Genetic Variants of RCC: Diagnosis and Management · Genetic Variants of RCC: Diagnosis and...

Genetic Variants of RCC: Diagnosis and Management

Cary N Robertson MD FACS Associate Professor Division of Urology

Duke University Medical Center Durham, North Carolina

Case Presentation • A 63-year-old man

– Microscopic hematuria at PCP visit; otherwise asymptomatic

– HTN controlled with a single medication

– ECOG PS 0

CT scan c/a/p

Open Radical Nephrectomy • Uneventful postoperative course

– Clear-cell RCC, Fuhrman grade 4; 10% sarcomatoid changes – 9 cm in size – Perirenal fat invasion (pT3a N0 M0); margins negative

Case Follow-Up

• 6-month follow-up – Multiple lung and soft tissue metastases

Mechanisms of Action: RCC

Syndrome (Inheritance Pattern)

Gene Locus, Gene Type (Protein)

Renal Tumor Pathology (Cumulative Cancer Risk)

Non-renal Tumors and Associated Abnormalities

AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.

von Hippel-Lindau syndrome (VHL) (AD) [1,2]

VHL 3p26, tumor suppressor (pVHL)

ccRCC (multifocal) (24%–45%)

CNS hemangioblastoma, retinal angiomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of epididymis and broad ligament

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD) [3-6]

FH 1q42.1, tumor suppressor (fumarase)

‘HLRCC-type RCC’ may be new entity (formerly called papillary type 2) (up to 32%)

Cutaneous leiomyomas, uterine leiomyomas (fibroids)

Birt-Hogg-Dubé syndrome (BHD) (AD) [7-10]

FLCN 17p11.2, tumor suppressor (folliculin)

Chromophobe oncocytic hybrid, papillary clear cell oncocytoma (15%–30%)

Cutaneous: fibrofolliculomas, trichodiscomas

Pulmonary: lung cysts, spontaneous pneumothoraces

Hereditary papillary renal cancer (HPRC) (AD) [11,12]

MET 7q34, proto-oncogene (hepatocyte growth factor receptor)

Papillary type 1 (approaching 100%) None known

https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#cit/section_2.14

Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes

https://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=460162&version=HealthProfessional&language=English

https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdqcit/section_2.1









Von Hippel-Lindau syndrome (VHL) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHL gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems: a. central nervous system (CNS) hemangioblastomas; retinal

angiomas b. clear cell RCCs (ccRCCs) and renal cysts c. pheochromocytomas, cysts, cystadenomas, and

neuroendocrine tumors (NETs) of the pancreas d. endolymphatic sac tumors (ELSTs) e. cystadenomas of the epididymis (males) and of the broad

ligament (females)



Von Hippel Lindau syndrome (VHL) The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26. Most affected individuals inherit a germline pathogenic variant of VHL from an affected parent and a normal (wild-type) VHL copy from their unaffected parent. VHL-associated tumors conform to Knudson’s “two-hit” hypothesis in which the clonal origin or first transformed cell of the tumor occurs only after both VHL alleles in a cell are inactivated. The inherited germline pathogenic variant in VHL represents the first "hit," which is present in every cell in the body. The second “hit” is a somatic pathogenic variant, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, VHL allele, creating a clonal neoplastic cell of origin, which may proliferate into a tumor mass. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#cit/section_2.14

Von Hippel Lindau syndrome (VHL) The number of VHL-affected individuals in the United States is estimated at between 6,000 and 7,000. Each offspring of an individual with VHL has a 50% chance of inheriting the VHL pathogenic variant allele from their affected parent. Patients diagnosed with VHL, who have no family history of VHL, have been estimated to comprise about 1/4 of VHL kindreds. The best-studied function of pVHL, linked to its ability to suppress tumor formation, is the regulation of hypoxia-inducible factor (HIF) activity. In the context of RCC, it appears that HIF2-alpha acts as an oncogene, and HIF1-alpha acts as a tumor suppressor gene. HIF2-alpha is now an established therapeutic target for VHL-related malignancies. Specific HIF2-alpha inhibitors are in preclinical and clinical testing. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all

Von Hippel Lindau syndrome (VHL) More than 55% of VHL-affected individuals develop only multiple renal cell cysts. Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2 or 4) and minimally invasive, and their rate of growth varies widely. Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur. RCCs often remain asymptomatic for long intervals. Transition from a cyst to a solid lesion is rare. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all

VHL GU manifestations: Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%–26%), which are virtually pathognomonic for VHL, especially when bilateral, and are rare in the general male population. More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL disease. Among symptomatic patients, the most common presentation is a painless, slow-growing scrotal swelling. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all

VHL associated conditions: Hemangioblastomas are the most common disease manifestation in patients with VHL, potentially affecting more than 70% of individuals. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients. The rate of pheochromocytoma formation in the VHL patient population is 25% to 30% with bilaterality occurring in some patients. Endolymphatic sac tumors (ELSTs) are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone. ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all

