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Background: Pleuropulmonary Blastoma (PPB) is an extremely uncommon, highly aggressive tumor that arises from either the lungs or pleura. According to Dehner, PPB was classified into three groups: type I (cystic), type II (mixed), and type III (solid). Type I tends to occur more commonly in infants and has a more favorable prognosis compared to types II and III. This tumor is very rare in pediatric age group; hence, there is no consensus on the optimal treatment regimen for it to date. Type I tumors, which resemble congenital lung cysts, can eventually progress to more aggressive type II and type III tumors. This article aims to increase general awareness of this pathology, clinical presentation, and differential diagnosis in order to identify this rare entity early in its course. By presenting 4 such cases, we highlight that PPB can be missed early in diagnosis and it is important to be alert when putting this rare tumor in differential diagnosis of cystic lung lesions. Methods: A retrospective study was conducted between 2015 and 2020 involving patients who had a definitive diagnosis of PPB with emphasis on clinical presentation, preoperative imaging studies, intra-operative findings, pathological reports, ancillary treatment, and outcomes. All patients were followed up every 6 months to monitor local recurrence and distant metastasis by undergoing physical exam and non-contrast enhanced CT of the chest. The primary outcome is to identify the mortality and morbidity (recurrence and distant metastasis) of PPB for cases admitted in our institute. Results: Four children were diagnosed with PPB during the study period. Clinically, patients presented with manifestations ranging from respiratory distress, fever to obstructive shock and radiologically, 2 cases were presented with mediastinal mass and the other 2 presented with pneumothorax. Regrettably, none of the cases were diagnosed pre-operatively. One lesion proved to be type I, 2 were type II and one was type III. All cases underwent chemotherapy using the combination of vincristine, Adriamycin and cyclophosphamide (VAC regimen). Recurrence was detected in a type II case, around 2 years after operation, and the other type II case developed brain metastasis that was discovered 3 years after operation. Type I case showed no local or distant metastasis. Conclusion: A prompt preoperative diagnosis and workup of cases of PPB is crucial to enable optimal intervention intraoperatively and early postoperative treatment. Though it is uncommon, PPB should be considered in the differential diagnosis of cystic lung lesions. [ABSTRACT FROM AUTHOR]

Abstract Background Pleuropulmonary Blastoma (PPB) is an extremely uncommon, highly aggressive tumor that arises from either the lungs or pleura. According to Dehner, PPB was classified into three groups: type I (cystic), type II (mixed), and type III (solid). Type I tends to occur more commonly in infants and has a more favorable prognosis compared to types II and III. This tumor is very rare in pediatric age group; hence, there is no consensus on the optimal treatment regimen for it to date. Type I tumors, which resemble congenital lung cysts, can eventually progress to more aggressive type II and type III tumors. This article aims to increase general awareness of this pathology, clinical presentation, and differential diagnosis in order to identify this rare entity early in its course. By presenting 4 such cases, we highlight that PPB can be missed early in diagnosis and it is important to be alert when putting this rare tumor in differential diagnosis of cystic lung lesions. Methods A retrospective study was conducted between 2015 and 2020 involving patients who had a definitive diagnosis of PPB with emphasis on clinical presentation, preoperative imaging studies, intra-operative findings, pathological reports, ancillary treatment, and outcomes. All patients were followed up every 6 months to monitor local recurrence and distant metastasis by undergoing physical exam and non-contrast enhanced CT of the chest. The primary outcome is to identify the mortality and morbidity (recurrence and distant metastasis) of PPB for cases admitted in our institute. Results Four children were diagnosed with PPB during the study period. Clinically, patients presented with manifestations ranging from respiratory distress, fever to obstructive shock and radiologically, 2 cases were presented with mediastinal mass and the other 2 presented with pneumothorax. Regrettably, none of the cases were diagnosed pre-operatively. One lesion proved to be type I, 2 were type II and one was type III. All cases underwent chemotherapy using the combination of vincristine, Adriamycin and cyclophosphamide (VAC regimen). Recurrence was detected in a type II case, around 2 years after operation, and the other type II case developed brain metastasis that was discovered 3 years after operation. Type I case showed no local or distant metastasis. Conclusion A prompt preoperative diagnosis and workup of cases of PPB is crucial to enable optimal intervention intraoperatively and early postoperative treatment. Though it is uncommon, PPB should be considered in the differential diagnosis of cystic lung lesions.

