoma — A germline pathogenic variant in the breast cancer susceptibility 1 (BRCA1)-associated protein 1 (BAP1) gene predisposes to familial clear cell RCC [4,59]. Further details about this syndrome are discussed separately. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'BAP1 gene'.)

Other tumors associated with BAP1 germline pathogenic variants include familial uveal melanoma, cutaneous melanoma and atypical Spitz tumors, and mesothelioma [60]. There is some evidence that meningioma and cholangiocarcinoma may also be linked to BAP1 pathogenic variants [61]. (See "Inherited susceptibility to melanoma", section on 'BAP1 gene' and "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Inherited susceptibility'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)

SUMMARY AND RECOMMENDATIONS

●Establishing the diagnosis – The most important step in establishing the diagnosis of a hereditary kidney cancer syndrome is recognizing the associated clinical features. These initial clinical features, along with the patient's family history, are effective means for identifying affected individuals who should undergo further evaluation for hereditary kidney cancer syndromes. (See 'Establishing the diagnosis' above.)

●Screening for cancer and genetic testing – The identification of an inherited genetic predisposition for renal cell carcinoma in a patient or family member may be an indication for screening for cancer or dictate a treatment strategy that can minimize or prevent disease-related morbidity. Discussions about the risks and benefits of genetic screening should involve a trained genetic counselor who can review any issues with patients prior to proceeding with genetic testing. (See "Genetic testing".)

●Hereditary kidney cancer syndromes – The hereditary kidney cancer syndromes are as follows (table 1):

•Polycystic kidney disease – For patients with polycystic kidney disease who develop renal cell carcinoma (RCC), tumors are more often bilateral, multicentric, and of sarcomatoid histology at presentation compared to those who develop sporadic RCC in the general population. (See 'Polycystic kidney disease' above.)

•Hereditary papillary renal cell carcinoma – Hereditary papillary renal carcinoma (HPRC) is an autosomal dominant cancer syndrome associated with pathogenic variants in the HPRC (MET) gene. HPRC manifests with multifocal and bilateral papillary renal tumors. (See 'Hereditary papillary renal carcinoma' above.)

•Hereditary leiomyomatosis and renal cell cancer – Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome linked to molecular alterations in the fumarate hydratase (FH) gene. HLRCC is associated with fumarate-hydratase deficient renal cell carcinoma, a papillary variant of RCC. (See 'Hereditary leiomyomatosis and renal cell cancer syndrome' above.)

-Treatment of unresectable or metastatic RCC – For patients with HLRCC and unresectable or metastatic renal cell carcinoma, we suggest bevacizumab plus erlotinib rather than other systemic agents (Grade 2C). (See 'Management' above.)

•Other syndromes – Other genetic syndromes associated with hereditary RCC include:

-Succinate dehydrogenase-deficiency – (See 'Succinate dehydrogenase deficiency' above.)

-Birt-Hogg-Dube syndrome – (See 'Birt-Hogg-Dubé syndrome' above.)

-Tuberous sclerosis complex – (See 'Tuberous sclerosis complex' above.)

-Von Hippel-Lindau disease – (See 'Von Hippel-Lindau disease' above.)

-Pathogenic variants in the breast cancer susceptibility 1 (BRCA1)-associated protein 1 (BAP1) gene – (See 'Hereditary BAP-1-associated renal cell carcinoma' above.)