A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications
Autor: | Selene C. Koo, Alyaa Al-Ibraheemi, Katherine A. Janeway, Jon C. Aster, Christy Fryer, Alanna J. Church, Marian H. Harris |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine Pathology medicine.medical_specialty Lineage (genetic) Adolescent DNA Copy Number Variations Myofibroma Bone Neoplasms Soft Tissue Neoplasms PDGFRB Nodular fasciitis Biology Pathology and Forensic Medicine Receptor Platelet-Derived Growth Factor beta Young Adult 03 medical and health sciences 0302 clinical medicine medicine Humans Copy-number variation Child Receptor Notch3 Gene Fibromatosis Infant medicine.disease Immunohistochemistry Parotid Neoplasms 030104 developmental biology Child Preschool 030220 oncology & carcinogenesis Female Surgery Anatomy |
Zdroj: | International Journal of Surgical Pathology. 28:128-137 |
ISSN: | 1940-2465 1066-8969 |
Popis: | Introduction. 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. |
Databáze: | OpenAIRE |
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