DCTN1-ALK gene fusion in inflammatory myofibroblastic tumor (IMT) of the CNS

Vidrine, Devan W.; Berry, John F.; Garbuzov, Anna; Falcon, Corey; Tubbs, R. Shane; Bui, Cuong J.

doi:10.1007/s00381-021-05219-3

Cited by 11 publications

(11 citation statements)

References 13 publications

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“…However, the ALK gene is highly promiscuous and has the potential to form gene fusions with diverse partners 1 . The 5′ gene partners of ALK identified in this study have all previously been reported in other ALK‐rearranged tumors 16–24,42–44 . Among mesenchymal neoplasms, until recently ALK fusions were largely confined to EFH and IMT 11–15 .…”

Section: Discussionsupporting

confidence: 60%

“…1 The 5 0 gene in other ALK-rearranged tumors. [16][17][18][19][20][21][22][23][24][42][43][44] Among mesenchymal neoplasms, until recently ALK fusions were largely confined to EFH and IMT. [11][12][13][14][15] EFH is a dermal-based histiocytoid neoplasm that is typically well-circumscribed with an overlying epidermal collarette and consists of histiocytoid to epithelioid cells that express ALK but do not express S100 or CD34.…”

Section: Discussionmentioning

confidence: 99%

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ALK‐rearranged Mesenchymal Neoplasms: A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors

Dermawan

DiNapoli

Mullaney

et al. 2022

Genes Chromosomes & Cancer

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Anaplastic lymphoma kinase (ALK) fusions are oncogenic drivers in diverse cancer types. Although well established in inflammatory myofibroblastic tumor (IMT) and epithelioid fibrous histiocytoma (EFH), ALK rearrangements also occur in the emerging family of kinase fusion-positive mesenchymal neoplasms. We investigated 9 ALKrearranged mesenchymal neoplasms (exclusive of IMT and EFH) arising in 6 males and 3 females with a wide age range of 10 to 78 years old (median 42 years). Tumors involved superficial and deep soft tissue (6) and viscera (3). Three were myxoid or collagenous low-grade paucicellular tumors with haphazardly arranged spindled cells.Three were cellular tumors with spindled cells in intersecting short fascicles or solid sheets. Three cases consisted of uniform epithelioid cells arranged in nests or solid sheets, with prominent mitotic activity and necrosis. Band-like stromal hyalinization was present in 6 cases. All tumors expressed ALK; four were positive for S100 and five were positive for CD34, while all were negative for SOX10. By targeted RNA sequencing, the breakpoints involved ALK exon 20; the 5 0 partners included KLC1, EML4, DCTN1, PLEKHH2, TIMP3, HMBOX1, and FMR1. All but two patients presented with localized disease. One patient had distant lung metastases; another had diffuse pleural involvement. Of the six cases with treatment information, five were surgically excised [one also received neoadjuvant radiation therapy (RT)], and one received RT and an ALK inhibitor. Of the four patients with follow-up (median 5.5 months), one remained alive with stable disease and three were alive without disease. We expand the clinicopathologic spectrum of ALK-fused mesenchymal neoplasms, including a low-grade malignant peripheral nerve sheath tumor-like subset and another subset characterized by epithelioid and high-grade morphology.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

ALK‐rearranged Mesenchymal Neoplasms: A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors

Dermawan

DiNapoli

Mullaney

et al. 2022

Genes Chromosomes & Cancer

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“…DCTN1 codes for dynactin subunit 1, which binds to microtubules and cytoplasmic dynein, playing an essential role in intracellular vesicular transport and cell division 33 . Apart from EFH, the DCTN1::ALK fusion has also been detected in non‐small cell lung cancer, inflammatory myofibroblastic tumor, granular cell tumor and myelomonocytic leukemia 34–36 . SPECC1L encodes for a protein that crosslinks microtubules and actin cytoskeleton and is postulated to play a role in cell adhesion, migration and division; SPECC1L gene mutations impact normal morphogenesis and craniofacial development 37 .…”

