PDGFRB and NOTCH3 mutations are detectable in a wider range of pericytic tumors, including myopericytomas, angioleiomyomas, glomus tumors, and their combined tumors

Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification and form a continuous morphological spectrum including those with combined morphology. However, no widely accepted criteria for classifying tumors with combined morphology are available. Recent studies have identified platelet-derived growth factor receptor-beta (PDGFRB) gene mutations in a subset of myofibromas, myopericytomas, and myopericytomatoses, but not in angioleiomyomas. NOTCH receptor 3 (NOTCH3) mutations have been reported in a subset of infantile myofibromatoses. We investigated PDGFRB and NOTCH3 mutations in 41 pericytic tumors of variable morphology, including some combined forms, to assess their potential role in classifying pericytic tumors. Our results show these mutations to be present in a variety of pericytic tumors, such as myopericytomas (PDGFRB, 3/11; NOTCH3, 4/11), myopericytomatoses (1/2, 1/2), myofibromas (3/6, 0/6), angioleiomyomas (2/13, 3/13), and glomus tumors (5/9, 1/9). Point mutations were identified in three tumors in PDGFRB exon 12 (Y562C, S574F, and G576S), twelve tumors in PDGFRB exon 14 (M655I, H657L, and N666K), and nine tumors in NOTCH3 exon 25 (A1480S/T, D1481N, G1482S, T1490A, E1491K, G1494S and V1512A). All PDGFRB mutations and NOTCH3 G1482S, T1490A and G1494S mutations were classified as ‘deleterious/damaging’ by more than four out of six pathogenicity prediction tools in silico. Five mutation-positive tumors, including myopericytoma-angioleiomyoma, myopericytomatosis-myofibroma, myofibroma-myopericytoma, and angioleiomyoma-myopericytoma, were of combined morphology. Thus, we found PDGFRB and NOTCH3 mutations to be detectable in a much wider variety of pericytic tumors than previously reported, and confirmed myopericytomas, myofibromas, angioleiomyomas, and glomus tumors as members harboring PDGFRB or NOTCH3 mutations. Our results thus suggest that PDGFRB or NOTCH3 mutations are not useful for subclassifying members of the pericytic tumor family.