Recurrent EWSR1-CREB3L1 Gene Fusions in Sclerosing Epithelioid Fibrosarcoma

Arbajian, Elsa; Puls, Florian; Magnusson, Linda; Thway, Khin; Fisher, Cyril; Sumathi, Vaiyapuri P.; Tayebwa, Johnbosco; Nord, Karolin Hansén; Kindblom, Lars‐Gunnar; Mertens, Fredrik

doi:10.1097/pas.0000000000000158

Cited by 136 publications

(124 citation statements)

References 7 publications

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“…However, a lack of FUS gene rearrangement should not be used to exclude the diagnosis of LGFMS, as occasional cases of LGFMS have been reported which lack FUS rearrangements and instead harbor an EWSR1-CREB3L1 fusion [27,28]. Interestingly, the EWSR1-CREB3L1 gene fusion is more commonly reported in sclerosing epithelioid fibrosarcoma (SEF) which exists on an overlapping morphologic spectrum with LGFMS and similarly exhibits frequent MUC4 positivity [29][30][31].…”

Section: Discussionmentioning

confidence: 94%

Low-Grade Fibromyxoid Sarcoma of the Head and Neck: A Clinicopathologic Series and Review of the Literature

Cowan

Thompson

Leon

et al. 2015

Head and Neck Pathol

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Low-grade fibromyxoid sarcoma (LGFMS) is a deceptively bland malignancy with potential for late recurrence and metastasis, which usually occurs in the deep soft tissues of the extremities and trunk. Most LGFMSs harbor a characteristic gene fusion of FUS-CREB3L2, and recently MUC4 immunostaining has been found to be highly sensitive and specific for the diagnosis. We present a dedicated series of head and neck LGFMS, including the first reported laryngeal case, as well as a review of reported head and neck cases. The surgical pathology archives of our three institutions were searched for cases of LGFMS arising within the head and neck, and four cases were identified. The H&E slides were reviewed, and immunohistochemistry were performed for pancytokeratin, p63, p40, EMA, S100 protein, β-catenin, actin, CD34, and MUC4. The patients were 6, 43, 45, and 73 years old (mean 41.8 years) and included three males and one female. The tumors were located in the posterior cervical spine, facial skin, mandible, and larynx. The tumors were treated with surgical excision, and all four had histologic features typical for LGFMS including alternating myxoid and fibrous areas with prominent curvilinear vasculature. All tumors were MUC4 positive (100%), 2/4 (50%) were p63 positive, 1/4 (25%) showed focal EMA positivity; all 4 were negative for pancytokeratin, p40, S100 protein, β-catenin, actin, and CD34. LGFMS is a low grade sarcoma that rarely develops in the head and neck. Due to its rarity, a pathologist may not consider LGFMS in the differential diagnosis of spindle cell neoplasms within the head and neck. Immunohistochemical staining is helpful, but stains should be selected carefully to avoid misdiagnosis.

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Section: Discussionmentioning

confidence: 94%

Low-Grade Fibromyxoid Sarcoma of the Head and Neck: A Clinicopathologic Series and Review of the Literature

Cowan

Thompson

Leon

et al. 2015

Head and Neck Pathol

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“…Clone preparation, hybridization, and analysis were performed as described. 15,16 On average 113 (range = 83-176) nuclei from different areas were evaluated per probe set in each case. Nuclei displaying separate green and red signals or a single 3′ signal were scored as positive.…”

