Are You Confident of the Diagnosis?

Diagnosis of a dermatofibrosarcoma protuberans (DFSP) is often difficult to make on initial presentation. A high index of clinical suspicion coupled with histopathologic confirmation are necessary to confidently diagnose this rare cutaneous sarcoma.

Characteristic findings on physical examination

DFSP usually presents as an asymptomatic, firm, pink to brown nodule, measuring from 1 to several centimeters in diameter, and fixed to the underlying tissue (Figure 1, Figure 2). Its slow growth pattern and indolent behavior often result in late referrals, up to 3 years after initial development. If neglected, the tumor enlarges and can protrude through the skin with subsequent ulceration.

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Figure 1.

Classic DFSP, characterized by an irregular pink to brown nodule, which appears scar-like.

Figure 2.

Another DFSP, also presenting as a pink to brown irregular nodule, studded with superficial erosions.

DFSP occurs on the trunk in 50-60% of cases with a predilection for the shoulder and pelvic areas, the proximal extremities in 20-30%, and the head and neck in 10-15%. The clinical differential diagnosis includes epidermal inclusion cyst, scar/keloid, large dermatofibroma, dermatomyofibroma, and morphea.

Making the diagnosis

A skin biopsy is essential to confirm the diagnosis of DFSP. An ample tissue specimen is necessary for accurate histologic interpretation, either by punch or incisional biopsy, to obtain adequate depth. The histopathologic features of DFSP are characterized by infiltrating fascicles of spindle-shaped cells, often beginning in deep reticular dermis. This proliferation may take on a storiform, or cartwheel-like pattern, and often infiltrates the subcutaneous fat and/or skeletal muscle with characteristic ‘honeycombing.’ There is often a Grenz zone noted, and occasionally epidermal thinning can be appreciated (Figure 3, Figure 4). Nuclear atypia and increased mitotic activity are usually absent.

Figure 3.

Low-power magnification of classic DFSP,demonstrating a storiform pattern of spindle cells in the dermis, invading into the underlying subcutaneous fat.

Figure 4.

High-power magnification of DFSP, demonstrating finger-like extension (honeycombing) of the surrounding fat.

Several histologic variants have been described: pigmented (Bednar tumor), myxoid (frequently seen in recurrent tumors), myoid, sclerosing, with granular cells, with multinucleated giant cells (resembling giant cell fibroblastoma), atrophic, and with fibrosarcomatous areas.

DFSP must be distinguished histologically from other fibrohistiocytic neoplasms, and immunohistochemical markers can be very helpful in confirming the diagnosis. The histologic differential diagnosis of a DFSP most often involves the differentiation from a dermatofibroma or dermatofibroma variants, but also includes malignant fibrous histiocytoma, atypical fibroxanthoma, and fibrosarcoma. Classically, DFSP stains positively for CD34 – a human hematopoietic progenitor cell antigen – and stains negative for factor XIIIa. This is in contrast to a dermatofibroma, which is CD34 negative and factor XIIIa positive. This is not always the case as a small minority of DFSPs can show factor XIIIa positivity, and up to 6% of cellular dermatofibromas will stain for CD34 (Figure 5). Overexpression of p53 in DFSP has also been described and associated with higher rates of proliferation.

Figure 5.

High-power magnification of DFSP demonstrating CD34 positive staining.

Other negative markers are equally important; DFSP is usually negative for S100A6 and vimentin, which are commonly positive in other fibrohistiocytic tumors. DFSP typically shows bland cells without significant atypia and pleomorphism. This helps to differentiate from atypical fibroxanthoma and malignant fibrous histiocytoma, which exhibit a high mitotic rate, marked cellular atypia, and cellular pleomorphism.

DFSP is a tumor that exhibits marked local extension via small, infiltrating fascicles. The extent of tumor involvement can be estimated by computed tomography (CT) and more precisely with magnetic resonance imaging (MRI). However, imaging studies frequently fail to detect the fine extension of tumor fascicles into adjacent connective tissue and fat, and therefore may underestimate actual tumor size.

Who is at Risk for Developing this Disease?

DFSP is a rare tumor, with an estimated incidence of 4.1 cases per million person-years, but still the most common sarcoma of the skin. It predominantly occurs in young to middle-aged adults, with a peak in the fourth and fifth decades of life. Women are affected slightly more often than men at a ratio of 1.14:1. A few cases have been reported in children. Giant cell fibroblastoma is regarded as a juvenile predecessor of DFSP.

DFSP has been reported in all races. The incidence of DFSP among African Americans was found to be almost double the incidence among American whites (6.5 vs 3.9 cases per million population). The Bednar tumor or pigmented variant of DFSP, in particular, is known to be more common in blacks, with an annual incidence 7.5 times higher than that seen in white patients.

What is the Cause of the Disease?

The etiology of DFSP is unknown. Recent advances in genetic research have implicated a specific chromosomal translocation in the pathogenesis of DFSP arising between chromosome regions 17q22 and 22q13. This t17:22 translocation is present in 90% of all DFSPs and represents a fusion product of the type I collagen (COL1A1) promoter region and the platelet-derived growth factor-beta (PDGFβ) receptor. The fusion product results in a ringed chromosome, which results in continuous activation of the PDGFβ signal transduction pathway.

