Congenital peribronchial myofibroblastic tumors harbor a recurrent EGFR kinase domain duplication.

Congenital peribronchial myofibroblastic tumor (CPMT) is a rare benign infantile pulmonary neoplasm that presents prenatally or early in infancy, and exhibits distinctive histologic features characterized by the presence of cartilaginous islands intermixed with bland spindle cells, not uncommonly displaying prominent mitoses. Despite its benign nature, CPMT can lead to fetal demise, postnatal respiratory distress, or complications from perinatal surgical resection. Although the morphologic and clinical features of CPMT are well-described, its molecular features and oncogenesis remain elusive. Following the detection of EGFR kinase domain duplication (KDD) of exons 18-25 in an index case, we identified three additional cases of morphologically classic and clinically well-characterized CPMTs from the archives and performed targeted RNA- and DNA-based profiling via next generation sequencing for detection of rearrangements, sequence variants and copy number variants on all cases. Two cases were detected prenatally, one patient presented at birth and one at 8 weeks of life. All tumors were resected, with follow-up period ranging from 0 days to 10 years. One patient died shortly after surgical resection, and the other three have had no recurrences. In all cases, EGFR KDD was detected. In two of four cases, gains of select whole chromosomes were noted. Our findings establish EGFR KDD as a recurrent oncogenic driver of CPMT. Notably, this alteration is also found in classical congenital mesoblastic nephromas (CMNs), infantile kidney tumors with which CPMTs share striking morphologic and clinical similarities. This strongly suggests CPMTs and classical CMNs share common oncogenesis, and represent the same tumor in different locations. EGFR KDDs have also been reported in neonatal soft tissue tumors with infantile fibrosarcoma-like histology and cartilaginous differentiation, raising questions about their relationship. EGFR KDD emerges as a diagnostic marker, potential therapeutic target, and a window into the oncogenesis of a distinct subset of infantile mesenchymal tumors.