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Translational Pediatrics Apr 2024-associated tumors are heterogeneous and affect several organs. -associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27...
BACKGROUND
-associated tumors are heterogeneous and affect several organs. -associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27 (H3K27me3) loss in nucleus by immunohistochemistry.
METHODS
We explored the H3K27me3 immunostaining pattern in other -associated tumors. Twelve tumors from eleven patients with confirmed mutations (sporadic and germline) data from a pancancer next-generation sequencing panel, and four tumors of pleuropulmonary blastoma (PPB) were retrieved from our database and stained with anti-H3K27me3 antibody.
RESULTS
The H3K27me3 expression in the nucleus showed heterogeneous mosaic loss in neoplastic Sertoli cell components in three of the five cases of moderately to poorly differentiated Sertoli-Leydig cell tumors. Among two tumors of -associated primary intracranial sarcoma, one showed complete loss of H3K27me3 in all neoplastic cells, whereas the other showed mosaic loss in the sarcomatous spindle cells. One -associated tumor with epithelial and mesenchymal differentiation, including pulmonary blastoma and PPB, showed mosaic loss of glandular epithelial and mesenchymal components. Four cases of type II PPB and a single case of type III PPB showed a similar mosaic loss of H3K27me3 staining restricted to large spindle cell components. All other components in all tumors-including Leydig cells; the areas of epithelial, cartilaginous, and rhabdomyomatous differentiation; and all cells of the remaining three cases (one papillary thyroid carcinoma and two cases of PPB type I)-demonstrated retained H3K27me3 staining.
CONCLUSIONS
H3K27me3 expression is not universally lost in -associated tumors and thus is not predictive of mutation status. The mosaic regional loss of H3K27me3 immunostaining is consistent in PPB type II and III, which can be a helpful diagnostic marker for these tumors and suggests a similarity to -associated intracranial sarcoma.
PubMed: 38715664
DOI: 10.21037/tp-24-61 -
Journal of Clinical Oncology : Official... Mar 2019DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard... (Clinical Trial)
Clinical Trial Observational Study
PURPOSE
DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of neoplasm incidence accounting for competing risks ("cumulative incidence") of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation.
PATIENTS AND METHODS
We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors ("neoplasms," excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival.
RESULTS
We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers.
CONCLUSION
This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.
Topics: Adolescent; Adult; Child; Cohort Studies; DEAD-box RNA Helicases; Female; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Pulmonary Blastoma; Registries; Ribonuclease III; Risk Factors; Young Adult
PubMed: 30715996
DOI: 10.1200/JCO.2018.78.4678 -
Thoracic Cancer Oct 2018A 65-year-old never-smoking woman presented to a local hospital, because an abnormal shadow was detected at the right lower lung field by annual chest X-ray. Computed... (Review)
Review
A 65-year-old never-smoking woman presented to a local hospital, because an abnormal shadow was detected at the right lower lung field by annual chest X-ray. Computed tomography (CT) revealed a 5-cm tumor in segment 6 of her right lung and an enlarged subcarinal lymph node, suggesting metastasis. The lung tumor was diagnosed as adenocarcinoma by a CT-guided percutaneous needle biopsy. She was referred to our hospital and underwent right lower lobectomy with lymph node dissection (ND2a-2). A histopathological examination of the tumor showed a biphasic proliferation made of carcinomatous and sarcomatous components. The carcinomatous component consisted of glandular structures of atypical cells that possessed chromatin-rich nuclear and clear cytoplasm, confirming high-grade fetal adenocarcinoma. The sarcomatous component consisted of immature spindle cells that differentiated into chondrosarcoma. Immunohistochemically, the glandular structures expressed membranous beta-catenin, and the ultimate diagnosis was blastomatoid variant of pulmonary carcinosarcoma. She received four courses of cisplatin plus vinorelbine as adjuvant chemotherapy and remained alive with neither recurrence nor distant metastasis at two and a half years after the operation. We experienced a rare case of blastomatoid pulmonary carcinoasarcoma.
