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Pathology, Research and Practice Oct 2022To study the causes of the rapid progression of pleuropulmonary blastoma and to identify molecular markers related to its prognosis.
OBJECTIVES
To study the causes of the rapid progression of pleuropulmonary blastoma and to identify molecular markers related to its prognosis.
MATERIALS AND METHODS
Three pairs of fresh frozen samples of pleuropulmonary blastoma tumors and adjacent normal tissues were analyzed for proteomics, focusing on the protein molecules with significantly increased expression in tumor tissues and related to the cell cycle and DNA replication. The top five protein molecules were selected and verified by immunohistochemistry. To analyze the correlation between the expression of verified protein molecules in pleuropulmonary blastoma and early recurrence/metastasis of pleuropulmonary blastoma.
RESULTS
Compared with the adjacent normal tissues, 1759 proteins were upregulated and 967 proteins were downregulated in pleuropulmonary blastoma. The top five proteins related to the cell cycle and DNA replication were ORC2, P75, Skp2, MCM4 and PCNA. However, only P75, MCM4 and PCNA were upregulated in pleuropulmonary blastoma as determined by immunohistochemistry. Further analysis showed that the expression of P75 in the recurrence/metastasis group was significantly higher than that in the no recurrence/metastasis group, while the expression of MCM4 and PCNA was not significantly different between the recurrence/metastasis group and the no recurrence/metastasis group.
CONCLUSIONS
MCM4, PCNA and P75 may all play an important role in the progression of pleuropulmonary blastoma. Among them, P75 is related to the prognosis and may be used as a marker to predict the prognosis of pleuropulmonary blastoma.
PubMed: 36067610
DOI: 10.1016/j.prp.2022.154067 -
Targeting mutant dicer tumorigenesis in pleuropulmonary blastoma via inhibition of RNA polymerase I.Translational Research : the Journal of... Aug 2023DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a...
DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a paucity of directly actionable molecular targets as these tumors are driven by loss-of-function mutations of DICER1. Therapeutic development for PPB is further limited by a lack of biologically and physiologically-representative disease models. Given recent evidence of Dicer's role as a haploinsufficient tumor suppressor regulating RNA polymerase I (Pol I), Pol I inhibition could abrogate mutant Dicer-mediated accumulation of stalled polymerases to trigger apoptosis. Hence, we developed a novel subpleural orthotopic PPB patient-derived xenograft (PDX) model that retained both RNase IIIa and IIIb hotspot mutations and recapitulated the cardiorespiratory physiology of intra-thoracic disease, and with it evaluated the tolerability and efficacy of first-in-class Pol I inhibitor CX-5461. In PDX tumors, CX-5461 significantly reduced H3K9 di-methylation and increased nuclear p53 expression, within 24 hours' exposure. Following treatment at the maximum tolerated dosing regimen (12 doses, 30 mg/kg), tumors were smaller and less hemorrhagic than controls, with significantly decreased cellular proliferation, and increased apoptosis. As demonstrated in a novel intrathoracic tumor model of PPB, Pol I inhibition with CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant Dicer tumors, inducing antitumor effects by decreasing H3K9 methylation and enhancing p53-mediated apoptosis.
Topics: Humans; RNA Polymerase I; Tumor Suppressor Protein p53; Pulmonary Blastoma; Carcinogenesis; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 36921796
DOI: 10.1016/j.trsl.2023.03.001 -
Maternal Health, Neonatology and... Mar 2023Pleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest...
BACKGROUND
Pleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest form of PPB occurring from birth to approximately two years of age, is often mistaken for a congenital pulmonary airway malformation, as the two entities can be difficult to distinguish on imaging and pathology. Diagnosis of PPB should prompt workup for DICER1 syndrome, an autosomal dominant tumor predisposition syndrome. We report a newborn with a congenital PPB presenting with tachypnea and hypoxia, who was found to have variant of uncertain clinical significance (VUS) in DICER1.
CASE PRESENTATION
A term female infant developed respiratory distress shortly after birth. Initial imaging was concerning for a congenital pulmonary airway malformation versus congenital diaphragmatic hernia, and she was transferred to a quaternary neonatal intensive care unit for management and workup. Chest CT angiography demonstrated a macrocytic multicystic lesion within the right lower lobe without systemic arterial supply. The pediatric surgery team was consulted, and the neonate underwent right lower lobectomy. Pathology revealed a type I PPB. Oncology and genetics consultants recommended observation without chemotherapy and single gene sequencing of DICER1, which identified a germline VUS in DICER1 predicted to alter splicing. RNA-sequencing from blood demonstrated that the variant resulted in an in-frame deletion of 29 amino acids in a majority of transcripts from the affected allele. Due to the patient's young age at presentation and high clinical suspicion for DICER1 syndrome, tumor surveillance was initiated. Renal and pelvic ultrasonography were unremarkable.
CONCLUSION
We present the case of a term neonate with respiratory distress and cystic lung mass, found to have a type I PPB with a germline VUS in DICER1 that likely increased her risk of DICER1-related tumors. Nearly 70% of patients with PPB demonstrate germline mutations in DICER1. Review of RNA sequencing data demonstrates the difficulty in classifying splice variants such as this. Penetrance is low, and many patients with pathogenic DICER1 variants do not develop a malignancy. Best practice surgical and oncologic recommendations include an individualized approach and tumor board discussion. This case highlights the importance of a multidisciplinary team approach and the utility of international registries for patients with rare diagnoses.
