Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

Paul G. Kemps; Hans J. Baelde; Ruben H.P. Vorderman; Ellen Stelloo; Joost F. Swennenhuis; Karoly Szuhai; Meindert H. Lamers; Boyd Kenkhuis; Maysa Al-Hussaini; Inge H. Briaire-de Bruijn; Suk Wai Lam; Judith V.M.G. Bovée; Arjen H.G. Cleven; Robert M. Verdijk; Carel J.M. van Noesel; Marijke R. van Dijk; Marijn A. Scheijde-Vermeulen; Annette H. Bruggink; Jan A.M. van Laar; Andrica C.H. de Vries; Wim J.E. Tissing; Cor van den Bos; Andreas von Deimling; Tom van Wezel; Astrid G.S. van Halteren; Pancras C.W. Hogendoorn

doi:10.1182/blood.2024025127

Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

Paul G. Kemps, Hans J. Baelde, Ruben H.P. Vorderman, Ellen Stelloo, Joost F. Swennenhuis, Karoly Szuhai, Meindert H. Lamers, Boyd Kenkhuis, Maysa Al-Hussaini, Inge H. Briaire-de Bruijn, Suk Wai Lam, Judith V.M.G. Bovée, Arjen H.G. Cleven, Robert M. Verdijk, Carel J.M. van Noesel, Marijke R. van Dijk, Marijn A. Scheijde-Vermeulen, Annette H. Bruggink, Jan A.M. van Laar, Andrica C.H. de VriesWim J.E. Tissing, Cor van den Bos, Andreas von Deimling, Tom van Wezel, Astrid G.S. van Halteren, Pancras C.W. Hogendoorn

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Juvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16 of 16 children and 1 of 5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others; all below 2 years of age with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1 of 6 with CLTC::SYK and 2 of 7 with CSF1R mutations, underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated–spleen tyrosine kinase expression was localized to CD163⁺ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, cyclin D1 expression, and variable phosphorylated–extracellular signal-regulated kinase expression. BRAF^V600E was detected in 1 child and 1 adult with CNS-xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion was detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

Original language	English
Pages (from-to)	2439-2455
Number of pages	17
Journal	Blood
Volume	144
Issue number	23
DOIs	https://doi.org/10.1182/blood.2024025127
Publication status	Published - 5 Dec 2024

Bibliographical note

Funding Information:
This work was supported by a grant from Stichting de Merel (P.G.K., T.v.W., A.G.S.v.H., and P.C.W.H.). P.G.K. received an MD/PhD grant from Leiden University Medical Center .

Funding Information:
The authors thank the immunolaboratories of the Departments of Pathology of Leiden University Medical Center and the Princess M\u00E1xima Center for Pediatric Oncology for performing additional immunohistochemical stains and M. J. Koudijs (Princess M\u00E1xima Center for Pediatric Oncology) for performing RNA sequencing. The authors also thank the Departments of Pathology of Maastricht University Medical Center, Haga Hospital, and Deventer Hospital for providing individual tissue samples; J. C. Jansen, J. P. W. Don Griot, M. Donker, and J. H. Allema for providing clinical information and/or images of individual patients. Finally, they thank the patients and/or their parents for allowing the use of medical photographs. This work was supported by a grant from Stichting de Merel (P.G.K. T.v.W. A.G.S.v.H. and P.C.W.H.). P.G.K. received an MD/PhD grant from Leiden University Medical Center. Contribution: P.G.K. A.G.S.v.H. and P.C.W.H. designed the study; H.J.B. and K.S. performed and/or supervised fluorescence in situ hybridization experiments; R.H.P.V. subjected the sequencing data to the published somatic variant calling pipeline24; M.H.L. performed the in silico structural analysis of the CLTC::SYK fusion; B.K. helped with multispectral immunofluorescence imaging; I.H.B.-d.B. supervised immunohistochemistry; M.A.-H. provided tissue samples of common and atypical dermatofibromas for methylation profiling; S.W.L. J.V.M.G.B. A.H.G.C. R.M.V. C.J.M.v.N. M.R.v.D. M.A.S.-V. and P.C.W.H. were involved in the routine pathologic evaluation of included patients and/or provided archived tissue samples; P.C.W.H. performed the central pathology review; A.H.B. helped with selecting the Palga search strategy and assisted in the Palga intermediary procedure; J.A.M.v.L. A.C.H.d.V. W.J.E.T. and C.v.d.B. were involved in the clinical care of patients and provided pseudonymized clinical data and images; J.F.S. and E.S. assisted in targeted locus capture\u2013based next-generation sequencing (TLC-NGS) panel design, performed TLC-NGS, and analyzed sequencing data for structural variants; A.v.D. coordinated the DNA methylation profiling; T.v.W. reviewed genetic variants called by the variant calling pipeline; P.G.K. collected all information, performed experiments, made the figures and tables, and drafted the manuscript; T.v.W. A.G.S.v.H. and P.C.W.H. revised the manuscript; all authors have reviewed and approved the manuscript before submission.