Systemic Implications and Complications

It is important for patients to know that people rarely die from DFSP. DFSP has a slow and locally infiltrative growth pattern with widespread subclinical extension and strong tendencies for local recurrence. The rate of local recurrence is variable and ranges from less than 10% to as high as 50-60% in some studies, depending on treatment method employed. Metastasis, however, is very unusual (<5% of cases). In the rare case of metastatic DFSP, spread is thought to occur hematogenously, usually affecting the lungs. As lymphatic metastases are so infrequent, sentinel lymph node biopsy and prophylactic lymphadenectomy are not recommended.

Fibrosarcomatous differentiation may be found in DFSP, and when present, have been associated with increased risk of local recurrence and metastasis; however, their true prognostic significance is still controversial.

Treatment Options

Table 1.

Table 1.
Medical Treatment Surgical Treatment Physical Modalities
Imatinib mesylate Wide local excision Radiation Therapy
Conventional chemotherapy Mohs Micrographic Surgery

Optimal Therapeutic Approach for this Disease

Surgery remains the therapeutic modality of choice for DFSP, with the accuracy of the initial procedure being the main prognostic factor for locoregional recurrence and overall survival. Mohs micrographic surgery (MMS) and wide local excision (WLE) are the two most commonly performed surgical treatment modalities. MMS is regarded as the best treatment for DFSP by many investigators, and has been shown to be the superior modality when compared to WLE. MMS enables the surgeon to microscopically examine peripheral and deep margins on a horizontally sectioned plane, confirming the presence of tumor-free margins. MMS is especially useful in areas where tissue conservation is essential, such as the distal extremities and face.

Standard surgical excision continues to be used, but must take into account clinically unapparent tumor fascicles, which can extend into adjacent tissue for long distances in a horizontal plane. Thus, the standard surgical margin for the treatment of DFSP is 2 to 3 cm. If smaller margins are employed, the risk of local relapse is high, with recurrence rates of up to 60% reported in some studies. Preoperative contrast-enhanced ultrasound has been proposed as a modality to guide surgical margins, however, there is only anecdotal evidence to support its use.

Treatment options for DFSP are summarized in Table 1.

DFSP is a radio-sensitive tumor, but results have been mixed. Radiation therapy (RT) has been used adjuvantly in patients with recurrent tumors and positive margins on excision in whom more extensive surgery is deemed functionally or cosmetically unacceptable. A systematic review showed that patients receiving adjuvant RT had lower recurrence rates compared to surgery alone, but this difference did not reach statistical significance. There have been few case reports of patients with inoperable DFSP due to poor health status or tumor unresectability treated successfully with radiation therapy as the only modality. Recurrent and metastatic DFSP can also be irradiated. However, definitive or salvage RT is only recommended under inoperable circumstances or if several attempts at surgical cure have failed to obtain clear margins.

Conventional chemotherapy has not been shown to be useful in the treatment of localized DFSP. Metastatic DFSP has been treated with systemic chemotherapeutic agents with mixed results.

A new molecular-based therapy for DFSP has been developed in the form of the imatinib mesylate (STI-571, trade name GleevecTM), a multikinase inhibitor targeting the PDGFβ pathway. Imatinib has been used in the treatment of unresectable locally advanced, recurrent, and metastatic DFSP, showing a response rate of about 70% in preliminary trials. More recently, neo-adjuvant Imatinib therapy has been employed to reduce preoperative tumor size, facilitating resection of previously unresectable disease in a few cases. Nevertheless, patients with metastatic disease have been shown to recur despite neo-adjuvant imatinib with surgical management. Sunitinib has also been shown helpful in the treatment of patients with locally advanced or inoperable DFSP after imatinib failure, helping to slow disease progression and decrease tumor size in several reported patients.

Patient Management

Patients need long-term follow-up to detect local recurrences and although rare, to monitor for the development of late metastases. Although no specific recommendations have been established, clinical examinations, including examination of lymph node basins, every 6 months for the first 3 years, and thereafter at 1-year intervals have been advised. Some clinicians advocate imaging on a regular basis, either by chest X-ray or CT, to evaluate for lung metastases, but there is little data to support this.

Unusual Clinical Scenarios to Consider in Patient Management

Unusual presentations of DFSP frequently occur, including the depressed indurated plaque of non-protuberant (atrophic) DFSP and pedunculated lesions that closely resemble neurofibromas or fibroepithelial polyps. Congenital DFSPs have also been described, as have DFSPs located on mucosal surfaces such as the oral cavity and vulva. A high index of clinical suspicion can lead to earlier diagnosis of DFSP and smaller tumor size at the time of treatment.

What is the Evidence?

