Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas

Abstract

Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions.

Recurrent SRF-RELA Fusions Define a Novel Subset of Cellular Myofibroma/Myopericytoma

“…Additionally a recent study has demonstrated that in fact >70% of both classic adult and infantile myofibromas are associated with distinct genetic abnormalities, i.e. PDGFRB mutations, different from our cohort of cases 9 . Moreover, our previous studies have shown that recurrent NOTCH gene rearrangements were only identified in glomus tumors, while the other pericytic/ perivascular tumors do not.…”

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas

“…We are aware that in cases with very low variant allele frequency (VAF) the mutations could have been missed. However, other groups were able to successfully detect somatic mutations in a high proportion of sporadic myofibroma cases using Sanger sequencing only . Therefore, if PDGFRB mutations were highly frequent in odontogenic myxoma, we should have been able to detect mutations at least in a few cases.…”

“…The present study revealed that, different from myofibromas, odontogenic myxomas do not harbor PDGFRB exon 12 and 14 mutations. Agaimy et al reported PDGFRB somatic mutations as molecular driver events in the majority of sporadic infantile and adult solitary myofibromas (75% and 69%, respectively). These genetic alterations were detected not only in the soft tissue tumors, but also in the intra‐osseous lesions (Table ) .…”

“…The age of the patients in our cohort varies from 21 to 81 years old. Most of the studies that analyzed PDGFRB mutations in myofibroblastic single or multiple lesions included samples from children or newborn patients . However, such mutations have also been reported in sporadic myofibroma cases from adult individuals …”

“…Platelet‐derived growth factor receptor beta (PDGFRB) is a mitogen for cells of mesenchymal origin, including smooth muscle cells . Recently, PDGFRB mutations were reported in myofibromas and myofibromatosis . Recurrent driver events are yet to be reported in odontogenic myxoma .…”