DICER1 syndrome, a rare autosomal dominant genetic disorder, stems from mutations in the DICER1 gene, disrupting RNA interference and leading to various tumors. These tumors, affecting organs like the lung, kidney, ovaries, and brain, pose diagnostic challenges due to diverse presentations. Understanding DICER1-associated tumors, including pleuropulmonary blastoma, ovarian Sertoli–Leydig cell tumors, and others, is vital for early detection and management. Surgical resection, chemotherapy, and targeted therapies are primary treatment modalities, with genetic counseling playing a crucial role. Multidisciplinary care is essential for optimal management, offering hope for improved outcomes in affected individuals.

DICER1 syndrome, a rare autosomal dominant genetic disorder, stems from mutations in the DICER1 gene, disrupting RNA interference and leading to various tumors. These tumors, affecting organs like the lung, kidney, ovaries, and brain, pose diagnostic challenges due to diverse presentations. Understanding DICER1-associated tumors, including pleuropulmonary blastoma, ovarian Sertoli–Leydig cell tumors, and others, is vital for early detection and management. Surgical resection, chemotherapy, and targeted therapies are primary treatment modalities, with genetic counseling playing a crucial role. Multidisciplinary care is essential for optimal management, offering hope for improved outcomes in affected individuals. [ABSTRACT FROM AUTHOR]

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

BackgroundPleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells.MethodsChildren with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually.ResultsBetween 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB.ConclusionsFor young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.

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 (P = 0.029), need for chemotherapy (P = 0.047), and female sex (P = 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. [ABSTRACT FROM AUTHOR]

Pleuropulmonary blastoma (PPB) is a rare childhood tumor originating from the lung or pleura, typically treated with surgery, chemotherapy (CTx), and/or radiation therapy (RTx). This study aimed to assess patient and tumor features, treatment methods, and survival rates in PPB. We retrospectively analyzed PPB patients under 18 from 2004 to 2019, using the National Cancer Database (NCDB). We assessed 5-year overall survival (OS) rates based on disease presentation and treatment regimens, using Kaplan–Meier curves and Cox proportional regression. Among 144 cases identified, 45.9% were female, with a median age of 2 years (interquartile range 1–3). In all, 62.5% of tumors originated from the lung, and 10.4% from the pleura. Moreover, 6.9% were bilateral, and the median tumor size was 8.9 cm, with 4.2% presenting with metastases. The 5-year OS rate was 79.6%, with no significant change over time (2004–2009, 77.6%; 2010–2014, 90.8%; 2015–2019, OS 75.3%; p = 0.08). In all, 5.6% received CTx alone, 31.3% surgery alone, 45.8% surgery/CTx, and 17.4% surgery/CTx/RTx. The OS rates were comparable between the surgery/CTx/RTx (80.0%) and surgery/CTx (76.5%) groups (adjusted Hazard Ratio, 1.72; 95% CI, 0.57–5.19; p = 0.34). Therefore, due to the unchanged survival rates over time, further prospective multicenter studies are needed to determine the optimal multimodal treatment regimens for this rare pediatric tumor. [ABSTRACT FROM AUTHOR]

Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1 -associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis. In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0–18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples. Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28). Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not. Level IV. • What is currently known about this topic? Distinction between benign congenital lung lesions and cystic type pleuropulmonary blastoma can be difficult. DICER1 genetic testing may be helpful in the differentiation. • What new information is contained in this article? This study is the first that systematically assessed the DICER1 mutation status in benign cystic lung lesions. No pathogenic variants were identified in CPAM tissues from 28 children. [ABSTRACT FROM AUTHOR]

DICER1 syndrome is a rare tumour predisposition syndrome, associated with a range of benign and malignant tumours, which may occur during childhood. A high index of suspicion is required to ensure appropriate diagnosis and testing, with early treatment and surveillance of at-risk individuals. In this report, we present 5 patients with variants in DICER1 identified following diagnosis of a minimally invasive thyroid follicular cell carcinoma, a pineoblastoma, a pleuropulmonary blastoma, a urethral rhabdomyosarcoma and on sibling testing. Each of these children have presented at a young age, and 2 have presented with characteristic tumours prior to the ages currently recommended for initiation of routine screening. We discuss their presentation, management and follow up, as well as a review of the current literature on each associated tumour in relation to our patients. Overall, we demonstrate that DICER1 is a heterogenous condition and that there is a need for cascade testing of family members as well as regular screening for tumour development in affected children, although consideration should be made regarding initiating this screening at an earlier age depending on clinical findings.

