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Soft Tissues: Dermatofibrosarcoma Protuberans

Written2008-08Kayuri Patel, Dolores Lopez-Terrada
Department of Pathology at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA

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Identity

ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho 8832/3 Dermatofibrosarcoma, NOS
Atlas_Id 5059
Phylum Soft Tissues::Dermatofibrosarcoma protuberans (Darier Ferrand)
Other namesDermatofibrosarcoma Protuberans
Darier Ferrand tumor
Darier-Hoffmann tumor
Note t(17;22)(q22;q13) is found in most if not all Dermatofibrosarcoma Protuberans cases

Clinics and Pathology

Disease Neoplasm of the deep dermis with extension to the subcutis, characterized by locally aggressive growth. Dermatofibrosarcoma Protuberans (DFSP) is primarily associated with the trunk, limbs, head, neck and vulva.
Epidemiology Rare soft tissue tumor, accounts for up to 1% of all soft tissue sarcomas.
Clinics Typically diagnosed in young to middle-aged adults and affects either sex and all races, however numerous pediatric and congential cases have been reported. The duration of the lesions prior to diagnosis is commonly more than 5 years, and decades in some cases.
Pathology Monotonous storiform pattern of uniform, cytologically bland spindle cells, with a characteristic honeycomb pattern of infiltration into the subcutaneous fat. Immunohistochemical staining demonstrates strong positivity for vimentin and CD34 and negativity for factor XIIIa staining. Apolipoprotein has also been described as a marker for DFSP.
 
From top to bottom: a) Typical dermatofibrosarcoma protuberans (H&E, 40x), b) Strong CD34 immunoreactivity (CD34, 40x).
Treatment Preferred treatment for DFSP is wide surgical excision with pathologically negative margins. Recently Imatinib mesylate therapy has been documented to induce extensive regression of primary and metastatic lesions.
Prognosis Despite the local invasiveness, DFSP rarely metastasizes. The risk for development of metastatic disease is only 5%. The extent of surgical excision determines the prognosis of the patient. To reduce the local recurrence rate, a wide surgical excision with adequate margins is used.

Cytogenetics

Cytogenetics
Morphological
Cytogenetically, DFSP is characterized by the presence of the recurrent t(17;22)(q22;q13) translocation or, more commonly, supernumerary ring chromosomes containing material from chromosomal regions 17q22 and 22q13 accompanied by simple chromosome trisomies. The translocation results in the fusion of the alpha chain type 1 of collagen (COL1A1) gene with the platelet-derived growth factor Beta (PDGFbeta) gene.
der(22)t(17;22)(q21;q13) in dermatofibrosarcoma protuberans, G-banding; - Courtesy Lisa Biazo and Charles D. Bangs
Cytogenetics Molecular Fluorescence in situ hybridization based approaches can be used to demonstrate the t(17;22), using gene specific probes to demonstrate PDGFbeta gene rearrangements as well as genetic gains and losses.
FISH of a DFSP case using a break-apart probe to the PDGFB locus shows tumor cells with one yellow signal indicating an intact PDGFB locus, and two or more green signals, representing additional copies of an unbalanced rearranged PDGFB locus (x100).

Genes involved and Proteins

Gene Name COL1A1
Location 17q21.31-q22
Note Molecular Location: From base pairs 45,616,456 to 45,633,999.
Dna / Rna COL1A1 is transcribed from centromere to telomere at 17q21.31-q22. The mRNA sequence contains 5927bp, comprising 52 exons and spans approximately 18kb. Exons 5 to 49 encode the alpha helical domain.
Protein The COL1A1 gene produces a component of type I collagen called the pro-a1(I) chain. The Alpha1 (I) chains of the type I collagen are synthesized as procollagen molecules containing amino and carboxy-terminal propeptides, which are removed by site-specific endopeptidase synthesizing the 1464 amino acid protein.

Gene Name PDGFB
Location 22q12.3-q13.1
Note Molecular Location: From base pairs 37,949,665 to 37,970,936.
Dna / Rna The PDGFbeta mRNA sequence contains 3373bp, comprising 7 exons and spans approximately 22kb. Exon 7 and most part of the exon 1 are non-coding sequences.
Protein The PDGFbeta chains are synthesized as 240 amino acids precursors molecules containing amino and carboxy-terminal propeptides, which are removed by site-specific endopeptidases. Two PDGFbeta precursor chains associate in dimers to form the mature PDGFBB after proteolysis.

