Annals of Surgical Oncology

, Volume 14, Issue 10, pp 2876–2886 | Cite as

Dermatofibrosarcoma Protuberans: Recent Clinical Progress

Bone and Soft Tissue Sarcomas

Abstract

Background

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor of low malignant grade characterized by a pattern of slow, infiltrative growth and a marked tendency to recur locally after surgical excision. Wide surgical resection is generally accepted as optimal treatment for DFSP. However, despite optimal surgical management, distant metastases may develop in up to 5% of patients. More than 90% of DFSP are characterized by a reciprocal chromosomal translocation, t(17;22). This rearrangement leads to constitutive activation of the platelet-derived growth factor receptor (PDGFR) as a result of deregulated ligand expression, thus providing a rationale for targeted inhibition of PDGFR as a treatment strategy for patients with unresectable locally advanced or metastatic DFSP.

Methods

This article reviews the current understanding of DFSP, with emphasis on molecular-level pathogenetic events and their implications for management, and evidence for the role of tyrosine kinase inhibition in improving the outcomes of patients with unresectable locally advanced or metastatic DFSP.

Results

Surgery with wide margins remains the cornerstone in the management of DFSP. Recently, imatinib, a potent, selective inhibitor of the PDGFR alpha and PDGFR beta protein-tyrosine kinases, has been reported to induce complete or partial remissions in most patients treated for advanced DFSP.

Conclusions

Imatinib is approved for treatment of adult patients with unresectable, recurrent, and/or metastatic DFSP who are not eligible for surgery. Future investigations will determine whether imatinib can also be used in the neoadjuvant setting to reduce tumor volume, thereby allowing resection of very large DFSP that would otherwise not be resectable.

Keywords

Dermatofibrosarcoma protuberans Platelet-derived growth factor receptor Imatinib Molecular-targeted therapy 

Notes

ACKNOWLEDGMENTS

Grant McArthur, MD, participated in the conception, design, and writing of this review. Dr. McArthur discloses the following potential conflicts of interest, which occurred within 3 years of beginning the work on this article: service as a consultant for Pfizer and Novartis; receipt of research funding from Pfizer and Novartis; and receipt of honoraria from Novartis.

