Establishment and Characterization of a Novel Pleuropulmonary Blastoma Cell Line.

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_001276760.3:c.212_213delTG; NP_001263689.1:p.Leu72ArgfsTer37) and compound heterozygous mutations of DICER1 (NM_177438.3:c. 4910C>A; NP_803187.1:Ser1637* and NM_177438.3:c. 5114A>T; NP_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.

Pediatric pleuropulmonary blastoma: analysis of four cases.

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.

Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

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.

Pleuropulmonary blastoma (PPB) with central nervous system metastasis: case report, imaging findings, and review of literature.

Pleuropulmonary blastoma (PPB) is a very rare tumor of the chest seen predominantly in young children with great heterogeneity and clinical, biochemical, and biological complexity and recognized, described, and classified as distinct from the pulmonary blastoma typically encountered in adults. Unfortunately, it has a poor and dismal prognosis and is mainly classified as cystic (type 1), mixed type (type 2), and solid (type 3). Herein, we present one case of PPB type 2 presenting clinically with a right pulmonary abscess, a rare clinical presentation of PPB, which was initially treated with surgery, and after approximately 1 year of follow-up, pulmonary rest-recurrence and central nervous system secondary deposits were detected. When a large pleural-based mass is identified in a young child, PPB should also be considered, especially in a patient with a positive oncological family history. Suggestive findings include the absence of chest wall invasion, presence of pleural fluid, right-sided location, and heterogeneous native (NECT) low attenuation with variable postcontrast enhancement. The authors believe that a modern therapeutic approach should consider these results for a better understanding of the genetic nature and complex mechanism and process of PPB disease development (both clinical and preclinical data concerning PPB pathophysiology are still lacking and are not completely understood) so that it would be possible to establish new possible therapeutic options (i.e. nuclear medicine theranostics in PPB treatment, developments and innovation in FLASH radiotherapy and proton therapy) and approaches, and so that, given the severity of the disease, it would be possible to indicate the importance of genetic testing and counseling of close relatives. In line with the previous, the rapid development of artificial intelligence could potentially bring the development of a novel fusion of radio mics and semantic features and MRI-based machine learning in distinguishing PPB from similar pathology.

Predictive Factors of Mortality in Pediatric Pleuropulmonary Blastoma: A Surveillance Epidemiology and End Results Database Analysis.

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.

Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary 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. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 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. CONCLUSIONS: For 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.

Imaging of pediatric pulmonary tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Pediatric pulmonary malignancy can be primary or metastatic, with the latter being by far the more common. With a few exceptions, there are no well-established evidence-based guidelines for imaging pediatric pulmonary malignancies, although computed tomography (CT) is used in almost all cases. The aim of this article is to provide general imaging guidelines for pediatric pulmonary malignancies, including minimum standards for cross-sectional imaging techniques and specific imaging recommendations for select entities.

Health-related quality of life in children and adolescents with pleuropulmonary blastoma: A report from the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood and is associated with germline DICER1 variants. Type I and Ir PPB are cystic lesions treated surgically, with a subset of children with type I receiving chemotherapy. Type II and III are more aggressive lesions, treated with surgery, intensive chemotherapy and potentially radiation. We sought to assess health-related quality of life (HRQoL) in children with PPB and known germline DICER1 variants. METHODS: Children with a diagnosis of PPB or germline DICER1 pathogenic variant without history of PPB or other DICER1-related neoplasm (DICER1+ only) were enrolled in the International PPB/DICER1 Registry. Parent reports for participants aged 2-17 years for the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 were collected. Fatigue, physical, and psychosocial function scores were compared. RESULTS: Analysis included 84 participants (PPB type Ir = 20, type I = 15, type II/III = 27, DICER1+ only = 22). Total fatigue scores of participants with type I and II/III PPB were lower compared to DICER1+ only, with effect size larger in type II/III (-0.82 vs. -0.40). Total psychosocial and physical functioning scores were lower in participants with type I and type II/III PPB compared to DICER1+ only, with larger effects noted in type II/III. Female sex was suggestive of worse HRQoL for both type I/Ir and type II/III cohorts. CONCLUSIONS: These data demonstrate the importance of regular HRQoL assessment in patients with a history of PPB as well as the importance and feasibility of studying HRQoL in children with rare tumors.

