Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

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.

Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 pathogenic variation.

Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.

Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy: A Report From the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS: Patients with known or suspected PPB were enrolled in the International PPB/DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

Implementation of Electronic Clinical Decision Support for Pediatric Appendicitis.

BACKGROUND AND OBJECTIVE: Computed tomography (CT) and ultrasound (US) are commonly used in patients with acute abdominal pain. We sought to standardize care and reduce CT use while maintaining patient safety through implementation of a multicomponent electronic clinical decision support tool for pediatric patients with possible appendicitis. METHODS: We conducted a quasi-experimental study of children 3 to 18 years old who presented with possible appendicitis to the pediatric emergency department (ED) between January 2011 and December 2013. Outcomes were use of CT and US. Balancing measures included missed appendicitis, ED revisits within 30 days, appendiceal perforation, and ED length of stay. RESULTS: Of 2803 patients with acute abdominal pain over the 3-year study period, 794 (28%) had appendicitis and 207 (26.1% of those with appendicitis) had a perforation. CT use during the 10-month preimplementation period was 38.8% and declined to 17.7% by the end of the study (54% relative decrease). For CT, segmented regression analysis revealed that there was a significant change in trend from the preimplementation period to implementation (monthly decrease -3.5%; 95% confidence interval: -5.9% to -0.9%; P = .007). US use was 45.7% preimplementation and 59.7% during implementation. However, there was no significant change in US or total imaging trends. There were also no statistically significant differences in rates of missed appendicitis, ED revisits within 30 days, appendiceal perforation, or ED length of stay between time periods. CONCLUSIONS: Our electronic clinical decision support tool was associated with a decrease in CT use while maintaining safety and high quality care for patients with possible appendicitis.

Nasal chondromesenchymal hamartoma in children with pleuropulmonary blastoma--A report from the International Pleuropulmonary Blastoma Registry registry.

OBJECTIVES: Nasal chondromesenchymal hamartoma (NCMH) is an uncommon chondro-stromal tumor of the nasal cavity and paranasal sinuses in infancy and childhood. Pleuropulmonary blastoma (PPB) is also a rare malignancy of lung and pleura in childhood and is the sentinel disease of an important familial tumor and dysplasia syndrome. This study identified NCMH in PPB patients. METHODS: The International PPB Registry collects cases of PPB using central pathology review and evaluation of clinical records. The Registry also evaluates PPB literature. Examples of NCMH occurring with PPB were identified. Clinical records, digital radiography and pathologic specimens of PPB-associated NCMH cases were analyzed. RESULTS: Among approximately 625 cases of PPB, four children developed NCMH. These cases are among 28 total reported NCMH cases. NCMH presented with sinonasal congestion and visible polypoid nasal masses and were diagnosed from ages 7 to 15 years, similar to older reported NCMH cases. NCMH involved the nasal cavity, paranasal sinuses and upper nasopharynx, was bilateral in three children and locally recurrent in one. In two children, NCMH had the characteristic pathologic spectrum of immature nodules of cartilage surrounded by spindle cell stroma, whereas the other two NCMH displayed mature chondroid nodules and a less varied fibrous stroma. NCMH was not identified in family members with PPB. CONCLUSIONS: NCMH developing in four children with PPB indicates that NCMH is part of the heredofamilial disease complex associated with PPB. Otorhinolaryngologists and pediatric oncologists should be aware that these two rare conditions occur together and that affected patients may have a familial predisposition to childhood malignant and dysplastic disease.