Tumor detection rates in screening carriers with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome based on prior tumor history

1545 Background: Patients with germline pathogenic variants (PVs) in the SDHx genes have increased risk for paragangliomas/pheochromocytomas (PGL/PCC), renal cell carcinomas, and gastrointestinal stromal tumors. Expert recommendation suggests individuals with SDHx PVs undergo biennial whole-body imaging and annual biochemical testing. This study aimed to evaluate tumor detection rate using standard biochemical and imaging protocols for individuals with SDHx PVs, particularly in those with and without SDHx-related tumor history, and in those with biochemical testing data. Methods: A retrospective longitudinal observational study at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute was conducted from the start of each center’s screening program through March 1, 2018. Individuals with SDHx PVs had clinical imaging with whole body MRI/CT and biochemical testing per expert recommendation. SDHx-related tumors identified during clinical screening were measured. Results: A total of 263 individuals with SDHx PVs completed 491 screens. Individuals with SDHB PVs were the most prevalent (n = 188, 71.5%). The average number of screens per subject was 1.87 (range 1-7). A majority (n = 194, 73.7%) of individuals did not have a prior history of PGL/PCC. Overall, SDHx-related tumors were detected in 17.1% (n = 45) of the cohort. Of the 46 scans that identified an SDHx-related tumor, 85% of them (n = 39) were baseline scans. SDHx-related tumors were identified in 18.6% (n = 36/194) of individuals that did not have a prior history of PGL/PCC, whereas they were identified in 13.0% (n = 9/69) of individuals that did have a prior history of PGL/PCC (p = 0.39). Biochemical testing was available for 70% (n = 343) of imaging screens, of which 18% (n = 61) had positive biochemistry. Of those with positive biochemistry, 19 tumors were identified on imaging (6%). Sixteen tumors were identified on imaging with negative biochemistry (5%) with a sensitivity of 54% and a specificity of 94%. Utilizing a cut-off of two times the upper limit of normal, 9.91% (n = 34) biochemical tests were positive, and 15 (44.12%) had an SDHx-related tumor on corresponding imaging. Conclusions: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumors were detected in subjects with a prior history of PGL/PCC and those with no prior history. This suggests life-long screening is important for all SDHx carriers. Imaging is a crucial piece of SDHx screening given biochemical testing’s sensitivity and specificity.