Background This study investigates the natural history of pediatric pleuropulmonary blastoma (PPB) and associated tumors in individuals with DICER1 gene mutations. PPB is a rapidly growing lung cancer that primarily affects children under 6 years of age and belongs to a group of rare tumors. Identification of a genetic predisposition underscores the need for personalized management of patients and families. ## Study Design The observational study, sponsored by the National Cancer Institute (NCI) and enrolling participants since February 2011, involves no therapeutic intervention. Participants provide annual updates through questionnaires, medical record submissions, physical and imaging examinations, and collection of blood, saliva, and tumor tissue samples. Individuals aged 18 and older complete questionnaires themselves, while minors are represented by a parent or guardian. ## Current Treatment Landscape and Distinction Standard care for PPB often combines surgery, chemotherapy, and radiation therapy, and prognostication remains challenging. Although this study does not assess treatment efficacy, it longitudinally records disease progression patterns and their association with genetic variants, thereby establishing a database essential for future targeted‑therapy development. ## Industry and Academic Impact Natural‑history data will furnish biotech companies with evidence to inform clinical trial design for PPB drug candidates. Moreover, the dataset enhances the potential to discover early‑diagnostic biomarkers for other DICER1‑associated tumors, reducing risk in the rare‑cancer therapeutic market.