Dermatofibrosarcoma Protuberans
A number sign (#) is used with this entry because dermatofibrosarcoma protuberans is caused in most cases by a specific fusion of the COL1A1 gene (120150) with the PDGFB gene (190040); see 190040.0002.
DescriptionDermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive, but rarely metastasizing tumor of the deep dermis and subcutaneous tissue. It typically presents during early or middle adult life and is most frequently located on the trunk and proximal extremities (Sandberg et al., 2003).
Clinical FeaturesDFSP was first described by Taylor (1890). Sirvent et al. (2003) stated that, because DFSP is relatively rare, grows slowly, and has a low level of aggressiveness, its clinical significance has been underestimated. In particular, they noted that the existence of pediatric cases has been overlooked.
Gardner et al. (1998) described a father and son with dermatofibrosarcoma protuberans. The tumors arose at ages 43 and 14 years, respectively.
Sandberg et al. (2003) described the case of a 57-year-old woman with a tumor of the breast suspected of being a DFSP. To confirm the diagnosis, molecular studies were performed on fixed tumor and revealed the presence of the COL1A1/PDGFB fusion product, characteristic of DFSP.
Clinical ManagementSirvent et al. (2003) stated that the preferred treatment for DFSP is wide surgical excision with pathologically negative margins. They noted that there is evidence from in vivo experiments (Greco et al., 2001) and from clinical observations in patients (Maki et al., 2002; Rubin et al., 2002) that the PDGF receptor tyrosine kinase antagonist imatinib mesylate (Gleevec; STI571) may be an effective treatment for metastatic or locally advanced DFSP.
Snow et al. (2004) reviewed treatment specifically by Mohs micrographic surgery applied in 29 patients. There was no reference to familial occurrence.
CytogeneticsSimon et al. (1997) characterized the breakpoints from translocations and rings in DFSP and its juvenile form, giant cell fibroblastoma, on the genomic and RNA levels. They found that these rearrangements fuse the PDGFB gene and the COL1A1 gene. Simon et al. (1997) commented that PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes was not fully understood. They noted that neither COL1A1 nor PDGFB had hitherto been implicated in tumor translocations. The gene fusions deleted exon 1 of PDGFB and released this growth factor from its normal regulation.
Kiuru-Kuhlefelt et al. (2001) suggested that cytogenetically, DFSP is often characterized by supernumerary ring chromosomes containing material from chromosomes 17 and 22. Kiuru-Kuhlefelt et al. (2001) used comparative genomic hybridization to analyze DNA copy number changes in 11 cases of typical DFSP and 10 cases of fibrosarcoma-DFSP. All cases in both groups exhibited a gain or high-level amplification on 17q and most also on 22q. This suggested that not only fusion of the COL1A1 and PDGFB genes but also DNA chromosome number gains in the 17q and 22q regions is crucial in the pathogenesis of DFSP. In the fibrosarcoma cases, the trend toward increase in number of DNA copy was not statistically significant.
Sirvent et al. (2003) reviewed the cytogenetics of DFSP. DFSP cells are characterized at the cytogenetic level by either supernumerary ring chromosomes, which have been shown by FISH techniques to be derived from chromosome 22 and to contain low-level amplified sequences from 17q22-qter and 22q10-q13.1, or t(17;22), that are most often unbalanced. Both the rings and linear der(22) contain a specific fusion of the COL1A1 gene with the PDGFB gene. Similar to other tumors, the COL1A1/PDGFB fusion is occasionally cryptic, associated with complex chromosomal rearrangements. Whereas rings have been observed mainly in adults, translocations have been reported in all pediatric cases. Molecular investigations have shown that the breakpoint in PDGFB is remarkably constant, placing exon 2 under the control of the COL1A1 promoter. In contrast, the COL1A1 breakpoint is variably located within the exons of the alpha-helical coding region (exons 6 to 49). No preferential COL1A1 breakpoint and no correlation between the breakpoint location and the age of the patient or any clinical histologic peculiarities have been described. Molecular studies have established the identity of 'classic' DFSP, giant cell fibroblastoma, Bednar tumor, adult superficial fibrosarcoma, and the granular cell variant of DFSP. In approximately 8% of DFSP cases, the COL1A1/PDGFB fusion is not found, suggesting that genes other than COL1A1 or PDGFB may be involved in a subset of cases. PDGFB may act as a mitogen in DFSP cells by autocrine stimulation of the PDGF receptor (173410).
Molecular GeneticsNakanishi et al. (2007) used RT-PCR to examine the COL1A1/PDGFB transcript using frozen biopsy specimens from 3 unrelated patients with DFSP and identified fusion of COL1A1 exon 25, exon 31, and exon 46, respectively, to exon 2 of the PDGFB gene. Clinical features and histopathology did not demonstrate any specific characteristics associated with the different transcripts.