Section: Discussionmentioning

confidence: 99%

“…33 Apart from EFH, the DCTN1::ALK fusion has also been detected in non-small cell lung cancer, inflammatory myofibroblastic tumor, granular cell tumor and myelomonocytic leukemia. [34][35][36] SPECC1L encodes for a protein that crosslinks microtubules and actin cytoskeleton and is postulated to play a role in cell adhesion, migration and division; SPECC1L gene mutations impact normal morphogenesis and craniofacial development. 37 SPECC1L::ALK fusions have only been reported in EFH and non-small cell lung cancer.…”

Section: Molecular Findingsmentioning

confidence: 99%

Molecular investigation of ALK‐rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion‐independent transcription activation

Georgantzoglou

Green

Winnick

et al. 2022

Genes Chromosomes & Cancer

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Epithelioid fibrous histiocytoma (EFH) is a rare cutaneous neoplasm, which is characterized by the presence of rearrangements involving the ALK gene. Although EFH was long considered a variant of fibrous histiocytoma, the identification of its unique genetic signature confirmed that it represents a distinct entity. The aim of the present study was to examine a cohort of ALK‐immunoreactive EFH cases to further characterize gene fusion partners. Next generation sequencing detected ALK fusions in 11 EFH cases identified in the pathology archives of two different institutions. The most common fusion partner was DCTN1 (N = 4) followed by CLTC (N = 2) and VCL (N = 2), while the remaining cases harbored fusions involving SPECC1L, PPFIBP1, and PRKAR1A. In one case no fusion was detected by NGS and FISH despite suitable sample quality. Notably, IHC demonstrated positive ALK expression and the level of aligned ALK reads was comparable to the fusion‐positive cases. To the best of our knowledge, this is the first report of CLTC as a fusion partner in EFH. The two CLTC rearranged cases in our cohort also represent the first two EFH cases in the literature that involve exon 19 of ALK, instead of exon 20. These findings underscore the remarkable plasticity of ALK as an oncogenic driver and further expand the list of its potential fusion partners in EFH. Lastly this is also the first report of ALK‐immunoreactive EFH with no underlying fusion suggesting a fusion independent transcription mechanism as seen in other tumors.

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“…IMT is usually encountered in the lung, retroperitoneum or pelvis, but a limited number of cases has been described in the CNS [26][27][28][29]. IMT is a rare tumor of intermediate biologic potential that, in the brain, tends to involve the dura and leptomeninges.…”

Section: Inflammatory Myofibroblastic Tumor (Imt) and Other Fibroblas...mentioning

confidence: 99%

Embryonal and non‐meningothelial mesenchymal tumors of the central nervous system – Advances in diagnosis and prognostication

Meredith

Alexandrescu

2022

Brain Pathology

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The 5th edition of the WHO Classification of Tumours of the Central Nervous System introduces new entities, and provides updated guidance regarding the diagnostic criteria for tumors of the central nervous system (CNS). CNS embryonal tumors and CNS non‐meningothelial mesenchymal tumors can be challenging for practicing pathologists, as the histologic features are not always specific to a particular entity, and integration of microscopic and molecular findings is necessary. This review on CNS embryonal and non‐meningothelial mesenchymal tumors is meant to provide an update with a focus on WHO changes and additions and on recent discoveries with diagnostic, prognostic, and therapeutic implications.

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DCTN1-ALK gene fusion in inflammatory myofibroblastic tumor (IMT) of the CNS

Cited by 11 publications

References 13 publications

ALK‐rearranged Mesenchymal Neoplasms: A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors

ALK‐rearranged Mesenchymal Neoplasms: A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors

Molecular investigation of ALK‐rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion‐independent transcription activation

Embryonal and non‐meningothelial mesenchymal tumors of the central nervous system – Advances in diagnosis and prognostication

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