Paucicellular Fibrointimal Proliferation Characterizes Pediatric Pulmonary Vein Stenosis: Clinicopathologic Analysis of 213 Samples From 97 Patients.

Pulmonary vein stenosis (PVS) is a luminal narrowing of extrapulmonary pulmonary veins. In pediatric patients, it arises following repair of congenital heart disease, particularly anomalous pulmonary venous return; in lung disease, especially prematurity; and rarely in isolation. The etiology is unknown and the course often fatal without lung transplantation. We hypothesized that systematic clinicopathologic review of pediatric PVS could provide further pathogenic insight. We included patients who underwent first resection of pulmonary venous tissue for symptomatic PVS at our pediatric referral center from 1995 to 2014. Clinical records and hematoxylin and eosin slides were reviewed. Subsets were immunostained for smooth muscle actin, Ki-67, β-catenin, estrogen receptor, and other markers and analyzed for USP6 gene rearrangement. A total of 97 patients (57% male; median age: 6 mo) were identified. Overall, 59 (61%) had prior congenital heart disease repair, 35 involving pulmonary vein manipulation. Samples included 213 separate anatomic sites (median: 2/patient). Histologically, all showed sparsely cellular intimal expansion composed of haphazardly arranged fibroblasts with slender nuclei in myxoid matrix. This tissue merged with underlying collagen. Most samples had a variably continuous sheath of cardiomyocytes. Ancillary tests supported a reactive fibroblastic proliferation; in particular, fibroblasts showed cytoplasmic β-catenin localization, no estrogen receptor expression, and no USP6 rearrangement. At last follow-up (mean: 2.3 y), 46% of patients had died of disease. Pediatric PVS uniformly consists of a paucicellular fibrointimal proliferation, irrespective of clinical scenario. It may be best conceived of as a form of reactive hyperplasia. As with other forms of vascular remodeling, trauma (iatrogenic or occult) is likely an inciting factor. A comprehensive understanding of the surgical pathology of PVS may further inform therapeutic strategies in this lethal disease.