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Soft Tissues: Angiomatoid fibrous histiocytoma

Written2005-10Carolina Vicente-Dueñas, Isidro Sánchez-García
Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain

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ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho 8836/1 Angiomatoid fibrous histiocytoma
Atlas_Id 5204
Phylum Soft Tissues::Angiomatoid fibrous histiocytoma
WHO/OMS Classification Soft Tissues
Other namesAngiomatoid malignant fibrous histiocytoma (AMFH)


Note Angiomatoid fibrous histiocytoma is a rare soft tissue tumor of low-grade malignancy that usually occurs in children and young adults. Eighty-eight percent of patients are 30 years of age or younger. Enzinger in 1979 first designated the tumor as angiomatoid malignant fibrous histiocytoma. The tumour was later renamed angiomatoid fibrous histiocytoma because of its slow growth and rare metastasis.
This tumor forms solid, lobulated sheets of plump to spindled cells having histiocytic features adjacent to areas of haemorrhage.

Clinics and Pathology

Note This tumour typically affects children and young adults, presenting as a painless, slowly growing subcutaneous soft tissue mass that is usually located in the extremities and less commonly in the trunk, head, and neck. Only 18% of reported cases involved deep structures, such as skeletal muscle or periosteum.
Disease Symptoms of anemia, weight loss, and fever are observed in a minority of cases; local symptoms, such as pain or tenderness, are extremely rare.
Embryonic origin Symptoms of anemia, weight loss, and fever are observed in a minority of cases; local symptoms, such as pain or tenderness, are extremely rare.
Clinics Clinically, the tumor is often mistaken for hematoma or hemangioma. The diagnosis of angiomatoid fibrous histiocytoma is made on the basis of histopathology and immunohistochemical studies. Three microscopic findings are characteristic of AFH: (1) solid arrays or nests of histiocyte-like cells, (2) hemorrhagic cyst-like spaces, and (3) aggregates of chronic inflammatory cells. Multifocal recent and old hemorrhages are a striking feature in this tumor. These spaces resemble vascular spaces, but they are not lined by endothelium. Inflammatory cells present include lymphocytes and plasma cells. A thick pseudocapsule and occasional germinal centers give this tumor a resemblance to a lymph node.
Immunohistochemical studies are helpful in differential diagnosis of AFH. It was reported that the histiocytic marker CD68 was positive in 9 of 19 (47%) cases of angiomatoid fibrous histiocytoma. Immunopositivity for myoid or myofibroblastic markers in more than 50% of cases has also been reported.
Treatment Local recurrence has been reported in 11% of patients and distant metastasis in 1%; wide excision is recommended as the treatment of angiomatoid fibrous histiocytoma. Local recurrence is attributed to the infiltrative margin and deep location of the tumour. Angiomatoid fibrous histiocytoma in the head and neck also can frequently recur, which may be a result of the difficulty of performing a wide local excision. If the tumor is unresectable or has metastasized, adjuvant chemotherapy may be helpful.


Note This disease is characterised by the translocations: t(12;16) (q13;p11) and t(12;22)(q13;q12).
t(12;16)(q13; p11) G- banding - Courtesy G. Reza Hafez, Eric B.Johnson, and Sara Morrison-Delap,UW Cytogenetic Services
Cytogenetics Molecular
  • FUS-ATF1 fusion gene in the t(12;16)(q13; p11).
  • EWSR1-ATF1 fusion gene in the t(12;22)(q13;q12)
  • Genes involved and Proteins

