Spindle Cell Tumors with RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors with NTRK Gene Fusions

Cristina R. Antonescu, Brendan C. Dickson, David Swanson, Lei Zhang, Yun Shao Sung, Yu-Chien Kao, Wei Chin Chang, Leili Ran, Alberto Pappo, Armita Bahrami, Ping Chi, Christopher D. Fletcher

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.

Original languageEnglish
JournalAmerican Journal of Surgical Pathology
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Gene Fusion
Neoplasms
RNA Sequence Analysis
Gene Rearrangement
Fibrosarcoma
Neurilemmoma
Viscera
Oncogene Proteins
Fluorescence In Situ Hybridization
Protein-Tyrosine Kinases
Protein Kinases
Genes

Keywords

  • fusion
  • infantile fibrosarcoma
  • lipofibromatosis-like neural tumor
  • NTRK
  • RET

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Spindle Cell Tumors with RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors with NTRK Gene Fusions. / Antonescu, Cristina R.; Dickson, Brendan C.; Swanson, David; Zhang, Lei; Sung, Yun Shao; Kao, Yu-Chien; Chang, Wei Chin; Ran, Leili; Pappo, Alberto; Bahrami, Armita; Chi, Ping; Fletcher, Christopher D.

In: American Journal of Surgical Pathology, 01.01.2019.

Research output: Contribution to journalArticle

Antonescu, CR, Dickson, BC, Swanson, D, Zhang, L, Sung, YS, Kao, Y-C, Chang, WC, Ran, L, Pappo, A, Bahrami, A, Chi, P & Fletcher, CD 2019, 'Spindle Cell Tumors with RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors with NTRK Gene Fusions', American Journal of Surgical Pathology. https://doi.org/10.1097/PAS.0000000000001297
Antonescu, Cristina R. ; Dickson, Brendan C. ; Swanson, David ; Zhang, Lei ; Sung, Yun Shao ; Kao, Yu-Chien ; Chang, Wei Chin ; Ran, Leili ; Pappo, Alberto ; Bahrami, Armita ; Chi, Ping ; Fletcher, Christopher D. / Spindle Cell Tumors with RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors with NTRK Gene Fusions. In: American Journal of Surgical Pathology. 2019.
@article{d3e30668958d496ea3825d823a61fdc1,
title = "Spindle Cell Tumors with RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors with NTRK Gene Fusions",
abstract = "A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.",
keywords = "fusion, infantile fibrosarcoma, lipofibromatosis-like neural tumor, NTRK, RET",
author = "Antonescu, {Cristina R.} and Dickson, {Brendan C.} and David Swanson and Lei Zhang and Sung, {Yun Shao} and Yu-Chien Kao and Chang, {Wei Chin} and Leili Ran and Alberto Pappo and Armita Bahrami and Ping Chi and Fletcher, {Christopher D.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1097/PAS.0000000000001297",
language = "English",
journal = "American Journal of Surgical Pathology",
issn = "0147-5185",
publisher = "Lippincott Williams and Wilkins",

}

TY - JOUR

T1 - Spindle Cell Tumors with RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors with NTRK Gene Fusions

AU - Antonescu, Cristina R.

AU - Dickson, Brendan C.

AU - Swanson, David

AU - Zhang, Lei

AU - Sung, Yun Shao

AU - Kao, Yu-Chien

AU - Chang, Wei Chin

AU - Ran, Leili

AU - Pappo, Alberto

AU - Bahrami, Armita

AU - Chi, Ping

AU - Fletcher, Christopher D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.

AB - A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.

KW - fusion

KW - infantile fibrosarcoma

KW - lipofibromatosis-like neural tumor

KW - NTRK

KW - RET

UR - http://www.scopus.com/inward/record.url?scp=85069228055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069228055&partnerID=8YFLogxK

U2 - 10.1097/PAS.0000000000001297

DO - 10.1097/PAS.0000000000001297

M3 - Article

AN - SCOPUS:85069228055

JO - American Journal of Surgical Pathology

JF - American Journal of Surgical Pathology

SN - 0147-5185

ER -