Von Hippel Lindau syndrome (VHL) Currently, the renal manifestations of VHL are still generally managed surgically or with thermal ablation. The available clinical evidence suggests that ablative approaches be reserved for small (≤3 cm), solid-enhancing renal masses in older patients with high operative risk, especially in patients facing salvage renal surgery because of a higher complication rate. Young age, tumor size larger than 4 cm, hilar tumors, and cystic lesions can be regarded as relative contraindications. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#cit/section_2.14

Von Hippel Lindau syndrome (VHL) Thermal ablative techniques utilize either heating or cooling of a mass in an effort to destroy the tumor. Some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success. Irreversible coagulopathy is widely accepted as an absolute contraindication. It must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications due to adhesions and scarring, especially along the tract of the ablative probes. In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management. https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all

Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. “The National Cancer Institute evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated before the largest lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months. Later series reinforced that this was an important threshold because 0 of 108 patients with tumors managed at 3 cm or smaller had evidence of distant spread. For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence. This threshold is now widely used to trigger surgical intervention for VHL-associated ccRCC. When surgery is performed on a patient with VHL, resection of more than a dozen renal tumors may be necessary. The use of intraoperative ultrasound to identify and then remove smaller lesions may delay the need for further surgical interventions.” Duffey BG, Choyke PL, Glenn G, et al.: The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol 172 (1): 63-5, 2004.

Von Hippel Lindau syndrome (VHL)

• “The evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHL function, identifying new targets, or discovering synthetic lethal strategies that can effectively eradicate RCC. “

• https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#cit/section_2.14

Hereditary Leiomyomatosis and Renal Cell Cancer

• Hereditary leiomyomatosis and renal cell cancer (HLRCC) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and RCC.

• https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all


• 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)

https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#section/all


• Germline pathogenic variants in FH, plus somatic variants and loss of heterozygosity (LOH) in RCC, suggest that loss of function in the fumarate hydratase protein is the basis of tumor formation in HLRCC and, further, that FH functions as a tumor suppressor gene.



• Cutaneous leiomyomas present as firm pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 years) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful.

• Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003


• In contrast to other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive.

• Approximately 10% to 32% of individuals with HLRCC who present with multiple cutaneous leiomyomas have RCC at the time of renal imaging

• Alam NA, Barclay E, Rowan AJ, et al.: Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 141 (2): 199-206, 2005


• RCC associated with HLRCC may constitute a new renal pathologic entity or a unique HLRCC type. Studies have reported the morphologic spectrum of RCC in HLRCC syndrome : 40 RCCs from 38 patients with germline FH pathogenic variants and HLRCC family histories. A number of histologic patterns were seen, including cystic, tubulo-papillary, tubulo-solid, and often mixed patterns.

• 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.


• Molecular 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, or individuals who have renal tumors with histologic characteristics consistent with HLRCC.



• 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.



• 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

• Pfaffenroth EC, Linehan WM: Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther 8 (6): 779-90, 2008


• Total nephrectomy or partial nephrectomy with a wide margin should be considered in individuals with a detectable renal mass, including small tumors 1 cm.

• RCC in the context of HLRCC is a considerably more ominous manifestation, and the 10% to 32% of HLRCC patients who develop RCC are at high risk of developing metastatic disease. Metastatic RCC associated with HLRCC is characterized by an aggressive clinical course and is uniformly fatal in the absence of effective intervention.

• 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.

Birt-Hogg-Dubé Syndrome

• Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant inherited hamartomatous disorder caused by germline pathogenic variants in the folliculin (FLCN) gene.

• 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


• FLCN encodes a transcript of 5.5 kb containing 14 exons. In BHD patients, FLCN pathogenic variants have been identified in all translated exons, except for exons 8 and 10. FLCN encodes a 64-kDa protein, folliculin (FLCN), which is highly conserved among species.

• The precise mechanisms by which inactivation of FLCN leads to tumorigenesis remain to be elucidated

• 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

Birt-Hogg-Dubé Syndrome • Both folliculin and two recently identified folliculin

interacting proteins, FNIP1 and FNIP2, appear to interact with AMPK.

• AMPK activation has been shown to upregulate HIF1 and is well studied as a transcriptional activator of several genes necessary for aerobic glycolysis.

• More recent work suggests that aerobic glycolysis is upregulated as a consequence of FLCN inactivation.

• The identification of a somatic "second hit" in most BHD-associated tumors strongly suggests that FLCN functions as a tumor suppressor.

• 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.


• The clinical characteristics of BHD include not only cutaneous manifestations (fibrofolliculomas, trichodiscomas), but also pulmonary cysts/history of spontaneous pneumothorax, and various histology types of renal tumors.

• 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.


• 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 48 years. The most common tumors are hybrid oncocytic tumors (a mixture of oncocytoma and chromophobe histologic cell types) (50%), chromophobe RCC (30%), and oncocytomas (9%). Clear cell and papillary tumors have been described but make up less than 10% of BHD renal tumors.

• 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

Birt-Hogg-Dubé Syndrome • Molecular 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 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, oncocytic, and/or oncocytic hybrid renal tumors.

• 4. A single oncocytic, 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.



• Renal tumors associated with BHD are relatively indolent. Most appropriately managed patients will require no more than one partial nephrectomy during their lifetimes. Metastatic disease, although described, is rare.