Topics: Aged; Carcinosarcoma; Female; Humans; Lung Neoplasms
PubMed: 30106243
DOI: 10.1111/1759-7714.12831 -
The Clinical Respiratory Journal Nov 2023Classic biphasic pulmonary blastoma (CBPB), a distinct type of lung cancer, is a dual-phasic tumor characterized by the co-existence of low-grade fetal adenocarcinoma... (Review)
Review
Classic biphasic pulmonary blastoma (CBPB), a distinct type of lung cancer, is a dual-phasic tumor characterized by the co-existence of low-grade fetal adenocarcinoma and primitive mesenchymal stroma. Accounting for less than 0.1% of surgically removed lung cancers, CBPB commonly presents in individuals during their fourth to fifth decades of life, with smoking as a significant risk factor. The optimal management strategy entails surgical resection, supplemented by chemotherapy to improve prognosis. The frontline chemotherapeutic agents typically include platinum agents and etoposide, with preoperative neoadjuvant chemotherapy potentially enabling operability for initially inoperable cases. In recent years, targeted therapies, such as antiangiogenic agents, have emerged as promising new treatment strategies for CBPB. For patients exhibiting brain metastases or deemed inoperable, radiation therapy proves to be a crucial therapeutic component. CBPB prognosis is adversely affected by factors such as early metastasis, tumor size exceeding 5 cm, and tumor recurrence. In this regard, serological markers have been identified as valuable prognostic indicators. To exemplify, we recount the case of a 44-year-old female patient with CBPB, wherein serum lactate dehydrogenase levels showed significant diagnostic value. This report further incorporates a comprehensive review of CBPB literature from the past 22 years.
Topics: Female; Humans; Adult; Pulmonary Blastoma; Neoplasm Recurrence, Local; Lung Neoplasms; Etoposide; Prognosis
PubMed: 37772674
DOI: 10.1111/crj.13701 -
Annals of Diagnostic Pathology Oct 2022DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary... (Comparative Study)
Comparative Study
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.
Topics: Female; Humans; Male; DEAD-box RNA Helicases; Desmin; Keratins; Mutation; Myogenin; Pulmonary Blastoma; Rhabdomyosarcoma, Embryonal; Ribonuclease III; RNA; Soft Tissue Neoplasms
PubMed: 35779311
DOI: 10.1016/j.anndiagpath.2022.152002 -
Journal of Thoracic Oncology : Official... Nov 2016The appropriate management of asymptomatic congenital pulmonary malformations (CPMs) remains controversial. Prophylactic surgery is recommended to avoid the risk for... (Review)
Review
INTRODUCTION
The appropriate management of asymptomatic congenital pulmonary malformations (CPMs) remains controversial. Prophylactic surgery is recommended to avoid the risk for development of pulmonary infections and to prevent the highly debated development of malignancy. However, the true risk for development of malignancy remains unknown. A systematic review analyzed all cases in which lung tumors associated with CPMs in both the pediatric and adult populations were described.
METHODS
A comprehensive literature search was carried out; it included all the cases in which an association between CPMs and malignant pulmonary lesions was reported.
RESULTS
In all, 134 publications were eligible for inclusion. In 168 patients CPM was found associated with lung tumor. The diagnosis was made in 76 children at a mean age of 3.68 ± 3.4, whereas in the adult population (n = 92) it was made at a mean age of 44.62 ± 16.09. Cough was the most frequent presenting symptom both in children and in adults. Most of the patients underwent lobectomy. The tumor most often associated with CPM was pleuropulmonary bastoma in children (n = 31) and adenocarcinoma (n = 20) or bronchioloalveolar carcinoma (n = 20) in adults. The CPM most frequenty associated with tumors in children was congenital cystic adenomatoid malformation (n = 37), especially type 1 (n = 21), whereas in adults it was bronchogenic cyst (n = 25), followed by congenital cystic adenomatoid malformation (n = 21).