    Gene NameFUS (fusion involved in t (12;16) in malignant liposarcoma)
    Location 16p11.2
    Dna / Rna FUS gene consists of 15 exons located within 11 kb of genomic DNA.
    Protein FUS protein, provisionally designated TLS (translocated in liposarcoma), and then called FUS, contains an RNA-recognition motif and is a component of nuclear riboprotein complexes. Lack of FUS in mice causes lethality into neonatal period, it influences lymphocyte development in a non-cell-intrinsic manner, it has an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli, and it is required for the maintenance of genomic stability. The involvement of a nuclear riboprotein in these processes in vivo indicates that FUS is important in genome maintenance.
    Somatic mutation FUS has been also shown a partner of gene fusions linked in other malignancies: fused to ERG in acute myeloid leukaemia with t(16;21) (p11;q22), fused to CREB3L2 in low-grade fibromyxoid sarcoma (LGFMS) by a translocation between chromosome bands 7q33-q34 (CREB3L2) and 16p11 (FUS), fused to ATF1 in histiocytoma or fused to CHOP gene in Myxoid Liposarcoma with t(13;16)(q13;p11).

    Gene NameATF1 (activating transcription factor 1)
    Location 12q13.12
    Dna / Rna 816 bp mRNA
    Protein ATF1 gene encodes a member of the CREB-ATF basic leucine-zipper (bZIP) family of transcription factors. This protein of 271 amino acids has a nuclear localization. Function: DNA binding protein, binds the consensus sequence: 5'GTGACGT (A/C) (A/G)-3'; cAMP-inducible transcription factor (cAMP-responsive enhancer-binding protein (CRE), like CREB. Is a member of the CREB protein family.
    Somatic mutation t(12;22)(q13;q12) in Angiomatoid Fibrous histiocytoma ATF1-EWSR1. It is also rearranged in clear cell sarcoma (CCS) with t(12;22) (q13;q12), creating an EWSR1-ATF1 fusion gene.

    Gene NameEWSR1 (Ewing sarcoma breakpoint region 1)
    Location 22q12.2
    Dna / Rna DNA spans over 40 kb; open reading frame: 2.0 kb, 17 exons. Transcription 2.4 kb mRNA; centromere to telomere direction; differential splicing
    Protein 656 amino acids; serine-tyrosine tandem repeats. It has a wide expression and functions as a RNA binding.
    Somatic mutation
  • Ewing tumours with: t(11;22)(q24;q12) --> FLI1 - EWSR1. Ewing tumours: including Ewing's Sarcoma and periphral primitive neuroectodermal tumour.
  • Ewing tumours with t(21; 22)(q21;q12) --> ERG - EWSR1. Ewing tumours (Ewing's Sarcoma and peripheral primitive neuroectodermal tumour).
  • Ewing tumours with t(7;22)(p22;q12) --> ETV1 - EWSR1. Ewing tumours (Ewing's Sarcoma and peripheral primitive neuroectodermal tumour).
  • Ewing tumours with t(17;22)(q12;q12) --> E1AF - EWSR1. Ewing tumours (Ewing's Sarcoma and peripheral primitive neuroectodermal tumour).
  • t(11;22)(p13;q12) / Intra abdominal desmoplastic small round cell sarcoma (IADSRCT) --> WT1 - EWSR1.
  • t(12;22)(q13;q12) / Angiomatoid Fibrous Histiocytoma --> ATF1 - EWSR1.
  • t(9;22)(q22;q12) / Myxoid Chondrosarcoma --> TEC - EWSR1

  • Result of the chromosomal anomaly

    Hybrid Gene
  • FUS-ATF1 fusion gene t(12;16)(q13;p11).
  • EWSR1-ATF1 fusion gene t(12;22)(q13 ;q12)
  • Fusion Protein
    Note FUS/ATF-1
    Description This fusion was generated by a translocation between chromosomal bands 16p11 and 12q 13, harbouring the FUS and ATF1 genes, respectively. FUS is interrupted at codon 175 (exon5) and fused to condon 110 (exon 5) of ATF1, resulting in an in-frame junction with a glycine to valina (GGT to GTT) transition.
    Description The fusion gene contains the N-terminus of FUS and the DNA binding domain of ATF-1 with a glycine to valine transition at the junction. This is similar to the EWS/ATF1 chimeric protein found in CCS (clear cell sarcoma).
    The normal ATF1 gene is transcribed from centromere to telomere, while the transcription of FUS seems to proceed in the opposite direction. Hence, the formation of FUS/ATF-1 is possible only if another genomic aberration, such as an inversion, occurs in addition to the chromosomal translocation. Such an event would be analogous to the formation of EWS/ERG in Ewing sarcoma and EWS/CHOP in myxoid liposarcoma.


