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

Koo, Selene and Janeway, Katherine and Harris, Marian and Fryer, Christy and Aster, Jon and Al-Ilbraheemi, Al and Church, Alanna (2019) A distinctive genomic and immunohistochemical profile for NOTCH3 and PDGFRB in infantile myofibroma with diagnostic and therapeutic implications. International journal of surgical pathology., 78 (19). ISSN 1940-2465; 1066-8969

Abstract

Myofibromas are rare tumors of pericytic lineage, typically affecting children, and are sometimes aggressive.
A subset of sporadic and familial myofibromas have activating variants in PDGFRB. The relationship of myofibroma and
PDGFRB to the NOTCH pathway has not yet been described. Methods. Ten myofibroma cases were sequenced with
a targeted panel of 447 genes, including copy number variation and selected fusions. Immunohistochemical analysis of
total NOTCH3 and activated NOTCH3 was assessed for all 10 myofibroma cases, and a series of histologic mimics (n
= 20). Results. Alterations identified by next-generation sequencing included PDGFRB sequence variants in 8/10 cases
(80%), a NOTCH3 variant in 1/10 cases (10%), and a NOTCH2 variant in 1/10 cases (10%). All 10 cases also showed a
pattern of low-amplitude (1.5- to 2-fold) copy number alterations including gains in PDGFRB and NOTCH3. Ten of 10
myofibromas (100%) showed cytoplasmic staining for total NOTCH3 and 9 of 10 cases (90%) showed nuclear staining
for activated NOTCH3. Within the control cohort of histologic mimics, 3 of 3 nodular fasciitis cases (100%) were
positive for activated and total NOTCH3, and the remaining 17 cases were negative for pan NOTCH3, while 3 of 3
desmoid-type fibromatosis cases (100%) showed patchy weak nuclear staining for activated NOTCH3. Discussion. Our
findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack PDGFRB
sequence variants. These results support the pericytic lineage of myofibroma. Identification of the characteristic genomic
alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis, and support the use of
targeted treatments.

Item Type: Article
Date Deposited: 12 Oct 2019 00:45
Last Modified: 12 Oct 2019 00:45
URI: https://oak.novartis.com/id/eprint/39650

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