Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associatedtumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.
Purpose Type I pleuropulmonary blastoma (PPB) is a rare, cystic lung neoplasm in infants characterized by subtle malignant changes and a good prognosis. Recurrences after type I PPB are usually advanced type II or type III neoplasms with a poor prognosis. This article describes the first collection of type I PPB cases, analyzes outcome based on treatments of surgery or surgery plus chemotherapy, and presents type I PPB management recommendations. Patients and Methods Type I PPB cases from the International PPB Registry and literature were evaluated using standard statistical methods for outcomes based on age at diagnosis, sex, thoracic side, surgical extent, length of follow-up, constitutional/familial disease, pre-existing lung cysts, intrathoracic findings, and treatments (surgery or surgery and chemotherapy). Results Thirty-eight type I PPB cases were identified: Registry (n = 30) and literature (n = 8). Twenty children had surgery alone; eight (40%) experienced recurrence; and four died. Eighteen children had surgery and adjuvant chemotherapy; one experienced recurrence and died. All recurrences were type II or III PPB. Recurrence-free survival was higher in the surgery + chemotherapy group (P = .01); overall survival did not differ (P = .18). The improved recurrence-free survival was found only in males. Four of nine children with recurrence survived. Conclusion Adjuvant chemotherapy appears to benefit type I PPB patients. Benefit limited to males requires broader substantiation. Salvage after types II and III recurrence is poor (four of nine; 44%). A rigorous surveillance schedule after type I PPB diagnosis might detect early recurrence and be an acceptable alternative to adjuvant chemotherapy.
9522 Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic Type I (T-I) lesion to cystic solid and solid high grade sarcoma (Type II and Type III). A regressed form of PPB (T-Ir) has been recognized pathologically. The outcome of both T-I and T-Ir has been only partially described. Methods: Retrospective analysis of 345 IPPBR cases showed 116 T-I or T-Ir. In all cases the PPB diagnosis was made on surgically removed cysts. The treating physician decided whether to use chemotherapy after surgery. Results: The pathologic diagnosis of the 91 PPB T-I and 25 T-Ir is now confirmed by central review (LPD and DAH). Patients with T-I were younger than T-Ir (median: 8 months vs. 48 months).Diagnosis after age 6 years included only one T-I compared to 10 T-Ir patients. Therapy is not known for 28 T-I and 2 T-Ir. Surgery was followed by chemotherapy in 31 T-I and 2 T-Ir. Six (5%) recurred with the same type, all were alive at last follow-up: 5 (5.5%) T-I, 1 (4%) T-Ir. Progression to high-grade Type II or III occurred in 9/91 (10%) T-I and 2/25 (8%) T-Ir. The addition of chemotherapy did not significantly reduce progressions (Fisher’s exact test). All of the tumor progressions were seen by 75 months of age; this finding is similar to broader IPPBR data: > 95% of patients are diagnosed with Type II/III by 72 months of age. Of the 9 patients with T-I who progressed, 5 ultimately died, whereas the 2 T-Ir who progressed were alive. At last follow-up 111/116 (95.6%) were alive. Conclusions: A cyst in an older individual most likely will be Type Ir. Type I and Type Ir are clinically similar with a small risk of progression to the advanced Type II/III up to 6 years of age. Outcome for those whose cystic PPBs progressed is poor. The role of chemotherapy remains uncertain for the prevention of progression in the pure cystic PPB Type I or Ir. [Table: see text]
The differential diagnosis of congenital lung lesions includes a variety of pulmonary malformations, and uncommon or rare neoplasms such as the pleuropulmonary blastoma (PPB) and congenital peribronchial myofibroblastic tumor (CPMT). Although most of the congenital lesions have a predominantly cystic appearance, the exceptions of a more solid process are the type 3 congenital cystic adenomatoid or pulmonary airway malformation (CCAM-CPAM) and the CPMT. The clinical and pathologic features of a unique solid or mixed solid/cystic lung mass composed of immature interstitial mesenchyme in association with irregular airspace-like structures mimicking abnormal incompletely developed lung are presented in this report of 10 infants (7 males, 3 females) whose tumor-like lesions were detected in the prenatal period to 3 months of age (median, 1-day old). A lobectomy was done in all 10 infants and 1 infant received adjuvant chemotherapy. One of the surgical resections occurred as an ex utero, antenatal procedure because of fetal ascites. There have been no reported recurrences in those patients with greater than 12 months of follow-up ranging from 15 to 182 months (9 cases). Because of the morphologic resemblance of this mass-like lesion to fetal lung at 20 to 24 weeks gestation (as though any further pulmonary development was arrested in these localized lesions), we are proposing the designation of fetal lung interstitial tumor (FLIT) whose pathogenetic relationship, if any, to type 1 (cystic) pleuropulmonary blastoma remains uncertain to date.
A variety of pathologies lead to pulmonary hypertension (PH), which is defined as a mean pulmonary artery pressure exceeding 25 mmHg at rest. To further diagnose and manage PH, patients undergo repeated right heart catheterizations (RHC) wherein a Swan-Ganz catheter is advanced into a branch of the pulmonary artery and a balloon is inflated to wedge the catheter tip. This article illustrates a protocol whereby pulmonary artery endothelial cells (PAECs) may be harvested from the balloon tips of Swan-Ganz catheters after RHC, and purified with an anti- CD146 affinity column technique to purify putative PAECs. These cells might be used to provide an in situ snapshot of the biological state of the pulmonary vasculature endothelium to complement hemodynamic measurements obtained during RHC. Harvested and purified PAECs may be used for either cell culture or for subsequent analytical assays such as flow cytometery.