    Angiomatoid fibrous histiocytoma in mediastinum.
    Asakura S, Tezuka N, Inoue S, Kihara N, Fujino S
    The Annals of thoracic surgery. 2001 ; 72 (1) : 283-285.
    PMID 11465207
    Angiomatoid malignant fibrous histiocytoma. A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome.
    Costa MJ, Weiss SW
    The American journal of surgical pathology. 1990 ; 14 (12) : 1126-1132.
    PMID 2174650
    Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features.
    Dal Cin P, Sciot R, Panagopoulos I, Aman P, Samson I, Mandahl N, Mitelman F, Van den Berghe H, Fletcher CD
    The Journal of pathology. 1997 ; 182 (4) : 437-441.
    PMID 9306965
    Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm.
    Enzinger FM
    Cancer. 1979 ; 44 (6) : 2147-2157.
    PMID 228836
    Angiomatoid malignant fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype.
    Fanburg-Smith JC, Miettinen M
    Human pathology. 1999 ; 30 (11) : 1336-1343.
    PMID 10571514
    EWS-erg and EWS-Fli1 fusion transcripts in Ewing's sarcoma and primitive neuroectodermal tumors with variant translocations.
    Giovannini M, Biegel JA, Serra M, Wang JY, Wei YH, Nycum L, Emanuel BS, Evans GA
    The Journal of clinical investigation. 1994 ; 94 (2) : 489-496.
    PMID 8040301
    Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma.
    Hallor KH, Mertens F, Jin Y, Meis-Kindblom JM, Kindblom LG, Behrendtz M, Kalén A, Mandahl N, Panagopoulos I
    Genes, chromosomes & cancer. 2005 ; 44 (1) : 97-102.
    PMID 15884099
    An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.
    Ichikawa H, Shimizu K, Hayashi Y, Ohki M
    Cancer research. 1994 ; 54 (11) : 2865-2868.
    PMID 8187069
    Angiomatoid fibrous histiocytoma: a case report and review of the literature.
    Jacobs IA, Chevinsky A
    Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2000 ; 26 (5) : 491-492.
    PMID 10816241
    Molecular genetics of chromosome translocations involving EWS and related family members.
    Kim J, Pelletier J
    Physiological genomics. 1999 ; 1 (3) : 127-138.
    PMID 11015571
    Fine-needle aspiration cytology of angiomatoid malignant fibrous histiocytoma.
    Lemos MM, Karlen J, Tani E
    Diagnostic cytopathology. 2005 ; 33 (2) : 116-121.
    PMID 16007669
    MRI of angiomatoid fibrous histiocytoma.
    Li CS, Chan WP, Chen WT, Chang CP, Shih LS, Chen RC, Tu HY
    Skeletal radiology. 2004 ; 33 (10) : 604-608.
    PMID 15258704
    Understanding mesenchymal cancer: the liposarcoma-associated FUS-DDIT3 fusion gene as a model.
    Pé PA, Sánchez-García I
    Seminars in cancer biology. 2005 ; 15 (3) : 206-214.
    PMID 15826835
    Fusion of the EWS and CHOP genes in myxoid liposarcoma.
    Panagopoulos I, Höglund M, Mertens F, Mandahl N, Mitelman F, Aman P
    Oncogene. 1996 ; 12 (3) : 489-494.
    PMID 8637704
    Fusion of the FUS and ATF1 genes in a large, deep-seated angiomatoid fibrous histiocytoma.
    Raddaoui E, Donner LR, Panagopoulos I
    Diagnostic molecular pathology : the American journal of surgical pathology, part B. 2002 ; 11 (3) : 157-162.
    PMID 12218455
    FUS/ERG gene fusions in Ewing's tumors.
    Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N
    Cancer research. 2003 ; 63 (15) : 4568-4576.
    PMID 12907633
    Evaluation of CD68 and other histiocytic antigens in angiomatoid malignant fibrous histiocytoma.
    Smith ME, Costa MJ, Weiss SW
    The American journal of surgical pathology. 1991 ; 15 (8) : 757-763.
    PMID 1676879
    A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG.
    Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, Denny CT
    Nature genetics. 1994 ; 6 (2) : 146-151.
    PMID 8162068
    Pathologic quiz case: a large cystic thigh mass in a 10-year-old boy.
    Wang H, Jafri J, Recant W, Montag AG
    Archives of pathology & laboratory medicine. 2000 ; 124 (5) : 783-784.
    PMID 10782174
    Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.
    Waters BL, Panagopoulos I, Allen EF
    Cancer genetics and cytogenetics. 2000 ; 121 (2) : 109-116.
    PMID 11063792
    EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts.
    Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G
    Nature genetics. 1993 ; 4 (4) : 341-345.
    PMID 8401579
    Combinatorial generation of variable fusion proteins in the Ewing family of tumours.
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    PMID 8223458


