Natural History of Rare Tumor Risk Syndromes: A Scoping Review to Inform Cost-Effectiveness Models

Abstract

Background Hereditary cancer syndromes account for approximately 10% of all cancers. Many of these, classified as rare tumor risk syndromes (RTRS), lack comprehensive data on natural history, lifetime cancer risk, and the long-term impact of surveillance. These evidence gaps limit the development of decision-analytic disease progression models and cost-effectiveness analyses needed to support healthcare decision-making. Objective To map the available evidence on the natural history, cancer risk, and surveillance strategies in selected RTRS to inform disease progression models and future economic evaluations. Methods A scoping review was conducted on 8 RTRS: Birt-Hogg-Dubé syndrome, familial gastrointestinal stromal tumor, familial melanoma, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell cancer, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Systematic searches of PubMed, Embase, and relevant gray literature sources were performed between April and June 2026 for studies published since 2010. Results After screening 16 631 records, 80 studies were included in the review. Findings indicate significant heterogeneity in data availability and surveillance effectiveness. Some RTRS have relatively well-defined surveillance recommendations, whereas others remain poorly characterized. Across studies, cancer incidence was markedly higher and occurred earlier than in the general population, with lifetime cancer risks approaching 100% in certain syndromes. However, only 44% of studies reported follow-up protocols and fewer than 12% compared surveillance with expectant management. Limited data on postdiagnosis survival further complicates economic evaluations of alternative care strategies. Conclusions The evidence base for RTRS is heterogeneous, particularly regarding longitudinal outcomes and comparative surveillance strategies. These limitations restrict the parameterization of disease progression models and the evaluation of the cost-effectiveness of surveillance strategies, leaving substantial uncertainty about optimal management strategies. Significant evidence gaps remain in the natural history and management of RTRS. This review provides a foundation for future cost-effectiveness analyses by mapping existing evidence and identifying critical knowledge gaps in RTRS care.