Pleuropulmonary blastoma (PPB) is a rare childhood tumor originating from the lung or pleura, typically treated with surgery, chemotherapy (CTx), and/or radiation therapy (RTx). This study aimed to assess patient and tumor features, treatment methods, and survival rates in PPB. We retrospectively analyzed PPB patients under 18 from 2004 to 2019, using the National Cancer Database (NCDB). We assessed 5-year overall survival (OS) rates based on disease presentation and treatment regimens, using Kaplan–Meier curves and Cox proportional regression. Among 144 cases identified, 45.9% were female, with a median age of 2 years (interquartile range 1–3). In all, 62.5% of tumors originated from the lung, and 10.4% from the pleura. Moreover, 6.9% were bilateral, and the median tumor size was 8.9 cm, with 4.2% presenting with metastases. The 5-year OS rate was 79.6%, with no significant change over time (2004–2009, 77.6%; 2010–2014, 90.8%; 2015–2019, OS 75.3%; p = 0.08). In all, 5.6% received CTx alone, 31.3% surgery alone, 45.8% surgery/CTx, and 17.4% surgery/CTx/RTx. The OS rates were comparable between the surgery/CTx/RTx (80.0%) and surgery/CTx (76.5%) groups (adjusted Hazard Ratio, 1.72; 95% CI, 0.57–5.19; p = 0.34). Therefore, due to the unchanged survival rates over time, further prospective multicenter studies are needed to determine the optimal multimodal treatment regimens for this rare pediatric tumor.

While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children’s Oncology Group Rare Tumor committee, divided into the Retinoblastoma and Infrequent Tumor subcommittees. The Infrequent Tumor subcommittee has traditionally included an emphasis on globally rare tumors such as adrenocortical carcinoma, nasopharyngeal carcinoma, or those tumors that are rare in young children, despite being common in adolescents and young adults, such as colorectal carcinoma, thyroid carcinoma, and melanoma. Pleuropulmonary blastoma, gonadal stromal tumors, pancreatic tumors including pancreatoblastoma, gastrointestinal stromal tumor, nonmelanoma skin cancers, neuroendocrine tumors, and desmoplastic small round cell tumors, as well as other carcinomas are also included under the heading of the Children’s Oncology Group Rare Tumor committee. While substantial challenges exist in rare cancers, inclusion and global collaboration remain key priorities to ensure high quality research to advance care.

Background: Pleuropulmonary blastoma (PPB) is a rare form of sarcoma that originates in the pulmonary tissue. It has three anatomical types: I (mostly cystic), (solid and cystic), and III (mostly solid). We present a case of type I PPB presenting as a large cystic lung lesion managed thoracoscopically. Case presentation: A 5-month-old male with no prior medical history presented with symptoms resembling pneumonia. Blood work results were normal. Chest x-ray showed a large cyst occupying the lower part of the left hemithorax causing severe mediastinal shift. A computerized tomography (CT) with intravenous contrast was done and revealed a lesion suspicious for a congenital cystic pulmonary malformation (CPAM). No systemic arterial vessels were going to the cystic lesion. A thoracoscopy was done using one-lung ventilation. Complete resection of the cystic mass was accomplished thoracoscopically using a coagulation device and endo-staplers. A chest tube was left in place. The patient had an uneventful recovery and was discharged home in a stable condition. The pathology analysis confirmed a completely resected type I PPB. At four months of follow-up there have been no signs of recurrence. Conclusion: PPB must be included in the differential diagnosis of children with cystic lung lesions. Complete thoracoscopic excision is possible.

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

Congenital cystic pulmonary lesions (CCPLs) are represented by the following entities: congenital pulmonary airway malformation (CPAM), formerly congenital cystic adenomatoid malformation, extra- and intralobar sequestration (EIS), congenital lobar emphysema (overexpansion), and bronchogenic cyst. The developmental model of CPAM histogenesis by Stocker proposed perturbations designated as CPAM type 0 to type 4 without known or specific pathogenetic mechanisms along the airway from the bronchus to the alveolus. This review highlights mutational events either at the somatic level in KRAS (CPAM types 1 and possibly 3) or germline variants in congenital acinar dysplasia, formerly CPAM type 0, and pleuropulmonary blastoma (PPB), type I, formerly CPAM type 4. The potential for overt malignant progression exists in the case of PPB type I and CPAM type 1 in some cases to well-differentiated mucinous adenocarcinoma. On the other hand, CPAM type 2 is an acquired lesion resulting from interruption in lung development secondary to bronchial atresia. The latter is also regarded as the etiology of EIS whose pathologic features are similar, if not identical, to CPAM type 2. These observations have provided important insights into the pathogenetic mechanisms in the development of the CPAMs since the Stocker classification. [ABSTRACT FROM AUTHOR]

