Calculating optimal surveillance for detection of von Hippel–Lindau-related manifestations

Abstract

Abstractvon Hippel-Lindau (VHL) mutation carriers develop benign and malignant tumors, requiring regular surveillance. The aim of this study was to calculate the optimal organ-specific age to initiate surveillance and optimal intervals to detect initial and subsequent VHL-related manifestations. In this study, we compare these results with the current VHL surveillance guidelines. We collected data from 82 VHL mutation carriers in the Dutch VHL surveillance program. The cumulative proportion of carriers diagnosed with a first VHL-related manifestation was estimated by the Kaplan-Meier method. The Poisson distribution model was used to calculate average time to detection of the first VHL-related manifestation and subsequent manifestations. We used this to calculate the optimal organ-specific age to initiate surveillance and the surveillance interval that results in a detection probability of 5%. The calculated organ-specific ages to initiate surveillance were 0 years (birth) for adrenal glands, 7 years for the retina, 14 years for the cerebellum, 15 years for the spinal cord, 16 years for pancreas, and 18 years for the kidneys. The calculated surveillance intervals were 4 years for the adrenal glands, biennially for the retina and pancreas, and annually for the cerebellum, spinal cord, and kidneys. Compared with current VHL guidelines, the calculated starting age of surveillance was 6 years later for the retina and 5 years earlier for adrenal glands. The surveillance intervals were two times longer for the retina and four times longer for the adrenal glands. To attain a 5% detection probability rate per organ, our mathematical model indicates that several modifications of current VHL surveillance guidelines should be considered.

Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

“…Historically, these guidelines were based on expert consensus, with early screening targeted to tumor spectrum, risk levels, and typical ages of presentation (7,(23)(24)(25). Recent efforts have employed mathematical modeling methodologies, informed by the available clinical data, 16/unknown to predict the ideal ages to initiate surveillance and the most appropriate frequency for ongoing screening (26). Our current consensus recommendations for screening of vHLrelated tumors incorporate the elements of existing paradigms into a new surveillance regimen, with an emphasis on pediatric patients (Table 4).…”

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

“…Two studies have systematically investigated vHL surveillance recommendations in relation to optimal surveillance initiation and frequency. 4,9 So far, individualized surveillance in relation to factors such as age or genotype has not been explored.…”

“…8 This further corresponds with previous findings of annual examinations as the most optimal retinal surveillance frequency. 4 By contrast, Kurizinga et al 9 recently recommended that retinal surveillance should be performed every second year instead of yearly as currently recommended. However, both previous studies are based on overall manifestation frequencies that did not take into account that the risk of a new retinal manifestation may differ for children, teenagers, and adults.…”

“…We recommend CNS surveillance every 1-2 years, starting from the late teens, in compliance with current guidelines as well as the two previous surveillance studies. 4,8,9 We stress that surveillance recommendations apply to asymptomatic patients without manifestations in the concerned organ system. Once a manifestation is diagnosed, individual follow-up should be assessed.…”

“…Prophylactic surveillance is essential to facilitate early diagnosis of the manifestations and to enable intervention, either surgical or individually intensified follow-up measures of the organ in question. 2,8,9 The unpredictable mode of disease progression, however, can cause uncertainty for patients and health professionals and complicates both genetic counseling and surveillance organization. Current surveillance guidelines are based on the notion that risk of tumor development is constant throughout a vHL patient's entire lifetime.…”