Introduction

Dermatofibrosarcoma protuberans (DFSP) is a low to intermediate grade soft-tissue sarcoma originating from the dermal layer of the skin. Although historically it has been attributed to fibroblastic origin, DFSP is now thought to originate from mesenchymal stem cells according to the currently dominant cancer stem cell hypothesis.¹  In 1924, Darier and Ferrand first described the entity of DFSP as a "progressive and recurring dermatofibroma," underscoring its predilection for local recurrence.² DFSP is a locally aggressive tumor and despite sharing some histologic features with fibrohistiocytic tumors, it tends to grow in a more infiltrative manner. Three-dimensional reconstructions of DFSP have shown that the tumor can assume irregular shapes and extend in a villous or finger-like manner.³ 

These irregular, tentacle-like extensions are believed to be responsible for the common clinical dilemma of local recurrence following inadequate resection.⁴ Metastases are rare and usually occur late in the disease course.

Epidemiology

DFSP comprises roughly .01% of all malignant tumors and approximately 2 to 6 percent of all soft-tissue sarcomas.^5-6 The estimated incidence is 0.8 to 5 cases per 1 million persons per year,^7-11 which is roughly 1,000 new cases per year in America. The incidence among blacks (6.5 per million) is almost double that among whites (3.9 per million).¹²  It most commonly affects patients between 20 and 50 years of age, although it has been described in both children and in the elderly.¹³ Congenital DFSP is a recognized entity but is extremely uncommon.^13-16

Clinical Features

DFSP usually has a long slow indolent course, with early tumors appearing as painless areas of cutaneous thickening (Figure 1). They may have pink, dark red or even bluish discoloration, particularly at the periphery. Over time, they develop into a larger nodular mass, and ultimately can develop into a large fungating lesion (Figure 2). When they grow into the epidermal layer of the skin, they may eventually ulcerate. Unlike tumors of the subcutaneous tissue, DFSP is adherent or intimate with its overlying skin. Typically it is not adherent to underlying structures, with most tumors being superficial and less than 5 cm in size at time of diagnosis.¹⁷

The duration of tumor growth ranges from months to years and may, in some cases, span decades. DFSP often is mistaken for lipomas, deep-seated epidermal cysts, scars, hypertrophic scars, keloids, dermatofibromas, nodular fasciitis, and insect bites¹⁸ and a delayed diagnosis is not uncommon. The trunk is the most common location (47%), followed by lower extremity (20%), upper extremity (18%), and finally head and neck (14%).¹⁷

DFSP is a malignant tumor, but only metastasizes 1-4% of the time.¹⁷ Metastasis is a late clinical outcome and typically occurs only after several local recurrences.¹⁹

Diagnosis of DFSP

Although routine imaging is not necessary, magnetic resonance imaging (MRI) may be helpful to evaluate the gross local extent of the tumor and may be important in preoperative planning for larger tumors. As with many other soft tissue tumors, T1-weighted images demonstrate low signal characteristics while T2-weighted images exhibit higher signal. While MRI can adequately delineate the bulk of the tumor, it does not define microscopic tumor extension. Furthermore, it does not clearly define recurrent lesions or lateral infiltration which is typical of this entity.²⁰  In patients with prolonged or recurrent DFSP or when sarcomatous changes are evident (DFSP-FS (see below)) a CT of the chest should be obtained to evaluate for pulmonary metastases.⁴ A CT scan of the local area may be useful if bony involvement is suspected.⁴

Diagnosis is made using either a core needle or an open incisional biopsy. While the role of fine needle aspiration is established in cases of recurrent disease, initial biopsies should be larger samples that demonstrate the histologic architecture of the tumor.²¹

Staging

Although the American Joint Committee on cancer has not set forth a system specific for staging of DFSP, it is often staged according to the American Musculoskeletal Tumor Society Staging System which is based upon tumor grade and compartmentalization.²² A more recently published system in accordance with the Short German guidelines for DFSP distinguishes local tumor (Grade I) from nodal dissemination (Grade II) and from metastatic disease (Grade III).²³

Histopathology

DFSP has a characteristic histologic appearance of monomorphous bland spindle cells arranged in a storiform or "whorled" pattern (Figure 3). Early lesions may demonstrate a "Grenz zone," which is a tumor-free region separating the tumor from the epidermis. Unusual variants of DFSP include the Bednar tumor that is denoted by melanin-containing cells,²⁴ myxoid DFSP that contains areas of interstitial mucin, and the atrophic type.

Approximately 15% of cases contain a component of high-grade sarcoma. This is frequently, but not exclusively, a fibrosarcoma and therefore is usually referred to as DFSP-FS. The high-grade sarcoma portion can be variable in size, at times encompassing the majority of the underlying DFSP lesion. Even in cases that develop a high grade sarcomatous component, metastatic disease is rare and local recurrence remains the main concern.