Pleuro Pulmonary Blastoma is a lung cancer affecting children's lung tissues. The development of the DICER1 gene in the patients leads to PPB. This disease causes trouble breathing along with lung infections. It can only be found by analyzing the DNA sequence of the PPB tissues. The DNA sequence of the tissues affected by cancer is extracted from the infections. The DNA sequences reveal the hereditary cause of the PPB, which can help in detecting the abnormalities of their family members. DNA sequences are complex, and it is impossible to rely on manual clinical methods to give faster and more accurate predictions. Several research works have suggested machine learning models which process the DNA sequences to detect PPB. However, machine learning algorithms cannot understand the complex DNA patterns of cancer tissues. This paper designs and implements a deep learning algorithm, a novel Deep Convolution Neural Network, to overcome such difficulties. The whole DNA sequence can be processed by more layers involved in the DCNN. The proposed DCNN learns the DNA sequence data part by part and compares it with the ground truth values, identifying odd data and abnormal sequence patterns to predict the presence of PPB. The DCNN is implemented in Python software with the DICER1 gene dataset for predicting the PPB. From the result of the experiment, the efficacy of the proposed DCNN model is verified and compared with other traditional models to evaluate the performance. The proposed CNN obtained 98.67% of accuracy for CT image classification and 96% of accuracy for DICER1-DNA data analysis.

Pleuropulmonary blastoma (PPB) is among the rarest malignant tumors diagnosed in children. PPBs can be histopathologically classified into 3 types: cystic tumor (type I), mixed cystic and solid tumor (type II), and pure solid tumor (type III). We describe a case of type III PPB that was detected in a prenatal fetus, confirmed using histopathological methods. To the best of our knowledge, this is the first case describing a type III PPB detected in a fetus. Prenatal ultrasonography is an excellent tool for detecting pulmonary lesions during the diagnostic phase, and the possibility of PPB should be considered when solid tumors are detected. Early detection can allow for the performance of full resection, leading to a better prognosis for this cancerous tumor.

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. [ABSTRACT FROM AUTHOR]

Pleuropulmonary blastoma (PPB) is a tumor occurring almost exclusively in infants and young children. This is the most common primary-lung malignancy in childhood. There is age-associated progression through a distinctive sequence of pathologic changes, from a purely multicystic lesion type I to a high-grade sarcoma type II and III. While complete resection is the cornerstone treatment for type I PPB, aggressive chemotherapy with a less favorable prognosis is associated with type II and III. DICER1 germline mutation is positive in 70% of children with PPB. Diagnosis is challenging, as it resembles congenital pulmonary airway malformation (CPAM) in imaging. Although PPB is an extremely rare malignancy, over the past five years we have encountered several children diagnosed with PPB in our medical center. Herein, we present some of these children and discuss diagnostic, ethical, and therapeutic challenges. [ABSTRACT FROM AUTHOR]

Abstract DICER1 syndrome is an autosomal dominant tumour predisposition syndrome usually affecting persons under 30 years of age. Many of the associated benign and malignant lesions occur almost exclusively in DICER1 syndrome. One such tumour, pituitary blastoma (pitB), overexpresses PRAME 500x above control levels. PRAME (PReferentially expressed Antigen in MElanoma) is expressed in malignancies that are not DICER1‐related (e.g. melanoma). To address whether PRAME expression is part of the DICER1 phenotype, or simply a feature of pitB, a series of 75 DICER1‐mutated specimens and 33 non‐mutated specimens was surveyed using immunohistochemistry for PRAME, together with EZH2, which complexes with PRAME. In DICER1‐mutated specimens, positive staining for PRAME was only seen in malignant tumours; 7 of 11 histological types and 34/62 individual tumours were positive, while non‐tumourous lesions were always negative. Pleuropulmonary blastoma (PPB) showed a continuum in staining, with type I lesions being PRAME negative (n = 7) but all type II and type III lesions PRAME positive (n = 7). Similarly, cystic nephroma (CN) was negative (n = 8), with anaplastic sarcoma of the kidney being positive (n = 2). However, one atypical CN with mesenchymal cell proliferation was PRAME‐positive. Embryonal rhabdomyosarcoma (RMS) with DICER1 pathogenic variants (PVs) was positive for PRAME (5/6), but the same tumour type without DICER1 PVs was also positive (9/15). Staining for EZH2 corresponded to that seen with PRAME, validating the latter. This study leads us to conclude that (1) PRAME expression occurs in two‐thirds of DICER1‐related malignancies; (2) PRAME may be a marker for the progression that certain DICER1‐related lesions are thought to undergo, such as PPB and CN; and (3) PRAME expression in some tumours, such as RMS, appears to be an intrinsic feature of the tumour, rather than specifically related to DICER1 PVs. Therapy directed against PRAME may offer novel treatment options in patients with the DICER1 syndrome.

