The Child with PPB

The Constitutional/Familial/Syndromic Manifestations of PPB

Pleuropulmonary blastoma is a strikingly genetic and familial disease. The PPB/DICER1 Registry currently estimates that approximately 40% of cases have a genetic basis. This is the PPB Family Tumor and Dysplasia Syndrome and it may be manifested in the patient or family or both (see Registry Publications Priest 1996; Boman 2006; Priest 2009). In general this syndrome involves neoplastic and dysplastic disease appearing mostly in the first 5-6 years of life but with some conditions appearing up to the late teens or early 20’s. Although the entire phenotype of this syndrome is not yet known, there do not appear to be neoplasias in later years associated with PPB.

In the PPB patient, the PPB Family Tumor and Dysplasia Syndrome means that multiple dyplasias may exist or develop. In the lungs, bilateral and/or multifocal lung cysts are present in approximately 15% of children. Bilateral Type I PPB has been observed in several cases. Cystic nephroma is the most common non-pulmonary neoplasia (~10% incidence in PPB patients or relatives) (see Registry Publications, Boman 2006). In a small subset of children, PPB, cystic nephroma and small bowel polyps have been observed (Boman 2006). Several PPB patients have developed other tumors such as Sertoli-Leydig ovarian tumors, intra-ocular medulloepithelioma (diktyoma), or nasal chondromesenchymal hamartoma. Taken together this unique set of diseases is different from any other familial neoplasia syndrome.

A few children with PPB have had what appear to be treatment-related second malignant neoplasms, but despite their apparent propensity to neoplasia, the frequency of treatment-related neoplasms in these children does not appear to be different from other cancer survivors. The PPB/DICER1 Registry is aware of three PPB children with apparent treatment-related malignancies: glioblastoma multiforme following radiation for PPB brain metastasis, thyroid carcinoma after chest radiation, and acute myelomonocytic leukemia following chemotherapy for PPB including alkylating agents and etoposide.

In the PPB patient’s family, there may be other PPBs, lung cysts (such as" Type Ir PPB"), cystic nephroma, childhood cancers including sarcomas and leukemias, ovarian and testicular tumors (especially Sertoli-Leydig tumors, seminomas, and dysgerminomas) and other soft tissue dysplasias. These conditions usually involve young people. Siblings, parents, grandparents, aunts, uncles, etc (when they were young) are typically involved, although distant cousins may manifest a characteristic illness with intervening relatives normal. Several families have more than one PPB, in some cases in up to three generations. Nodular thyroid hyperplasias and cancers are very common in these families but may be a coincidental finding because of their frequency in the general population.

Conditions which constitute the PPB Family Tumor and Dysplasia Syndrome are summarized in Cases of Cystic Nephroma Associated with PPB and Dysplastic and Neoplastic Conditions in PPB Patients and their Families.

Genetic and Molecular Findings in PPB - 2009

In April 2009, the PPB/DICER1 Registry and collaborators reported at the American Association for Cancer Research finding germline loss-of-function mutations in the gene DICER1 in 11 families affected by PPB, lung cysts, cystic nephroma and rhabdomyosarcoma. This mutation may be related to the predisposition to PPB and other neoplasias in these families. This work has subsequnetly been published (see Registry Publications, Hill Science 2009). For the complete abstract: Genetics of PPB.

DICER1 codes for DICER1, a cytoplasmic endoribonuclease which cleaves precursors (produced in the nucleus by Drosha enzyme) into 22-base miRNA and siRNA. These small silencing RNAs are critical in controling the expression of messenger RNA (mRNA). DICER1 also participates in the RNA-induced silencing complex (RISC) in which mRNA is degraded or its expression suppressed.

In addition to the DICER1 mutation, this research revealed a possible novel cancer induction mechanism: in PPB, pulmonary epithelial cells (present in Type I and II PPB) are histologically benign, but immunohistochemical staining for DICER1 revealed segmental or focal DICER1 loss, whereas IHC staining for DICER1 in histologically-malignant mesenchymal cells was normal. The implication is that dysregulated autocrine signals from epithelial to mesenchymal cells - signals which are known to be important for normal branching morphogenesis in developing lung - induces cyst formation and malignancy in mesenchymal cells (see Registry Publications, Hill 2009).

These findings in 11 PPB families must be extended to more families and to cases of "sporadic" PPB. The PPB Registry continues actively to investigate the genetic and molecular basis for the PPB Family Tumor and Dysplasia Syndrome. The International PPB/DICER1 Registry is conducting a major study of genetic inheritance in PPB patients and their families. We ask that all PPB patients and their families consider participating. Visit or for more information. Physicians encountering all cases of PPB are encouraged to contact the PPB/DICER1 Registry for enrollment and for additional information.