REFERENCES

  1. 1.
    Chang CK, Jacobs IA, Salti GI. Outcomes of surgery for dermatofibrosarcoma protuberans. Eur J Surg Oncol 2004;30:341–5PubMedCrossRefGoogle Scholar
  2. 2.
    Gloster HM Jr. Dermatofibrosarcoma protuberans. J Am Acad Dermatol 1996;35(3 Pt 1):355–74PubMedCrossRefGoogle Scholar
  3. 3.
    Fiore M, Miceli R, Mussi C, et al. Dermatofibrosarcoma protuberans treated at a single institution: a surgical disease with a high cure rate. J Clin Oncol 2005;23:7669–75PubMedCrossRefGoogle Scholar
  4. 4.
    Gloster HM, Jr., Harris KR, Roenigk RK. A comparison between Mohs micrographic surgery and wide surgical excision for the treatment of dermatofibrosarcoma protuberans. J Am Acad Dermatol 1996;35:82–7PubMedCrossRefGoogle Scholar
  5. 5.
    Mendenhall WM, Zlotecki RA, Scarborough MT. Dermatofibrosarcoma protuberans. Cancer 2004;101:2503–8PubMedCrossRefGoogle Scholar
  6. 6.
    Szollosi Z, Nemes Z. Transformed dermatofibrosarcoma protuberans: a clinicopathological study of eight cases. J Clin Pathol 2005;58:751–6PubMedCrossRefGoogle Scholar
  7. 7.
    Wacker J, Khan-Durani B, Hartschuh W. Modified Mohs micrographic surgery in the therapy of dermatofibrosarcoma protuberans: analysis of 22 patients. Ann Surg Oncol 2004;11:438–44PubMedCrossRefGoogle Scholar
  8. 8.
    Snow SN, Gordon EM, Larson PO, Bagheri MM, Bentz ML, Sable DB. Dermatofibrosarcoma protuberans: a report on 29 patients treated by Mohs micrographic surgery with long-term follow-up and review of the literature. Cancer 2004;101:28–38PubMedCrossRefGoogle Scholar
  9. 9.
    Bowne WB, Antonescu CR, Leung DH, et al. Dermatofibrosarcoma protuberans: a clinicopathologic analysis of patients treated and followed at a single institution. Cancer 2000;88:2711–20PubMedCrossRefGoogle Scholar
  10. 10.
    Nakra T, Cook T, Douglas RS, Goldberg RA. Dermatofibrosarcoma protuberans metastatic to the orbit. Arch Ophthalmol 2004;122:1240–1PubMedCrossRefGoogle Scholar
  11. 11.
    Yokoyama Y, Murakami Y, Sasaki M, et al. Pancreatic metastasis of dermatofibrosarcoma protuberans. J Gastroenterol 2004;39:798–800PubMedCrossRefGoogle Scholar
  12. 12.
    Shimizu A, O’Brien KP, Sjoblom T, et al. The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 1999;59:3719–23PubMedGoogle Scholar
  13. 13.
    Sjoblom T, Shimizu A, O’Brien KP, et al. Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 2001;61:5778–83PubMedGoogle Scholar
  14. 14.
    McArthur GA, Demetri GD, van Oosterom A, et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol 2005;23:866–73PubMedCrossRefGoogle Scholar
  15. 15.
    Greco A, Roccato E, Miranda C, Cleris L, Formelli F, Pierotti MA. Growth-inhibitory effect of STI571 on cells transformed by the COL1A1/PDGFB rearrangement. Int J Cancer 2001;92:354–60PubMedCrossRefGoogle Scholar
  16. 16.
    Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 1996;56:100–4PubMedGoogle Scholar
  17. 17.
    Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000;295:139–45PubMedGoogle Scholar
  18. 18.
    Dewar AL, Cambareri AC, Zannettino AC, et al. Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 2005;105:3127–32PubMedCrossRefGoogle Scholar
  19. 19.
    Okuda K, Weisberg E, Gilliland DG, Griffin JD. ARG tyrosine kinase activity is inhibited by STI571. Blood 2001;97:2440–8PubMedCrossRefGoogle Scholar
  20. 20.
    Maki RG, Awan RA, Dixon RH, Jhanwar S, Antonescu CR. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer 2002;100:623–6PubMedCrossRefGoogle Scholar
  21. 21.
    McArthur G. Molecularly targeted treatment for dermatofibrosarcoma protuberans. Semin Oncol 2004;31(2 Suppl 6):30–6PubMedCrossRefGoogle Scholar
  22. 22.
