In 2013, approximately 65,000 people will be diagnosed with kidney cancer and two-thirds will be men.1 The term kidney cancer generally refers to any cancer arising in the kidney or renal pelvis. However, this article will focus on the most common type of kidney cancer seen in adults, renal cell carcinoma (RCC).1 RCC arises from cells in the tubules of the filtration portion of the kidney. There are several histologic subtypes. Clear cell is the most common form (75%-80%), followed by papillary types 1 and 2 (10%-15%), chromophobe (5%), and collecting duct (<1%).1-5 Each subtype possesses unique clinical characteristics, genetic alterations, and responses to therapy.
Similar to other types of cancer, the majority of RCC cases are sporadic. Sporadic RCC typically presents as a solitary lesion and is diagnosed in the sixth decade of life and beyond.5,6 Hereditary RCC, on the other hand, typically develops earlier in life and often involves bilateral, multifocal tumors.4 Unlike sporadic RCC, which is more common in men, the gender distribution in hereditary forms tends to be equal7 or have a greater female preponderance.8 The most well-recognized RCC syndromes are von Hippel-Lindau (VHL), hereditary leiomyomatosis and renal cell carcinoma (HLRCC), Birt-Hogg-Dubé (BHD), and hereditary papillary renal carcinoma (HPRC). Approximately 4% of all RCC cases are due to an inherited susceptibility.6 As RCC continues to be associated with additional genes, however, and because it is believed that the majority of hereditary RCC cases go unrecognized, it is likely that this is an underestimate.6
With the exception of HPRC, each syndrome is associated with its own, unique extrarenal manifestations. In some syndromes, extrarenal manifestations are the most common, and RCC develops only in a small subset. There are 2 primary goals for medical management of RCC: prevention of metastatic disease and preservation of renal function.6 Some suggest a surveillance protocol for VHL, HPRC, and BHD, which observes the patient with serial imaging until the largest renal lesion becomes 3 cm in size, at which time surgical intervention in the form of nephron-sparing surgery is warranted.9 At present, preventive screening measures for RCC are applied only in people with an increased risk of developing the condition. Thus, genetic diagnosis is imperative in helping to obtain surveillance for at-risk family members and developing tailored medical management for the patient with RCC.
A summary of VHL, HLRCC, BHD, and HPRC follows. Genetic counseling and possibly genetic testing should be included in patients with a personal or family history of any of the following:
- Bilateral and/or multifocal RCC
- RCC under age 50
- RCC and another primary cancer in the same individual
- RCC and a family history of cancer
- RCC and nonrenal manifestations associated with hereditary RCC (in patient and/or family members), such as hemangioblastomas, pheochromocytomas, cutaneous leiomyomas, fibrofolliculomas, and pneumothorax
Of the 4 syndromes—VHL, HLRCC, BHD, and HPRC—VHL is the most recognized and described. It is an autosomal-dominant, multisystem condition linked to mutations in the VHL gene. Penetrance is high, approaching 90% to 100%, and expressivity varies greatly. Manifestations include kidney, adrenal, pancreatic, reproductive adnexal organs, and central nervous system (CNS) lesions.
Renal findings include both cysts and RCC. Of those with VHL syndrome, the lifetime risk of developing RCC is 25% to 45%, almost always clear cell.2 Individuals may develop 600 tumors and 1100 cysts per kidney.3,9 The average age at onset of renal manifestations is 39 years.2 Approximately 10% to 20% of individuals will have adrenal findings in the form of pheochromocytomas, either in one or both glands.10 Pancreatic findings consist of both pancreatic cancer and cysts, which may be numerous but are usually simple cysts. Up to 17% of individuals with VHL may develop neuroendocrine tumors of the pancreas.11 Men often have epididymal tumors, which typically do not cause problems; in women, papillary cystadenoma of the broad ligament may be seen, although rarely.11
CNS involvement is high, with the majority of patients having hemangioblastomas (60%-80%) and some developing endolymphatic sac tumors (10%-15%).10 CNS hemangioblastoma is the cardinal feature of VHL, the majority found in the brain (80%), followed by the spinal cord (20%).10 Retinal hemangioblastomas, sometimes called retinal angiomas, are often the initial manifestation of VHL, affecting up to 70% of individuals; the average age at diagnosis is 25 years, but they may present in childhood.11 Approximately 10% of individuals with VHL develop endolymphatic sac tumors, which result in varying severities of deafness; these are often misdiagnosed as Menière disease and may be an initial presenting feature of VHL.11
HLRCC is unique among other hereditary RCC syndromes in that most kidney tumors seen in HLRCC are unifocal and unilateral.12 Similar to the other RCC syndromes, HLRCC is inherited in an autosomal-dominant fashion. The syndrome was initially reported in 200113 and is associated with mutations in the FH gene. The number of families who develop renal cancer varies widely in the literature; therefore, a specific renal cancer risk for carriers of the FH mutation has not yet been determined. The incidence in families is believed to range from 10% to 40%.2,14 Age of onset is also challenging; patients are diagnosed between the ages of 30 and 45, but on occasion, onset occurs prior to age 20.12 Surveillance recommendations for these families also vary, but intensive screening for renal cancer is usually suggested beginning at age 18 or 20, and due to reports of childhood onset, the youngest being age 11, some authors suggest surveillance even in childhood.12
