Dermatofibrosarcoma protuberans (DFSP) is a rare soft-tissue malignancy of cutaneous mesenchymal cell origin representing less than 0.1% of all cancers.1,2 DFSP is characterized by slow, infiltrative growth with substantial local invasion. Broad subclinical extension is common, with infiltration of subcutaneous tissue, fascia, or muscle. DFSP is associated with a high rate of local recurrence, particularly for tumors of the head and neck. Although DFSP can occur in childhood or congenitally, it predominantly presents in adults between age 20 and 50 years, with lesions most commonly located on the trunk or proximal extremities.3–5 Tumors classically appear as indurated, erythematous, or skin-colored plaques that may develop nodular or telangiectatic, atrophic areas. Slow clinical progression and difficulty distinguishing DFSP from benign scarring or dermatofibroma histologically can contribute to diagnostic delays.
Classical DFSP rarely metastasizes and is infrequently fatal. Approximately 10% of tumors can transform into a fibrosarcomatous variant with high-grade histology and poorer prognosis because of greater invasive and metastatic potential. For high-risk DFSP, chest radiograph or CT may be performed to exclude pulmonary metastasis, because the lung is the most common site of spread.6–8 Surgical excision with careful margin evaluation is the preferred treatment for DFSP. Low recurrence rates have been shown after Mohs micrographic surgery (MMS) or wide local excision, with en face margin evaluation performed using complete circumferential peripheral and deep margin assessment.9–14 However, in surgically difficult cases, complete excision may result in cosmetic deformity or functional disability. Using imatinib mesylate in the neoadjuvant setting may represent a partial solution to this problem in properly selected patients.
Molecular Pathogenesis of DFSP
The primary cytogenetic aberration detected in more than 90% of patients with DFSP involves a reciprocal chromosomal translocation between chromosomes 17 and 22, often with formation of supernumerary ring chromosomes. This rearrangement fuses the type I alpha I collagen gene (COL1A1), encoding the most abundant protein in the body, and the beta chain of platelet-derived growth factor (PDGFB) gene, generating amplified expression of PDGFB. Overstimulation of the cell-surface receptor tyrosine kinase PDGF receptor (PDGFR) by its ligand PDGFB, a potent growth factor, is thought to contribute to tumorigenesis.15–17 No correlation exists between COL1A1 breakpoints and any particular clinical or histopathologic characteristics.18,19
Imatinib in the Treatment of DFSP
Understanding the molecular pathogenesis of DFSP serves as a basis for targeted therapy using imatinib, a selective tyrosine kinase inhibitor (TKI) with efficacy against the tyrosine kinase receptors PDGFR, KIT, and Abl/Bcr-Abl.20 First approved by the FDA in 2001 for chronic myelogenous leukemia (CML), imatinib's approved useage was expanded in 2006 to include single-agent or adjuvant treatment for patients with unresectable, recurrent, or metastatic DFSP at a dose of 800 mg daily.21 Single-agent or adjuvant imatinib is also cited as an alternative to conventional chemotherapy and radiation therapy in the 2010 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Dermatofibrosarcoma Protuberans (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).22
A limited number of case reports and series have shown that imatinib can induce partial or complete regression of DFSP in approximately one half to two thirds of patients treated for FDA-approved indications. In fact, this drug offers a comparatively effective adjuvant option for patients with difficult DFSPs, considering that conventional chemotherapy is largely considered to be ineffective and radiation therapy can induce new or more aggressive tumors.23–26 Recent published data from 2 phase II clinical trials enrolling patients with locally advanced or metastatic DFSP showed a nearly 50% response rate with no significant difference in efficacy between imatinib doses of 400 and 800 mg daily.27 Extrapolating from the cumulative published experience with imatinib for treating DFSP, targeted therapy using other PDGFR-inhibiting TKIs may also play a role, especially if advances are made in selectivity, potency, or toxicity.
