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Dermatology > MALIGNANT NEOPLASMS
Dermatofibrosarcoma Protuberans
Article Last Updated: Jun 12, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Chih-Shan Jason Chen, MD, PhD, Assistant Professor, Department of Dermatology, State University of New York at Stony Brook; Director, Dermatologic Surgery and Mohs Micrographic Surgery Unit, MSK Skin Cancer Center, Memorial Sloan-Kettering Cancer Center; Chief, Dermatologic Surgery, Northport Veterans Affairs Medical Center
Chih-Shan Jason Chen is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, American Society for Dermatologic Surgery, and Society for Investigative Dermatology
Coauthor(s):
Daniel Mark Siegel, MD, MS, Director, Procedural Dermatology Fellowship Program, Clinical Professor of Dermatology, Department of Dermatology, State University of New York Downstate
Editors: Abdul-Ghani Kibbi, MD, Chairman and Professor, Department of Dermatology, American University of Beirut Medical Center, Lebanon; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; John G Albertini, MD, Consulting Staff, Dermatologic Surgery, The Skin Surgery Center; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
DFSP, sarcomatous tumors resembling keloid, hypertrophic morphea, progressive and recurring dermatofibroma, fibrosarcomatous tumors with attenuated dermal surfaces, fibrosarcoma of the skin
Background
Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon soft tissue neoplasm with intermediate-to-low grade malignancy. Although metastasis rarely occurs, DFSP is a locally aggressive tumor with a high recurrence rate.
Although DFSP may have been reported in the literature as early as 1890, Darier and Ferrand first described it in 1924 as a distinct cutaneous disease entity called progressive and recurring dermatofibroma. Hoffman officially coined the term dermatofibrosarcoma protuberans in 1925.
Pathophysiology
DFSP is a cutaneous malignancy that arises from the dermis and invades deeper subcutaneous tissue (eg, fat, fascia, muscle, bone). The cellular origin of DFSP is not clear at this time. Evidence exists that supports the cellular origin being fibroblastic, histiocytic, or neuroectodermal. Cultured DFSP tumor cells have increased growth response to platelet-derived growth factor (PDGF)–B. Cytogenetic studies may reveal specific lesions in DFSP tumor cells, such as reciprocal translocations of chromosomes 17 and 22, t(17;22), and supernumerary ring chromosomes composed of interspersed sequences from bands 17(17q22) and 22(22q12). These rearrangements fuse the collagen type I alpha 1 (COL1A1) and the PDGF-B chain (PDGFB, c-sis proto-oncogene) genes. The collagen promoter drives COL1A1 and PDGFB fusion protein production. The fusion protein is then processed into functional PDGF-B and subsequently interacts with PDGF receptor on the cell surface of DFSP tumor cells. The activation of the PDGF receptor tyrosine kinase triggers the proliferation of DFSP tumor cells.
Frequency
United States
DFSP accounts for less than 0.1% of all malignant neoplasms and approximately 1% of all soft tissue sarcomas. The incidence has been estimated to be 0.8-5 cases per million population per year in 2 separate studies. In a most recent study based on data from 9 cancer registries from 1973-2002, the annual incidence of DFSP in the United States is 4.2 per million cases per year.1
International
The annual incidence of DFSP is reported as 3 cases per million population from a population-based cancer registry from 1982-2002 in France.2
Mortality/Morbidity
DFSP is a locally aggressive tumor with a high recurrence rate. Although metastasis of DFSP is rare (only 1-4% reported), almost all metastatic cases have been associated with local recurrence and a poor prognosis. Most of the patients with metastatic DFSP have died within 2 years. A small subset of DFSP patients presents with fibrosarcomatous progression. This fibrosarcomatous progression DFSP variant is more aggressive in nature and the clinical outcome usually is poor.
Race
DFSP has been reported in persons of all races, and no racial predilection seems to exist in the previous reports. However, a recent study conducted by Criscione and Weinstock1 found the incidence among blacks (6.5 cases per million population) was almost double the incidence among whites (3.9 cases per million population). An uncommon pigmented variant of DFSP, called the Bednar tumor, is found predominantly in black patients.
Sex
Several studies reveal an almost equal sexual distribution or a slight male predominance. In a large study3 of 902 patients with DFSP conducted by Rutgers et al, 514 (57%) patients were male and 388 (43%) patients were female.
Age
DFSP usually occurs in adults aged 20-50 years. Rarely, DFSP has been reported in newborns and elderly individuals (80 y).
History
DFSP is a very slowly growing tumor. Because of the slow progression, the diagnosis is often delayed.
- It may start as a small asymptomatic papule, which is likely ignored.
- The tumor may gradually enlarge into a lumpy nodule, or it may evolve into an atrophic and/or sclerotic plaque.
Physical
- DFSP usually presents as a large indurated plaque several centimeters in diameter. It is composed of firm, irregular nodules varying in color from flesh to reddish brown.
- Sometimes, it may present as a morphealike, atrophic, sclerotic, violaceous plaque without nodularity that may ulcerate as it slowly increases in size.