• Stamatakis L, Metwalli AR, Middelton LA, et al.: Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 12 (3): 397-402, 2013


• Approximately 25% to 35% of individuals with BHD develop renal tumors which are multifocal in 65% of cases and often bilateral.

• Renal tumors associated with BHD seem to occur at a younger age than do sporadic forms of RCC.

• Median age at diagnosis is 48 to 50 years. • Most renal tumors associated with BHD are slow

growing.

• 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.

HPRC

• Hereditary papillary renal cancer (HPRC) is an autosomal dominant inherited predisposition to the development of bilateral and multifocal type 1 papillary RCC.

• The known major risk factors for HPRC are a biologic relative with bilateral multifocal papillary RCC and/or a known activating pathogenic variant in the tyrosine kinase domain of the MET proto-oncogene.

• Linehan WM, Pinto PA, Srinivasan R, et al.: Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics. Clin Cancer Res 13 (2 Pt 2): 671s-679s, 2007.

HPRC • The MET gene is located on chromosome 7q31.2 and encodes

a 1,390 amino-acid protein • The beta subunit of MET was identified as the cell-surface

receptor for hepatocyte growth factor (HGF) [236] 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

• 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

HPRC • A novel pathogenic variant was identified in exon 16 of

the MET gene in two large North American HPRC families.

• HPRC is highly penetrant (approaching 100%). • To date, all cases of HPRC present with type 1 papillary

RCC. • Most germline MET pathogenic variants are missense

variants in the tyrosine kinase domain, leading to constitutive activation of the MET protein, with subsequent development of papillary RCC.

• 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.

HPRC

• To date, the only recognized manifestation of HPRC is kidney cancer.

• The mean age of onset is 42 years. • Renal tumors in HPRC are most commonly bilateral and

multifocal. • In contrast with many other RCC syndromes, renal cysts

are less common in HPRC. • When renal tumors become large, they can

metastasize, most commonly to the lungs.

• 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.

• Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994

HPRC

• The HPRC phenotype is limited to the type 1 papillary renal tumor histopathology.

• In HPRC, type 1 papillary RCC histology is described as well differentiated/low grade.

• Adenomas and multiple microscopic papillary lesions are found in the surrounding renal parenchyma.

• It has been estimated that patients with HPRC may develop up to 3,400 incipient renal tumors per kidney.

• 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

HPRC

• Papillary RCCs possess specific imaging characteristics that differ from ccRCCs. These tumors are generally hypovascular and enhance only 10 to 30 Hounsfield units after intravenous administration of contrast material.

• Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003

HPRC

• HPRC-related type 1 papillary RCCs, particularly small tumors confined to the kidneys, tend to be indolent.

• Once HPRC renal tumors reach 3 cm in size, a nephron-sparing partial nephrectomy is usually recommended to minimize the risk of metastatic spread.


HPRC

• Genetic testing for HPRC may be recommended if an individual has one or both 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

• Surveillance and presymptomatic screening of individuals at risk of HPRC is expected to improve prognosis through early diagnosis.


Syndrome (Inheritance Pattern)

Gene Locus, Gene Type (Protein)

Renal Tumor Pathology (Cumulative Cancer Risk)

Non-renal Tumors and Associated Abnormalities

AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.

von Hippel-Lindau syndrome (VHL) (AD) [1,2]

VHL 3p26, tumor suppressor (pVHL)

ccRCC (multifocal) (24%–45%)

CNS hemangioblastoma, retinal angiomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of epididymis and broad ligament

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD) [3-6]

FH 1q42.1, tumor suppressor (fumarase)

‘HLRCC-type RCC’ may be new entity (formerly called papillary type 2) (up to 32%)

Cutaneous leiomyomas, uterine leiomyomas (fibroids)

Birt-Hogg-Dubé syndrome (BHD) (AD) [7-10]

FLCN 17p11.2, tumor suppressor (folliculin)

Chromophobe oncocytic hybrid, papillary clear cell oncocytoma (15%–30%)

Cutaneous: fibrofolliculomas, trichodiscomas

Pulmonary: lung cysts, spontaneous pneumothoraces

Hereditary papillary renal cancer (HPRC) (AD) [11,12]

MET 7q34, proto-oncogene (hepatocyte growth factor receptor)

Papillary type 1 (approaching 100%) None known

https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq#cit/section_2.14

Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes











Mechanisms of Action: RCC

REFERENCE

• The International Society of Urological Pathology (ISUP)Vancouver Classification of Renal Neoplasia

John R. Srigley, MD,* Brett Delahunt, MD,w John N. Eble, MD,z Lars Egevad, MD, PhD, Jonathan I. Epstein, MD,8 David Grignon, MD,z Ondrej Hes, MD, PhD,z Holger Moch, MD, Rodolfo Montironi, MD, Satish K. Tickoo, MD,ww Ming Zhou, MD, PhD, Pedram Argani, MD, and The ISUP Renal Tumor Panel Am J Surg Pathol Volume 37, Number 10, October 2013

Genetic Variants of RCC: Diagnosis and Management · Genetic Variants of RCC: Diagnosis and...

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