Dermatofibrosarcoma Protuberans 

Updated: Mar 06, 2020
Author: Raman K Madan, MD; Chief Editor: William D James, MD 

Overview

Background

Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon soft tissue neoplasm of intermediate- to low-grade malignancy. 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.[1] Note the images below.

Dermatofibrosarcoma protuberans manifesting as an Dermatofibrosarcoma protuberans manifesting as an irregular red-to-violaceous plaque on the chest.
Closer view of dermatofibrosarcoma protuberans. It Closer view of dermatofibrosarcoma protuberans. It has an irregular surface and borders with palpable dermal and subcutaneous induration.

Pathophysiology

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous malignancy that arises from the dermis and invades deeper tissue (eg, fat, fascia, muscle, bone).

The cellular origin of DFSP is not clear. Evidence supports the cellular origin being fibroblastic, histiocytic, or neuroectodermal. DFSP manifests partial features of each. Therefore, many authorities suggest pluripotential progenitor cells, such as undifferentiated mesenchymal cells, may be the origin of DFSP, because they have the capacity to differentiate into all 3 cell types.[2]

Cultured DFSP tumor cells have increased growth in response to platelet-derived growth factor (PDGF)–beta. Cytogenetic studies reveal specific abnormalities 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-beta 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 the 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.[2, 3, 4, 5, 6, 7, 8]

Etiology

The cause of dermatofibrosarcoma protuberans (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 burn scars and sites of vaccinations have been reported as sites of DFSP.[9]

Epidemiology

Frequency

United States

Dermatofibrosarcoma protuberans (DFSP) accounts for less than 0.1% of all malignant neoplasms and approximately 1% of all soft tissue sarcomas. DFSP is the most common type of cutaneous sarcoma. The incidence of DFSP has been estimated to be 0.8-5 case per million population per year in 2 separate studies.[2] In a another study based on data from 9 cancer registries from 1973-2002, the annual incidence of DFSP in the United States is 4.2 cases per million population per year.[8]

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.[10] A study of the population-based National Cancer Registry shows the incidence of DFSP is approximately 4 cases per million per year in Sweden from 1990-2005.[11]

Race

Dermatofibrosarcoma protuberans (DFSP) has been reported in persons of all races, and no racial predilection seems to exist in previous reports. However, a study conducted by Criscione and Weinstock found the incidence among African Americans (6.5 cases per million population) was almost double the incidence among American whites (3.9 cases per million population).

An uncommon pigmented variant of DFSP, accounting for 1% of all DFSP cases, is called the Bednar tumor. Annual incidence of Bednar tumor among blacks is 7.5 times higher than that of white patients.[8] Note the images below.

Bednar tumor, a pigmented variant of dermatofibros Bednar tumor, a pigmented variant of dermatofibrosarcoma protuberans, contains melanin-rich dendritic cells scattered among neoplastic spindle-shaped cells.
A featureless reddish brown plaque on the arm of a A featureless reddish brown plaque on the arm of a white female. Another example of Bednar tumor.

Sex

Several studies of dermatofibrosarcoma protuberans (DFSP) reveal an almost equal sexual distribution or a slight male predominance. In a large study of 902 patients with DFSP conducted by Rutgers et al, 514 (57%) patients were male and 388 (43%) patients were female.[12] A study based on 405 DFSP cases from the Swedish National Cancer Registry between 1990 and 2005 shows a very small difference in annual incidence of male (4.4 cases per million) versus female (4.0 cases per million).[11] However, a larger cancer registry study of 2885 cases reveals females might have a slightly higher incidence of DFSP, 4.4 cases versus 4.2 cases per million population per year.[8]

Age

Dermatofibrosarcoma protuberans (DFSP) usually occurs in adults aged 20-50 years. Rarely, DFSP has been reported in newborns and elderly individuals (80 y).[13]

Prognosis

Dermatofibrosarcoma protuberans (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. For the classic form of DFSP, the risk is assumed to be only 0.5%. According to the literature, the overall risk for the development of metastatic disease is 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.[8] The lungs are the most common site of distant metastasis that occurs via hematogenous spread. Usually, metastatic disease is preceded by multiple local recurrences.[14]

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.[15]

The extent of surgical excision determines the prognosis for 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 progression of the malignancy.[1, 16, 17]

Age older than 50 years is also a risk factor associated with a poor clinical outcome.[18]

Patient Education

Patients are advised to seek evaluation by a dermatologist if they have noticed a slow-growing skin lump or scarlike lesion on any part of their body.

