Current treatment options for dermatofibrosarcoma protuberans

Abstract

Dermatofibrosarcoma protuberans (DFSP) is rare, infiltrating dermal neoplasm, characterized by indolent growth and low probability of metastases. The critical event in DFSP development is the rearrangement of chromosome 17 and 22, leading to transcriptional up-regulation of platelet-derived growth factor, providing an autocrine and/or paracrine stimulus. The cornerstone of treatment for localized DFSP is complete surgical resection with microscopically negative margins. Adjuvant radiotherapy is suggested in cases of positive margins when re-excision is not feasible. The first effective systemic therapy in DFSP introduced into clinical practice was imatinib, demonstrating dramatic activity in advanced cases. Current results indicate that some DFSP patient initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned resectable after imatinib therapy and this rational approach leading to complete remission maybe potentially curative. The clinical experience with other tyrosine kinase inhibitors is limited and imatinib remains the gold standard treatment of locally unresectable/metastatic DFSP. This review summarizes state of the art and perspectives on the DFSP management.

Keywords:

• dermatofibrosarcoma protuberans
• imatinib
• molecular targeted therapy
• neoadjuvant therapy
• tyrosine kinase inhibitor

Financial & competing interests disclosure

P Rutkowski has received honoraria from Novartis, Pfizer and Bayer, and has served as a member of advisory board for Novartis and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• From a molecular point of view dermatofibrosarcoma protuberans (DFSP) is characterized by distinctive, reciprocal rearrangement of chromosomes 17 and 22 in the form of translocation t(17;22)(q22;q13) and often supernumerary ring chromosome that leads to the fusion of collagen type I α1 chain gene (COL1A1) to the PDGF B-chain gene (PDGFB).

• These molecular changes in DFSP can be detected by the fluorescent in situ hybridization or reverse transcription PCR technique, which is especially useful in the diagnosis of fibrosarcomatous transformation (FS-DFSP), metastatic and atypical DFSP cases.

• That rearranged PDGF gene leads to production of functional PDGF that can bind to and activate PDGF receptors on tumor cells, providing an autocrine and/or paracrine mitogenic stimulus leading to malignant transformation.

• The crucial treatment for localized DFSP consists of complete surgical resection with microscopically negative margins. Adjuvant radiotherapy is suggested in the case of positive margins when re-excision is not feasible.

• The first effective systemic therapy in DFSP introduced into clinical practice was imatinib mesylate, demonstrating dramatic activity in advanced cases. Imatinib therapy is currently the standard of care in therapy of inoperable and/or metastatic cases of DFSP, and this targeted therapy may potentially facilitate resection or decrease possible disfigurement. The confirmation of the molecular target (COL1A1–PDGFB fusion) presence should be performed prior to the start of imatinib therapy.

• The neoadjuvant imatinib strategy leading to tumor downstaging and decrease of excision morbidity by tissue-sparing appears to be very attractive in patients with tumors considered initially irresectable or resectable only at the cost of major functional morbidity.

• The clinical experience with other tyrosine kinase inhibitors in DFSP is very limited and currently imatinib remains the gold standard in therapy of localized unresectable or metastatic DFSP. Further studies are necessary for understanding the mechanisms of secondary resistance to imatinib and development of second-line options for systemic therapy.

Notes