Immunohistochemical analysis can be utilized to aid in the diagnosis. Staining for CD34 is commonly employed, and sensitivity has been reported as being between 84 and 100 percent (Figure 4).^25-27 Positivity for CD34 is lost within the areas of sarcomatous change in cases of DFSP-FS. In addition, staining for hyaluronate and vimentin is expected to be positive in DFSP, while staining for CD44, factor XIIIa and S100 is expected to be negative. Apolipoprotein D is expressed in DFSP and may be useful in differentiating the tumors from malignant fibrous histiocytoma (DFSP tx c PDGF receptor inhibitor).  Furthermore, the fusion gene COL1A1/PDGFB can be detected in the tissue by means of FISH (fluorescence in-situ hybridization).²⁸

Genetics

There is evidence that DFSP may originate from cutaneous mesenchymal stem cells that code for a cell surface protein termed nestin.²⁹ Nestin may also be useful for differentiating DFSP from dermatofibromas and may have application in intraoperative staining in the context of Moh’s surgery.

More than 90% of DFSPs exhibit a specific cytogenetic abnormality, either a supernumerary ring chromosome combining chromomoses 17 and 22 or an unbalanced chromosomal translocation between chromosomes 17 and 22.  It is now evident that the ring chromosomes are the more common abnormality and the translocation is typically only found in pediatric DFSP.^1,4  Regardless, the result is identical, and is defined by the fusion of the platelet-derived growth factor-B gene (PDGFB; chromosome 22) with the strongly expressed collagen 1 alpha 1 gene (COL1A1; chromosome 17). This leads to upregulated expression of the fusion oncogene and fully functional PDGFB.^30-32 This serves as a self-stimulatory or autocrine growth signal, which in turn leads to uncontrolled cell division and tumorigenesis.  Nonetheless, in 8% of cases of otherwise confirmed DFSP, the fusion transcript of COL1A1 and PDGFB is not identified, suggesting possible additional genes that may be involved in DFSP.⁴

Treatment of Dermatofibrosarcoma Protuberans

The mainstay of treatment of DFSP has been surgery.  Because of the high rates of recurrence, historical recommendations have sought 5 cm margins.³³

Recent NCCN guidelines recommend margins of 2 to 4 cms using conventional surgical management (Figures 5-7). Local recurrences can often be salvaged with further resection but the risk of local morbidity and the risk of metastasis both increase.  Occasionally, isolated metastatic disease can be surgically addressed.⁴

With the advent of Mohs surgery, complete excision with microscopic margins has yielded excellent outcomes and offers the benefit of decreased surgical morbidity. In a comparative study of wide resection versus Mohs surgery, wide resection was associated with a recurrence rate of 13% whereas Mohs surgery had no recurrences at 5 years.³⁴ Evidence is accumulating that Mohs surgery is the optimal surgical choice for most DFSP lesions with the exceptions of the aforementioned large/advanced DFSP that may require more extensive surgical and reconstructive procedures.^35,36

Conventional chemotherapy appears to offer little utility, however, treatment with the molecular targeted therapy Imatinib, has yielded some limited but encouraging results to date.⁴ Imatinib mesylate was designed as an abl-kinase inhibitor to treat Philadelphia chromosome positive leukemia (chronic myelogenous leukemia). Imatinib inhibits two additional kinases: c-KIT and PDGFR accounting for its efficacy in DFSP.²⁸  The application of Imatinib to DFSP has been limited but encouraging.  In one series, 10 patients with either locally advanced or metastatic disease showed variable response to Imatinib treatment. Of note was the association shown in one patient between the lack of the t(17,22) translocation and the lack of response to Imatinib treatment.²⁷ It is now the recommendation to perform  molecular analysis prior to initiating Imatinib treatment to ensure that a t(17:22) mutation exists.³⁷  Additional reports of successful use in cases of metastatic or surgically unresectable DFSP have been published.  A female patient with recurrent DFSP of the upper back and metastasis to the axilla and lung responded well following one month of treatment. At 3 months, the tumor regressed markedly and computed tomography imaging showed near complete resolution of the lung metastasis.³⁸ A male patient with DFSP of the thigh and metastatic disease of the spine was treated with Imatinib for 4 months and shown to have a 75% reduction in tumor size, permitting surgical resection. The resected tumor showed no signs of malignancy, demonstrating a full histopathologic response to treatment.³⁹  Imatinib is approved for the treatment of adult patients with unresectable, recurrent, or metastatic DFSP who are not eligible for surgery. Response to Imatinib appears to be short-lived with many patients developing resistance through as of yet unknown mechanisms.  Nonetheless, the treatment has led to the resectability of tumors that were thought to be unresectable prior to treatment due to the proximity of adjacent vital structures.²⁸