Children's Oncology Group's 2023 blueprint for research: Rare tumors.

The Children's Oncology Group (COG) Rare Tumor Committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that do not fall within another COG disease committee. Current therapeutic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes.

Assessing the role of positron emission tomography and bone scintigraphy in imaging of pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography (PET) and bone scintigraphy (bone scans) in diagnostic evaluation and surveillance has not been documented to date. Available PET and bone scan data are presented in this study. PROCEDURES: Patients with PPB enrolled in the International PPB/DICER1 Registry and available PET imaging and/or bone scan reports were retrospectively abstracted. RESULTS: On retrospective analysis, 133 patients with type II and III (advanced) PPB were identified with available report(s) (PET scan only = 34, bone scan only = 83, and both bone scan and PET = 16). All advanced primary PPB (n = 11) and recurrent (n = 8) tumors prior to treatment presented with 18 F-fluorodeoxyglucose (FDG)-avid lesions, with median maximum standardized uptake values of 7.4 and 6.7, respectively. False positive FDG uptake in the thorax was noted during surveillance (specificity: 59%). Bone metastases were FDG-avid prior to treatment. Central nervous system metastases were not discernable on PET imaging. Sensitivity and specificity of bone scans for metastatic bone disease were 89% and 92%, respectively. Bone scans had a negative predictive value of 99%, although positive predictive value was 53%. Four patients with distant bone metastases had concordant true positive bone scan and PET. CONCLUSION: Primary, recurrent, and/or extracranial metastatic PPB presents with an FDG-avid lesion on PET imaging. Additional prospective studies are needed to fully assess the utility of nuclear medicine imaging in surveillance for patients with advanced PPB.

Congenital Pulmonary Airway Malformations With a Reconsideration and Current Perspective on the Stocker Classification.

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.

Intraventricular topotecan in the successful treatment of recurrent CNS pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the pleura and pulmonary mesenchyme, associated with pathogenic germline DICER1 mutations. Although the most common site of metastasis is the central nervous system (CNS), patients with CNS metastasis have dismal outcome. We report a case of a patient presenting with type II PPB and intracranial and bone metastases. We describe a multimodal therapy approach and highlight the use of intraventricular topotecan for isolated CNS recurrence. In addition, a new pathogenic germline mutation heterozygous for the c.1234delT of DICER1 was identified. Patient remains in remission 3 years after recurrence.

Pleuropulmonary blastoma (PPB) and other DICER1-associated high-grade malignancies are morphologically, genetically and epigenetically related - A comparative study of 4 PPBs and 6 sarcomas.

DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary blastomas (PPBs) and 6 sarcomas by mutation analysis, whole transcriptome sequencing and methylation profiling. 9/10 patients were female. PPB patients were 0-4 years. 3/4 were alive; 2 without disease. One patient died of metastatic disease (median follow-up, 16 months). Sarcoma patients were 16-56 years. Locations included: uterine cervix/corpus (3/1), soft tissue back/shoulder (1) and paravertebral (1). 5/6 patients were alive; 2 developed metastases: intracranial (1) and lung and kidney (1) (median follow-up, 17 months). The deceased patient previously had a PPB and a Sertoli-Leydig cell tumor. Histologically, tumors showed atypical primitive-looking cells with incomplete rhabdomyoblastic differentiation and cartilage (n = 5). Immunohistochemistry demonstrated desmin- (n = 9/10), myogenin- (n = 6/10) and keratin positivity (n = 1/1). Eight cases harbored biallelic DICER1 mutations with confirmed germline mutations in 4 cases. Two cases showed a monoallelic mutation. By RNA expression- and methylation profiling, distinct clustering of our cases was seen demonstrating a close relationship on (epi)genetic level and similarities to embryonal rhabdomyosarcoma. In conclusion, this study shows overlapping morphological, immunohistochemical and (epi)genetic features of PPBs and DICER1-associated high-grade sarcomas, arguing that these neoplasms form a spectrum with a broad clinicopathological range.