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© 2024 American Society of Hematology

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Kemps, P. G., Baelde, H. J., Vorderman, R. H. P., Stelloo, E., Swennenhuis, J. F., Szuhai, K., Lamers, M. H., Kenkhuis, B., Al-Hussaini, M., Briaire-de Bruijn, I. H., Lam, S. W., Bovée, J. V. M. G., Cleven, A. H. G., Verdijk, R. M., van Noesel, C. J. M., van Dijk, M. R., Scheijde-Vermeulen, M. A., Bruggink, A. H., van Laar, J. A. M., ... Hogendoorn, P. C. W. (2024). Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue. Blood, 144(23), 2439-2455. https://doi.org/10.1182/blood.2024025127

@article{9203406e5e56482394e72a69eca2b70f,

title = "Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue",

abstract = "Juvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16 of 16 children and 1 of 5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others; all below 2 years of age with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1 of 6 with CLTC::SYK and 2 of 7 with CSF1R mutations, underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated–spleen tyrosine kinase expression was localized to CD163+ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, cyclin D1 expression, and variable phosphorylated–extracellular signal-regulated kinase expression. BRAFV600E was detected in 1 child and 1 adult with CNS-xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion was detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.",

author = "Kemps, {Paul G.} and Baelde, {Hans J.} and Vorderman, {Ruben H.P.} and Ellen Stelloo and Swennenhuis, {Joost F.} and Karoly Szuhai and Lamers, {Meindert H.} and Boyd Kenkhuis and Maysa Al-Hussaini and {Briaire-de Bruijn}, {Inge H.} and Lam, {Suk Wai} and Bov{\'e}e, {Judith V.M.G.} and Cleven, {Arjen H.G.} and Verdijk, {Robert M.} and {van Noesel}, {Carel J.M.} and {van Dijk}, {Marijke R.} and Scheijde-Vermeulen, {Marijn A.} and Bruggink, {Annette H.} and {van Laar}, {Jan A.M.} and {de Vries}, {Andrica C.H.} and Tissing, {Wim J.E.} and {van den Bos}, Cor and {von Deimling}, Andreas and {van Wezel}, Tom and {van Halteren}, {Astrid G.S.} and Hogendoorn, {Pancras C.W.}",

