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Modern Pathology : An Official Journal... Jun 2021Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic),...
Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry.
Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.
Topics: Adolescent; Biomarkers, Tumor; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Prognosis; Pulmonary Blastoma; Registries; Survival Analysis; Tumor Suppressor Protein p53; Young Adult
PubMed: 33637876
DOI: 10.1038/s41379-021-00735-8 -
Clinical Radiology Apr 2021Hereditary ovarian tumour syndromes are a diverse group of hereditary syndromes characterised by the development of specific histotypes of ovarian neoplasms. While BRCA... (Review)
Review
Hereditary ovarian tumour syndromes are a diverse group of hereditary syndromes characterised by the development of specific histotypes of ovarian neoplasms. While BRCA syndromes are exclusively associated with high-grade serous carcinomas, patients with Lynch syndrome show a preponderance of endometrioid subtype of ovarian and endometrial carcinomas. Distinct non-epithelial phenotypes, such as sex cord stromal tumours with annular tubules, Sertoli-Leydig cell tumours, and small cell carcinoma of the hypercalcaemic type occur in patients with Peutz-Jeghers, DICER1, and rhabdoid tumour predisposition syndromes, respectively. Gorlin-Goltz syndrome is characterised by the development of bilateral, multiple ovarian fibromas in 14-24% of patients. Ovarian steroid cell tumours and broad ligament papillary cystadenomas are characteristically found in women with von Hippel-Lindau syndrome. Recent studies have allowed the characterisation of tumour genetics and associated oncological pathways that contribute to tumourigenesis. Implications of the diagnosis of these syndromes on screening, management, and prognosis are discussed.
Topics: Basal Cell Nevus Syndrome; Brain Neoplasms; Carcinoma, Ovarian Epithelial; Colorectal Neoplasms, Hereditary Nonpolyposis; DEAD-box RNA Helicases; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Kidney Neoplasms; Neoplastic Syndromes, Hereditary; Ovarian Neoplasms; Peutz-Jeghers Syndrome; Pulmonary Blastoma; Rhabdoid Tumor; Ribonuclease III; von Hippel-Lindau Disease
PubMed: 33353730
DOI: 10.1016/j.crad.2020.11.116 -
Turk Gogus Kalp Damar Cerrahisi Dergisi Jan 2020Pleuropulmonary blastoma is a rare and aggressive childhood tumor of mesenchymal origin. It has a poor prognosis and mainly classified as cystic (type 1), mixed type...
Pleuropulmonary blastoma is a rare and aggressive childhood tumor of mesenchymal origin. It has a poor prognosis and mainly classified as cystic (type 1), mixed type (type 2), and solid (type 3). Herein, we present two cases of pleuropulmonary blastoma type 3 presenting with pneumothorax, a rare clinical presentation of pleuropulmonary blastoma, which was successfully treated with surgery.
PubMed: 32175165
DOI: 10.5606/tgkdc.dergisi.2020.18215 -
Problemy Endokrinologii Oct 2023DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a... (Review)
Review
DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a dusfunction of the endoribonuclease DICER, which plays an important role in the processing of microRNAs with subsequent regulation of the control of the expression of oncogenes and tumor suppressor genes. Clinical manifestations of dyseropathies is very different and may include both endocrine manifestations - multinodular goiter, differentiated thyroid cancers, ovarian stromal tumors, pituitary blastoma, and non-endocrine formations - pleuropulmonary blastoma, cystic nephroma, pineoblastoma. The presence of somatic mutations of the DICER1 gene is a resultant stage in the pathogenesis of dyseropathies, determining the further path of oncogenesis. At present, DICER1 syndrome is diagnosed extremely rarely, which leads to late detection of the components of the disease in the patient, late diagnosis of neoplasms, lack of family counseling. Diagnosis at the early stages of the disease, the development of screening programs for the management of these patients allows minimizing the risks of developing more malignant, aggressive forms of the disease.
Topics: Humans; Ribonuclease III; DEAD-box RNA Helicases; Mutation; Female; Thyroid Neoplasms; Goiter, Nodular; Pulmonary Blastoma
PubMed: 38796764
DOI: 10.14341/probl13383 -
JCO Precision Oncology Sep 2023Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and...
Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of -related cancers and cascade testing of family members. However, some patients with -associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.
Topics: Male; Female; Humans; Sertoli-Leydig Cell Tumor; Ovarian Neoplasms; Introns; Germ-Line Mutation; Mutation; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37883719
DOI: 10.1200/PO.23.00189 -
Indian Journal of Thoracic and... Oct 2019Pleuropulmonary blastoma (PPB) is a rare, malignant tumor of the lung and is the most common primary pulmonary malignancy in children. Here, we report a case of a boy...
