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A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications.
Int J Surg Pathol 2019; :1066896919876703IJ

Abstract

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.

Authors+Show Affiliations

Boston Children's Hospital, Boston, MA, USA. Nationwide Children's Hospital, Columbus, OH, USA.Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.Boston Children's Hospital, Boston, MA, USA.Novartis Institutes for Biomedical Research, Cambridge, MA, USA.Brigham and Women's Hospital, Boston, MA, USA.Boston Children's Hospital, Boston, MA, USA.Boston Children's Hospital, Boston, MA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31566039

Citation

Koo, Selene C., et al. "A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications." International Journal of Surgical Pathology, 2019, p. 1066896919876703.
Koo SC, Janeway KA, Harris MH, et al. A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications. Int J Surg Pathol. 2019.
Koo, S. C., Janeway, K. A., Harris, M. H., Fryer, C. J., Aster, J. C., Al-Ibraheemi, A., & Church, A. J. (2019). A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications. International Journal of Surgical Pathology, p. 1066896919876703. doi:10.1177/1066896919876703.
Koo SC, et al. A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications. Int J Surg Pathol. 2019 Sep 29;1066896919876703. PubMed PMID: 31566039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications. AU - Koo,Selene C, AU - Janeway,Katherine A, AU - Harris,Marian H, AU - Fryer,Christy J, AU - Aster,Jon C, AU - Al-Ibraheemi,Alyaa, AU - Church,Alanna J, Y1 - 2019/09/29/ PY - 2019/10/1/entrez PY - 2019/10/1/pubmed PY - 2019/10/1/medline KW - NOTCH3 KW - PDGFRB KW - infantile myofibroma KW - myofibroma SP - 1066896919876703 EP - 1066896919876703 JF - International journal of surgical pathology JO - Int. J. Surg. Pathol. N2 - 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. SN - 1940-2465 UR - https://www.unboundmedicine.com/medline/citation/31566039/A_Distinctive_Genomic_and_Immunohistochemical_Profile_for_NOTCH3_and_PDGFRB_in_Myofibroma_With_Diagnostic_and_Therapeutic_Implications L2 - http://journals.sagepub.com/doi/full/10.1177/1066896919876703?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -