Epidemiological features and survival outcomes in patients with malignant pulmonary blastoma: a US population-based analysis.

BACKGROUND: Pulmonary blastoma (PB) is a rare lung primary malignancy with poorly understood risk factors and prognosis. We sought to investigate the epidemiologic features and long-term outcomes of PB. METHODS: A population-based cohort study was conducted to quantify the death risk of PB patients. All subjects diagnosed with malignant PB from 1988 to 2016 were screened from the Surveillance, Epidemiology and End Results database. Cox regression model of all-cause death and competing risk analysis of cause-specific death were performed. RESULTS: We identified 177 PB patients with a median survival of 108 months. The 5 and 10-year survival rate in all PB patients were 58.2 and 48.5%, as well as the 5 and 10-year disease-specific mortality were 33.5 and 38.6%. No sex or race disparities in incidence and prognosis was observed. The death risk of PB was significantly associated with age at diagnosis, clinical stage, histologic subtype and surgery treatment (p<0.01). On multivariable regression analyses, older age, regional stage and no surgery predicted higher risk of both all-cause and disease-specific death in PB patients. CONCLUSION: We described the epidemiological characteristics of PB and identified its prognostic factors that were independently associated with worse clinical outcome.

Inequalities in diagnosis and registration of pediatric very rare tumors: a European study on pleuropulmonary blastoma.

Very rare tumors (VRTs) account for up to 11% of childhood cancers. Dedicated national groups and registries only exist in some European countries. Pleuropulmonary blastoma (PPB) is a very rare intrathoracic pediatric tumor with a potentially severe prognosis. Due to its rarity, it sometimes goes unrecognized. We investigated PPB diagnostic capability and possible correlations between diagnostic performance and VRT-dedicated activities. The number of cases of PPB registered between 2000 and 2014 at pediatric oncology centers in Europe was compared with the number of expected cases. Data sources included VRT registries, population-based cancer registries, and hospital registries. Data were obtained for 25 countries, grouped into 4 geographical regions. The expected cases were 111, and the observed cases were 129. The observed-to-expected ratio was 1.86 for Northern Europe, 1.33 for Southern Europe, 1.22 for Central Europe, and 0.65 for Eastern Europe. More cases than expected were registered in all countries with an official VRT registry.Conclusion: The number of cases observed is consistent with expectations, but disparities exist across Europe. Difficulties in diagnosing PPB emerged in most Eastern countries. The incidence rate of PPB may be underestimated. The creation of VRT-dedicated groups and a European Registry for VRTs could help to reduce inequalities.What is Known:• Very rare pediatric tumors are often not recognized, despite representing almost 11% of childhood cancers .• Pleuropulmonary blastoma is a rare pediatric tumor with a poor prognosis.What is New:• The ability to diagnose and register pleuropulmonary blastoma varies in Europe.Registries dedicated to very rare pediatric tumors improve the diagnostic rates.• The incidence rate of pleuropulmonary blastoma may currently be underestimated.

The prevalence of DICER1 pathogenic variation in population databases.

The DICER1 syndrome is associated with a variety of rare benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN) and Sertoli-Leydig cell tumor (SLCT). The prevalence and penetrance of pathogenic DICER1 variation in the general population is unknown. We examined three publicly-available germline whole exome sequence datasets: Exome Aggregation Consortium (ExAC), 1,000 Genomes (1,000 G) and the Exome Sequencing Project (ESP). To avoid over-estimation of pathogenic DICER1 variation from cancer-associated exomes, we excluded The Cancer Genome Atlas (TCGA) variants from ExAC. All datasets were annotated with snpEff and ANNOVAR and variants were classified into four categories: likely benign (LB), unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). The prevalence of DICER1 P/LP variants was 1:870 to 1:2,529 in ExAC-nonTCGA (53,105 exomes) estimated by metaSVM and REVEL/CADD, respectively. A more stringent prevalence calculation considering only loss-of-function and previously-published pathogenic variants detected in ExAC-nonTCGA, yielded a prevalence of 1:10,600. Despite the rarity of most DICER1 syndrome tumors, pathogenic DICER1 variation is more common than expected. If confirmed, these findings may inform future sequencing-based newborn screening programs for PPB, CN and SLCT, in which early detection improves prognosis.

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. Design, Setting, and Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Main Outcomes and Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. Conclusions and Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Diagnosis and treatment of pleuropulmonary blastoma in children: A single-center report of 41 cases.