    This paper should be referenced as such :
    Vicente-Dueas ; Sanchez-Garcia, I
    Angiomatoid fibrous histiocytoma (AFH)
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):127-130.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]

    Genes ATF2 EWSR1 FUS KCNH1

    Translocations implicated (Data extracted from papers in the Atlas)

     t(12;16)(q13;p11) FUS/ATF1
     t(12;22)(q13;q12) EWSR1/ATF1
     t(2;22)(q34;q12) EWSR1/CREB1

    External links

    Mitelman database t(12;16)(q13;p11) [CaseList]     t(12;16)(q13;p11) [Transloc - MCList]   FUS/ATF1 Fusion - MCList]
    COSMIC[ FUS ]   [ ATF1 ]
    Mitelman database t(12;22)(q13;q12) [CaseList]     t(12;22)(q13;q12) [Transloc - MCList]   EWSR1/ATF1 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ ATF1 ]
    Mitelman database t(2;22)(q34;q12) [CaseList]     t(2;22)(q34;q12) [Transloc - MCList]   EWSR1/CREB1 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ CREB1 ]
    arrayMap Topo ( C47,C49) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Mitelman databaseEWSR1/ATF1[MCList]    EWSR1 (22q12.2) ATF1 (12q13.12)   t(12;22)(q13;q12)
    TICdbEWSR1/ATF1    EWSR1 (22q12.2) ATF1 (12q13.12)
    COSMIC_fusionEWSR1 (22q12.2) CREB1 (2q33.3)    [fusion264] [fusion265] [fusion266] [fusion267] [fusion268]
    Mitelman databaseEWSR1/CREB1[MCList]    EWSR1 (22q12.2) CREB1 (2q33.3)   t(2;22)(q33;q12)
    TICdbEWSR1/CREB1    EWSR1 (22q12.2) CREB1 (2q33.3)
    COSMIC_fusionFUS (16p11.2) ATF1 (12q13.12)    [fusion296] [fusion327]
    Mitelman databaseFUS/ATF1[MCList]    FUS (16p11.2) ATF1 (12q13.12)   
    Mitelman databaseFUS/ATF1[MCList]    FUS (16p11.2) ATF1 (12q13.12)   t(12;16)(q13;p11)
    TICdbFUS/ATF1    FUS (16p11.2) ATF1 (12q13.12)
    Disease databaseSoft Tissues: Angiomatoid fibrous histiocytoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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    indexed on : Tue Oct 12 14:40:09 CEST 2021

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