note = "Funding Information: This work was supported by a grant from Stichting de Merel (P.G.K., T.v.W., A.G.S.v.H., and P.C.W.H.). P.G.K. received an MD/PhD grant from Leiden University Medical Center . Funding Information: The authors thank the immunolaboratories of the Departments of Pathology of Leiden University Medical Center and the Princess M\u00E1xima Center for Pediatric Oncology for performing additional immunohistochemical stains and M. J. Koudijs (Princess M\u00E1xima Center for Pediatric Oncology) for performing RNA sequencing. The authors also thank the Departments of Pathology of Maastricht University Medical Center, Haga Hospital, and Deventer Hospital for providing individual tissue samples; J. C. Jansen, J. P. W. Don Griot, M. Donker, and J. H. Allema for providing clinical information and/or images of individual patients. Finally, they thank the patients and/or their parents for allowing the use of medical photographs. This work was supported by a grant from Stichting de Merel (P.G.K. T.v.W. A.G.S.v.H. and P.C.W.H.). P.G.K. received an MD/PhD grant from Leiden University Medical Center. Contribution: P.G.K. A.G.S.v.H. and P.C.W.H. designed the study; H.J.B. and K.S. performed and/or supervised fluorescence in situ hybridization experiments; R.H.P.V. subjected the sequencing data to the published somatic variant calling pipeline24; M.H.L. performed the in silico structural analysis of the CLTC::SYK fusion; B.K. helped with multispectral immunofluorescence imaging; I.H.B.-d.B. supervised immunohistochemistry; M.A.-H. provided tissue samples of common and atypical dermatofibromas for methylation profiling; S.W.L. J.V.M.G.B. A.H.G.C. R.M.V. C.J.M.v.N. M.R.v.D. M.A.S.-V. and P.C.W.H. were involved in the routine pathologic evaluation of included patients and/or provided archived tissue samples; P.C.W.H. performed the central pathology review; A.H.B. helped with selecting the Palga search strategy and assisted in the Palga intermediary procedure; J.A.M.v.L. A.C.H.d.V. W.J.E.T. and C.v.d.B. were involved in the clinical care of patients and provided pseudonymized clinical data and images; J.F.S. and E.S. assisted in targeted locus capture\u2013based next-generation sequencing (TLC-NGS) panel design, performed TLC-NGS, and analyzed sequencing data for structural variants; A.v.D. coordinated the DNA methylation profiling; T.v.W. reviewed genetic variants called by the variant calling pipeline; P.G.K. collected all information, performed experiments, made the figures and tables, and drafted the manuscript; T.v.W. A.G.S.v.H. and P.C.W.H. revised the manuscript; all authors have reviewed and approved the manuscript before submission. Publisher Copyright: {\textcopyright} 2024 American Society of Hematology",

year = "2024",

month = dec,

day = "5",

doi = "10.1182/blood.2024025127",

language = "English",

volume = "144",

pages = "2439--2455",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "23",

}

Kemps, PG, Baelde, HJ, Vorderman, RHP, Stelloo, E, Swennenhuis, JF, Szuhai, K, Lamers, MH, Kenkhuis, B, Al-Hussaini, M, Briaire-de Bruijn, IH, Lam, SW, Bovée, JVMG, Cleven, AHG, Verdijk, RM, van Noesel, CJM, van Dijk, MR, Scheijde-Vermeulen, MA, Bruggink, AH, van Laar, JAM, de Vries, ACH, Tissing, WJE, van den Bos, C, von Deimling, A, van Wezel, T, van Halteren, AGS & Hogendoorn, PCW 2024, 'Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue', Blood, vol. 144, no. 23, pp. 2439-2455. https://doi.org/10.1182/blood.2024025127

TY - JOUR

T1 - Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

AU - Kemps, Paul G.

AU - Baelde, Hans J.

AU - Vorderman, Ruben H.P.

AU - Stelloo, Ellen

AU - Swennenhuis, Joost F.

AU - Szuhai, Karoly

AU - Lamers, Meindert H.

AU - Kenkhuis, Boyd

AU - Al-Hussaini, Maysa

AU - Briaire-de Bruijn, Inge H.

AU - Lam, Suk Wai

AU - Bovée, Judith V.M.G.

AU - Cleven, Arjen H.G.

AU - Verdijk, Robert M.

AU - van Noesel, Carel J.M.

AU - van Dijk, Marijke R.

AU - Scheijde-Vermeulen, Marijn A.

AU - Bruggink, Annette H.

AU - van Laar, Jan A.M.

AU - de Vries, Andrica C.H.

AU - Tissing, Wim J.E.

AU - van den Bos, Cor

AU - von Deimling, Andreas

AU - van Wezel, Tom

AU - van Halteren, Astrid G.S.

AU - Hogendoorn, Pancras C.W.