 

Presentation

History

Dermatofibrosarcoma protuberans (DFSP) is a very slowly growing tumor. Because of the slow progression, the diagnosis is often delayed for months to years.

DFSP may start as a small asymptomatic papule or nonindurated patch. The tumor may gradually enlarge into a lumpy nodule, or it may evolve into an atrophic and/or sclerotic plaque. Accelerated growth, ulceration, and hemorrhage may be observed when DFSP grows.

Physical Examination

Dermatofibrosarcoma protuberans (DFSP) usually presents as a large, indurated plaque several centimeters in diameter. DFSP is composed of firm, irregular nodules varying in color from flesh to reddish brown. Telangiectasia may be apparent on the surface or at the periphery.

Sometimes, DFSP may present as a morphealike, atrophic, sclerotic, violaceous plaque without nodularity that may ulcerate as it slowly increases in size.

A large dermatofibrosarcoma protuberans is seen on A large dermatofibrosarcoma protuberans is seen on the abdomen. It has an appearance of atrophic plaque, while foci of nodularity also can be seen.

Mostly the tumor is mobile upon palpation; however, fixation to deeper structures such as fascia, muscle, and bone may occur in the later stage of the tumor.

DFSP most commonly occurs on the trunk (42-72%), followed by the proximal extremities (16-30%). DFSP rarely occurs above the neck (10-16%)[1] and extremely rarely on the breast.[19]

 

DDx

 

Workup

Laboratory Studies

No blood test is available to help detect or diagnose dermatofibrosarcoma protuberans (DFSP).

Imaging Studies

In most cases of dermatofibrosarcoma protuberans (DFSP), no imaging studies are used unless metastatic disease is suspected after a thorough history taking and a complete physical examination. Note the following:

Dermoscopy is still evolving. A small study looking at 15 cases of DFSP found the median number of dermoscopic features was four per lesion. In the study, the following dermoscopic features were noted: delicate pigmented network (87%), vessels (80%), structureless light-brown areas (73%), shiny white streaks (67%), pink background coloration (67%), and structureless hypopigmented or depigmented areas (60%). When detected, vessels were of the arborizing type in 11 of 12 cases and presented as either unfocused only or both unfocused and focused. Further studies are still required to determine whether dermoscopy can help to identify suspected DFSP.[20]

Chest radiography may be ordered for baseline screening for pulmonary metastasis in high-risk cases, such as recurrence or suspicion for a fibrosarcoma variant of DFSP.[14]

Computed tomography scanning is indicated if direct bone involvement or metastasis is suspected.[1]

Studies support a role of magnetic resonance imaging (MRI) for preoperative assessment in larger or atypical lesions and recurrent disease. With its high soft tissue resolution and contrast, MRI may be helpful for defining the approximate tumor border and depth of invasion.[14, 21, 22, 23]

Ultrasonography may be helpful for monitoring local DFSP or regional lymph node metastasis.

Reports suggest fluorodeoxyglucose (FDG)–positron emission tomography scanning may be helpful in monitoring metastatic disease.[16, 24]

Other Tests

Although cytogenetic testing of dermatofibrosarcoma protuberans (DFSP) is not established as a standard workup, reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) are suggested as screening tools for the presence of COL1A1-PDGFB fusion gene prior to initiation of oral imatinib molecular-targeted therapy.[25] DFSP tumors lacking the classic t(17,22) translocation mutation seem to respond poorly to imatinib.[16, 25]

DFSP-FS (fibrosarcomatous variant) is a variant of DFSP that exhibits more aggressive behavior than DFSP, with lower recurrence-free survival and greater metastatic potential. As a result of the similar clinical presentation, it is necessary to have histopathological differentiation to determine prognosis.[26]

Procedures

A skin biopsy is essential for definitive diagnosis of dermatofibrosarcoma protuberans (DFSP).

Histologic Findings

In the plaque type of dermatofibrosarcoma protuberans (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.[2, 18] Note the images below.

Dermatofibrosarcoma protuberans (DFSP) tumor cells 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.
Higher-power view of dermatofibrosarcoma protubera Higher-power view of dermatofibrosarcoma protuberans reveals subcutaneous adipocytes entrapped by densely infiltrative spindle-shaped tumor cells.