PubMed: 36922881
DOI: 10.1186/s40748-023-00148-2 -
Journal of Indian Association of... 2024Pleuropulmonary blastoma (PPB) is a rare malignancy associated with mutations in the DICER1 gene. Early-stage disease (PPB type I) mimics cystic lung malformations and...
PURPOSE
Pleuropulmonary blastoma (PPB) is a rare malignancy associated with mutations in the DICER1 gene. Early-stage disease (PPB type I) mimics cystic lung malformations and develops in infants <1 year of age, and PPB type II and III arises in older children. The objective of this study was to analyze predictive factors of mortality in pediatric patients aged 0-19 years diagnosed with PPB between 2000 and 2019 in the USA.
METHODS
A retrospective analysis of pediatric patients (0-19 years) in the Surveillance Epidemiology and End Results database was conducted from 2000 to 2019 with a diagnosis of PPB using International Classification of Disease for Oncology, third edition code 8973/3 and rare tumor code 45. Demographics, incidence, staging, treatment, and mortality were extracted. A mortality risk predictive equation was developed using logistic regression. Statistical analysis was conducted through Microsoft Excel Analysis ToolPak and Solver.
RESULTS
There were a total of 71 new cases of PPB during the study period, with 16 (22%) deaths. The demographic analysis demonstrated that 40/71 (56.3%) patients were female, 57/71 (80.3%) were White, and 64/71 (90.1%) resided in metropolitan areas. Regression analysis demonstrated a statistically significant correlation between mortality and stage ( = 0.029), need for chemotherapy ( = 0.047), and female sex ( = 0.019). There was no significant correlation between mortality and need for radiation, race, or age at diagnosis. Multiple logistic regression analysis generated a predictive equation of mortality dependent on the stage of PPB, need for chemotherapy, and sex. This equation has an 82% accuracy, 81% sensitivity, and an 18% false positive rate.
CONCLUSION
PPB is a rare disease. Distinguishing PPB from benign cystic lung malformations in infancy is important to avoid progression to Type II and III PPB. Advanced stages of PPB have a greater need for systemic chemotherapy and radiation with a poor prognosis.
PubMed: 38912026
DOI: 10.4103/jiaps.jiaps_235_23 -
Pediatric and Developmental Pathology :... 2022
Topics: DEAD-box RNA Helicases; Humans; Kidney; Ribonuclease III; Sarcoma
PubMed: 36123785
DOI: 10.1177/10935266221111632 -
Journal of Bronchology & Interventional... Jan 2024
Topics: Humans; Pulmonary Blastoma; Kidney Neoplasms; Neoplastic Syndromes, Hereditary; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 38014858
DOI: 10.1097/LBR.0000000000000955 -
Gynecologic Oncology Jul 2024Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and...
OBJECTIVE
Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT.
METHODS
Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available.
RESULTS
In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85).
CONCLUSION
Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.
Topics: Humans; Sertoli-Leydig Cell Tumor; Female; Ovarian Neoplasms; DEAD-box RNA Helicases; Pulmonary Blastoma; Registries; Adult; Ribonuclease III; Middle Aged; Young Adult; Aged; Male; Adolescent; Chemotherapy, Adjuvant; Sex Cord-Gonadal Stromal Tumors; Testicular Neoplasms; Lung Neoplasms
PubMed: 38657450
DOI: 10.1016/j.ygyno.2024.04.005 -
Fetal ultrasound and magnetic resonance imaging: a primer on how to interpret prenatal lung lesions.Pediatric Radiology Dec 2020Fetal lung lesions include common lesions such as congenital pulmonary airway malformation (CPAM), bronchopulmonary sequestration (BPS) and combined CPAM-BPS hybrid... (Review)
Review
Fetal lung lesions include common lesions such as congenital pulmonary airway malformation (CPAM), bronchopulmonary sequestration (BPS) and combined CPAM-BPS hybrid lesions, as well as less common entities including congenital lobar emphysema/obstruction, bronchial atresia, bronchogenic cysts and rare malignant pulmonary lesions such as pleuropulmonary blastoma. Fetal lung lesions occur in approximately 1 in 15,000 live births and are thought to arise from a spectrum of abnormalities related to airway obstruction and malformation, with the lesion type depending on the timing of insult, level of bronchial tree involvement, and severity of obstruction. Lesions vary from small and asymptomatic to large and symptomatic with significant mass effect on surrounding structures. Accurate diagnosis and characterization of these anomalies is crucial for guiding patient counseling as well as perinatal and postnatal management. The goal of this review is to provide an overview of normal fetal lung appearance and imaging features of common and uncommon lesions on both ultrasound and MR imaging, and to discuss key aspects in reporting and evaluating the severity of these lesions.
Topics: Bronchopulmonary Sequestration; Cystic Adenomatoid Malformation of Lung, Congenital; Female; Humans; Lung; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pregnancy; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 33252753
DOI: 10.1007/s00247-020-04806-x -
Journal of Indian Association of... 2024
PubMed: 38912022
DOI: 10.4103/jiaps.jiaps_201_23 -
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