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Priest J.R.,International Pleuropulmonary Blastoma Registry | Williams G.M.,Childrens Hospitals and Clinics of Minnesota | Mize W.A.,Childrens Hospitals and Clinics of Minnesota | Dehner L.P.,University of Washington | McDermott M.B.,Our Ladys Hospital for Sick Children
International Journal of Pediatric Otorhinolaryngology | Year: 2010

Objectives: Nasal chondromesenchymal hamartoma (NCMH) is an uncommon chondro-stromal tumor of the nasal cavity and paranasal sinuses in infancy and childhood. Pleuropulmonary blastoma (PPB) is also a rare malignancy of lung and pleura in childhood and is the sentinel disease of an important familial tumor and dysplasia syndrome. This study identified NCMH in PPB patients. Methods: The International PPB Registry collects cases of PPB using central pathology review and evaluation of clinical records. The Registry also evaluates PPB literature. Examples of NCMH occurring with PPB were identified. Clinical records, digital radiography and pathologic specimens of PPB-associated NCMH cases were analyzed. Results: Among approximately 625 cases of PPB, four children developed NCMH. These cases are among 28 total reported NCMH cases. NCMH presented with sinonasal congestion and visible polypoid nasal masses and were diagnosed from ages 7 to 15 years, similar to older reported NCMH cases. NCMH involved the nasal cavity, paranasal sinuses and upper nasopharynx, was bilateral in three children and locally recurrent in one. In two children, NCMH had the characteristic pathologic spectrum of immature nodules of cartilage surrounded by spindle cell stroma, whereas the other two NCMH displayed mature chondroid nodules and a less varied fibrous stroma. NCMH was not identified in family members with PPB. Conclusions: NCMH developing in four children with PPB indicates that NCMH is part of the heredofamilial disease complex associated with PPB. Otorhinolaryngologists and pediatric oncologists should be aware that these two rare conditions occur together and that affected patients may have a familial predisposition to childhood malignant and dysplastic disease. © 2010 Elsevier Ireland Ltd. Source

Cross S.F.,The Childrens Hospital at Westmead | Arbuckle S.,The Childrens Hospital at Westmead | Priest J.R.,International Pleuropulmonary Blastoma Registry | Marshall G.,Center for Childrens Cancer and Blood Disorders | And 2 more authors.
Pediatric Blood and Cancer | Year: 2010

We present three cases of pleuropulmonary blastoma (PPB) in Australian children. Each had a family history of childhood tumors which collectively included PPB, infant lung cyst, cystic nephroma, medullo-epithelioma and a Sertoli-Leydig ovarian tumor. Two of the patients also had additional malignancies: a concurrent bladder rhabdomyosarcoma and a post therapy non-PPB malignant lung tumor. In two cases, the family histories were elicited years after the PPB diagnosis. Archived pathology material allowed revision of pathologic diagnoses from decades earlier. These cases illustrate the importance of detailed inquiry into family medical history and the pleiotropy of the PPB-related familial cancer predisposition syndrome, which appears to result from heterozygous DICER1 mutations. © 2010 Wiley-Liss, Inc. Source

Cummings N.M.,Papworth Hospital | Desai S.,Foundation Medicine | Thway K.,Royal Marsden Hospital | Stewart S.,Papworth Hospital | And 4 more authors.
American Journal of Surgical Pathology | Year: 2010

Pleuropulmonary synovial sarcoma is a rare malignancy that often presents like any other thoracic tumor with symptoms such as chest pain or cough. Here we describe 4 young adults who underwent surgery for apparently benign recurrent pneumothoraces and who, unexpectedly, were found upon histologic and molecular examination of the resection specimen to have cystic primary pleuropulmonary synovial sarcoma. These cases highlight (a) the importance of cytogenetic analysis in making the diagnosis, as confusion with other spindle cell sarcomas or cystic neoplasms can occur and (b) the importance of thorough examination of all resected tissue in cases of recurrent pneumothorax. © 2010 by Lippincott Williams & Wilkins. Source

Wagh P.K.,Cincinnati Childrens Hospital Medical Center | Gardner M.A.,Cincinnati Childrens Hospital Medical Center | Ma X.,Cincinnati Childrens Hospital Medical Center | Callahan M.,Cincinnati Childrens Hospital Medical Center | And 9 more authors.
Journal of Pathology | Year: 2015

Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of-function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm pleuropulmonary blastoma (PPB), which arises during lung development. DICER1 regulates many biological processes critical in development and disease pathogenesis. Significant challenges in defining the role of DICER1 in human disease are identifying cause-effect relationships and generating manipulatable systems that model the complexity of organ development and disease pathogenesis. Here we report the generation of a murine model for PPB and demonstrate that precise temporal and cell type-specific Dicer1 ablation is necessary and sufficient for the development of cystic lungs that histologically and phenotypically model PPB. Dicer1 ablation in the distal airway epithelium during early stages of lung development resulted in a cystic lung phenotype indistinguishable from PPB, whereas DICER1 function was not required for development of the proximal airway epithelium or during later stages of organogenesis. Mechanistic studies demonstrate that Dicer1 loss results in epithelial cell death, followed by cystic airway dilatation accompanied by epithelial and mesenchymal proliferation. These studies define precise temporal and epithelial cell type-specific DICER1 functions in the developing lung and demonstrate that loss of these DICER1 functions is sufficient for the development of cystic PPB. These results also provide evidence that PPB arise through a novel mechanism of non-cell-autonomous tumour initiation, in which the genetic abnormality initiating the neoplasm does not occur in the cells that ultimately transform, but rather occurs in a benign-appearing epithelial cell component that predisposes underlying mesenchymal cells to malignant transformation. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source

Messinger Y.H.,International Pleuropulmonary Blastoma Registry | Stewart D.R.,U.S. National Institutes of Health | Priest J.R.,International Pleuropulmonary Blastoma Registry | Williams G.M.,International Pleuropulmonary Blastoma Registry | And 9 more authors.
Cancer | Year: 2015

BACKGROUND: Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid). A germline mutation in DICER1 is the genetic cause in the majority of PPB cases. METHODS: Patients confirmed to have PPB by central pathology review were included, and their clinical characteristics and outcomes were reported. Germline DICER1 mutations were sought with Sanger sequencing. RESULTS: There were 435 cases, and a central review confirmed 350 cases to be PPB; 85 cases (20%) were another entity. Thirty-three percent of the 350 PPB cases were type I or type I regressed (type Ir), 35% were type II, and 32% were type III or type II/III. The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively. The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all deaths in this group were due to progression to type II or III. OS was significantly better for type II versus type III (P = .0061); the 5-year OS rates were 71% and 53%, respectively. Disease-free survival (DFS) was also significantly better for type II versus type III (P = .0002); the 5-year DFS rates were 59% and 37%, respectively. The PPB type was the strongest predictor of outcome. Metastatic disease at the diagnosis of types II and III was also an independent unfavorable prognostic factor. Sixty-six percent of the 97 patients tested had a heterozygous germline DICER1 mutation. In this subset, the DICER1 germline mutation status was not related to the outcome. CONCLUSIONS: Cystic type I/Ir PPB has a better prognosis than type II, and type II has a better outcome than type III. Surveillance of DICER1 carriers may allow the earlier detection of cystic PPB before its progression to type II or III PPB and thereby improve outcomes. © 2014 American Cancer Society. Source

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