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

Abstract

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.

Epithelioid Fibrous Histiocytoma with CARS-ALK Fusion: First Case Report

“…By analogy, a similar mechanism might play a role in EFH. The morphological findings in our case closely resemble those of both cases with CLTC - ALK fusions described by Georgantzoglou et al, who have identified the CLTC gene as a novel fusion partner of the ALK gene in two cases of EFH [ 6 ]. Indeed, both types of EFH were associated with predominantly fusiform to dendritic cells, instead of epithelioid cells, arranged in a whorled fashion, showing no exophytic growth or epidermal collarette and lacking a prominent capillary component.…”

Cutaneous VCL::ALK fusion ovoid‐spindle cell neoplasm

“…Certain fusion partners such as TPR and KANK1 , however, are associated with high‐grade spindled and pleomorphic morphology and aggressive behavior 1 . VCL::ALK fusion in the central nervous system has been reported as “epithelioid inflammatory myofibroblastic sarcoma,” 3 and is also found in variants of renal cell carcinoma (especially with sickle cell trait) 4–6 and epithelioid fibrous histiocytoma (EFH) 4–6 . It is true that superficial dermal tumors may exhibit better behavior than deep counterparts, as these may be detected earlier at a smaller size with complete excision, yet these are classified by the repertoire of reproducible features.…”

“…ALK‐immunoreactivity is detected in 88% of EFH, but is not present in benign fibrous histiocytoma or its variants. The most prevalent ALK fusions detected in EFH are SQSTM1‐ALK and VCL‐ALK , 4,7,9,13 although EML4 and TMP3 fusion partners may be observed. This tumor is confined to the upper dermis in older adults and does not have myoid stroma, deep dermal involvement, moderate cellularity, or focal S100 protein staining of tumor cells.…”

“…EFH usually arises on the lower extremities or head and neck, yet can also affect the trunk. 4,9 Limited to the upper dermis, EFH has rounded epithelioid cells with scant to abundant eosinophilic cytoplasm and pseudo-nuclear inclusions, 10 without classic peripheral collagen entrapment or infiltration by foamy histiocytes and lymphocytes. 13 ALK-immunoreactivity is detected in 88% of EFH, but is not present in benign fibrous histiocytoma or its variants.…”

“…morphologic and phenotypic details of other entities described with this fusion. [4][5][6][7][8][9][10][11][12][13][14][15][16][17]…”