- DFSP most commonly occurs on the trunk, followed by the proximal extremities. It rarely occurs above the neck.
Causes
Currently, the cause of DFSP is unknown. Laboratory studies have shown that chromosomal aberrations may contribute to the pathogenesis of DFSP; however, no evidence of hereditary or familial predisposition exists. In 10-20% of patients with this tumor, trauma at the site seems to be incriminated. Surgical and old burn scars and sites of vaccinations have all been reported as sites of DFSP.
Dermatofibroma
Epidermal Inclusion Cyst
Keloid and Hypertrophic Scar
Malignant Melanoma
Metastatic Carcinoma of the Skin
Morphea
Other Problems to be Considered
Lymphoma
Fibrosarcoma
Lab Studies
No blood test is available to help detect or diagnose DFSP.
Imaging Studies
In most of the instance, no imaging studies are used unless metastatic disease is suspected after a thorough history taking and a complete physical examination.
Recent studies seem to support a role of MRI for preoperative assessment in larger or atypical lesions and recurrent disease. MRI may be helpful to define the approximate tumor border and depth of invasion.4, 5
Procedures
A skin biopsy is essential for definitive diagnosis.
Histologic Findings
In the plaque type of DFSP, slender tumor cells with large, spindle-shaped nuclei are embedded fairly uniformly in the collagen stroma, parallel to the skin surface. Mitotic figures are sparse. The more characteristic findings are seen in the nodular type. These findings include the high cellularity and irregular, short, intersecting bands of tumor cells forming a storiform pattern. Also typical are cells radiating from a central hub of fibrous tissue forming a cartwheel pattern. The degree of cellular atypia is higher in nodular lesions than in plaque lesions. Occasionally, DFSP may show focal fibrosarcomatous changes with a characteristic herringbone pattern. The cellular atypia is then even more prominent with hyperchromatic nuclei and more mitotic figures.
In the pigmented variant of DFSP, also known as Bednar tumor, the melanin-containing dendritic cells are scattered between the neoplastic spindle-shaped cells.
Immunohistochemistry studies have shown moderate-to-strong staining of human progenitor cell antigen CD34 in tumor cells. CD34 is a useful marker that allows differentiation of DFSP tumor cells from normal stroma cells and dermatofibroma. In dermatofibroma, tumor cells are positive for factor XIIIa and are rarely positive for CD34. Additionally, immunostaining using CD34 as a marker is helpful in identifying tumor cells at the surgical margins, particularly when treating recurrent DFSP where tumor cell fascicles are often interspersed with the scar tissue.
Staging
The American Joint Committee on Cancer has not developed a staging system for DFSP.
Medical Care
Currently, chemotherapy is rarely used in the treatment of DFSP. Radiation therapy has had a limited role in the past, but, recently, it has been used as an adjunct to surgery. Radiation therapy may be recommended for patients if the margins of resection are positive or for situations where adequate wide excision alone may result in major cosmetic or functional deficits. Close follow-up care after radiation therapy is warranted because some of the tumors may become more aggressive. The development of molecularly targeted therapy holds promise as an additional treatment option. Originally approved for the treatment of chronic myelogenic leukemia, imatinib mesylate has been found to have significant therapeutic value in the treatment of DFSP. Imatinib is a potent and specific inhibitor of several protein-tyrosine kinases, including the PDGF receptors.
On October 19, 2006, the US Food and Drug Administration granted approval for imatinib mesylate (Gleevec) as a single agent for the treatment of DFSP. Imatinib mesylate is indicated for the treatment of adult patients with unresectable, recurrent, and/or metastatic DFSP. The recommended dose is 800 mg/d.
Surgical Care
Surgical excision remains the mainstay of treatment for DFSP. Recently, Mohs micrographic surgery has been increasingly accepted as the treatment of choice (see Mohs Micrographic Surgery).
Because of its infiltrating growth pattern, DFSP commonly extends far beyond the clinical margins; this accounts in part for the high recurrence rate after standard surgical excision. Hence, a wide excision of 3 cm or more of the margins, down to and including the fascia, is recommended for the treatment of DFSP. Despite such wide excisions, a recurrence rate of 11-20% is still observed. A superior cure rate (recurrence rate of 0-6%) and tissue conservation are seen when Mohs micrographic surgery is used; thus, it is now considered the treatment of choice, particularly when a lesion is located in the head and neck region.
Although some Mohs surgeons consider it unnecessary, taking an extra layer of tissue around the surgical defect at the completion of Mohs surgery for permanent pathology section and/or CD34 immunostaining may potentially enhance the cure rate.
Although medical therapy is not a first line treatment for localized DFSP, newly approved molecular targeted drug, imatinib mesylate, is an effective oral medication for unresectable, recurrent, and/or metastatic DFSP.
