Abstract A31: A distinctive genomic and immunohistochemical profile for NOTCH3 and PDGFRB in infantile myofibroma with diagnostic and therapeutic implications

Infantile myofibromas (IM) are rare benign neoplasms thought to derive from perivascular myoid cells. The prognosis is generally good, although about one-third of cases with multicentric involvement will also have visceral involvement, and the prognosis for these patients is poor. The use of combination cytotoxic chemotherapy (vincristine/dactinomycin and vinblastine/methotrexate) has proven effective in cases of multicentric disease with visceral involvement and in cases in which the disease has progressed and has threatened the life of the patient. The pathologic diagnosis of IM can be challenging, particularly with small biopsies, since IM exist on a morphologic spectrum with myopericytomas, glomangiopericytomas, and glomus tumors, and other spindle cell neoplasms are also on the histologic differential. Most families with autosomal dominant infantile myofibromatosis have germline variants in PDGFRB. In one case of autosomal dominant IM a NOTCH3 variant was identified in the absence of a PDGFRB variant. Most sporadic infantile myofibromas also have identifiable variants in PDGFRB. To date, however, there have been no genetic variants or immunohistochemical stains that are 100% sensitive or specific in diagnosing IM. Nine cases of infantile myofibroma/myofibromatosis were identified from the case archives of Boston Children’s Hospital. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue sections and sequenced using a clinically validated targeted panel of 447 genes for 9 cases. Immunohistochemical stain for activated NOTCH3 was performed. The histopathology of each case was reviewed by two pediatric pathologists. Of the nine IM cases, 7 had one or more sequence variants in PDGFRB. One case had a NOTCH3 sequence variant and one had a NOTCH2 sequence variant. All nine cases (100%) had a distinctive pattern of copy alterations including gains of PDGFRB and NOTCH3. One case failed immunohistochemical staining; of the remaining 8 IM cases, all 8 showed nuclear staining for activated NOTCH3. We describe a distinctive pattern of genomic alterations in infantile myofibromatosis, including a high prevalence (7/9 cases) of alterations in PDGFRB, several of which are known to be activating, and copy number alterations including copy number gains of PDGFRB and NOTCH3 in all 9 cases. The p.N666K, p.D850V (both seen in this study), and p.R561C variants have been shown to result in constitutive activation of PDGFRB, transform cells and induce tumor formation, and render tumor sensitivity to tyrosine kinase inhibitors. In vascular smooth muscle cells, PDGFRB has been shown to be an immediate downstream target of NOTCH3 signaling. The consistent presence of activated NOTCH3, detected by immunohistochemistry in all IM cases, confirms that the genomic changes have functional effect. The NOTCH signaling pathway is the target of inhibitors including gamma-secretase inhibitors; some NOTCH-mutated leukemias have been shown to be sensitive to inhibition, suggesting that these inhibitors may also be useful in NOTCH-mutated myofibromas. Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in infantile myofibromas. Identification of the characteristic genomic alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis. Furthermore, targeted inhibitors are available for both PDGRFB and NOTCH, and may be of use in patients with visceral or multicentric disease. Citation Format: Selene C. Koo, Calicchio Monica, Benjamin Ferland, Marian H. Harris, Jon C. Aster, Katherine A. Janeway, Alyaa Al-Ibraheemi, Alanna J. Church. A distinctive genomic and immunohistochemical profile for NOTCH3 and PDGFRB in infantile myofibroma with diagnostic and therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A31.