Atypical fibrous histiocytoma of the skin with <scp>CD30</scp> and p80/<scp>ALK1</scp> positivity and <scp>ALK</scp> gene rearrangement

Szablewski, Vanessa; Laurent-Roussel, Sara; Rethers, Luc; Rommel, Antoine; Vaneechout, Pascal; Camboni, Alessandra; Willocz, Pascal; Copie‐Bergman, Christiane; Ortonne, Nicolas

doi:10.1111/cup.12352

Cited by 22 publications

(18 citation statements)

References 12 publications

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“…8 In addition, in a separate study, ALK rearrangement was described in two tumors reported as 'atypical fibrous histiocytoma'; however, according to the morphologic description ('with epithelioid features') and the histologic images in that study, those two lesions may actually represent examples of epithelioid fibrous histiocytoma. 9 In the present study, we found ALK expression in 88% of epithelioid fibrous histiocytomas, which is therefore the most consistent immunohistochemical finding to date in these tumors. ALK overexpression correlated with ALK rearrangement.…”

Section: Discussionsupporting

confidence: 88%

“…Two cases have been studied by next-generation sequencing, which surprisingly identified the fusion genes VCL-ALK and SQSTM1-ALK (one case each). 8 Two prior lesions diagnosed as 'atypical' fibrous histiocytoma were reported to show ALK rearrangement 9 and also appear to represent examples of epithelioid fibrous histiocytoma. Corresponding ALK expression was detectable by immunohistochemistry in these four cases.…”

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confidence: 99%

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ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

et al. 2015

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Epithelioid benign fibrous histiocytoma, also known as 'epithelioid cell histiocytoma,' has traditionally been considered a morphologic variant of cutaneous fibrous histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous histiocytoma and separately in two cases reported as 'atypical' fibrous histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous histiocytoma, to determine its value for the diagnosis of epithelioid fibrous histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous histiocytomas, 41 other cases of fibrous histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated (n = 13), and not in one ALK expression-negative epithelioid fibrous histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous histiocytoma and histologic variants. Modern Pathology (2015) 28, 904-912;

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

et al. 2015

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“…The conclusion that ALK and PRKC activation constitute alternative, and not overlapping, pathogenetic pathways in epithelioid FH was supported by the finding that the two cases with PRKCB rearrangement were negative for ALK expression, whereas the other five cases were positive (Table 1); there were no obvious morphological or clinical differences between PRKC-and ALK-positive epithelioid FH, but it should be kept in mind that very few cases were analyzed. Also two tumors diagnosed as atypical FH were recently reported to have ALK rearrangements, as shown by FISH or IHC, 5 but, in our opinion, the morphologic description and images would fit better with epithelioid FH. The single atypical FH (Case 24) that we could analyze by FISH was negative for PRKCB, PRKCD, and ALK rearrangements (Table 1).…”

Section: Rna-seq and Fish On Ffpe Sections From Bfh C Walther Et Almentioning

confidence: 70%

“…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 represented different morphological and clinical subsets; the results of that study prompted transcriptome sequencing (RNA-Seq) of RNA from formalin-fixed paraffin-embedded (FFPE) tissue from a second set of FH.…”

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confidence: 96%

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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“…Recently epithelioid and atypical BFH were shown to harbor fusions activating the ALK protein [19][20][21]. These findings, too, indicate that BFHs are true neoplasms.…”

Section: Introductionmentioning

confidence: 97%