MDACC 2018: Where Do We Stand with Genetic Screening for Familial Syndromes of RCC and Optimal Management of Patients with VHL?

Houston, TX ( Hereditary RCC syndromes are distinct clinical entities with defined genetic lesions that can help us to understand the overall tumor biology of kidney cancer (7). Tuberous sclerosis is an autosomal dominant syndrome characterized by development of angiomyolipomas, rather than RCC, related to alteration in the TSC1 and TSC2 genes. These patients are followed with regular cross-sectional imaging at 2-3 year intervals and intervened upon when tumors reach a size putting them at risk for spontaneous hemorrhage (usually 3-4cm). Hereditary papillary RCC syndrome is characterized by multifocal type 1 papillary RCCs with c-Met oncogene mutation and tend to appear later in life. If patient has a known family history, genetic testing and annual cross-sectional imaging follow-up beginning at age 30 should be implemented. Birt-Hogg-Dube syndrome (mutations of folliculin gene involved in the nutrient sensing pathway) is a very rare disorder but has one of the most notable clinical presentations featuring cutaneous fibrofolliculomas and spontaneous pneumothorax. Approximately 15-20% of these patients will develop RCC (typically chromophobe subtype) or oncocytoma.

Hereditary leiomyomatosis and RCC syndrome (alteration of fumerate hydratase) also has cutaneous manifestations (leiomyomas), in addition to uterine fibroids in women; 20% of afflicted patients will develop type 2 papillary RCC. Though usually solitary, they tend to grow and progress rapidly with high proclivity for distant metastasis. Mutation in another kreb cycle enzyme, succinate dehydrogenase, is responsible for the aptly named SDHx syndromes. The BAP1 familial syndrome was recently described (8) after finding that germline mutation of BPA1 was associated with worse outcomes in patients with “spontaneous” clear cell RCC. Von Hippel Lindau disease, a specific focus of Dr. Jonasch’s personal research, has various manifestations throughout multiple organ systems, including multifocal and recurrent RCCs. The VHL clinic at MDACC is a multidisciplinary care team comprised of endocrinologists, pediatricians, neurologists, urologists, and medical oncologists started within the past decade.

Though surgical removal of larger tumors (>3cm) is considered standard, medical therapy with tyrosine kinase inhibitors has been shown to reduce size of RCCs, pancreatic lesion, and hemangioblastomas (9). As a closing message, Dr. Jonasch advocates for increased awareness of hereditary RCC syndromes and germline genetic testing for all patients diagnosed with an RCC who are less than 46 years-old.

Hereditary RCC Syndromes

Presented By: Eric Jonasch, MD, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA


7. Ho, T.H. and E. Jonasch, Genetic kidney cancer syndromes. J Natl Compr Canc Netw, 2014. 12(9): p. 1347-55.
8. Pena-Llopis, S., S. Vega-Rubin-de-Celis, A. Liao, et al., BAP1 loss defines a new class of renal cell carcinoma. Nat Genet, 2012. 44(7): p. 751-9.
9. Jonasch, E., I.E. McCutcheon, D.S. Gombos, et al., Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol, 2018. 19(10): p. 1351-1359.

Written by: Justin T. Matulay, MD and Ashish M. Kamat, MD, (@UroDocAsh). Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 13th Update on the Management of Genitourinary Malignancies, The University of Texas (MDACC - MD Anderson Cancer Center) November 9-10, 2018, Dan L. Duncan Building, Houston, TX