Multimodality treatment including whole pleura radiation therapy for DICER1-associated pediatric pleuropulmonary blastoma.

Limited data are available regarding radiation therapy in pediatric pleuropulmonary blastoma (PPB). We report the case of a 3-year-old girl with type II PPB successfully treated with trimodality therapy including multiagent chemotherapy, resection, and whole pleura radiation therapy. While longer follow-up is required to confirm ultimate local tumor control and long-term post-treatment sequelae, currently 3.5 years following therapy, she is well, without recurrent disease or observable toxicity. The goal of this report is to add our experience to the literature regarding PPB, its management, and treatment, as prospective randomized controlled trials are not feasible due to the rarity of this disease.

Pleuropulmonary blastoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico-pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo- or adjuvant treatments can be challenging taking into account potential long-term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

Thoracic Sertoli-Leydig cell tumor: An alternative type of pleuropulmonary blastoma associated with DICER1 variation.

A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl.

Children with progressive and relapsed pleuropulmonary blastoma: A European collaborative analysis.

BACKGROUND: Children with progressive (PD) or relapsed disease (RD) of pleuropulmonary blastoma (PPB) type II/III are known to have a very poor outcome. METHODS: A retrospective review of children registered in national and European databases and trials (2000-2018) with diagnosis of PPB type II/III and PD or RD was performed. RESULTS: A total of 35 patients with PPB were analysed: patients with PD (n = 9) and RD (n = 26). Patients experienced PD at the median age of 3.9 years [range, 0.5-17.8] despite surgery, chemotherapy (CHT, n = 9) and radiotherapy (RT, n = 1) with a median time to progression of 0.58 years [range, 0.02-1.27] from diagnosis. All of them died. Patients suffered from RD at the median age of 4.3 years [1.7-15.1], median delay to relapse 1.03 years [range, 0.03-2.95]. RD occurred locally (n = 12), combined (n = 1) and in metastatic sites (n = 13): central nervous system (n = 11) and unspecified site (n = 2). Patients were treated with salvage CHT (n = 20), surgery (n = 10) ± RT (n = 10). After a median follow-up of 4.2 years [range, 2.1-14.6], a second complete remission (CR) was achieved in nine out of 26 patients. Patients were alive in the second CR (n = 6), in the third CR (n = 1), in partial remission (n = 2) and lost of follow-up (n = 1). Five-year event-free survival (EFS) and overall survival (OS) for patients with RD were both 37% (±19, CI 95%). Local therapy (surgery, RT) had a favourable impact on OS (p = 0.03 and 0.02, respectively). CONCLUSIONS: Cure of patients with RD of PPB type II/III with multimodal treatment is possible but rare. Progressive PPB is fatal and patients need new treatment options.

Pleuropulmonary Blastoma with Hotspot Mutations in RNase IIIb Domain of DICER 1: Clinicopathologic Study of 10 Cases in a Single-Institute Experience.