Numerous studies have investigated the use of radiotherapy in the treatment of DFSP and DFSP is considered a radio-sensitive tumor. Currently, there is limited objective data to support its routine use; however, successful application has been reported in a few small series. In one study, 10 patients with DFSP (one of which was DFSP-FS) were treated with surgery and post-operative radiotherapy. At the time of latest follow-up (21-185 months) nine of the patients remained free from recurrence. The patient with DFSP-FS experienced a local recurrence and eventually died with disease.⁴⁴ Radiation therapy (RT) can be used to decrease the risk of local recurrence when surgery and RT are combined. Haas et. al. studied 21 patients treated surgically, noting local control of 67% and in 17 patients treated with combined therapy (surgery and radiation therapy) the local control was 82%.⁴⁵  In other reviews, it was concluded that adjuvant radiotherapy may be considered in patients where repeated surgery may cause mutilation or functional impairment.^45-46

Prognosis

The general prognosis for DFSP is excellent. The overall rate of distant metastasis is only 5% and regional metastasis is 1%.⁴⁷ Historically, recurrence rates have been high, ranging from 11%- 53%, but with the advent of Mohs surgery, the rates have dropped. Even with recurrent DFSP, Mohs surgery has a 98% cure rate.⁴⁸

Metastasis is associated with a poor prognosis, with few patients surviving beyond two years. With initial encouraging results using Imatinib, improved prognosis even in cases of metastatic disease may be realized.

Introduction

Dermatofibrosarcoma protuberans (DFSP) is a rare dermal tumor (comprising approximately 1% of soft tissue sarcomas) with typically indolent growth over years and a probability of regional/distant metastases of less than 2-3%.^1,2 The disease most commonly affects adults aged 20-50 years. The estimated incidence of DFSP is 3 to 4.2 cases per million people per year, with equal sexual distribution.^3,4 In DFSP harboring areas of high-grade fibrosarcoma (called fibrosarcomatous DFSP or DFSP-FS) metastases develop in the range of 8-15%,^5,7 which is evidence of its more aggressive behavior. Distant metastases are usually localized in the lungs and less commonly in the lymph nodes. The standard treatment of this cutaneous sarcoma is radical, wide local excision; however a high rate of local control is also reported with the application of Mohs micrographic surgery.⁸ Since achieving negative margins is critical to prevent local relapse, the recommended margin of surgical excision is usually above 2 cm.¹ Radical surgery often requires the use of reconstructive techniques and may result in cosmetic disfigurement or functional impairment. Such mutilating procedures might be avoided if appropriate Mohs micrographic surgery can be applied.⁹ If radical resection is not feasible, radiotherapy may be applied to reduce the risk of local recurrence. The dose of radiotherapy varies within the range of 50-70 Gy.¹⁰ Overall, local recurrences have been reported in the range of 24-90%.^1,11

Molecular Biology

Almost all cases of DFSP are characterized by the distinctive reciprocal rearrangement of chromosomes 17 and 22 in the form of translocation t(17;22)(q22;q13) and often a supernumerary ring chromosome.^12-16 This rearrangement results in the fusion of collagen type I a1 chain gene (COL1A1) to the platelet-derived growth factor (PDGF) B-chain gene (PDGFB). This COL1A1-PDGFB fusion may be identified in virtually all DFSP cases by sensitive molecular diagnostic tests: the fluorescence in-situ (FISH) method or multiplex reverse transcription polymerase chain reaction (RT-PCR), which is extremely important for differential diagnosis of atypical, metastatic DFSP or DFSP-FS.^17,18 The consequences of these molecular events include the deregulation of PDGFB chain expression, the unscheduled expression of COL1A1/PDGFB fusion protein processing to mature homodimer PDGF-BB, and the continuous autocrine activation of PDGFR receptor B (PDGFRB), which is protein tyrosine kinase acting as a potent growth factor.^19-21 The rearranged PDGF gene leads to the production of functional platelet-derived growth factor that can bind to and activate platelet-derived growth factor receptors on tumor cells, providing an autocrine and/or paracrine mitogenic stimulus, leading to malignant transformation.²² In some cases of DFSP with no evidence of the 17;22 chromosomal translocation, other molecular abnormalities were shown, such as t(5;8).²³

Clinical Results

Advances in the understanding of the molecular mechanisms of DFSP have resulted in the introduction of targeted therapy acting on PDGFR to clinical practice. Imatinib mesylate is a tyrosine kinase inhibitor specifically directed toward BCR/ABL, KIT, FMS (the receptor for Colony Stimulating Factor 1), ARG (ABL-related gene) and PDGFR alpha and beta. It is an effective systemic therapy in most cases of DFSP. Imatinib competes with the adenosine triphosphate (ATP) molecule, blocking the tyrosine kinase receptor’s ability for autophosporylation, which results in inhibition of the damaged pathway of signal transduction and restoration of proper intracellular signaling.