    Rubin BP, Schuetze SM, Eary JF, et al. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002;20:3586–91PubMedCrossRefGoogle Scholar
  23. 23.
    Labropoulos SV, Fletcher JA, Oliveira AM, Papadopoulos S, Razis ED. Sustained complete remission of metastatic dermatofibrosarcoma protuberans with imatinib mesylate. Anticancer Drugs 2005;16:461–6PubMedCrossRefGoogle Scholar
  24. 24.
    Naeem R, Lux ML, Huang SF, Naber SP, Corson JM, Fletcher JA. Ring chromosomes in dermatofibrosarcoma protuberans are composed of interspersed sequences from chromosomes 17 and 22. Am J Pathol 1995;147:1553–8PubMedGoogle Scholar
  25. 25.
    Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Dermatofibrosarcoma protuberans and giant cell fibroblastoma. Cancer Genet Cytogenet 2003;140:1–12PubMedCrossRefGoogle Scholar
  26. 26.
    Simon MP, Pedeutour F, Sirvent N, et al. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet 1997;15:95–8PubMedCrossRefGoogle Scholar
  27. 27.
    Heldin CH, Ostman A, Ronnstrand L. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1998;1378:F79–113PubMedGoogle Scholar
  28. 28.
    O’Brien KP, Seroussi E, Dal Cin P, et al. Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas. Genes Chromosomes Cancer 1998;23:187–93PubMedCrossRefGoogle Scholar
  29. 29.
    Wang J, Hisaoka M, Shimajiri S, Morimitsu Y, Hashimoto H. Detection of COL1A1-PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues. Diagn Mol Pathol 1999;8:113–9PubMedCrossRefGoogle Scholar
  30. 30.
    Greco A, Fusetti L, Villa R, et al. Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans. Oncogene 1998;17:1313–9PubMedCrossRefGoogle Scholar
  31. 31.
    Mentzel T, Beham A, Katenkamp D, Dei Tos AP, Fletcher CD. Fibrosarcomatous (“high-grade”) dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. Am J Surg Pathol 1998;22:576–87PubMedCrossRefGoogle Scholar
  32. 32.
    Stojadinovic A, Karpoff HM, Antonescu CR, et al. Dermatofibrosarcoma protuberans of the head and neck. Ann Surg Oncol 2000;7:696–704PubMedCrossRefGoogle Scholar
  33. 33.
    Martin L, Piette F, Blanc P, et al. Clinical variants of the preprotuberant stage of dermatofibrosarcoma protuberans. Br J Dermatol 2005;153:932–6PubMedCrossRefGoogle Scholar
  34. 34.
    West RB, Harvell J, Linn SC, et al. Apo D in soft tissue tumors: a novel marker for dermatofibrosarcoma protuberans. Am J Surg Pathol 2004;28:1063–9PubMedCrossRefGoogle Scholar
  35. 35.
    Ramakrishnan VSA, Ehrlich M, Powell S, Lucci A Jr. Atypical dermatofibrosarcoma protuberans in the breast. Breast J 2005;11:217–8PubMedCrossRefGoogle Scholar
  36. 36.
    Mizutani K, Tamada Y, Hara K, et al. Imatinib mesylate inhibits the growth of metastatic lung lesions in a patient with dermatofibrosarcoma protuberans. Br J Dermatol 2004;151:235–7PubMedCrossRefGoogle Scholar
  37. 37.
    McArthur GA. Dermatofibrosarcoma protuberans: a surgical disease with a molecular savior. Curr Opin Oncol 2006;18:341–6PubMedCrossRefGoogle Scholar
  38. 38.
    Rutgers EJ, Kroon BB, Albus-Lutter CE, Gortzak E. Dermatofibrosarcoma protuberans: treatment and prognosis. Eur J Surg Oncol 1992;18:241–8PubMedGoogle Scholar
  39. 39.
    Khatri VP, Galante JM, Bold RJ, Schneider PD, Ramsamooj R, Goodnight JE, Jr. Dermatofibrosarcoma protuberans: reappraisal of wide local excision and impact of inadequate initial treatment. Ann Surg Oncol 2003;10:1118–22PubMedCrossRefGoogle Scholar
  40. 40.
    Mohs FE. Chemosurgery. Clin Plast Surg 1980;7:349–60PubMedGoogle Scholar
  41. 41.
    Nouri K, Lodha R, Jimenez G, Robins P. Mohs micrographic surgery for dermatofibrosarcoma protuberans: University of Miami and NYU experience. Dermatol Surg 2002;28:1060–4PubMedCrossRefGoogle Scholar
  42. 42.