INTRODUCTION: Pleuropulmonary blastoma (PPB) is a rare sarcomatous malignancy involving the lung and pleura which occurs in early childhood. Cystic PPB in the early stage can be misdiagnosed as other cystic diseases. Early detection of this entity is important for appropriate treatment and prevention of disease progression. Hotspot mutations in the ribonuclease IIIb (RNase IIIb) domain of DICER1 have been reported to have a crucial role as genetic factors of PPB and DICER1 familial syndrome. We reviewed the clinicopathologic findings of PPB and the status of DICER1 hotspot mutation and patients' clinical course. METHODS: We retrospectively reviewed all patients with histologically confirmed PPB at Asan Medical Center between 2000 and 2017. Ten cases were identified in the database, and their clinicopathologic parameters were evaluated. PPB was classified into the following 3 pathologic subtypes: type I (purely cystic), type II (mixed cystic and solid), and type III (entirely solid). The status of DICER1 mutation in 2 hotspot regions of the RNase IIIb domain was evaluated by Sanger sequencing. RESULTS: The most frequent PPB type was II (6 cases), followed by I and III (2 cases each). The age at diagnosis ranged from 16 months to 15 years. All patients underwent surgery, and all patients received adjuvant or neoadjuvant chemotherapy. Four of 7 patients had missense mutations in the RNase IIIb hotspot; the base and predicted corresponding amino acid changes were c.5113 G>A (p.E1705K), c.5407 G>A (p.E1803K), c.5425 G>A (p.G1809R), and c.5428 G>T (p.D1810Y). There was no particular association between the presence of the hotspot mutation and histologic type. Nine patients survived with no evidence of disease for a median interval of 93 (range, 13-199) months. Only 1 patient diagnosed with type III PPB at the age of 18 years had recurrence after 20.8 months and eventually died 66 months after the initial diagnosis. CONCLUSIONS: Late detection of solid PPB is associated with poor prognosis. Considering the rarity of PPB disease and the importance of DICER1 hotspot mutation in pathogenesis, DICER1 hotspot mutation testing and identification in the early cystic stage can improve patient outcomes.

Programmed Death Ligand 1 Expression and Related Markers in Pleuropulmonary Blastoma.

INTRODUCTION: Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic DICER1 variants. We investigated checkpoint inhibitor markers including Programmed Death Ligand 1 (PD-L1), PD1, CD8 and tumor mutational burden (TMB) in PPB. MATERIAL AND METHODS: Cases were collected from departmental archives and the International PPB/DICER1 Registry. Immunohistochemistry (IHC) for PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) genes were performed. In addition, normal-tumor paired whole exome sequencing (WES) was performed in two cases. RESULTS: Twenty-five PPB cases were studied, consisting of Type I (n = 8, including 2 Ir), Type II (n = 8) and Type III (n = 9). PD-L1 combined positive score (CPS) of 1, 4 and 80 was seen in three (3/25, 12.0%) cases of Type II PPB with negative staining in the remaining cases. PD-1 and CD8 stains demonstrated positive correlation (P < .05). The density of PD1 and CD8 in the interface area was higher than within tumor (P < .05). The MMR proteins were retained. TMB was 0.65 mutations/Mb in type II PPB with high expression of PD-L1, and 0.94 mutations/Mb in one negative PD-L1 case with metastatic tumor. CONCLUSION: A small subpopulation of PPB patient might benefit from checkpoint immunotherapy due to positive PD-L1 staining.

Pleuropulmonary blastoma: Difficulty in diagnosis and treatment of a case in Vietnam.

Pleuropulmonary blastoma (PPB) is a rare malignant tumor in childhood cancer. This type of tumor is difficult to identify and can easily be misdiagnosed. The International PPB protocol is a complicated and aggressive protocol. It is not easily applicable to developing countries where hospitals do not have enough resources. Here we present a challanging case of a patient successfully treated in Vietnam, using limited medical resources. The patient (22 month old, male) was diagnosed with congenital cystic adenomatoid malformation in his 1st hospital admission. After 6 months of onset, the patient was diagnosed with PPB type II in the fourth hospitalization following analysis of a lung CT scan and a pathology report. After the aggressive chemotherapy regimen, the patient had two episodes of severe neutropenia and infection from which he recovered. The patient received chemotherapy and surgery treatment at our hospital, but received radiation under general anesthesia and rehabilitation therapy to improve respiration at another hospital over 600 km away. It has been 1.5 years after entering remission, and he is starting kindergarten. Lung CT scan and pathology should be analyzed to avoid missing diagnosis of PPB in patients with cystic or mixed cystic and solid lung lesions. Biopsies from cases of suspected PPB should be sent for expert pathology review. Two factors important to the successful application of the protocol are good supportive care and the multidisciplinary collaboration between medical facilities to provide proper resources during treatment. We hope to recreate more successful outcomes not only in Vietnam but also in all developing countries.