Result of the chromosomal anomaly

Fusion Protein
Note COL1A1 and PDGFbeta both encoded as pro-peptides are processed by proteolytic cleavage at N and C-terminus to give mature proteins. Sequences analyses of the chimerical COL1A1/PDGFbeta fusion transcripts has shown that the COL1A1/PDGFbeta putative proteins exhibit a pro-peptide structure, with a preserved N-terminus COL1A1 pro-peptide containing the signal peptide and the N and C-terminus PDGFbeta maturation cleavage sites. The result of this characteristic rearrangement of COL1A1and PDGFbeta is the transcriptional up-regulation of the PDGFB gene. The associated COL1A1-PDGFbeta fusion protein is posttranslationally processed to a functional PDGFbeta and results in PDGFbeta-mediated autocrine and/or paracrine activation of platelet-derived growth factor receptor-beta (PDGFBB).
  

Bibliography

Mesenchymal Tumors
Fletcher C,
Diagnostic Histopathology of Tumors. 2007; Churchill Livingstone 3rd Ed.; vol 2: 1489-1491.
 
Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225.
McArthur GA, Demetri GD, van Oosterom A, Heinrich MC, Debiec-Rychter M, Corless CL, Nikolova Z, Dimitrijevic S, Fletcher JA.
J Clin Oncol. 2005; 23: 866-873.
PMID 15681532
 
Ring chromosomes in dermatofibrosarcoma protuberans are composed of interspersed sequences from chromosomes 17 and 22.
Naeem R, Lux ML, Huang SF, Naber SP, Corson JM, Fletcher JA.
Am J Pathol. 1995; 147: 1553-1558.
PMID 7495279
 
Dermatofibrosarcoma protuberans COL1A1-PDGFB fusion is identified in virtually all dermatofibrosarcoma protuberan cases when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluorescence in situ hybridization assays.
Patel KU, Szabo SS, Hernandez VS, Prieto VG, Abruzzo LV, Lazar AJ, Lopez-Terrada D.
Human Pathology. 2008; 39: 184-193.
PMID 17950782
 
PDGFB.
Simon MP, Maire G, and Pedeutour F.
Atlas Genet Cytogenet Oncol Haematol. February 2001.
 
Apo D in soft tissue tumors: a novel marker for dermatofibrosarcoma protuberans.
West RB, Harvell J, Linn SC, Liu CL, Prapong W, Hernandez-Boussard T, Montgomery K, Nielsen TO, Rubin BP, Patel R, Goldblum JR, Brown PO, van de Rijn M.
Am J Surg Pathol. 2004; 2 : 1063-1069.
PMID 15252314
 

Citation

This paper should be referenced as such :
Patel, K ; Lopez-Terrada, D
Soft tissue tumors: Dermatofibrosarcoma protuberans
Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):600-602.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/DermFibroSarcProtID5059.html


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

Genes ACTB COL1A1 GLI1 PDGFB

Translocations implicated (Data extracted from papers in the Atlas)

 t(17;22)(q22;q13) COL1A1-PDGFB

External links

Mitelman database t(17;22)(q22;q13) COL1A1-PDGFB [Case List]    t(17;22)(q22;q13) COL1A1-PDGFB [Association List] Mitelman database (CGAP - NCBI)
arrayMap Topo ( C47,C49) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionCOL1A1 (17q21.33) PDGFB (22q13.1)    [fusion1285] [fusion1286] [fusion1289] [fusion1290] [fusion1291] [fusion1292] [fusion1293] [fusion1294] [fusion531] [fusion532] [fusion533] [fusion534] [fusion535] [fusion536] [fusion537] [fusion538] [fusion539] [fusion540] [fusion541] [fusion542] [fusion543] [fusion544] [fusion545] [fusion546] [fusion547] [fusion548] [fusion549] [fusion550] [fusion551] [fusion552] [fusion553] [fusion554] [fusion555] [fusion556] [fusion557] [fusion558] [fusion559] [fusion560] [fusion561] [fusion562] [fusion563] [fusion564] [fusion565] [fusion591] [fusion592] [fusion593] [fusion594] [fusion595] [fusion596] [fusion597] [fusion598] [fusion599] [fusion600] [fusion601] [fusion602] [fusion603] [fusion604] [fusion605] [fusion606] [fusion607] [fusion608] [fusion626] [fusion627] [fusion634] [fusion635] [fusion636] [fusion637] [fusion638] [fusion639] [fusion640] [fusion641] [fusion642] [fusion643] [fusion644] [fusion645] [fusion646] [fusion647] [fusion648] [fusion649] [fusion650] [fusion651] [fusion652] [fusion653] [fusion654] [fusion655] [fusion656] [fusion815] [fusion816] [fusion817] [fusion818] [fusion819] [fusion820]
Mitelman databaseCOL1A1/PDGFB[MCList]    COL1A1 (17q21.33) PDGFB (22q13.1)   t(17;22)(q21;q13)
TICdbCOL1A1/PDGFB    COL1A1 (17q21.33) PDGFB (22q13.1)
 
Disease databaseSoft Tissues: Dermatofibrosarcoma Protuberans
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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