The associated renal cancer, papillary type 1, is also more aggressive and more prone to metastasis than with other RCC syndromes. Early radical treatment by nephrectomy has been proposed due to the aggressive natures of these tumors. It has also been suggested that renal cancer surveillance be restricted to families with previous cases of renal cancer or specific FH mutations, but there is no evidence that family history or type of FH mutation can predict renal cancer risk. Therefore, current data indicate that surveillance should be aimed at all carriers of the FH mutation. Collecting-duct RCC and mixed cystic, papillary, and tubulopapillary RCC have also been reported in HLRCC families.2
In addition to RCC, individuals with HLRCC are at risk of developing cutaneous and uterine leiomyomas. Cutaneous leiomyomas are typically distributed on the head, neck, trunk, and extremities. The majority of individuals (76%) will present with 1 or more cutaneous leiomyomas, with mean age of presentation being 25 years.14 Uterine leiomyomas are present in all females with HLRCC and are distinct from those found in the general population in that the age of onset is younger (often under age 30) and the fibroids are numerous and larger; myomectomy or hysterectomy is sometimes required.14
Similar to HLRCC, BHD has been associated with renal tumors and cutaneous manifestations. Additionally, BHD is associated with pulmonary cysts and spontaneous pneumothoraces. Inheritance is also autosomal dominant, and the syndrome is linked to mutations in the FLCN gene. Similar to VHL and HPRC, renal tumors tend to be bilateral and multifocal. Kidney tumor types are more diverse than in the other RCC syndromes and include oncocytic hybrid tumor (67%), chromophobe RCC (23%), and renal oncocytoma (3%); clear cell RCC and papillary renal carcinoma have also been reported. The average age at diagnosis is 48 years.15 Similar to other syndromes, a specific renal cancer risk has not yet been definitely determined; however, the prevalence of kidney tumors in families ranges from 6.5% to 34%.15 As the associated tumors tend to be slow growing, bilateral, and multifocal, the use of nephron-sparing surgery to preserve functioning renal tissue is recommended.
Numerous cutaneous findings are associated with BHD and include fibrofolliculomas, trichodiscomas, acrochordons, perifollicular fibromas, and angiofibromas.15 The follicular tumors are typically distributed over the face, neck, and upper trunk.15,16 As fibrofolliculomas are the only skin finding specific for BHD, a dermatologic diagnosis can be made when 5 or more facial or truncal papules are present with at least one being a histologically confirmed fibrofolliculoma.15 The average age of onset is in the third and fourth decades of life.15
In addition to being at increased risk for renal neoplasms and cutaneous findings, individuals are also at risk for pulmonary disease consisting of multiple lung cysts and spontaneous pneumothoraces.16 Almost 90% of individuals have multiple, bilateral lung cysts, which are typically asymptomatic, and 24% of individuals have a history of pneumothorax.15
Unlike the other syndromes, the sole manifestation of HPRC is type 1 papillary renal carcinoma. However, it is important to keep in mind that type 1 and type 2 papillary renal carcinomas are often not distinguished in the initial pathology. This syndrome is also inherited in an autosomal-dominant fashion with variable penetrance and is associated with mutations in the MET gene. Similar to VHL and BHD, individuals are at risk of developing multiple and/or bilateral tumors. The risk is greatest in the sixth through eighth decades.2,6
It is important to realize that VHL, HLRCC, BHD, and HPRC are not the only inherited syndromes associated with RCC; other syndromes reported in the literature include Cowden syndrome, hereditary paraganglioma and pheochromocytomas associated with SDHB mutations, tuberous sclerosis, Li-Fraumeni syndrome, and Lynch syndrome.17
- Typically, hereditary renal cancer presents at an earlier age and is often multifocal and/or bilateral. Most syndromes are characterized by a particular histologic subtype of renal cancer and other associated features.
- Genetic diagnosis can help obtain surveillance for at-risk family members. Additionally, with the exception of HLRCC, surgical management tries to focus on nephron-sparing surgery.
- Pathology can be useful in diagnosing hereditary RCC. However, as it is believed most hereditary RCC cases remain undiagnosed, it is likely we may see expanded phenotyping in the future.
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14. Pithukpakorn M, Toro JR. Hereditary leiomyomatosis and renal cell cancer. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 2006. http://www.ncbi.nlm.nih.gov/books/NBK1252/. Updated November 2, 2010. Accessed May 13, 2013.
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