Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors

Yu-Chien Kao, Valentina Ranucci, Lei Zhang, Yun Shao Sung, Edward A. Athanasian, David Swanson, Brendan C. Dickson, Cristina R. Antonescu

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases. Although a t(1;10) translocation resulting in TGFBR3-MGEA5 fusion has been reported as a recurrent genetic event in MIFS, this abnormality is seen only in a subset of cases. As no studies to date have investigated the spectrum of alternative genetic alterations in TGFBR3-MGEA5 fusion negative MIFS, we undertook a genetic analysis of this particular cohort for further molecular classification. Triggered by an index case occurring in the finger of a 37-year-old female and harboring a novel TOM1L2-BRAF fusion by targeted RNA sequencing we investigated potential recurrent BRAF abnormalities by screening a large group of 19 TGFBR3-MGEA5 fusion negative MIFS by fluorescence in situ hybridization. There were 6 (32%) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification. Interestingly, VGLL3 amplification, a recurrent genetic abnormality coexisting with t(1;10) in some MIFS, was also detected by fluorescence in situ hybridization in 4/6 (67%) BRAF-rearranged MIFS, but not in the BRAF-amplified case. Up-regulated VGLL3 mRNA expression was also demonstrated in the index case by RNA sequencing. The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36 to 74 y; M:F=4:3). The histologic spectrum ranged from predominantly solid growth of plump histiocytoid to epithelioid tumor cells with focal myxoid change to a predominantly myxoid background with scattered tumor cells. Varying degree of inflammatory infiltrates and large tumor cells with virocyte-like macronucleoli were observed in most cases. Immunohistochemical stains of phosphorylated ERK, a downstream effector of BRAF activation, were positive in all 4 cases tested (2 diffuse strong, 2 focal strong). Unlike t(1;10), BRAF rearrangements were only found in MIFS but not in 6 hemosiderotic fibrolipomatous tumor (HFLT) lacking TGFBR3-MGEA5 fusions (including 2 pure HFLT, 2 hybrid HFLT-MIFS, and 2 associated with pleomorphic hyalinizing angiectatic tumors).

Original languageEnglish
Pages (from-to)1456-1465
Number of pages10
JournalAmerican Journal of Surgical Pathology
Volume41
Issue number11
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Gene Rearrangement
Sarcoma
Neoplasms
RNA Sequence Analysis
Fluorescence In Situ Hybridization
Fingers
Epithelioid Cells
Wrist
Forearm
Foot
Knee
Cohort Studies
Coloring Agents
Extremities
Neoplasm Metastasis
Recurrence

Keywords

  • amplifications
  • BRAF
  • fusions
  • MAPK
  • myxoinflammatory fibroblastic sarcoma
  • VGLL3

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors. / Kao, Yu-Chien; Ranucci, Valentina; Zhang, Lei; Sung, Yun Shao; Athanasian, Edward A.; Swanson, David; Dickson, Brendan C.; Antonescu, Cristina R.

In: American Journal of Surgical Pathology, Vol. 41, No. 11, 01.01.2017, p. 1456-1465.

Research output: Contribution to journalArticle

Kao, Yu-Chien ; Ranucci, Valentina ; Zhang, Lei ; Sung, Yun Shao ; Athanasian, Edward A. ; Swanson, David ; Dickson, Brendan C. ; Antonescu, Cristina R. / Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors. In: American Journal of Surgical Pathology. 2017 ; Vol. 41, No. 11. pp. 1456-1465.
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abstract = "Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases. Although a t(1;10) translocation resulting in TGFBR3-MGEA5 fusion has been reported as a recurrent genetic event in MIFS, this abnormality is seen only in a subset of cases. As no studies to date have investigated the spectrum of alternative genetic alterations in TGFBR3-MGEA5 fusion negative MIFS, we undertook a genetic analysis of this particular cohort for further molecular classification. Triggered by an index case occurring in the finger of a 37-year-old female and harboring a novel TOM1L2-BRAF fusion by targeted RNA sequencing we investigated potential recurrent BRAF abnormalities by screening a large group of 19 TGFBR3-MGEA5 fusion negative MIFS by fluorescence in situ hybridization. There were 6 (32{\%}) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification. Interestingly, VGLL3 amplification, a recurrent genetic abnormality coexisting with t(1;10) in some MIFS, was also detected by fluorescence in situ hybridization in 4/6 (67{\%}) BRAF-rearranged MIFS, but not in the BRAF-amplified case. Up-regulated VGLL3 mRNA expression was also demonstrated in the index case by RNA sequencing. The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36 to 74 y; M:F=4:3). The histologic spectrum ranged from predominantly solid growth of plump histiocytoid to epithelioid tumor cells with focal myxoid change to a predominantly myxoid background with scattered tumor cells. Varying degree of inflammatory infiltrates and large tumor cells with virocyte-like macronucleoli were observed in most cases. Immunohistochemical stains of phosphorylated ERK, a downstream effector of BRAF activation, were positive in all 4 cases tested (2 diffuse strong, 2 focal strong). Unlike t(1;10), BRAF rearrangements were only found in MIFS but not in 6 hemosiderotic fibrolipomatous tumor (HFLT) lacking TGFBR3-MGEA5 fusions (including 2 pure HFLT, 2 hybrid HFLT-MIFS, and 2 associated with pleomorphic hyalinizing angiectatic tumors).",
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AU - Zhang, Lei

AU - Sung, Yun Shao

AU - Athanasian, Edward A.

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