Malignant biphasic tumors of the lungs are rare, more so in the pediatric population. Here, we present the whole-genome characterization of a pleuropulmonary blastoma Type III and an unclassified biphasic thoracic embryonal neoplasm. The pleuropulmonary blastoma harbored pathogenic DICER1 germline and somatic mutations, and additional somatic variants in TP53 and BCOR. The other malignant tumor demonstrated a t(11;19) balanced translocation with a YAP1::LEUTX fusion that was confirmed by fluorescence in situ hybridization. No DICER1 germline or somatic mutation was present. YAP1 and LEUTX have been implicated in tumorigenesis of various neoplasms, and YAP1 fusion genes are an emerging oncogenic entity in a variety of malignancies. In this study we highlight the importance of whole-genome characterization of rare and unclassified tumors to identify biologic mechanisms and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Pleuropulmonary blastoma (PPB) is a rare primitive malignant lung cancer that occurs in pediatric age. Its main differential diagnosis is congenital cystic pulmonary malformation (CPAM).A 30-day-old infant with respiratory failure obtained a chest x-ray and a computed tomography scan (CT) which revealed hypertensive pneumothorax with multifocal bilateral cysts. After thoracic drainage, the patient underwent multiple thoracoscopic pulmonary resections. The first histological diagnosis was of type 2 CPAM.During the radiological follow-up, an increase in the number and dimension of the lesions was detected. Thus, a histological revision was performed, leading to the diagnosis of type I PPB, at nine months. The patient subsequently underwent chemotherapy.At the five-year follow-up appointment, chest magnetic resonance (MR) and CT scans showed a dimensional increase in size of the lesions, with the risk of recurrent pneumothorax. An upper right lobectomy and wedge resection of the residual cysts were performed.Control MR scans showed normalization of the lung parenchyma and the patient showed substantial clinical improvement.

Pleuropulmonary blastoma is a rare pediatric primary lung tumor. We report a case of a child with Down syndrome and a large ventricular septal defect presenting with pleuropulmonary blastoma initially misdiagnosed as spontaneous pneumothorax. Following tube thoracostomy drainage of the pneumothorax, the child underwent surgical closure of the ventricular septal defect. However, the postoperative period was complicated by recurrent left pleural collection requiring prolonged intercostal tube drainage and two thoracotomies to evacuate the necrotic pleural material. The biopsy of the necrotic material was suggestive of type III pleuropulmonary blastoma. In view of the high propensity of metastasis associated with this variant of a tumor, the patient was started on chemotherapy. This case report highlights the possibility of pleuropulmonary blastoma presenting as pneumothorax and emphasizes the need to consider the etiology, before intervening in a child presenting with spontaneous pneumothorax. [ABSTRACT FROM AUTHOR]

Purpose: Pleuropulmonary blastoma (PPB) is an infrequently encountered childhood malignant intrathoracic neoplasm associated with unfavorable clinical behavior. Since a well-characterized preclinical model is essential for developing competent agents for PPB, we aim to establish and characterize the world's first cell line of PPB, and attempt to perform the cytotoxicity assay on the PPB cell line., Experimental Design: The index case is a 2-year-old female who developed a right thoracic tumor that was surgically removed and treated with multi-agent chemotherapy. The patient is free from recurrence, although it was 9 years after the diagnosis when she developed a thyroid tumor. We performed in vitro cultivation of the isolated neoplastic cells from the tumor, cytogenetic findings and molecular analysis, and tetrazolium colorimetric assay., Result: The histology was consistent with PPB. Serial passage of cultivation produced a continuously growing cell line, KCMC-PPB-1. Conventional cytogenetic analysis of the established cell line revealed complex numerical and structural chromosomal abnormalities, including add(17)(p11). Mutation analysis on the cultured cells revealed amino-acid substitution mutation on exon 4 of TP53 (NM&#95;001276760.3:c.212&#95;213delTG; NP&#95;001263689.1:p.Leu72ArgfsTer37) and compound heterozygous mutations of DICER1 (NM&#95;177438.3:c. 4910C>A; NP&#95;803187.1:Ser1637* and NM&#95;177438.3:c. 5114A>T; NP&#95;803187.1:Glu1705Val). The cultivated cells demonstrated vulnerability to bortezomib on cytotoxicity assay., Conclusion: Our KCMC-PPB-1 is the first genuine, molecularly characterized PPB cell line. The cell line is transplantable to nu/nu mice; therefore, it is suitable for a preclinical model for new drug development. The cytotoxicity assay demonstrated that bortezomib is active in the current PPB model., (© 2024 Wiley Periodicals LLC.)

Pleuropulmonary blastoma (PPB) is a rare tumor that arises from mesenchymal cells of the lung or pleura. PPB is classified as type I (cystic), type Ir (regressed), type II (cystic and solid), or type III (solid). Here, we report the case of a 2-year-old boy with type II PPB. The patient was treated with neoadjuvant chemotherapy, and the tumor was completely surgically resected. A DICER1 mutation was detected in the tumor specimen. The risk of recurrence is high, and long–term follow–up is required.

Pleuropulmonary blastoma is a rare intrathoracic tumor in children. It is associated with poor prognosis and diagnosis is based on histological examination. We conducted a didactic study involving a 3-year-old child with severe acute respiratory distress associated with hemothorax; radiological and thoracoscopic examination suggested malignant pleuropulmonary process. Anatomopathological examination with radioclinical comparison allowed for the diagnosis of solid-cystic pleuropulmonary blastoma type II. Unfortunately, given the severity of the clinical features, the child died within a few weeks due to multiple organ failure. Pathologist experience is very important to recognize the disease and to start adequate treatment as soon as possible. This allows for a tumor regression rate up to 90% after neoadjuvant treatment and a 5-year survival rate of at least 53% for aggressive forms: solid and solidocystic tumors. [ABSTRACT FROM AUTHOR]

Pleuropulmonary blastoma (PPB) is a rare but aggressive pediatric tumor originates from either lung or pleura. It was recently linked to the DICER I mutation as a part of predisposition syndrome for different type of tumor. It is characterized histologically by a primitive, variably mixed blastomatous and sarcomatous tissue. PPB is classified into four subtypes: cystic (type I and type Ir); cystic and solid (type II); solid (type III).PPB has no characteristic imaging findings. Integrated imaging can help to make a differential diagnosis and to recognize the subtypes in order to set up therapy. An early recognition and differentiation from congenital airway malformations and other benign cysts are very important.The treatment consists in a multimodal therapy including surgery and chemoterapy.We report a case of 3 years old female admitted at our hospital with fever, non productive cough and dyspnea, who was diagnosed with type II PPB.

We are presenting a rare case with the simultaneous occurrence of pleuropulmonary blastoma and an intra lobar pulmonary sequestration. Although there have been cases reported previously with pleuropulmonary blastoma associated with congenital pulmonary malformations, the association with an intra lobar pulmonary sequestration is very rare. The patient, a female, 6-month-old child arrived at our pediatric service with the clinic of cough, respiratory distress, and fever after being treated for 2 weeks for left lung bronchopneumonia according clinical signs and radiographic description but without clinical improvements. Contrast enhanced CT images showed the simultaneous presence of 2 different lesions in the left lung, a heterogeneous mass in the superior lobe without delineation with mediastinal structure compatible with a pleuropulmonary blastoma and a consolidation in the inferior lobe with bronchogram present and a systemic vessel feeding compatible with an intra lobar pulmonary sequestration, both confirmed by histologic examinations after the surgical intervention. Although it is very rare, the simultaneous presence of these distinct embryogenic lesions may occur and radiologist should be aware as the imaging diagnosis may be very helpful for the further management of the patient.