Drug Category: Molecular targeted therapy
Before starting imatinib therapy, cytogenetic studies to confirm PDGFB gene rearrangement may be necessary in predicting the clinical response. Chromosome translocation t(17,22) is detected in More than 90% of DFSP.
| Drug Name | Imatinib mesylate (Gleevec) |
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| Description | Inhibitor of receptor tyrosine kinase for PDGF. Inhibits PDGF-B receptor-mediated cellular events, the key pathogenetic pathway in DFSP. |
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| Adult Dose | 800 mg/d PO divided bid |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | CYP3A4 inhibitors (ketoconazole increases distribution of imatinib); CYP3A4 substrates (simvastatin increases maximum concentration of imatinib by a 2- to 3.5-fold factor); CYP3A4 inducers (phenytoin decreases AUC by approximately one fifth of typical AUC); likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5 |
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| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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| Precautions | Dose must be reduced or interrupted if edema or anemia occur, transaminase or bilirubin levels become elevated, or grade 3-4 neutropenia or thrombocytopenia develops; pediatric patients commonly experience musculoskeletal pain
Adverse effects include congestive heart failure, increased risk of hypereosinophilic cardiac toxicity, grade 3-4 gastrointestinal and tumor site bleeding, pleural effusion, and gastrointestinal perforation (including fatalities); increased risk of edema, severe congestive heart failure, and left ventricular dysfunction reported in elderly persons (>65 y); fatigue, hypokalemia, and hypophosphatemia reported; monitor CBC counts qwk for first month, q2wk for second month, and periodically thereafter; perform liver function tests at baseline and then monthly or as clinically indicated |
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Further Outpatient Care
- Because of the high local recurrence rate of DFSP, patients require close follow-up care after treatment.
- Most recurrences occur within 3 years of the primary excision. Patients should be seen every 3-6 months during this period of time and annually thereafter.
- A recent literature review of DFSP case series treated with Mohs surgery shows that 50% of recurrences appear within the first 3 years after operation and 25% of local recurrences were detected after 5 years. A large case review from a series of 159 patients treated at Memorial Sloan-Kettering Cancer Center (New York) showed the medium time to development of a local recurrence was 32 months. The indolent nature of DFSP requires lifelong surveillance for recurrence.
- In each follow-up visit, a complete history and a review of systems, as well as complete physical examinations, including skin examination and palpation of the excision site and regional lymph nodes, should be performed. Extensive workup is not warranted unless metastatic disease is suspected.
Prognosis
- DFSP is characterized by its aggressive local invasion. The tumor invades local tissue by extending tentaclelike projections underneath healthy skin rendering complete removal of the tumor very difficult. Incomplete removal of these neoplastic cells results in a high local recurrence rate.
- Despite the local invasiveness, DFSP rarely metastasizes. The risk for development of metastatic disease is only 5%, including 1% with regional lymph node metastasis and 4% with distant metastasis. Regional lymph node involvement represents a sign of poor prognosis; most patients die within 2 years. The lungs are the most common site of distant metastasis that occurs via hematogenous spread. Usually, metastatic disease is preceded by multiple local recurrences.
- The extent of surgical excision determines the prognosis of the patient. To reduce the local recurrence rate, a wide surgical excision with adequate margins or Mohs technique, are used. The latter imparts a better outcome.
- Histologic features of DFSP may also serve as prognostic indicators. A high number of mitotic figures, increased cellularity, DNA aneuploidy, TP53 gene overexpression, and the presence of fibrosarcomatous changes within the tumor are poor prognostic indicators. Of note, fibrosarcomatous variants of DFSP lacking a genetic marker of translocation between chromosomes 17 and 22 may not respond to imatinib. The loss of the t(17,22) cytogenetic marker in the fibrosarcomatous progression DFSP variant may represent the progression of the malignancy.
- Age older than 50 years is also a risk factor associated with a poor clinical outcome.
Medical/Legal Pitfalls
- Because of the rarity of DFSP, misdiagnosis and delayed diagnosis often occur. When encountering an atypical scarlike lesion, the clinician should consider skin biopsy.
| Media file 1:
Dermatofibrosarcoma protuberans manifesting as an irregular red-to-violaceous plaque on the chest. |
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| Media file 2:
Closer view of dermatofibrosarcoma protuberans. It has an irregular surface and borders with palpable dermal and subcutaneous induration. |
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| Media file 3:
Bednar tumor, a pigmented variant of dermatofibrosarcoma protuberans, contains melanin-rich dendritic cells scattered among neoplastic spindle-shaped cells. |
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| Media file 4:
Dermatofibrosarcoma protuberans (DFSP) tumor cells take over the dermis and subcutaneous adipose tissue and then approach the fascia plane. The tumor nodule manifests with high cellularity. Under histopathologic examination, these DFSP tumor cells are spindle shaped. They tend to grow in a storiform pattern in the center portion of the tumor. They may also grow in a diffuse infiltrative pattern at the periphery, forming a honeycomb pattern. Often, no defined border can be recognized between the tumor and normal tissue. |
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| Media file 5:
Higher-power view of dermatofibrosarcoma protuberans reveals subcutaneous adipocytes entrapped by densely infiltrative spindle-shaped tumor cells. |
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Dermatofibrosarcoma Protuberans excerpt Article Last Updated: Jun 12, 2007
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