Section: Fishmentioning

confidence: 99%

Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing

Walther

Hofvander

Nilsson

et al. 2015

Laboratory Investigation

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Benign fibrous histiocytomas (FH) can be subdivided into several morphological and clinical subgroups. Recently, gene fusions involving either one of two protein kinase C genes (PRKCB and PRKCD) or the ALK gene were described in FH. We here wanted to evaluate the frequency of PRKCB and PRKCD gene fusions in FH. Using interphase fluorescence in situ hybridization on sections from formalin-fixed paraffin-embedded (FFPE) tumors, 36 cases could be analyzed. PRKCB or PRKCD rearrangements were seen in five tumors: 1/7 regular, 0/3 aneurysmal, 0/6 cellular, 2/7 epithelioid, 0/1 atypical, 2/10 deep, and 0/2 metastatic lesions. We also evaluated the status of the ALK gene in selected cases, finding rearrangements in 3/7 epithelioid and 0/1 atypical lesions. To assess the gene fusion status of FH further, deep sequencing of RNA (RNASeq) was performed on FFPE tissue from eight cases with unknown gene fusion status, as well as on two FH and six soft tissue sarcomas with known gene fusions; of the latter eight positive controls, the expected fusion transcript was found in all but one, while 2/8 FH with unknown genetic status showed fusion transcripts, including a novel KIRREL/PRKCA chimera. Thus, also a third member of the PRKC family is involved in FH tumorigenesis. We conclude that gene fusions involving PRKC genes occur in several morphological (regular, cellular, aneurysmal, epithelioid) and clinical (cutaneous, deep) subsets of FH, but they seem to account for only a minority of the cases. In epithelioid lesions, however, rearrangements of PRKC or ALK were seen, as mutually exclusive events, in the majority (5/7) of cases. Finally, the study also shows that RNA-Seq is a promising tool for identifying gene fusions in FFPE tissues. Benign fibrous histiocytoma (FH) can be subdivided into several morphological and clinical subgroups. Morphological variants include cellular, aneurysmal, epithelioid, and atypical types, and clinical manifestations range from benign tumors of the skin, deep soft tissues or skeleton to, rarely, metastasizing tumors. [1][2][3] We recently showed that both cutaneous and deep FH may carry specific gene fusions, in which a membereither PRKCB and PRKCD-of the gene family encoding protein kinase C (PRKC) is juxtaposed with a gene encoding a membrane-associated protein. 4 The pathogenetic mechanism was assumed to involve the uncoupling of the carboxy-terminal kinase domain of the PRKC protein from its regulatory domain, and its ectopic localization through fusion with the amino-terminal part of a membrane-associated protein. It has also recently been shown that some cases of epithelioid, and possibly also atypical, FH may harbor fusions activating the ALK protein. 5,6 The connection between ALK rearrangements and FH was further evaluated and strengthened by Doyle et al., showing that ALK fusions were restricted to the epithelioid subtype. 7 To study the frequency and distribution of PRKCB and PRKCD fusions in FH, we used interphase fluorescence in situ hybridization (FISH) on a series of tumors that...

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“…LGFMS is characterized by expression of the MUC4 protein, like SEF, and about 90% of cases show a distinctive t (7; 16) (q33; p11) that results in FUS-CREB3L2 gene fusion [3,11,17,21]. The use of MUC4 immunostaining and molecular techniques to identify FUS and EWSR1 rearrangements has clear utility in the recognition of SEF, despite the reports of immunoexpression in up to 70% of cases suggesting that at least a subset are related to LGFMS [3,20].…”

Section: Discussionmentioning

confidence: 99%

Sclerosing Epithelioid Fibrosarcoma – A Rare Sacral Lesion and Literature Review

Rocha¹,

Moreno²,

Silva³

et al. 2017

J Spine

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Sclerosing epithelioid fibrosarcoma (SEF) is a singular entity, recognized as malignant fibroblastic sarcoma variant, which deviates from classic type due to the indolent progression and late metastasis. Typically occurring in middle aged adults, it presents a predilection for deep soft tissues, particularly skeletal muscle. It often involves the fascia or periosteum, and less frequently it may invade or arise from bone. Diagnosis and recognition are critical, as the generally bland appearance or when intraosseous similarity with an osteoid lesion, can lead to misdiagnosis. We herein present a case showing an unusual location and challenging radiological morphological and surgical features.

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Recurrent EWSR1-CREB3L1 Gene Fusions in Sclerosing Epithelioid Fibrosarcoma

Cited by 136 publications

References 7 publications

Low-Grade Fibromyxoid Sarcoma of the Head and Neck: A Clinicopathologic Series and Review of the Literature

Low-Grade Fibromyxoid Sarcoma of the Head and Neck: A Clinicopathologic Series and Review of the Literature

Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing

Sclerosing Epithelioid Fibrosarcoma – A Rare Sacral Lesion and Literature Review

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