Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP) looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012, and analyzing the molecular profile of 5 DFSP and 5 FS-DFSP by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, immunohistochemistry). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4/23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP) while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon, by promoting the expression of epigenetic regulators such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represent a druggable target.
- Received February 26, 2016.
- Revision received May 11, 2016.
- Accepted May 16, 2016.
- Copyright ©2016, American Association for Cancer Research.