OBJECTIVE: This study was performed to investigate the age at onset, clinical manifestations, pathological types and features, treatment, and prognosis of pleuropulmonary blastoma (PPB) in children in an attempt to reduce the misdiagnosis rate and achieve early detection and timely intervention. METHODS: We retrospectively studied the clinical data of 41 pediatric patients with PPB who were treated in our center from March 2002 to November 2018. The data comprised the age at onset, clinical manifestations, characteristics of familial diseases, pathological types, surgical procedures, and prognosis. RESULTS: Twenty male and 21 female patients were included, with a 0.95:1.00 male:female ratio. In total, 51.2% of the patients were misdiagnosed as having nonneoplastic lesions at the first presentation. The interval from symptom onset to surgery/chemotherapy ranged from 5 to 210 days. The pathological types were type I (cystic) PPB (n = 5, 11.9%), for which the median age at diagnosis was 21 months (range, 8-24 months); (solid/cystic) II PPB (n = 12, 28.6%), for which the median age at diagnosis was 37 months (range, 22-112 months); and type III (solid) PPB (n = 23, 54.8%), for which the median age at diagnosis was 39 months (range, 19-156 months). The pathologic type was undefined in one patient (2.4%). The patients were mainly treated by surgery and chemotherapy. The 5-year disease-free survival rate was 69.2%. CONCLUSION: The clinical manifestations of PPB are nonspecific, its misdiagnosis rate is high, and it has a poor prognosis. Pediatricians should be aware of the seriousness of PPB. The possibility of PPB should be considered in children with pneumothorax, multiple pulmonary cystic lesions, a family history of pulmonary cysts, a family history of PPB, or space-occupying lesions associated with DICER1 syndromes. The lesion should be closely monitored and surgically removed if necessary. The nature of the lesion should be identified early to minimize the risk of progression of the PPB to worse types because of misdiagnosis and missed diagnosis. Multidisciplinary treatment including surgery, chemotherapy, and/or radiotherapy can be applied to patients with PPB. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level III.

Pulmonary adenocarcinomas of the fetal lung type: a clinicopathologic study indicating differences in histology, epidemiology, and natural history of low-grade and high-grade forms.

Seven cases of high-grade adenocarcinoma of fetal lung type (H-FLAC) are compared with nine cases of pulmonary endodermal tumor resembling fetal lung or low-grade adenocarcinoma of fetal lung type (L-FLAC). Of the seven patients with of H-FLAC, four were men and three were women. All of the patients but one were in their 60s or 70s. Five patients were smokers. After resection of the tumor, three patients died of metastases, two patients are alive with no evidence of disease, and two patients died of a postoperative complication. Histologically, H-FLAC and L-FLAC have both complex glandular structures resembling fetal lung and neuroendocrine differentiation. Two cases of H-FLAC had stromal proliferation typical of biphasic pulmonary blastoma. The H-FLAC was distinguished from L-FLAC by the presence of disorganized glands, large vesicular nuclei, prominent nucleoli, pronounced anisonucleosis, absence of morules, transition to conventional adenocarcinoma, broad areas of necrosis, desmoplastic stroma, overexpression of p53 protein, and production of alpha-fetoprotein. High and low grades of FLAC explain discrepancies in previously reported clinicopathologic features of FLAC. The H-FLAC needs to be distinguished from L-FLAC. Both forms may have stromal components, so both have been referred to as blastomas. The H-FLAC represents the prototype of so-called pulmonary blastoma predominantly seen in the elderly, whereas L-FLAC and its biphasic form predominate in the middle-aged population.

[Pulmonary blastoma and related primary malignant pulmonary neoplasms]. / Pulmonary blastoma i pokrewne pierwotne nowotwory zlosliwe pluca.

During the last decade more diagnoses of pulmonary blastoma were made worldwide than in previous decades. Whether this increased frequency is caused by better diagnostic procedures (immunochemistry, electron microscopy) or by the growing number of patients having this neoplasm is difficult to distinguish. We present controversies concerning pulmonary blastoma and related biphasic primary pulmonary neoplasms. We agree with Wick et al. that cases in children (called pleuropulmonary blastoma) should be differentiated from cases in adults, which show many similarities to bronchogenic lung cancer. However, our opinion is that the new classification system proposed by Wick et al. does not take into account cases of PB in young adults with intropulmonary growth of the tumor.

Treatment and prognostic factors in pleuropulmonary blastoma: an EXPeRT report.