In the pigmented variant of DFSP, also known as Bednar tumor, the melanin-containing dendritic cells are scattered between the neoplastic spindle-shaped cells.[27]

In the juvenile form (giant cell fibroblastoma), cleftlike pseudovascular spaces are lined by multinucleated cells. The intervening tumor may have loose hypocellular areas and areas that resemble mature DFSP.

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 in which tumor cell fascicles are often interspersed with the scar tissue.[28, 29] Note the image below.

DFSP demonstrates strong CD34 staining with immuno DFSP demonstrates strong CD34 staining with immunohistochemistry.

Staging

The American Joint Committee on Cancer has not developed a staging system for dermatofibrosarcoma protuberans (DFSP). Because of its very low risk of metastasis, DFSP can be viewed as mostly a local disease. The following simple staging system published in “Short German guidelines: dermatofibrosarcoma protuberans” may be helpful in clinical use[14] :

  • Stage I - Primary tumor, localized disease

  • Stage II - Lymph node metastasis

  • Stage III - Distal metastasis

 

Treatment

Medical Care

Currently, conventional chemotherapy is rarely used in the treatment of dermatofibrosarcoma protuberans (DFSP). Limited case reports have not shown any significant value of conventional chemotherapy in the treatment of DFSP.[30, 31]

Radiation therapy (RT) 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 in which adequate wide excision alone may result in major cosmetic or functional deficits. Postoperative adjuvant RT may reduce the risk of recurrence when clear surgical margins are not confident.[32] The complete radiation therapy dose ranges from 50-70 Gy. Overall, the risk of severe complications from RT is low. Close follow-up care after radiation therapy is warranted because some DFSP tumors may become more aggressive.[1, 14, 33, 34]

Based on the knowledge that constitutively activated PDGFB-PDGFR-beta signaling pathway plays a central role in the proliferation of DFSP tumor cells, the development of molecularly targeted therapy holds promise as an additional treatment option.[35] Originally approved for the treatment of chronic myelogenic leukemia, imatinib mesylate has been found to have significant therapeutic value in the treatment of DFSP.[36] Imatinib is a potent and specific inhibitor of several protein-tyrosine kinases, including the platelet-derived growth factor (PDGF) receptors.[5, 37]

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 oral dose is 800 mg/d.[16, 38]

With limited clinical data to date, a response rate of approximately 65% has been achieved among DFSP patients treated with imatinib. A small subset of DFSP patients lacking the classic t(17,22) gene aberration seems to have no response to imatinib.[1]

Neoadjuvant imatinib therapy for DFSP has been proposed in recent studies.[25, 39] Using imatinib as a preoperative therapy agent in locally advanced or recurrent DFSP may decrease tumor load, promote tumor cell apoptosis, and subsequently reduce the extent of surgery. Caution should be used when applying such a therapeutic strategy, because the potential exists for creating a skip area wherein discontiguous tumor may obscure the accurate pathology assessment of surgical margins.

Surgical Care

Surgical excision remains the mainstay of treatment for dermatofibrosarcoma protuberans (DFSP).[40] Despite controversy, Mohs micrographic surgery has been increasingly accepted as the treatment of choice, while others advocate wide local excision.[13, 34, 41, 42, 43] The fundamental difference of these two techniques is the pathology processing. Usually, the specimen from wide excision is sectioned in conventional bread-loaf fashion, while the Mohs specimen is freshly frozen and sectioned en face along the margins. Mohs surgery requires less tissue removal and allows complete margin assessment. However, large tumor can be a challenge for this very time-consuming procedure.

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.[44] Hence, a wide excision of 2-3 cm or more of the margins beyond clinically identifiable tumor border, down to and including the fascia, is recommended for the treatment of DFSP.[13, 32, 41] Despite wide local excisions, an average recurrence rate of 15.7% is still observed among 1201 body cases and 51.8% is observed among 193 head and neck cases, as reported in the literature since 1951. A superior cure rate (an overall average recurrence rate of 1.3% among 463 cases reported) and tissue conservation are seen when Mohs micrographic surgery is used; thus, Mohs micrographic surgery is now considered the treatment of choice,[45] particularly when a lesion is located in the head and neck region.[18, 41, 46, 47, 48, 49, 50, 51]