    Massey RA, Tok J, Strippoli BA, Szabolcs MJ, Silvers DN, Eliezri YD. A comparison of frozen and paraffin sections in dermatofibrosarcoma protuberans. Dermatol Surg 1998;24:995–8PubMedCrossRefGoogle Scholar
  43. 43.
    Garcia C, Viehman G, Hitchcock M, Clark RE. Dermatofibrosarcoma protuberans treated with Mohs surgery. A case with CD34 immunostaining variability. Dermatol Surg 1996;22:177–9PubMedCrossRefGoogle Scholar
  44. 44.
    National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Dermatofibrosarcome protuberans. Version 1.2006. Available at http://www.nccn.org/professionals/physicians_gls/PDF/dfsp.pdf. Accessed July 27, 2006
  45. 45.
    Suit H, Spiro I, Mankin HJ, Efird J, Rosenberg AE. Radiation in management of patients with dermatofibrosarcoma protuberans. J Clin Oncol 1996;14:2365–9PubMedGoogle Scholar
  46. 46.
    Ballo MT, Zagars GK, Pisters P, Pollack A. The role of radiation therapy in the management of dermatofibrosarcoma protuberans. Int J Radiat Oncol Biol Phys 1998;40:823–7PubMedCrossRefGoogle Scholar
  47. 47.
    Dagan R, Morris CG, Zlotecki RA, Scarborough MT, Mendenhall WM. Radiotherapy in the treatment of dermatofibrosarcoma protuberans. Am J Clin Oncol 2005;28:537–9PubMedCrossRefGoogle Scholar
  48. 48.
    Lindner NJ, Scarborough MT, Powell GJ, Spanier S, Enneking WF. Revision surgery in dermatofibrosarcoma protuberans of the trunk and extremities. Eur J Surg Oncol 1999;25:392–7PubMedCrossRefGoogle Scholar
  49. 49.
    Price V, Zielenska M, Smith C, Chilton-Macneill S, Malkin D, Pappo A. Clinical and molecular characteristics of pediatric gastrointestinal stromal tumors (GISTs) [abstract]. Proc Am Soc Clin Oncol 2004;23:804Google Scholar
  50. 50.
    Price VE, Fletcher JA, Zielenska M, et al. Imatinib mesylate: an attractive alternative in young children with large, surgically challenging dermatofibrosarcoma protuberans. Pediatr Blood Cancer 2005;44:511–5PubMedCrossRefGoogle Scholar
  51. 51.
    Corless CL, Heinrich MC, Dimitrijevic S, et al. Correlation of imatinib response with activation of KIT and PDGF receptors in a variety of cancers: results of the CSTIB2225 trial [abstract]. Proc Am Soc Clin Oncol 2003;22:783Google Scholar
  52. 52.
    van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3PubMedCrossRefGoogle Scholar
  53. 53.
    Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80PubMedCrossRefGoogle Scholar
  54. 54.
    Imatinib in dermatofibrosarcoma protuberans (DFSP): sponsored by Dermatologic Cooperative Oncology Group. ClinicalTrials.gov identifier: NCT00122473Google Scholar
  55. 55.
    Neoadjuvant imatinib in dermatofibrosarcoma protuberans: sponsored by Sarcoma Alliance for Research Through Collaboration. ClinicalTrials.gov identifier: NCT00243191Google Scholar
  56. 56.
    A short course of neoadjuvant Gleevec (imatinib mesylate) in dermatofibrosarcoma protuberans: sponsored by University of Michigan Cancer Center. ClinicalTrials.gov identifier: NCT00176709Google Scholar
  57. 57.
    Imatinib mesylate in treating patients with locally advanced or metastatic dermatofibrosarcoma protuberans or giant cell fibroblasoma: sponsored by European Organization for Research and Treatment of Cancer. ClinicalTrials.gov identifier: NCT00085475Google Scholar
  58. 58.
    Imatinib mesylate in treating patients with locally recurrent or metastatic dermatofibrosarcoma protuberans (DFSP) or transformed fibrosarcomatous DFSP: sponsored by Southwest Oncology Group and National Cancer Institute. ClinicalTrials.gov identifier: NCT00084630Google Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  1. 1.Peter MacCallum Cancer CentreEast MelbourneAustralia

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