BACKGROUND: Pleuropulmonary blastoma (PPB) is an aggressive embryonal malignancy presenting in early childhood, presumably arising from pleuropulmonary mesenchyme. The European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) analysed its data on this tumour. METHODS: This analysis concerns patients aged 0-17years with histologically-confirmed PPB registered up to 2008 in national databases in Italy, France and the United Kingdom and Poland. Lesions were classified as type I, II or III according to Dehner's classification. FINDINGS: Sixty-five patients were considered (13 type I, 24 type II and 28 type III). Most tumours were large (91% >5cm) and invaded the parietal pleura (29), mediastinum (10), major vessels (four) or pericardium (three). Regional nodes were involved in two cases, and three had metastases. The median follow-up was 5years (0.6-22). For type I patients, 5-year progression free survival (PFS) was 83.3% and overall survival 91.7%; six patients received no further treatment after surgery, but two relapsed. All type II/III PPB had chemotherapy (CT) and their 5-year PFS was 42.9% (27.7-57.2). On univariate analysis, favourable prognostic factors were: complete tumour resection at diagnosis (p=0.008); and absence of invasiveness (p=0.02); for type II/III tumours, type of CT was also a significant factor (patients given doxorubicin fared better, with a 5-year PFS of 70% versus 31.3% [p=0.01]). INTERPRETATIONS: Type I PPB patients' outcome was satisfactory. Complete resection at diagnosis seems important but rarely feasible for type II/III tumours, who benefited from doxorubicin-containing CT regimens. These results will inform the EXPeRT group's PPB treatment guidelines.

Ciliary body medulloepithelioma: four cases associated with pleuropulmonary blastoma--a report from the International Pleuropulmonary Blastoma Registry.

BACKGROUND AND AIMS: Ciliary body medulloepithelioma (CBME) is a rare embryonal ocular tumour of children under age 10 years. Pleuropulmonary blastoma (PPB) is a rare embryonal lung tumour in young children and the sentinel disease of the PPB Family Tumour and Dysplasia Syndrome, a distinctive predisposition leading to unusual dysontogenetic-dysplastic and neoplastic conditions in PPB patients and their relatives. Germline mutations of DICER1 gene, a key regulator of gene silencing, underlie this syndrome. CBME occurs with PPB. The authors' aim was to identify CBME cases associated with PPB. METHODS: The authors evaluated International PPB Registry and literature PPB cases for CBME, including review of pathologic specimens. RESULTS: Four CBME were observed among 550-600 PPB cases; three in patients and one in a parent. One CBME was clinically diagnosed; three were confirmed pathologically (one benign teratoid CBME; one benign non-teratoid CBME; one case, details not available). CONCLUSIONS: These observations suggest that CBME is a manifestation of the tumour predisposition associated with PPB. Paediatric oncologists and ophthalmologists should be aware that CBME can occur in PPB patients or their relatives and that CBME may indicate a hereditable tumour predisposition for a child or family.

[Child pleuropulmonary blastoma]. / Pleuropneumoblastome de l'enfant.

Pleuropulmonary blastoma is an extremely rare and aggressive thoracic tumour seen exclusively in children. The initial symptoms are respiratory and non specific and the chest X-ray done in that context reveals a thoracic mass. The chest CT scan then leads to the diagnosis of a cystic, mixt or solid mass. The diagnosis will be affirmed on anatomopathology of the tumour or biopsy. There are three different histological types: type I, cystic, type II, cystic and solid and type III, solid exclusively. Type I is less aggressive and its treatment is essentially surgical. Types II and III are highly aggressive and require surgery associated to polychemotherapy. In all cases, surgery is essential and should be the most complete possible. Extension and follow-up exams will include bone scan and brain imagery searching for metastasis as well as abdominal ultrasound searching associated renal lesions because 30% of pleuropulmonary blastoma are part of a familial predisposition syndrome.

Is congenital cystic adenomatoid malformation a premalignant lesion for pleuropulmonary blastoma?

BACKGROUND: The relationship between congenital cystic adenomatoid malformation (CCAM) and pleuropulmonary blastoma (PPB), whether causal, correlational, or coincidental, remains controversial. There is a lack of consensus as to the optimal treatment of patients with asymptomatic CCAM. METHOD: We reviewed all cases of CCAM and PPB seen at our institution from 1999 to 2008. Institutional Research Ethics Board approval was obtained. The incidence of CCAM and PPB, respectively, was calculated based on birth numbers during the study period. RESULTS: Seventy-four CCAMs were resected over the study period in 129 children diagnosed with CCAM. Five PPBs were diagnosed during the study period. Three of the 5 PPB cases were initially diagnosed as CCAMs. These PPBs were not clinically or radiologically distinguishable from CCAMs. In our referral area, the incidence of CCAM was 1 in 12,000; and the incidence of PPB was 1 in 250,000 live births. The mortality rate for PPB in this cohort was 20%. CONCLUSION: Asymptomatic cystic lung malformations represent a therapeutic dilemma. In this cohort, the incidence of PPB among apparently benign lung lesions was 4%. No clinical or radiological markers differentiated benign CCAMs from PPBs. Our experience provides further justification for resection of all CCAMs. This should be discussed with parents until CCAMs and PPBs can be clearly distinguished preoperatively.

