10060 Background: Pleuropulmonary blastoma (PPB) is a rare malignancy of the lung presenting in young children. The International PPB Registry (IPBBR) has pathologically confirmed more than 400 cases of PPB. Three pathologic subtypes correlate with age and outcome: Type I, a purely cystic lesion often cured by surgery alone; Type II, a combined cystic and solid lesion; and Type III, a purely solid high-grade sarcoma. Previously reported five-year survival rates for Types II and III PPB are 67% and 51%, respectively. Historically, treatment for Types II and III PPB has not been uniform. The IPPBR conducted the first prospective treatment study to evaluate the response of Type II and III PPB to a standardized chemotherapy regimen. Methods: Treatment records were obtained forpatients with Type II and III PPB who enrolled on the IPBBR Treatment and Biology registry. A regimen of 36 weeks of ifosfamide, vincristine, actinomycin and doxorubicin (IVADo) was recommended. Sixty-two patients were treated on the IVADo regimen; 42 completed 3 or more cycles of induction IVADo and were considered fully assessable for analyses. The IVADo group was compared as a group to 200 historical IPPBR confirmed PPB patients who received regimens other than IVADo for both event-free survival (EFS) and overall survival (OS). Results: Of the 42 patients, 25 (60%) were males and 17 (40%) females; median age at diagnosis was 35 months (range 19-83). There were 24 (57%) Type II; 4 (10%) Type II/III, and 14 (33%) Type III. At a median follow-up of 28 months (range 2-71), 10 (24%) relapsed; 6 (14%) died at 12-24 months. Compared to the historical group, the IVADo group had better EFS (Log-rank test, p=0.008) and better OS (p=0.04). At 5 years, IVADo had better EFS: 70.8% (95% CI 55.3-86.3%) vs. 44.7% (95% CI 37.1-52.4%), and better OS 79.2% (64.1-94.2%) vs. 60.1% (52.3-67.9%). Conclusions: To date, the IPPBR treatment study represents the only cohort of patients with Type II and Type III PPB that have been treated uniformly. The standardized use of IVADo showed improvement in EFS and OS compared to the historical group. Importantly, the follow-up of the IVADo cohort is shorter, and there are late events and deaths in the historical group, limiting our conclusion. Clinical trial information: NCT01464606.
8542 Background: Pleuropulmonary Blastoma (PPB) is a rare childhood tumor of the chest wall and lung with three distinct pathology subtypes: type I—entirely cystic; type II—cystic and solid; type III—entirely solid. Poor outcomes have been observed in patients with types II and III PPB. Common sites of metastatic involvement are the brain and bones. In numerous cases, other dysplastic and/or neoplastic conditions occur in the PPB patient or in young, close relatives. Methods: The PPB Registry, established in 1988, collects diagnostic, treatment, and outcome data about this disease for patients worldwide. Results: Registry and literature cases reveal the following conditions associated with PPB in 30 families: Familial cases: -9 patients with relatives having childhood or young adult cancers -3 families with 2 PPB patients in each; an additional family with a child with PPB and another child with a brain sarcoma undistinguishable from PPB -6 patients with relatives having dysplasia in childhood or young adulthood Metachronous or synchronous conditions: -4 patients with additional cancers -5 patients with bilateral PPB -12 patients with additional dysplastic conditions Common associated dysplastic conditions are lung cysts and cystic nephroma. Other associated neoplastic conditions include germ-cell tumors, brain tumors, lymphoma and leukemia, sarcomas, histiocytosis, Wilms' tumor, thyroid tumors, neuroblastoma, and Sertoli-Leydig tumor. Conclusion: 19 of 82 registry patients (23%) with central PPB pathology review have a constitutional or familial association with other neoplasias/dysplasias. At least 3 PPB patients have relatives with germ cell tumors, an association that needs further exploration. Similarly, the preponderance of renal malformations/tumors implies a possible common genetic pathway. PPB is an extraordinary marker for familial childhood dysplasia and neoplasia which deserves intensive molecular study. No significant financial relationships to disclose.
10024 Background: Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood lung cancer that is often the first manifestation of the PPB-DICER1 familial tumor predisposition which includes other benign and malignant conditions. The initial genetic mutation is inherited by a germ-line loss of function of DICER1 gene which was discovered by Hill et al. It is proposed that loss of DICER1 expression alters miRNA regulation of key regulatory cellular mechanisms which promote tumor growth. PPB can progress from the purely cystic, curable Type I to a high-grade Type III having a dismal prognosis. We sought to determine the frequency of DICER1mutation in the largest cohort of PPB patients to date. Methods: We obtained germ-line DNA from saliva or blood samples from 113 PPB patients collected from 2005-2012. DNA was extracted using the Maxwell 16 Research System (Promega Corporation, Madison WI). Sample quality and quantity was checked using the Nanodrop 2000 (Thermo Scientific, Wilmington, DE). Sequencing was performed using the Sanger sequencer. For a subset of cases we used targeted sequencing services or full gene sequence analysis (Ambry Genetics, Aliso Viejo, CA). Results: Seventy-four (65.5%) PPB patients were found to have deleterious DICER1germ-line mutations. The most common mutation type found was small insertion/deletions. These 74 samples were composed of 7 (9.5%)Type Ir PPBs, 22 (29.7%)Type I PPBs, 24 (32.4%) Type II PPBs, and 21 (28.4%)Type III PPBs. The following Table shows a summary of mutation types identified. Conclusions: Our results confirm that DICER1 germline mutations are the most common genetic alterations in PPB making it critical for genetic testing to be performed at diagnosis. Additionally, this underscores the need for important correlative studies to describe the genotype-phenotype relationship in order for appropriate screening guidelines to be developed and implemented to allow for early detection. While a majority of cases are explained by germline DICER1 mutations using current sequencing methods, further investigation is warranted to elucidate other possible mechanisms in the development of PPB. [Table: see text]
Human and animal solid tumors elaborate a factor which is mitogenic to capillary endothelial cells. This factor has been called tumor-angiogenesis factor. The important components of TAF are RNA and protein. It is suggested that blockade of this factor (inhibition of angiogenesis) might arrest solid tumors at a tiny diameter of a few millimeters.
Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.
Pleuropulmonary blastoma (PPB) is the most common primary lung tumor of infants and young children and is known to be associated with pathogenic variants in the DICER1 gene. In addition to PPB, DICER1-associated conditions include a variety of other benign and malignant tumors including cystic nephroma and Wilms tumor, ovarian Sertoli-Leydig cell tumor and gynandroblastoma, multinodular goiter and thyroid carcinoma and certain childhood brain tumors among others. Early identification of individuals most at risk for DICER1- associated conditions may allow family education, targeted surveillance and identification of DICER1-related tumors and conditions in their earliest and most curable form. Given the rarity of these conditions, international collaboration is underway and encouraged.
