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

Abstract

Epithelioid fibrous histiocytoma (EFH) is a type of uncommon skin tumor mostly harboring Anaplastic Lymphoma Kinase (ALK) gene rearrangement, with different fusion partners reported. Whether this tumor is a separate entity or has a relationship with conventional fibrous histiocytomas is still a matter of debate. Benign course is the rule after complete surgical excision. A rare subtype of EFH with fusiform cells has been described, with specific fusion partners. Inflammatory myofibroblastic tumor (IMT) is a type of soft tissue tumor rarer than EFH, and it can display distant metastases. Some cases of primary cutaneous IMT included two with Cysteinyl-tRNA Synthetase 1 (CARS)-ALK rearrangement. IMT can have the same fusion partners as EFH, such as DCTN1, TMP3 or EML4 genes. We report the case of a 42-year-old woman presenting EFH with fusiform morphology harboring CARS-ALK fusion and discuss similarities and differences with IMT.

A Novel Fusion Partner, SP100, Drives Nuclear Dot Localization of ALK in Epithelioid Fibrous Histiocytoma

“…DNA was analyzed using a targeted massively parallel sequencing platform which incorporates 447 cancer-related genes and which can detect structural rearrangements in 60 genes (including ALK), as previously described. 14,15 The 447 genes targeted were as follows: ABCB11,ABL1,ACVR1,AKT1,AKT2,AKT3,ALK,APC,AR,AR-AF,ARHGAP35,ARHGEF12,ARIDA,ARID1B, ARID2,ASXL1,ATM,ATR,ATRX,AURKA,AURKB,AXIN2,AX-L,B2M,BABAM1,BAP1,BARD1,BCL11B, BCL2,BCL2L1,BCL2L12,BCL6,BCOR,BCORL1,BLM,BMP-R1A,BRAF,BRCA1,BRCA2,BRCC3,BRD3, BRD4,BRE,BRIP1,BUB1B,C17ORF70,C19ORF40,C10OR-F86,CALR,CARD11,CASP8,CBFA2T3,CBFB, CBL,CBLB,CCND1,CCND2,CCND3,CCNE1,CD274,CD79-B,CDC73,CDH1,CDH4,CDK12,CDK4,CDK6, CDK8,CDKN1A,CDKN1B,CDKN1C,CDKN2A,CDKN2B,C-DKN2C,CEBPA,CHEK1,CHEK2,CIC,CIITA, COL7A1,CREBBP,CRKL,CRLF2,CRTC1,CSF3R,CTCF,CT-LA4,CTNNA1,CTNNB1,CUX1,CXCR4,CYLD, DAXX,DCLRE1C,DDB1,DDB2,DDR2,DICER1,DIS3,DIS3-L2,DKC1,DMC1,DNMT3A,DOCK8,EGFR, EGLN1,ELANE,EME1,ENG,EP300,EPCAM,ERBB2,ERB-B3,ERBB4,ERCC1,ERCC2,ERCC3,ERCC4, ERCC5,ERCC6,ERG,ESR1,ETV1,ETV4,ETV5,ETV6,EWS-R1,EXO1,EXT1,EXT2,EZH2,FAH,FAM175A, FAM46C,FAN1,FANCA,FANCB,FANCC,FANCD2,FANCE,-FANCF,FANCG,FANCI,FANCL,FANCM,FAS, FAT1,FBXW7,FGFR1,FGFR2,FGFR3,FGFR4,FH,FLCN,F-LT1,FLT3,FLT4,FOXA1,FOXL2,FUS, GALNT12,GATA2,GATA3,GATA4,GATA6,GBA,GEN1,GL-I1,GLI2,GNA11,GNAQ,GNAS,GPC3,GREM1, H19,H3F3A,H3F3B,HABP2,HELQ,HFE,HIST1H3B,HIST1-H3C,HMBS,HNF1A,HOXB13,HRAS,ID3,ID4, IDH1,IDH2,IGF1R,IGF2,IKZF1,IL7R,ITK,JAK1,JAK2,JA-K3,JAZF1,KAT6A,KAT6B,KCNQ1,KDM5A,KDM5 C,KDM6A,KDR,KEAP1,KIF1B,KIT,KLF2,KLF4,KLLN,KM-T2A,KMT2D,KRAS,LIG4, LMO1,LMO2,MAF,MAFB,MAP2K1,MAP2K2,MAP2K4,MA-P3K1,MAPK1,MAX,MBD4,MCL1,MCM8, MDM2,MDM4,MECOM,MED12,MEF2B,MEN1,MET,MG-A,MITF,MLH1,MLH3,MPL,MRE11A,MSH2,MSH6,MTA1,-MTAP,MTOR,MUS81,MUTYH,MYB,MYBL1,MYC,MYCL1,-MYCN,MYD88,NBN,NEIL1, NEIL2,NEIL3,NF1,NF2, NFE2L2,NFKBIA,NFKBIE,NFKBIZ,NKX2-1,NKX3-1,NOTCH1,NOTCH2, NOTCH3,NPM1,NR0B1,NRAS,NRG1,NSD1,NT5C2,NTH-L1,NTRK1,NTRK2,NTRK3,OGG1,PALB2,PARK2,PAX5,PA-XIP1,PBRM1,PDCD1LG2,PDGFRA,PDGFRB,PHF6,PHO-X2B,PIK3C2B,PIK3CA,PIK3R1,PIM1,PML,PMS1,PMS2,P- Perinuclear dot-like PRKAR2A::ALK Kazlouskaya et al 5 3/3 (100) Cytoplasmic DCTN1::ALK Dawson et al 12 1/1 (100) Perinuclear dot-like PRKAR2A::ALK Mansour et al 6 3/3 (100) Cytoplasmic AP3D1::ALK COL1A::ALK LRRFIP2::ALK Secco et al 8 1/1 (100) Cytoplasmic CARS::ALK…”

“…2 In recent years, new morphologic variants have been described, including those which show a spindled and chondroblastoma-like morphology. 3–8…”

“…2 In recent years, new morphologic variants have been described, including those which show a spindled and chondroblastoma-like morphology. [3][4][5][6][7][8] The defining molecular feature of EFH is the presence of anaplastic lymphoma kinase (ALK) gene fusions 9,10 which lead to hyperactive ALK signaling. At least 14 different ALK fusion partners have been described to date (summarized in Table 1).…”

An Unusual Case of an ALK‐Negative Epithelioid Fibrous Histiocytoma in the External Auditory Canal

“…1 Though originally considered a rare morphologic variant of dermatofibroma/ benign fibrous histiocytoma (BFH), the World Health Organization now considers EFH to be a biologically distinct entity. 1,5 Arguments in favor of their separate classification point to the absence of ALK rearrangements in BFH, although a subset of EFH is ALK negative. 1,4 EFH is most frequently observed in the lower extremities of young to middle-aged adults.…”

“…Epithelioid fibrous histiocytoma (EFH) is a benign cutaneous fibrohistiocytic tumor that commonly features predominant epithelioid morphology and anaplastic lymphoma kinase (ALK) gene fusion 1 . Though originally considered a rare morphologic variant of dermatofibroma/benign fibrous histiocytoma (BFH), the World Health Organization now considers EFH to be a biologically distinct entity 1,5 . Arguments in favor of their separate classification point to the absence of ALK rearrangements in BFH, although a subset of EFH is ALK negative 1,4 .…”