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. Alternatively, some have adopted modified Mohs techniques, or so-called "slow Mohs," by using rush paraffin sections instead of a fresh tissue technique.[46, 49, 52, 53, 54] Mohs surgery may not be readily accessible in many parts of the world. The physician should exercise clinical judgment to offer the best treatment available for the patient and consider multidisciplinary collaboration. Studies have demonstrated a low recurrence rate after surgery for DFSP if a multidisciplinary approach and careful pathology margin assessment are used.[55, 56]

Consultations

In dermatofibrosarcoma protuberans (DFSP), an informative consultation includes proper staging, prognostic evaluation, explanation of treatment options, and planning. All these depend on thorough history taking and physical examination. Imaging studies may facilitate the assessment of local invasion and distal metastasis. Multidisciplinary collaboration between a dermatologist, surgical oncologist, plastic surgeon, medical oncologist, radiation oncologist, and pathologist is necessary in locally advanced, recurrent, or metastatic cases of DFSP.

Long-Term Monitoring

Because of the high local recurrence rate of dermatofibrosarcoma protuberans (DFSP), patients require close follow-up care after treatment. Most recurrences occur within 3 years of the primary excision. Patients should be seen every 6 months during this period and annually thereafter.[14]

A 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 are 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 the development of a local recurrence was 32 months. The indolent nature of DFSP requires lifelong surveillance for recurrence.[18]

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. An extensive workup is not warranted unless metastatic disease is suspected.

 

Medication

Medication Summary

Although medical therapy is not a first-line treatment for localized dermatofibrosarcoma protuberans (DFSP), the approved molecular-targeted drug, imatinib mesylate, is an effective oral medication for unresectable, recurrent, and/or metastatic DFSP.

Molecular-targeted therapy

Class Summary

Before starting imatinib therapy, cytogenetic studies to confirm PDGFB gene rearrangement may be necessary for predicting the clinical response. Chromosome translocation t(17,22) is detected in more than 90% of DFSP tumors.

Imatinib mesylate (Gleevec)

Imatinib mesylate is an inhibitor of receptor tyrosine kinase for PDGF. It inhibits PDGF-B receptor-mediated cellular events, the key pathogenetic pathway in DFSP.

 

Questions & Answers

Overview

What is dermatofibrosarcoma protuberans (DFSP)?

What is the pathophysiology of dermatofibrosarcoma protuberans (DFSP)?

What causes dermatofibrosarcoma protuberans (DFSP)?

What is the prevalence of dermatofibrosarcoma protuberans (DFSP) in the US?

What is the global prevalence of dermatofibrosarcoma protuberans (DFSP)?

What are the racial predilections of dermatofibrosarcoma protuberans (DFSP)?

What are the sexual predilections of dermatofibrosarcoma protuberans (DFSP)?

In which age group is dermatofibrosarcoma protuberans (DFSP) most prevalent?

What is the prognosis of dermatofibrosarcoma protuberans (DFSP)?

What is included in patient education about dermatofibrosarcoma protuberans (DFSP)?

Presentation

Which clinical history findings are characteristic of dermatofibrosarcoma protuberans (DFSP)?

Which physical findings are characteristic of dermatofibrosarcoma protuberans (DFSP)?

DDX

What are the differential diagnoses for Dermatofibrosarcoma Protuberans?

Workup

What is the role of lab testing in the diagnosis of dermatofibrosarcoma protuberans (DFSP)?

What is the role of imaging studies in the diagnosis of dermatofibrosarcoma protuberans (DFSP)?

What is the role of cytogenetic testing in the diagnosis of dermatofibrosarcoma protuberans (DFSP)?

What is the role of biopsy in the diagnosis of dermatofibrosarcoma protuberans (DFSP)?

Which histologic findings are characteristic of dermatofibrosarcoma protuberans (DFSP)?

How are dermatofibrosarcoma protuberans (DFSP) staged?

Treatment

How is dermatofibrosarcoma protuberans (DFSP) treated?

What is the role of surgery in the treatment of dermatofibrosarcoma protuberans (DFSP)?

Which specialist consultations are beneficial to patients with dermatofibrosarcoma protuberans (DFSP)?

What is included in long-term monitoring of patients with dermatofibrosarcoma protuberans (DFSP)?

Medications

What is the role of mesylate in the treatment of dermatofibrosarcoma protuberans (DFSP)?

Which medications in the drug class Molecular-targeted therapy are used in the treatment of Dermatofibrosarcoma Protuberans?