• Comprehensive exome and DNA methylation analysis of 8 pulmonary blastomas (PB). • Somatic DICER1 pathogenic variants are the major driver of PB. • DICER1 somatic variants often act in conjunction with CTNNB1 hotspot variants. • PBs have methylation patterns similar to that of DICER1 -associated mesenchymal tumors. Pulmonary blastoma is a rare, biphasic, adult-onset lung tumor. In this study, we investigate whether DICER1 pathogenic variants are a feature of pulmonary blastomas through in-depth analysis of the molecular events defining them. We performed exome-wide sequencing and DNA methylation profiling of 8 pulmonary blastomas from 6 affected persons. We identified biallelic somatic DICER1 pathogenic variants in 7 of 8 cases. The remaining case had a solitary missense pathogenic variant in the RNase IIIb domain of DICER1. Six of 8 cases carried a CTNNB1 hotspot variant and 4 of 8 had a somatic pathogenic variant in TP53. Methylation analysis showed that the pulmonary blastomas clustered with other DICER1 -mutated tumors and not with other more common types of lung cancer. We conclude somatic DICER1 pathogenic variants are the major driver of pulmonary blastoma and are likely to act in conjunction with CTNNB1 hotspot variants that are often present. [ABSTRACT FROM AUTHOR]

DICER1 syndrome is an autosomal dominant tumour predisposition syndrome usually affecting persons under 30 years of age. Many of the associated benign and malignant lesions occur almost exclusively in DICER1 syndrome. One such tumour, pituitary blastoma (pitB), overexpresses PRAME 500x above control levels. PRAME (PReferentially expressed Antigen in MElanoma) is expressed in malignancies that are not DICER1‐related (e.g. melanoma). To address whether PRAME expression is part of the DICER1 phenotype, or simply a feature of pitB, a series of 75 DICER1‐mutated specimens and 33 non‐mutated specimens was surveyed using immunohistochemistry for PRAME, together with EZH2, which complexes with PRAME. In DICER1‐mutated specimens, positive staining for PRAME was only seen in malignant tumours; 7 of 11 histological types and 34/62 individual tumours were positive, while non‐tumourous lesions were always negative. Pleuropulmonary blastoma (PPB) showed a continuum in staining, with type I lesions being PRAME negative (n = 7) but all type II and type III lesions PRAME positive (n = 7). Similarly, cystic nephroma (CN) was negative (n = 8), with anaplastic sarcoma of the kidney being positive (n = 2). However, one atypical CN with mesenchymal cell proliferation was PRAME‐positive. Embryonal rhabdomyosarcoma (RMS) with DICER1 pathogenic variants (PVs) was positive for PRAME (5/6), but the same tumour type without DICER1 PVs was also positive (9/15). Staining for EZH2 corresponded to that seen with PRAME, validating the latter. This study leads us to conclude that (1) PRAME expression occurs in two‐thirds of DICER1‐related malignancies; (2) PRAME may be a marker for the progression that certain DICER1‐related lesions are thought to undergo, such as PPB and CN; and (3) PRAME expression in some tumours, such as RMS, appears to be an intrinsic feature of the tumour, rather than specifically related to DICER1 PVs. Therapy directed against PRAME may offer novel treatment options in patients with the DICER1 syndrome. [ABSTRACT FROM AUTHOR]

Pleuropulmonary blastoma is a rare, aggressive, malignant tumor of the lungs or pleura that primarily affects children. Pleuropulmonary blastoma is classified into 3 types based on morphology, including cystic (type I), mixed (type II), or solid (type III). These morphological types correlate with prognosis. In this article, we present a case of type III pleuropulmonary blastoma in a 2-year-old girl. The patient was treated with tumoral resection and chemotherapy; however, she experienced local recurrence and spinal metastasis after 5 months of treatment.

Background: Children with acute febrile respiratory illnesses are commonly seen in the emergency department. Apart from the initial stabilization, they need to be assessed for the underlying cause, and clinicians should formulate differential diagnoses to start treatment. Radiological investigations including x-ray and ultrasonography are often used to narrow down the initial possibilities based on history and examination. A child presenting with an opaque hemithorax is one such scenario. Clinical Description: A 3-year-old boy presented with a short duration of fever, cough and respiratory distress. Examination showed rightward mediastinal shift with dull percussion note and reduced breath sounds over the left hemithorax, along with congested neck veins, stridor and left sided wheeze. Chest x-ray showed an opacified left hemithorax and ultrasonography suggested moderate pleural effusion. Management: Complicated pneumonia with parapneumonic effusion (or empyema) was considered, but a diagnostic pleural tap was dry. The possibilities were revised to include cystic space occupying lesions with mediastinal compression. Computed tomography of the chest confirmed a mass lesion with predominantly cystic components. The patient underwent surgical excision, and histopathology showed pleuropulmonary blastoma. Conclusion: Although respiratory infections are common in childhood, clinical evaluation and judicious use of imaging modalities can uncover less common conditions. Although bedside ultrasonography is a handy tool in the emergency department, it is not infallible.

