Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome (Hill et al., 2009). PPBs contain both epithelial and mesenchymal cells. Early ... Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome (Hill et al., 2009). PPBs contain both epithelial and mesenchymal cells. Early in tumorigenesis, cysts form in lung airspaces, and these cysts are lined with benign-appearing epithelium. Mesenchymal cells susceptible to malignant transformation reside within the cyst walls and form a dense 'cambium' layer beneath the epithelial lining. In a subset of patients, overgrowth of the mesenchymal cells produces a sarcoma, a transition that is associated with a poorer prognosis (Priest et al., 1996). In approximately 35% of families in which a child has PPB, the patient or a family member manifests 1 or more additional conditions from an unusual array of dysontogenetic-dysplastic and malignant conditions, known as the 'PPB family tumor and dysplasia syndrome' (PPBFTDS). Cystic nephroma, which are benign lesions of the kidney, are found in 9 to 10% of family members affected by PPB (summary by Bahubeshi et al., 2010). Larger studies have shown that DICER1 mutations are associated with a variety of tumor types, indicating that this disorder can be considered a tumor predisposition syndrome (summary by Slade et al., 2011).
Priest et al. (1996) collected information on the families of 45 children with pleuropulmonary blastoma (PPB) as well as on the children themselves. Pleuropulmonary blastoma is a rare and distinct intrathoracic neoplasm. The tumor arises from the lung, ... Priest et al. (1996) collected information on the families of 45 children with pleuropulmonary blastoma (PPB) as well as on the children themselves. Pleuropulmonary blastoma is a rare and distinct intrathoracic neoplasm. The tumor arises from the lung, pleura, or both, appears to be purely mesenchymal in phenotype, and usually occurs in children younger than 5 years of age. It lacks malignant epithelial elements, a feature that distinguishes it from the classic adult-type pulmonary blastoma, a neoplasm that has a biphasic histologic pattern in most cases. In 12 of the 45 patients an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients or in their young relatives. The diseases found in association included other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias, and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of p53 (191170), WT1 (607102), and WT2 (194071) were not found in preliminary investigations. Priest et al. (1996) suggested that the occurrence of PPB points to a constitutional and heritable predisposition to dysplastic or neoplastic disease and that such patients and their families should be investigated accordingly. - Clinical Variability Delahunt et al. (1993) reported a family in which a 27-month-old girl and a 31-month-old boy underwent nephrectomy for cystic nephroma and were free of disease in the contralateral kidney 16 and 14 years later, respectively. Their 28-month-old sister underwent pleuropneumonectomy with postoperative chemotherapy for PPB and died of recurrent disease 9 months later. Delahunt et al. (1993) postulated the inheritance of a germline mutation predisposing to the development of these tumors. Hill et al. (2009) studied 11 families with more than 1 affected member. Individuals were classified as affected if they had either PPB, lung cysts, cystic nephroma, or embryonal rhabdomyosarcoma. Bahubeshi et al. (2010) reported 2 unrelated families with cystic nephroma with or without PPB. Cystic nephroma is a benign kidney tumor with differentiated septa and without blastemal elements. In 1 family, a 7-month-old boy developed cystic nephroma and was alive at age 5 years. His sister, who was diagnosed with cystic nephroma and PPB at age 4 years, died at age 5 years. In addition, their mother and 2 additional maternal relatives had goiter. In a second family, 2 brothers diagnosed with cystic nephroma at ages 2 and 3 years were still alive at ages 4 and 7 years, respectively. CT scan in 1 brother showed 2 lung cysts, likely a subtle manifestation. Genetic analysis identified a different heterozygous mutation in the DICER1 gene in each family (see, e.g., 606241.0006). Slade et al. (2011) identified constitutional DICER1 mutations in 19 of 823 index patients with a variety of childhood tumors. Of the 19 probands, 10 had PPB only, 2 had cystic nephroma, 3 had ovarian Sertoli-Leydig cell tumors, 1 had Wilms tumor and ovarian Sertoli-Leydig cell tumors, 1 had PPB and intraocular medulloepithelioma, 1 had medulloblastoma/infratentorial primitive neuroectodermal tumor, and 1 had a germ cell tumor. Inheritance was investigated in 17 families, and 25 relatives were found to carry the DICER1 mutation. Seventeen relatives were unaffected, but 1 mother had ovarian Sertoli-Leydig cell tumor, 1 half-sib had cystic nephroma, and 6 relatives had nontoxic thyroid cysts or goiter. The findings indicated that DICER1 mutations are associated with a variety of tumors, but most commonly PPB, cystic nephroma, and ovarian Sertoli-Leydig cell tumors, and that the penetrance is incomplete. Slade et al. (2011) proposed the designation 'DICER1 syndrome.' Analysis of tumor tissue and cancer cell lines indicated that somatic DICER1 mutations are unlikely to contribute to tumor pathogenesis. Foulkes et al. (2011) identified 7 different heterozygous truncating mutations in the DICER1 gene in 7 families with a variety of tumor types, including cervical embryonal rhabdomyosarcoma, cervical primitive neuroepithelial tumor-Ewing sarcoma, Sertoli-Leydig cell tumor, multinodular goiter, cystic nephroma, pleiomorphic sarcoma, and Wilms tumor. Other findings included pleuropulmonary blastoma, and lung cysts. One mutation carrier in 1 family had complex cardiac defects, including transposition of the great arteries, bicuspid pulmonary valve, atrial septal defect, and small patent ductus arteriosus, and a mutation carrier in another family had pulmonary sequestration. Examination of tumor tissue from several patients did not show loss of heterozygosity for DICER1, indicating that some different second events must be required for tumor formation. However, the findings indicated that germline DICER1 mutations serve as a conditioning context for the development of multiple tumor types.
Of the 72 genes within the 7-Mb region of interest, Hill et al. (2009) chose DICER as an attractive candidate because of its role in lung development. Harris et al. (2006) had shown that conditional loss of DICER1 ... Of the 72 genes within the 7-Mb region of interest, Hill et al. (2009) chose DICER as an attractive candidate because of its role in lung development. Harris et al. (2006) had shown that conditional loss of DICER1 in the developing mouse lung results in cystic airways, disruption of branching morphogenesis, and mesenchymal expansion that resembles the early stage of PPB. Hill et al. (2009) identified heterozygous germline mutations in DICER1 by sequencing genomic DNA from affected members in each of 11 families (4 included in the linkage study and 7 additional families). In 10 of the families, the mutation resulted in proteins truncated proximal to the 2 carboxy-terminal RNaseIII functional domains in DICER1 and thus likely caused loss of function. In 1 family, a missense mutation (L1583R; 606241.0001) affected an evolutionarily conserved amino acid. Obligate carriers with DICER1 mutations are phenotypically normal, which suggested that loss of 1 DICER allele is compatible with normal development and insufficient for tumor formation. Hill et al. (2009) performed immunohistochemistry of DICER1 from PPB tumors and found that, in 6 of the 7 families harboring PPBs with a residual epithelial cystic component, expression from the wildtype allele was lost in tumor-associated epithelium but was retained in the mesenchymal tumor cells. Hill et al. (2009) hypothesized that PPB may arise through a novel mechanism of non-cell-autonomous cancer initiation. Conceivably, loss of DICER1 in developing lung epithelium alters miRNA-dependent regulation of diffusible growth factors that promote mesenchymal cell proliferation.