PPB is caused by heterozygous germline pathogenic variants in the DICER1 gene, which encodes dicer 1, ribonuclease III — an enzyme central to microRNA processing and gene regulation. Loss-of-function DICER1 variants disrupt normal cellular regulatory mechanisms. Approximately 65% of children with PPB carry a germline DICER1 pathogenic variant. In approximately 80% of DICER1-associated PPB cases, the germline variant is inherited from a parent; approximately 20% arise as de novo germline variants. The condition follows autosomal dominant inheritance. The penetrance of germline DICER1 pathogenic variants is reduced and age dependent; by age ten years, approximately 5.3% of non-proband carriers of a germline variant have developed a neoplasm. Microscopically, PPB tumors may show features of chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, or undifferentiated sarcoma depending on tumor type.

The diagnosis of DICER1-related PPB is established by identification of a heterozygous germline pathogenic variant in DICER1 through molecular genetic testing. Testing approaches include single-gene DICER1 sequence analysis, multigene hereditary cancer panels, or comprehensive genomic testing such as exome or genome sequencing. On histopathology, the tumor may display features of multiple sarcoma subtypes. Type I PPB is radiographically indistinguishable from benign congenital cystic lung malformations, making histopathological and molecular evaluation central to establishing the diagnosis. Identification of a somatic DICER1 pathogenic variant in tumor tissue may also prompt evaluation for an underlying germline variant. No universally accepted clinical diagnostic criteria exist; diagnosis relies on the combination of clinical, imaging, histologic, and molecular genetic findings.

No FDA-approved targeted therapies are listed in the certified packet for PPB. Treatment approaches described in the GeneReviews literature for DICER1 tumor predisposition are based on tumor type. Type I PPB is addressed with complete surgical removal with or without adjuvant chemotherapy; five-year overall survival is 89% for this type. Type Ir PPB is managed with surgical resection alone or observation in certain clinical circumstances, with PPB-related survival of 100% following resection. Types II and III PPB are approached with aggressive surgical resection combined with intensive chemotherapy; when tumor extent precludes initial resection, biopsy followed by neoadjuvant chemotherapy and subsequent resection has been performed. Chemotherapy alone is insufficient to eradicate solid PPB. Radiation therapy has been used for recurrence, metastasis, or local control of unresectable residual disease. Solid PPB components are friable, requiring careful surgical technique to minimize tumor disruption during resection.

Prognosis in PPB is closely tied to tumor type. Five-year survival rates reported in the GeneReviews chapter on DICER1 tumor predisposition are 89% for type I, 71% for type II, and 53% for type III PPB. Type Ir PPB carries 100% PPB-related survival following resection; PPB-related deaths in type I PPB have occurred only with progression to type II or III. Brain parenchyma is the most common site of distant metastasis. Pathogenic variant location within DICER1 influences overall tumor risk. Variants in EGFr domains 1–6 appear to be associated with greater risk and earlier disease, while variants in domains 7–34 have a higher population frequency and likely a milder or potentially non-penetrant clinical course. Established genotype-phenotype correlations specific to PPB outcomes have not been firmly defined.

Multiple active clinical investigations are underway for PPB and DICER1-related conditions. A Phase 3 trial sponsored by the Children's Oncology Group is evaluating standardized surgical and chemotherapy approaches for type I PPB and the addition of topotecan to standard treatment for types II and III PPB across international centers. The National Cancer Institute sponsors a long-term natural history study of DICER1-related PPB cancer predisposition syndrome, enrolling since 2011. An international PPB/DICER1 registry continues to collect longitudinal data from participants globally to characterize clinical spectrum and treatment outcomes. An NCI clinical genetics eligibility screening study is actively enrolling. An international observational study of pediatric patients with rare tumors includes PPB among its enrolled conditions.