CONCLUSIONS
CPMs should be followed up and never underestimated because they may conceal a tumor. Apparently, there is no age limit for malignant progression of CPMs and no limit of the interval between first detection of the CPM and appearance of the associated tumor.
Topics: Adenocarcinoma; Adult; Child, Preschool; Congenital Abnormalities; Female; Humans; Lung Neoplasms; Male
PubMed: 27423390
DOI: 10.1016/j.jtho.2016.06.023 -
Respiratory Medicine Case Reports 2021Pulmonary blastoma is an aggressive lung cancer with incidence ranging from 0.25-0.5 of all the reported lung cancers. Although, pulmonary blastoma is seen commonly in...
Pulmonary blastoma is an aggressive lung cancer with incidence ranging from 0.25-0.5 of all the reported lung cancers. Although, pulmonary blastoma is seen commonly in childhood its very rare in adults. Surgical treatment is often the treatment of choice, but benefits of neoadjuvant chemotherapy are unclear. People with DICER1 syndrome commonly develop Pulmonary blastoma and do have concomitant or previous history of benign or malignant tumours in extra pulmonary site like kidney, thyroid, ovary cervix testicle and eye. As per our knowledge, this is the first case of adult pulmonary blastoma previously diagnosed with urothelial cancer and a strong familial predilection of malignancy, with negative genetic test for DICER1 mutations.
PubMed: 34820260
DOI: 10.1016/j.rmcr.2021.101556 -
Frontiers in Oncology 2021The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung...
BACKGROUND AND OBJECTIVES
The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy.
METHODS
The DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparisons between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls and between a pleuropulmonary blastoma (PPB) and controls were performed. Moreover, each malformed sample was pairwise compared with its respective control. All differentially methylated regions (DMRs) with an adjusted p-value <0,05 were studied.
RESULTS
Every comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors.
CONCLUSIONS
Methylation anomalies already described in lung tumors and also shared by the PPB were found in congenital lung malformations, regardless the histology. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.
PubMed: 34262872
DOI: 10.3389/fonc.2021.689833 -
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 the Formosan Medical... Nov 2022The purpose of this study is to compare the clinical characteristics and surgical outcomes of thoracotomy and video-assisted thoracoscopic surgery (VATS) in children...
BACKGROUND
The purpose of this study is to compare the clinical characteristics and surgical outcomes of thoracotomy and video-assisted thoracoscopic surgery (VATS) in children with congenital lung malformations (CLMs) in a tertiary referring center and to report our modified biportal VATS setting.
METHODS
This is a single-center retrospective chart review study including children who underwent surgical resection for CLMs between January 2007 and December 2020. Patient characteristics and surgical outcomes were compared between open and thoracoscopy, as well as conventional VATS and biportal VATS. Biportal setting included an anterior utility wound and a camera trocar wound with one-lung ventilation.
RESULTS
A total of 100 patients were identified. Twenty patients received thoracotomy, and 80 patients received VATS (67 conventional and 13 biportal VATS). The median age at operation was 0.4 months in the thoracotomy group and 4.7 months in the VATS group. More patients in the thoracotomy group had preoperative symptoms, comorbidities, and emergent operations. The patients who underwent thoracotomy had significantly longer postoperative ICU stays, chest tube durations, hospital stays, and more complications. The pathological analysis revealed 67 congenital pulmonary airway malformations, 27 pulmonary sequestration, 6 hybrid lesions, and one accompanying pleuropulmonary blastoma. Compared to conventional VATS, the ICU stay was shorter in the biportal VATS group, with comparable operative durations, hospital stay and complications.
CONCLUSION
VATS for CLMs is associated with better postoperative recovery and fewer complications. Biportal VATS is also a safe and feasible approach.
Topics: Child; Humans; Length of Stay; Lung; Lung Diseases; Lung Neoplasms; One-Lung Ventilation; Pneumonectomy; Postoperative Complications; Retrospective Studies; Thoracic Surgery, Video-Assisted; Thoracotomy; Treatment Outcome
PubMed: 35331621
DOI: 10.1016/j.jfma.2022.03.003