Breuninger, H, Sebastian, G, Garbe, C. “Dermatofibrosarcoma protuberans–an update”. J Dtsch Dermatol Ges. vol. 2. 2004. pp. 661-7. (An outstanding and comprehensive review of the clinical manifestations, pathogenesis, histology, differential diagnosis, and treatment of DFSP. Highlights include tables listing the histologic variants of DFSP, clinical differential diagnosis, and immunohistologic differential diagnosis with positive and negative staining patterns.)

Fields, RC, Hameed, M, Qin, LX, Moraco, N, Jia, X, Maki, RG. “Dermatofibrosarcoma protuberans (DFSP): Predictors of recurrence and the use of systemic therapy”. Ann Surg Oncol. vol. 18. 2011. pp. 328-36. (A large study of 244 patients with DFSP, examining clinicopathologic factors associated with disease-free survival and evaluating response to multimodality therapy. Authors found that disease-free survival is strongly predicted by tumor depth in primary tumors and margin status in recurrent tumors, and that multimodality treatment can be effective but is not curative.)

Han, A, Chen, EH, Niedt, G, Sherman, W, Ratner, D. “Neoadjuvant imatinib therapy for dermatofibrosarcoma protuberans”. Arch Dermatol. vol. 145. 2009. pp. 792-6. (This series of four patients with locally advanced or recurrent DFSP were treated with neoadjuvant imatinib mesylate therapy before undergoing Mohs micrographic surgery; patients had an average tumor size reduction of 36.9%. The authors concluded that neoadjuvant imatinib mesylate therapy is a well-tolerated, novel approach to DFSP that reduces tumor burden and facilitates resection.)

Korkolis, DP, Liapakis, IE, Vassilopoulos, PP. “Dermatofibrosarcoma protuberans: clinicopathological aspects of an unusual cutaneous tumor”. Anticancer Res. vol. 27. 2007. pp. 1631-4. A thorough review of the histopathologic diagnosis of DFSP and discussion of clinical management.

Criscione, VD, Weinstock, MA. “Descriptive epidemiology of dermatofibrosarcoma protuberans in the United States, 1973 to 2002”. J Am Acad Dermatol. vol. 56. 2007. pp. 968-73. (An extensive population-based epidemiologic study of DFSP spanning 29 years, looking at overall annual incidence, according to both race and sex, and also analyzing relative 5-year survival [99.2%].)

Stacchiotti, S, Pantaleo, MA, Negri, T, Astolfi, A. “Efficacy and biological activity of imatinib in metastatic dermatofibrosarcoma protuberans (DFSP)”. Clin Cancer Res. vol. 15:22. 2016. pp. 837-46. (This study follows 10 patients with metastatic DFSP treated with imatinib. There were 8 partial responses, 1 stable disease and 1 progression of disease. They also followed the RNAseq transcriptional profile.)

West, KL, Cardona, DM, Su, Z, Puri, PK. “Immunohistochemical markers in fibrohistiocytic lesions: factor XIIIa, CD34, S-100, and p75”. Am J Dermatopathol. vol. 36. 2014. pp. 414-419. (This was a small retrospective review that confirmed CD34 and factor XIIIa as the most reliable immunohistochemical markers for DFSP.)

Fu, Y, Kang, H, Zhao, H, Hu, J, Zhang, H. “Sunitinib for patients with locally advanced or distantly metastatic dermatofibrosarcoma protuberans but resistant to imatinib”. Int J Clin Exp Med. vol. 8. 2015. 15. pp. 8288-94. (This article confirms imatimib as the first line drug for locally advanced or inoperable DFSP, with Sunitinib as a good approach to those patients with imatinib failure.)

Lowe, GC, Onajin, O, Baum, CL, Otley, CC. “A comparison of Mohs micrographic surgery and wide local excision for treatment of dermatofibrosarcoma protuberans with long-term follow-up: the Mayo Clinic Experience”. Dermatol Surg. 2016. Oct 4. (This article compared recurrences in patients treated with Mohs mircrographic surgery [MMS] [n=67] and those treated with wide excision [WE] [n=91]. There were 2 recurrences [3%] in the MMS group versus 28 [30.8] in the WE group.)

Ma, C, Sun, Y, Yang, X, Zhang, Q, Zhang, C, Cui, L. “Improving precision of resection by pre-surgery inspections with contrast-enhanced ultrasound for dermatofibrosarcoma protuberans”. Dermatol Ther. 2016. Aug 29. (This is a single case report of the use of contrast enhanced ultrasound to decrease the margin of wide excision of a DFSP.)

Chen, YT, Tu, WT, Lee, WR, Huang, YC. “The efficacy of adjuvant radiotherapy in dermatofibrosarcoma protuberans: a systemic review and meta-analysis”. J Eur Acad Dermatol Venereol. vol. 30. 2016. pp. 1107-14. (This publication is a met analysis of 12 studies and establishes the use of radiation in select cases.)

Kreicher, KL, Kurlander, DE, Gittleman, HR, Barnholtz-Sloan, JS, Bordeaux, JS. “Incidence and survival of primary dermatofibrosarcoma protuberans in the United States”. Dermatol Surg. vol. 42. 2016. pp. S24-31. (This article uses data from 18 registries to establish the epidemiologic profile of DFSP.)