Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions

Kojima, Naoki; Mori, Taisuke; Motoi, Toru; Kobayashi, Eisuke; Yoshida, Masayuki; Yatabe, Yasushi; Ichikawa, Hitoshi; Kawai, Akira; Yonemori, Kan; Antonescu, Cristina R.; Yoshida, Akihiko

doi:10.1016/j.modpat.2022.100083

Cited by 10 publications

(15 citation statements)

References 49 publications

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“…FCM and touch smear cytology of the tumor tissue revealed a dimCD30+ spindle cell population, suggesting an unusual mesenchymal neoplasm. With literature support, 2,3,7 the biopsy specimen was immediately analyzed using an IHC panel, including CD30, and subsequent comprehensive next‐generation sequencing. In the context of an aggressive clinical course, the success of this diagnostic and therapeutic sequence highlights the importance of the early identification of CD30 expression.…”

Section: Discussionmentioning

confidence: 99%

“…The evolving classification of this family now includes tumors harboring ALK fusions with various fusion partners 6 . However, the sensitivity of immunohistochemistry (IHC) for of S100 and CD34 in these tumors is about 70%; their co‐expression is approximately 50% 3,7 . Thus, these markers of cellular differentiation have limited efficacy for obtaining a definitive diagnosis of this entity.…”

Section: Introductionmentioning

confidence: 99%

“…about 70%; their co-expression is approximately 50%. 3,7 Thus, these markers of cellular differentiation have limited efficacy for obtaining a definitive diagnosis of this entity.…”

mentioning

confidence: 99%

“…Studies have identified high expression of CD30 in spindle cell neoplasms with NTRK, BRAF, RAF1, or RET translocations, 2,3,7 and the sensitivity of CD30 expression is approximately 70%. 3,7 Since many other mesenchymal tumors with spindle cell morphology express S100 or CD34, such as nerve sheath tumors or fibro-/myofibroblastic tumors (e.g., solitary fibrous tumors and dermatofibrosarcoma protuberans), CD30 expression may have higher specificity, enabling these spindle cell neoplasms to be distinguished from other morphological or immunohistochemical mimics. However, the expression status of CD30 in spindle cell neoplasms with oncogenic kinase alterations has received little research attention.…”

mentioning

confidence: 99%

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CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry

Iwakoshi,

Kikui,

Nakashima

et al. 2024

Genes Chromosomes & Cancer

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An emerging group of spindle cell neoplasms harboring fusions involving NTRK or non‐NTRK kinase genes often share characteristic S100 and/or CD34 expression; however, the diagnostic utility of immunohistochemical stains is not well established in this family owing to their lack of specificity. Recently, CD30 expression in spindle cell neoplasms with kinase gene fusions, such as NTRK, BRAF, RAF1, and RET, has been increasingly identified. We herein report a 10‐year‐old girl with high‐grade spindle cell sarcoma of the neck. Prior to histopathological evaluation, flow cytometry (FCM) analysis and touch smear cytology of the tumor tissue revealed CD34+ and dimCD30+ spindle cell populations. Histopathologically, the case was characterized by monomorphic spindle‐shaped cytomorphology with CD30, S100, and CD34 positivity and harbored close similarities with spindle cell neoplasms with NTRK or non‐NTRK gene fusions. Subsequently, a comprehensive next‐generation sequencing sarcoma panel identified a rare PLEKHH2::ALK fusion, and a diagnosis of ALK‐rearranged spindle cell neoplasm was made. The patient showed significant tumor response to single‐agent treatment with alectinib, an ALK‐tyrosine kinase inhibitor. This case supports that CD30 is expressed in an ALK‐rearranged mesenchymal neoplasm. The benefit of the early detection of CD30 expression by FCM for a prompt diagnosis and treatment is highlighted in the context of an aggressive clinical course. This case represents a learning experience regarding the need to the check the status of CD30 expression in these tumors and suggests the potential clinical benefits of CD30‐targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…about 70%; their co-expression is approximately 50%. 3,7 Thus, these markers of cellular differentiation have limited efficacy for obtaining a definitive diagnosis of this entity.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry

Iwakoshi,

Kikui,

Nakashima

et al. 2024

Genes Chromosomes & Cancer

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“…Most cases harbor an NTRK fusion transcript (74.0-87.2%), but some other rare fusions or complex deletions have been described, as BRAF or EGFR. 9 In the past, identification of apoptosis in histologic sections has demonstrated that programmed cell can occur spontaneously in a range of pediatric neoplasms that mainly occur in infants, such as neuroblastoma, myofibroma, desmoid type fibromatosis and even some IFS. [10][11][12][13][14][15] In neuroblastoma, the mechanism(s) underlying spontaneous regression are still currently a matter of speculation.…”

mentioning

confidence: 99%

Infantile fibrosarcoma: Is spontaneous regression possible?

Orbach

Sparber‐Sauer

Corradini

et al. 2023

Pediatric Blood & Cancer

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RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

Motta,

Barresi,

Pizzi

et al. 2024

The Journal of Pathology

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Infantile fibrosarcomas (IFS) and congenital mesoblastic nephroma (CMN) are rare myofibroblastic tumors of infancy and early childhood commonly harboring the ETV6::NTRK3 gene fusion. IFS/CMN are considered as tumors with an ‘intermediate prognosis’ as they are locally aggressive, but rarely metastasize, and generally have a favorable outcome. A fraction of IFS/CMN‐related neoplasms are negative for the ETV6::NTRK3 gene rearrangement and are characterized by other chimeric proteins promoting MAPK signaling upregulation. In a large proportion of these tumors, which are classified as IFS‐like mesenchymal neoplasms, the contributing molecular events remain to be identified. Here, we report three distinct rearrangements involving RAF1 among eight ETV6::NTRK3 gene fusion‐negative tumors with an original histological diagnosis of IFS/CMN. The three fusion proteins retain the entire catalytic domain of the kinase. Two chimeric products, GOLGA4::RAF1 and LRRFIP2::RAF1, had previously been reported as driver events in different cancers, whereas the third, CLIP1::RAF1, represents a novel fusion protein. We demonstrate that CLIP1::RAF1 acts as a bona fide oncoprotein promoting cell proliferation and migration through constitutive upregulation of MAPK signaling. We show that the CLIP1::RAF1 hyperactive behavior does not require RAS activation and is mediated by constitutive 14‐3‐3 protein‐independent dimerization of the chimeric protein. As previously reported for the ETV6::NTRK3 fusion protein, CLIP1::RAF1 similarly upregulates PI3K‐AKT signaling. Our findings document that RAF1 gene rearrangements represent a recurrent event in ETV6::NTRK3‐negative IFS/CMN and provide a rationale for the use of inhibitors directed to suppress MAPK and PI3K‐AKT signaling in these cancers. © 2024 The Pathological Society of Great Britain and Ireland.

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Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions

Cited by 10 publications

References 49 publications

CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry

CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry

Infantile fibrosarcoma: Is spontaneous regression possible?

RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

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