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.
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
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
A core needle biopsy (or core biopsy) involves removal of a very small amount of tumor and is performed by inserting a hollow needle through the skin and into the organ or abnormality to be investigated. The needle is then advanced within the cell layers to remove a sample or core. This procedure takes a few minutes to perform and may be undertaken in an outpatient setting.
An incisional biopsy removes only a portion of the tumor for the pathologist to examine. An incisional biopsy is generally reserved for tumors that are larger and offers the pathologist a larger specimen with which to work. This type of biopsy has a slightly higher diagnostic success rate and is usually carried out in the operating room.
An excisional biopsy involves removal of the entire tumor and is typically reserved for very small lesions in which an incisional biopsy or a core needle biopsy is not practical. It is usually performed in cases where removing the entire lesion along with a narrow margin of normal tissue is easily accomplished and tolerated by the patient. This is also often performed in the operating room.
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
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
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
A chromosomal translocation is an abnormal rearrangement of DNA between chromosomes. When the translocation occurs between two nonhomologous chromosomes, it is termed a reciprocal translocation. Reciprocal translocations are usually harmless in carriers; however, there is an increased risk for miscarriages or children with abnormalities. A Robertsonian translocation involves two acrocentric chromosomes that fuse near the centromere region with loss of the short arms. The resulting karyotype leaves only 45 chromosomes since two chromosomes have fused together. Like other translocations, carriers of Robertsonian translocations are phenotypically normal, but there is a risk of unbalanced gametes which lead to miscarriages or abnormal offspring.
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
Who treats DFSP?
Dermatologists routinely diagnose and treat lesions of the skin. Most cases of DFSP can be adequately treated by a dermatologist in an outpatient setting. In cases of very large or advanced DFSP, or where major reconstructive surgery will be needed, a multidisciplinary approach is recommended. This involves an oncologist, dermatologist, and a pathologist. In cases involving the deep tissues or bones, the participation of an orthopaedic surgeon specializing in tumor surgery may be necessary. In cases where extensive surgical reconstruction will be necessary, a plastic surgeon may be called upon.
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
Mohs surgery, created by Dr. Fredrick E. Mohs, is microscopically controlled surgery that is highly effective for common types of skin cancer. The surgery involves four steps:
- Surgical removal of tissue.
- Mapping the piece of tissue, freezing and cutting the tissue and staining with H&E or other stains.
- Interpretation of microscope slides.
- Reconstruction of the surgical defect.
The procedure is usually performed in a physician's office under local anesthetic. A small scalpel is utilized to cut around the visible tumor. A very small surgical margin is utilized, usually with 1 to 1.5 mm of "free margin" or uninvolved skin. Because the Mohs procedure is microscopically controlled, it provides precise removal of tumor, while healthy tissue is spared.
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
DFSP's Response to Imatinib
The effectiveness of Imatinib in the treatment of DFSP is likely related to the tumor’s dependence on this pathway with the common translocation driving the constitutive expression of the PDGF ligand. This is a unique example of a tumor that responds to a specific targeted therapy which is not based on genetic amplification or mutation. The limitation on developing imatinib clinically for the treatment of DFSP is that it is a benign to intermediate grade tumor in which complete surgical resection obviates the need for systemic therapy. Imatinib likely will be only applicable to the subset of patients with unresectable, recurrent or metastatic disease. However, phase II trials of treating DFSP with Imatinib are currently in progress and while some of them have recently been completed, only preliminary results are available to date.40-42 Additional PDGF receptor inhibitors, including sunitinib, pazopanib and sorafenib, are currently undergoing evaluation as well.4,43
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
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.