The observation that autocrine overproduction of PDGFB from gene rearrangement is a key pathogenetic factor^19,20 and provoked the in vitro research, which showed inhibition of DFSP cell growth after exposure to imatinib mesylate.^22,24 The further demonstration of the inhibitory effect of imatinib on six different DFSP cell lines in vitro and in vivo²⁵ led to the investigation of this new therapeutic approach in the clinic. The first reports on six patients suggested the usefulness of imatinib in metastatic and locally advanced DFSP.^26-31 The next series of ten patients with locally advanced and/or metastatic DFSP treated in the Imatinib Target Exploration Consortium Study B2225 showed 100% response rate (50% were complete responses) in locally advanced cases and one partial response lasting seven months in the metastatic setting.³² These observations resulted in imatinib’s registration as the therapy of choice in inoperable and/or metastatic DFSP. In a phase II trial³³ evaluating the activity of imatinib in life-threatening malignancies expressing imatinib-sensitive tyrosine kinase, DFSP was the only one out of five tumor types where notable activity was shown with extensive regression in ten of twelve cases (50% partial remissions, 33.3% complete remissions).

Combined analysis of two prematurely closed phase II, single arm, open-label trials (European Organisation for Research and Treatment of Cancer no. 62027 and the Southwest Oncology Group no. S0345) regarding the efficacy of imatinib in advanced (inoperable and/or metastatic) DFSP has demonstrated a clinical benefit rate exceeding 70% for twenty-five patients with advanced DFSP, with median time to progression of 1.7 years.³⁴ Another study³⁵ on fifteen patients who did not qualify for clinical trials has proven the striking activity of imatinib mesylate in advanced DFSP, with clinical benefit rate approaching 80% as well as median Progression Free Survival (PFS) and Overall Survival (OS) were not reached. It has been shown that DFSP-FS is also sensitive to imatinib, although responses seem to be shorter in duration.³⁶ DFSP-FS tumors lacking the 17;22 chromosomal translocation³² do not respond to imatinib. The presence of a molecular target (COL1A1-PDGFB) is obligatory to confirm diagnosis of DFSP in every case prior to the start of imatinib therapy.

Given the fact that complete, wide surgical excision is the standard treatment in localized resectable DFSP cases, neoadjuvant imatinib therapy leading to tumor downstaging and less cosmetic disfigurement, functional impairment and excision morbidity appears very attractive. Lebbe et al.³⁷ presented a preliminary report on twenty-five resectable DFSP (median size – 4.5 cm) treated in a phase II trial with preoperative imatinib at the dose of 600 mg. daily. Objective partial response according to RECIST was observed in nine cases (36%). Present results indicate that some DFSP cases initially evaluated as unresectable/metastatic or necessitating disfiguring surgery were evaluated as resectable after imatinib therapy. This rational approach leading to complete remission may be potentially curative, although longer follow-up is needed. Further studies are necessary for elucidating whether preoperative imatinib therapy reduces the need for wide surgical margins or whether imatinib has activity as adjuvant therapy in cases of positive margins after excision or in other high-risk patients.

The dose of imatinib used in mentioned studies ranged from 400 to 800 mg. daily. Available clinical data are not sufficient to determine the optimal dose of initial imatinib treatment, since objective responses were observed both with lower and higher dosing schedules.

The majority of patients treated with imatinib experience side effects during treatment, but almost all are mild and manageable; the most common being fluid retention/edema, anemia, fatigue, nausea, skin rash, thrombocytopenia, vomiting, neutropenia and diarrhea.³³

Future Directions

There is still uncertainty concerning the mechanisms of imatinib action and resistance in the treatment of DFSP, as well as a need to identify novel molecular markers predicting response to such therapy. It was presumed that imatinib’s effect resulted from the inhibition of phosphorylation of PDGFR. Unexpectedly, the clinical activity of imatinib is striking even in DFSP that expresses a relatively low amount of activated PDGFRB. If tumor cells are dependent on that signaling mechanism, it seems that the inhibition of low-level receptor tyrosine kinases may still be clinically effective.

Summary

Imatinib is currently the gold standard therapy of inoperable, metastatic, or recurrent cases of DFSP. Such treatment may potentially facilitate resection or decrease disfigurement related to an extensive surgical procedure. A significant percentage of patients may be rendered free of disease by excision of residual disease following partial response on imatinib. Current therapy of DFSP with the 17;22 chromosomal translocation should be definitively conducted by a multidisciplinary team, including an oncological surgeon. The use of imatinib mesylate as initial therapy to decrease the extent of wide surgical resection and related morbidity should be always considered.