Cerebral metastasis and other central nervous system complications of pleuropulmonary blastoma.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare tumor of pleura and lung in young children. Central nervous system (CNS) complications, particularly cerebral parenchymal metastases, occur in aggressive forms of PPB: Types II and III PPB. This article evaluates cerebral and meningeal metastases, cerebrovascular events (CVA) caused by tumor emboli, spinal cord complications, and intracranial second malignancies in PPB. PROCEDURE: International PPB Registry and literature cases were evaluated for CNS events. Cerebral metastasis patients were evaluated for gender, side of origin of PPB, PPB Type, interval from diagnosis to metastasis, status of chest disease, treatment, and outcome. Standard statistical methods were used to calculate the cumulative probability of cerebral metastasis and survival following metastasis. RESULTS: Thirty-nine cases of cerebral metastasis were identified in 5/53 Registry Type II cases, 15/44 Registry Type III cases, and 19/143 literature Type II/III cases. Metastases occurred 1-60, median 11.5 months after diagnosis. Chest disease was controlled in 50% of children at time of metastasis. The cumulative probability of cerebral metastasis by 5 years from diagnosis was 11% for Type II patients (95%CI (confidence interval): 2-20%) and 54% for Type III patients (95%CI: 31-76%). Seven children survive cerebral metastasis. Other CNS complications were post-operative CVA (five cases), spinal cord invasion or compression (six), leptomeningeal disease (three), and second intracranial malignancies (two). CONCLUSIONS: Cerebral metastasis is more frequent in PPB than in other childhood sarcomas. Clinicians should screen for this complication. Diverse other CNS complications are less common and require careful diagnosis.

Lung tumours in children.

Primary lung tumours in children are rare and metastatic lung disease is uncommon. The majority of children who present with a primary or secondary pulmonary malignancy will present co-incidentally while seeking attention for another medical problem, or with non-specific abnormalities such as cough with collapse or consolidation on the chest radiograph. With improved techniques of medical imaging for diagnostic and therapeutic purposes and improved outcomes of childhood malignancies, the role of the respiratory paediatrician in the ongoing care of oncology patients is likely to increase.

Pleuropulmonary blastoma: a clinicopathologic study of 50 cases.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a unique dysontogenetic neoplasm of childhood that appears as a pulmonary and/or pleural-based mass and is characterized histologically by a primitive, variably mixed blastematous and sarcomatous appearance. METHODS: Histologic material from all cases was reviewed and the tumors subclassified as type I (purely cystic), type II (cystic and solid), or type III (purely solid). Data regarding presenting symptoms, family history, operative findings, pathologic subtypes, therapeutic interventions, and outcome were correlated with survival by standard statistical methods. RESULTS: The series was comprised of 24 males and 26 females. Respiratory difficulty with or without fever was the most common clinical symptom reported. Cyst formation in the affected lung was identified radiographically in 19 children (38%) at or before the definitive pathologic diagnosis. The ages at presentation of the 7 type I, 24 type II, and 19 type III PPBs were significantly different: 10, 34, and 44 months, respectively (P < 0.001). Local recurrence developed in 1 of 7 type I PPBs (14%) and in 18 of 43 type II and III PPBs (46%); distant metastasis occurred in 13 patients, chiefly to the brain/spinal cord or bone, and was observed only in those with type II or type III PPB. Patients with pleural or mediastinal involvement fared significantly worse than those without such involvement. Five-year survival was 83% for type I and 42% for types II and III. Survival differences on the basis of pathologic subtype did not reach statistical significance. CONCLUSIONS: PPB is an aggressive, intrathoracic neoplasm of early childhood with an unfavorable outcome. Although survival differences among patients with different histologic subtypes of disease did not reach statistical significance, the apparently better outcome for patients with purely cystic type I tumors may be borne out in a large series. These observations support the premise that type I and III PPB are bridged morphologically by type II PPB with its combined cystic and solid features. The PPB should be regarded as the pulmonary dysontogenetic analogue to Wilms' tumor in the kidney, neuroblastoma in the adrenal gland, and hepatoblastoma in the liver. Molecular genetic investigations, especially in constitutional PPB, should be revealing. In view of the poor outcomes for patients with types II and III, new and aggressive therapies must be developed.

Le pneumoblastome chez l'enfnt

Within the last five years, the authors were responsible for 3 lihlegirls suffering from respiratory problems which radiologic investigations had attributed a pulmonary solid mass. Each patient was treated surgically. Post operative histological study incovered a pneumoblastoma with its three characteristic cellular components. One year later, evolution was favorable in one patient; whereas the two others died rapidly in spite of a complementary anti cancerous chemotherapy