N1 - Funding Information: This work was supported by a grant from Stichting de Merel (P.G.K., T.v.W., A.G.S.v.H., and P.C.W.H.). P.G.K. received an MD/PhD grant from Leiden University Medical Center . Funding Information: The authors thank the immunolaboratories of the Departments of Pathology of Leiden University Medical Center and the Princess M\u00E1xima Center for Pediatric Oncology for performing additional immunohistochemical stains and M. J. Koudijs (Princess M\u00E1xima Center for Pediatric Oncology) for performing RNA sequencing. The authors also thank the Departments of Pathology of Maastricht University Medical Center, Haga Hospital, and Deventer Hospital for providing individual tissue samples; J. C. Jansen, J. P. W. Don Griot, M. Donker, and J. H. Allema for providing clinical information and/or images of individual patients. Finally, they thank the patients and/or their parents for allowing the use of medical photographs. This work was supported by a grant from Stichting de Merel (P.G.K. T.v.W. A.G.S.v.H. and P.C.W.H.). P.G.K. received an MD/PhD grant from Leiden University Medical Center. Contribution: P.G.K. A.G.S.v.H. and P.C.W.H. designed the study; H.J.B. and K.S. performed and/or supervised fluorescence in situ hybridization experiments; R.H.P.V. subjected the sequencing data to the published somatic variant calling pipeline24; M.H.L. performed the in silico structural analysis of the CLTC::SYK fusion; B.K. helped with multispectral immunofluorescence imaging; I.H.B.-d.B. supervised immunohistochemistry; M.A.-H. provided tissue samples of common and atypical dermatofibromas for methylation profiling; S.W.L. J.V.M.G.B. A.H.G.C. R.M.V. C.J.M.v.N. M.R.v.D. M.A.S.-V. and P.C.W.H. were involved in the routine pathologic evaluation of included patients and/or provided archived tissue samples; P.C.W.H. performed the central pathology review; A.H.B. helped with selecting the Palga search strategy and assisted in the Palga intermediary procedure; J.A.M.v.L. A.C.H.d.V. W.J.E.T. and C.v.d.B. were involved in the clinical care of patients and provided pseudonymized clinical data and images; J.F.S. and E.S. assisted in targeted locus capture\u2013based next-generation sequencing (TLC-NGS) panel design, performed TLC-NGS, and analyzed sequencing data for structural variants; A.v.D. coordinated the DNA methylation profiling; T.v.W. reviewed genetic variants called by the variant calling pipeline; P.G.K. collected all information, performed experiments, made the figures and tables, and drafted the manuscript; T.v.W. A.G.S.v.H. and P.C.W.H. revised the manuscript; all authors have reviewed and approved the manuscript before submission. Publisher Copyright: © 2024 American Society of Hematology

PY - 2024/12/5

Y1 - 2024/12/5

N2 - Juvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16 of 16 children and 1 of 5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others; all below 2 years of age with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1 of 6 with CLTC::SYK and 2 of 7 with CSF1R mutations, underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated–spleen tyrosine kinase expression was localized to CD163+ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, cyclin D1 expression, and variable phosphorylated–extracellular signal-regulated kinase expression. BRAFV600E was detected in 1 child and 1 adult with CNS-xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion was detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

AB - Juvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16 of 16 children and 1 of 5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others; all below 2 years of age with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1 of 6 with CLTC::SYK and 2 of 7 with CSF1R mutations, underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated–spleen tyrosine kinase expression was localized to CD163+ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, cyclin D1 expression, and variable phosphorylated–extracellular signal-regulated kinase expression. BRAFV600E was detected in 1 child and 1 adult with CNS-xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion was detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

UR - http://www.scopus.com/inward/record.url?scp=85208181776&partnerID=8YFLogxK

U2 - 10.1182/blood.2024025127

DO - 10.1182/blood.2024025127

M3 - Article

C2 - 39316650

AN - SCOPUS:85208181776

SN - 0006-4971

VL - 144

SP - 2439

EP - 2455

JO - Blood

JF - Blood

IS - 23

ER -

Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

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