Cytogenetic confirmation using fluorescence insitu hybridization or reverse-transcriptase polymerase chain reaction may be used to confirm the diagnosis of DFSP or the presence of selected tyrosine kinase receptors in preparation for molecular targeted therapy with imatinib.18,19,28 Tumors without evidence of the t(17;22) chromosomal translocation or that do not depend on PDGFR signaling for growth do not respond to imatinib. Pretreatment testing for the presence of t(17;22) may indicate the potential for a clinical response.24,29
Role for Neoadjuvant Imatinib
Preoperative off-label imatinib therapy may yield partial responses with greater potential for a surgical cure in selected patients with DFSP. Of 16 patients in an EORTC study treated for 14 weeks with 800 mg daily of neoadjuvant imatinib, 4 achieved complete remission after wide local excision.27 Han et al.30 reported clinical responses with a mean decrease of 36.9% in preoperative tumor sizes and 100% local control up to 4 years after MMS in a small series of 4 patients who had taken 800 mg daily of imatinib for 3 months before surgery. Reduction in the clinically apparent tumor size and thickness corresponded with histologic findings of markedly decreased cellularity characterized by fewer CD34+ cells, along with significant hyalinization of dermal collagen (Figure 1). A similar effect has been seen using neoadjuvant imatinib in the treatment of gastrointestinal stromal tumors, and is likely the result of apoptosis.30–32 Case reports and data culled from phase II trials featuring small case series have substantiated the use of neoadjuvant imatinib in facilitating complete surgical excision through shrinking the tumor burden.33–37
Potential Pluses and Minuses of Neoadjuvant Imatinib
When undertaking preoperative neoadjuvant therapy with imatinib, the objective is to reduce tumor size for surgically challenging cases, including when the tumor is located in an area of cosmetic or functional significance or when incomplete excision is anticipated, which would result in a high risk of local recurrence. For properly selected patients, neoadjuvant imatinib may minimize the chance for disfigurement and enhance the possibility of a surgical cure. Although studies of limited numbers of patients suggest that neoadjuvant imatinib can be effective, long-term outcomes with respect to local margin control and disease-free survival are unknown. The limitations of collecting randomized, prospective clinical data for rare malignancies such as DFSP can be formidable. The decreased cellularity and hyalinization detected histologically after treatment with imatinib also raises the theoretical possibility of discontiguous inhibitory effects resulting from neoadjuvant imatinib treatment, with subsequent generation of skip lesions that could obscure identification of the true negative margin. This concern has not as yet been supported by data in the published literature or observed in patients treated with neoadjuvant imatinib for DFSP who were followed for up to 4 years after MMS.30–34
(A) The recurrent lesion on the scalp before imatinib therapy, measuring 7.3 × 6.5 cm. (B) A specimen from the center of the lesion before imatinib therapy, showing spindle cells in a storiform pattern typical of dermatofibrosarcoma protuberans (hematoxylin-eosin, original magnification X20). (C) The lesion size was reduced to 7.0 × 5.5 cm after a 3 month course of imatinib 400 mg twice daily. (D) A specimen from the center of the tumor after imatinib therapy showing decreased cellularity as well as significant hyalinization (hematoxylin-eosin, original magnification X20).
From Han A, Chen EH, Niedt G, et al. Neoadjuvant imatinib therapy for dermatofibrosarcoma protuberans. Arch Dermatol 2009;145:792–796, with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 8; 10.6004/jnccn.2010.0065
Although imatinib is generally well-tolerated with a favorable therapeutic index, each patient should be evaluated for pharmacologic benefits and risk of toxicity. Most adverse effects are mild and seldom limit the tolerability of the drug. Gastrointestinal irritation, fatigue, myalgias, peripheral edema, xerosis, and a maculopapular skin eruption (particularly in older patients) are most commonly encountered. Hematologic toxicity, which is fortunately less frequently observed, may be evaluated through serial complete blood cell counts. Monitoring of weight changes may help identify drug-induced edema. Serious adverse effects are rare, but severe edema, medication-induced cutaneous eruptions, such as Stevens-Johnson Syndrome, and organ failure have all been reported.21,38
Although imatinib is an uncommon cause of heart failure, cardiac safety is a special consideration in a small number of older patients with preexisting cardiac conditions. In addition to evaluating patient comorbidities, a careful medication history is important to assess potential drug interactions. Imatinib is primarily metabolized by the cytochrome P450 (CYP) 3A4 enzyme system. Concentrations of common drugs metabolized by these liver enzymes may therefore increase and the plasma level of imatinib may be altered. Careful monitoring or dosage adjustment is essential in the setting of hepatic impairment. Because targets, including PDGFR, are involved in bone metabolism, long-term use of imatinib may induce osteogenesis.21,38 An advantage of a limited course of imatinib as neoadjuvant therapy is that toxicities associated with long-term use may be avoided, but the ideal dose and duration of preoperative treatment is still unknown. Importantly, the potential teratogenicity of imatinib in animal studies limits its use in pregnancy and during lactation. Finally, as shown in the treatment of CML, measuring trough plasma concentrations of imatinib and maintaining an appropriate circulating dosage may correspond with improved clinical outcomes because drug bioavailability can vary.39 A multidisciplinary management approach facilitates safe use and monitoring in patients taking this drug.
Appropriate patient selection involves careful consideration of various factors. Tumor determinants include DFSP size, location, subtype, and the feasibility of complete excision. Small, low-grade tumors or tumors located in areas with significant skin and soft tissue laxity do not generally require neoadjuvant therapy, because surgical excision is straightforward to perform in these cases. For large or recurrent lesions, tumors on the head and neck, or those in proximity to critical structures may be good settings for neoadjuvant therapy with imatinib, particularly if an opportunity exists to preserve function or improve the likelihood of negative margins after surgery. If there is a chance that surgical treatment of a larger tumor may be inadequate, neoadjuvant imatinib may be able to reduce the tumor size and theoretically improve tumor resectability.
Conclusions
Insufficient data precludes the endorsement of a single treatment modality for high-risk DFSP. Although limited data are available on the use of imatinib in patients with DFSP, the existing data suggest that this drug may be beneficial as neoadjuvant therapy in properly selected individuals. Additional studies are needed to better elucidate the parameters for patient selection and treatment regimens. Because imatinib has a favorable safety profile, off-label use of this drug in the appropriate setting may mitigate unfavorable cosmetic or functional outcomes and even enhance surgical outcomes, suggesting that its beneficial effects have the potential to significantly outweigh its risks.
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