Fetal lung interstitial tumor (FLIT) is a rare pediatric lung tumor with radiological features similar to developmental pulmonary malformations and other congenital lung neoplasms. There are about 17 cases of FLIT reported worldwide till date. We report the first case of FLIT in the Indian literature which was diagnosed in the early postnatal period (at the 21st day of life) by pathological examination. The tumor exhibited a novel focal micropapillary architecture, in addition to the previously described microscopic features. We discuss the pathogenesis and differential diagnoses of FLIT and review the literature.

Abstract Pulmonary cysts and neoplasms, especially congenital or occurring at a young age, should be thoroughly investigated. Evaluation for DICER1 mutations should be performed if there is a family history of this syndrome, the lung cyst/neoplasm is a pleuropulmonary blastoma, or other clinical manifestations of this syndrome are present or develop.

Abstract Background Pleuropulmonary blastomas (PPB) are rare aggressive paediatric lung malignancies and are among the most common DICER1-related disorders: it is estimated that 75–80% of children with a PPB have the DICER1 mutation. DICER1 mutations are responsible for familial tumour susceptibility syndrome with an increased risk of tumours. In approximately 35% of families with children manifesting PPB, further malignancies may be observed. Symptoms of DICER1 syndrome may vary, even within monozygotic twins. Preventive screening of carriers with DICER1 mutations is important and follow-up is undertaken as recommended by the 2016 International PPB Register. Case presentation We present two pairs of monozygotic twins. In one pair of 4-year, 2-month old girls, both with DICER1 mutation, one developed PPB(II) and her identical sibling had acute transient hepatitis. In the other pair of 19-month-old female babies, one had a history of bronchopulmonary hypoplasia and developed PPB(III) without DICER1 mutation, and her identical sibling had allergic asthma. Both patients with PPB were treated with R0 resection and received 12 cycles of postoperative chemotherapy. At the most recent review, the twins had been followed up for six and eight years, respectively, and they all remained healthy. However, the height and weight of the patients with PPB were lower than those of their respective identical sister. Conclusions PPB is rare, especially in monozygotic twins. We emphasise the importance of genetic testing and follow-up in monozygotic twins with PPB. During the follow-up, children surviving PPB should be monitored closely for growth and development disorders which caused by chemotherapy.

Background: Nasal chondromesenchymal hamartomas are benign, rare nasal tumors associated with DICER1 pathogenic germ-line variation. They can be locally destructive and recurrent if not completely resected. Methodology: In this single-center, case-control study, otorhinolaryngology evaluations and review of systems questionnaires of DICER1-carriers and controls enrolled in the DICER1 Natural History Study at the National Cancer Institute were collected. Review of these medical records were analyzed to determine if DICER1-carriers experienced different sinonasal clinical manifestations compared to controls. Additionally, the number of diagnoses of nasal chondromesenchymal hamartoma cases in the NCI DICER1 study was compared against the total person years of observation of DICER1-carriers in the study to determine the total number of cases per person-years of observation. Lastly, both the NCI DICER1 study and the International Pleuropulmonary Blastoma/DICER1 Registry were queried for unpublished cases of nasal chondromesenchymal hamartomas. Results: There were no clinical differences in sinonasal symptomatology between DICER1-carriers and control patients seen in the ENT clinic. We observed of two cases of nasal chondromesenchymal hamartoma in a total of 555 person-years of monitoring DICER1-carriers. We include six unpublished nasal chondromesenchymal hamartoma cases. When combined with a comprehensive literature review, 38% of nasal chondromesenchymal hamartoma cases had at least one additional DICER1-associated tumor and 24% of the NCMH were found in the ethmoid sinus, the most commonly involved paranasal sinus. Conclusions: We quantify the risk of developing nasal chondromesenchymal hamartomas in our cohort of 236 DICER1-carriers, report six unpublished cases, and provide an updated review of the literature.

Background: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear., Methods: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance., Results: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively., Conclusion: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors., (© 2024 Wiley Periodicals LLC.)