Pleuropulmonary blastoma (PPB) is a rare, malignant tumor of the lung and is the most common primary pulmonary malignancy in children. Here, we report a case of a boy who was diagnosed with type I regressed PPB after being mislabeled with congenital pulmonary malformation. A 10-year-old boy presented to our hospital with a history of worsening dyspnea. Since birth, his clinical status and radiographic images were concerning for congenital lobar emphysema that was managed conservatively. A chest computed tomography (CT) scan confirmed the persistence of a large cystic lesion and a diagnostic and therapeutic cystectomy was performed. Microscopic examination confirmed the presence of PPB type Ir. Patient was managed surgically alone with no added chemotherapy, as there was no overall survival benefit. PPB Ir has an overall favorable clinical outcome. Limited follow-up data are available due to the rarity of the lesion and the overlap with other congenital cystic lung malformations.
PubMed: 33061055
DOI: 10.1007/s12055-019-00814-1 -
International Journal of Clinical and... 2015In infants, pleuropulmonary blastoma is a rare but aggressive tumor. The typical histopathological presentation includes the aggregation of malignant primitive small...
In infants, pleuropulmonary blastoma is a rare but aggressive tumor. The typical histopathological presentation includes the aggregation of malignant primitive small cells, usually observed in sheets. So as to provide proper and timely treatment, the differential diagnosis includes pulmonary blastoma, sarcomatoid mesothelioma, fetal rhabdomyoma, synovial sarcoma, and primitive neuroectodermal tumor. Herein, we will present one male pediatric patient with pleuropulmonary blastoma. The patient was a 4-month-old male infant, who had a prolonged cough and dyspnea for 4 months that was complicated by cyanosis for 3 days. A physical examination revealed a solid mass in the right lung that was sized 9.0 × 6.0 × 4.0 cm and had a grayish-white cross section. The boundary between the mass and lung tissue was clear; the mass already occupied a great portion of the lung. A microscopic examination suggested that the tumor was composed of round or orbicular-ovate primitive fetal cells. The cells were medium sized, having little cytoplasm, but had a clearly visualized nucleolus and active karyokinesis. The tumor mass was biphasic, namely, fasciculated sarcoma (composed of spindle-shaped cells and short spindle-shaped cells) and malignant fibrous histiocytoma containing well-differentiated cartilage islands or cartilaginous nodes. Immunohistochemistry was performed for further detection: vimentin (+), S-100 protein (+), CK (AE1/AE3), EMA and TTF-1 in residual epithelial components (+), NSE (focal +), SMA (mesenchymal cells, focal +), CD99 (weak +), Bcl-2 (weak +), desmin (-), myoglobin (-), calretinin (-), calponin (-), FLI (-), MyoD-1 (-), and CD34 (-). Pleuropulmonary blastoma is extremely rare but highly aggressive neoplasm in children. Its typical histopathological presentation is the aggregation of primitive malignant small cells. Combining imaging and histopathological examinations and clinical data should help in determining the diagnosis of pleural pulmonary blastoma.
Topics: Biomarkers, Tumor; Humans; Infant; Lung; Lung Neoplasms; Male; Pulmonary Blastoma
PubMed: 26722577
DOI: No ID Found -
Modern Pathology : An Official Journal... Jan 2020DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have...
DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have been identified in DICER1-associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1-associated ovarian sarcoma in a 5-year-old female, a somatic DICER1-associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1-associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1-associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.
Topics: Adolescent; Brain Neoplasms; Child, Preschool; DEAD-box RNA Helicases; Female; Genetic Predisposition to Disease; Humans; Male; Mutation; Ovarian Neoplasms; Peritoneal Neoplasms; Ribonuclease III; Sarcoma
PubMed: 31537896
DOI: 10.1038/s41379-019-0366-x -
Klinische Padiatrie Sep 2022Complete tracheal ring deformity (CTRD) is a rare abnormality of unknown etiology characterized by circumferentially continuous cartilaginous tracheal rings leading to...
Complete tracheal ring deformity (CTRD) is a rare abnormality of unknown etiology characterized by circumferentially continuous cartilaginous tracheal rings leading to variable degrees of tracheal stenosis with or without additional heart and lung malformations. Pleuropulmonary blastomas (PPB) are rare malignant mesenchymal tumors, which occur almost exclusively in young children. Pathogenic germline variants are associated with PPB but also with other tumors like rhabdomyosarcoma or syndromic diseases like GLOW (Global developmental delay, lung cysts, overgrowth and Wilms tumor) syndrome. Here, we report a case with CTRD and recurrent pneumothoraces who additionally developed PPB on the genetic background of a pathogenic variant.
Topics: Child; Child, Preschool; Cysts; DEAD-box RNA Helicases; Humans; Lung Diseases; Lung Neoplasms; Pulmonary Blastoma; Ribonuclease III
PubMed: 35114704
DOI: 10.1055/a-1699-2026 -
The Journal of Pathology May 2015Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of-function DICER1...
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.
Topics: Animals; DEAD-box RNA Helicases; Disease Models, Animal; Epithelium; Germ-Line Mutation; Humans; Lung Neoplasms; Mice; Pulmonary Blastoma; Ribonuclease III
PubMed: 25500911
DOI: 10.1002/path.4500