Dataset Information

Two cases of spindle cell tumors with S100 and CD34 co-expression showing novel RAF1 fusions.

ABSTRACT:

Background

Recently, a novel group of CD34 and S100 co-expression spindle cell tumors with distinctive stromal and perivascular hyalinization harboring recurrent gene fusions involving RET, RAF1, BRAF, and NTRK1/2 gene has been identified.

Case presentation

In this study, we reported two Chinese male patients with soft tissue tumors presenting in the right knee joint and the left thigh, respectively. For both patients, the tumors were completely excised with clear margin. Microscopically, case 1showed morphological overlap with neurofibroma, and case 2 showed overlap with lipomatous solitary fibrous tumor. Both tumors showed co-expression of S100 and CD34, and absence of SOX10. Genomic profiling with DNA-based next-generation sequencing (NGS) assay was performed and revealed KIF5B-RAF1 (K16:R8) and TLN2-RAF1 (T54:R8) rearrangements. RNA-based NGS and RT-PCR were performed to confirm the gene fusion.

Conclusions

Though systemic therapy was not indicated in these two patients, identification of targetable kinase fusions may help to refine tumors with an ambiguous immunoprofile, and provides suggestions for targeted therapy in rare aggressive cases.

SUBMITTER: Gong LH

PROVIDER: S-EPMC9563504 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Two cases of spindle cell tumors with S100 and CD34 co-expression showing novel RAF1 fusions.

Gong Li-Hua LH Liu Wei-Feng WF Niu Xiao-Hui XH Ding Yi Y

Diagnostic pathology 20221013 1

<h4>Background</h4>Recently, a novel group of CD34 and S100 co-expression spindle cell tumors with distinctive stromal and perivascular hyalinization harboring recurrent gene fusions involving RET, RAF1, BRAF, and NTRK1/2 gene has been identified.<h4>Case presentation</h4>In this study, we reported two Chinese male patients with soft tissue tumors presenting in the right knee joint and the left thigh, respectively. For both patients, the tumors were completely excised with clear margin. Microsco ...[more]

PMID: 36229858

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Project description: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.

Project description:A subset of melanomas is characterized by fusions involving genes that encode kinases. Melanomas with RAF1 fusions have been rarely reported, mostly in clinical literature. To investigate this distinctive group of melanomas, we searched for melanomas with activating structural variants in RAF1, utilizing our case archive of clinical samples with comprehensive genomic profiling (CGP) by a hybrid capture-based DNA sequencing platform. Clinical data, pathology reports, and histopathology were reviewed for each case. RAF1 breakpoints, fusion partners, and co-occurring genetic alterations were characterized. From a cohort of 7119 melanomas, 40 cases (0.6%) featured fusions that created activating structural variants in RAF1. Cases with activating RAF1 fusions had median age of 62 years, were 58% male, and consisted of 9 primary tumors and 31 metastases. Thirty-nine cases were cutaneous primary, while one case was mucosal (anal) primary. Primary cutaneous melanomas showed variable architectures, including wedge-shaped and nodular growth patterns. Cytomorphology was predominantly epithelioid, with only one case, a desmoplastic melanoma, consisting predominantly of spindle cells. RAF1 5' rearrangement partners were predominantly intrachromosomal (n = 18), and recurrent partners included MAP4 (n = 3), CTNNA1 (n = 2), LRCH3 (n = 2), GOLGA4 (n = 2), CTDSPL (n = 2), and PRKAR2A (n = 2), all 5' of the region encoding the kinase domain. RAF1 breakpoints occurred in intron 7 (n = 32), intron 9 (n = 4), intron 5 (n = 2), and intron 6 (n = 2). Ninety-eight percent (n = 39) were wild type for BRAF, NRAS, and NF1 genomic alterations (triple wild type). Activating RAF1 fusions were present in 2.1% of triple wild-type melanomas overall (39/1882). In melanomas with activating RAF1 fusions, frequently mutated genes included TERTp (62%), CDKN2A (60%), TP53 (13%), ARID2 (10%), and PTEN (10%). Activating RAF1 fusions characterize a significant subset of triple wild-type melanoma (2.1%) with frequent accompanying mutations in TERTp and CDKN2A. CGP of melanomas may improve tumor classification and inform potential therapeutic options, such as consideration of specific kinase inhibitors.

Dataset Information

Two cases of spindle cell tumors with S100 and CD34 co-expression showing novel RAF1 fusions.

Background

Case presentation

Conclusions

Publications

Two cases of spindle cell tumors with S100 and CD34 co-expression showing novel RAF1 fusions.

Similar Datasets

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