AUA 2018: Long Term Outcomes for Patients with Von Hippel Lindau and Pheochromocytoma: Defining the Best Candidates for Active Surveillance

San Francisco, CA (UroToday.com) Von Hippel Lindau (VHL) is a germline mutation in 3p25-26 (the short arm of chromosome 3). While it has many clinical manifestations, including angiomatosis, hemangioblastomas, pancreatic cysts (pancreatic serous cystadenoma), endolymphatic sac tumor, and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women), it is significant to urologists for 2 specific conditions: renal cell carcinoma (RCC) and pheochromocytoma. Patients with VHL associated RCC are known to have a more aggressive, often bilateral disease – aggressive management is warranted as recurrences are high.

However, less is known about the natural history of patients with VHL and pheochromocytoma. As the authors from the National Cancer Institute and the National Institutes of Health note, with the long history of interest in VHL associated renal masses, patients with VHL have a 7-18% lifetime risk of developing pheochromocytoma. Specifically, they focus on the outcome of patients placed on active surveillance (AS), for a period of time. As AS has become more popular for small renal masses (SRMs), its utility in pheochromocytoma is also clinically important. 

Importantly, this is NOT a study of pure AS for pheochromocytoma, as all (or most) patients ultimately underwent surgical resection. However, as all patients had a period of AS, they can help better elucidate the natural history of these lesions. They included all patients with confirmed VHL, had a period of AS, and underwent resection. They included patients with paraganglioma – pheochromocytoma outside the adrenal gland. Lesions were stratified based on size at initial assessment into 3 categories: less than 1 cm, 1-2 cm, and greater than 2cm. Growth rate per year was calculated using the following formula: (size [end of surveillance period]- size [beginning of surveillance period])/ time( years). Naturally, this doesn’t necessarily identify growth spurts vs. steady growth… 

Of 54 families followed with VHL, 72 patients met all inclusion criteria; median length of follow up was 17 years. There were 38 masses that underwent a period of surveillance in 26 patients. It is unclear what happened to the remaining of the 72 patients.

  • They included catecholamine evaluation. Serum catecholamines were obtained in the sitting position. Urine catecholamines were from a 24 hour urine collection.
While the median age at which surveillance was began was 30, patients ranged from age 7 to 61. Not all patients were offered active surveillance first – indications for intervention were catecholamine levels > 2x upper limit of normal, symptoms or size > 2 cm. Importantly, many patients also underwent intervention if they were undergoing surgery for other indications – which was often.

The median time on surveillance was 4.3 years (range 0.3 -20.1) prior to intervention. The median size of mass when starting surveillance was 1.0 cm (range 0.3-2.5 cm) and the median size when the mass was resected was 2.0 (range 0.3-4.5). The median growth rate for all masses was 1mm per year (range -0.23-1.06), which is much slower than RCC; however, this was size dependent – the median growth rate for masses under 1.0 cm was less than those larger than 2.0 cm (0.3mm per year vs. 3.2 mm/year). 

  • He did note that patients had a non-linear growth pattern. Periods of indolence followed by growth
  • However, the inflection point seems to be approximately 2 cm. 
No patients on surveillance developed metastatic disease.

In our discussion, Thomas Sanford did note that this has changed his institution’s management. They are more comfortable monitoring small masses in patients with VHL. However, he did note that VHL related pheochromocytomas are a small population – other pheochromocytomas should be treated differently.

Limitations / Discussion Points:

1. Single-institution case series with inherent biases. However, as this is a new concept, they were understandably cautious in their selection.
2. Pathology would be important to help inform the discussion regarding the need for surgery or intervention.

However, this study continues to add to the growing literature that appropriately selected patients for different malignancies may benefit from active surveillance.


Presented by: Thomas Sanford, MD
Co-Authors: Rashid Siddiqui, Daniel Su, Julie An, Adam Metwalli
Author Affiliation: National Cancer Institute / National Institutes of Health, Maryland

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, | twitter: @tchandra_uromd at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA