The incidence of DFSP ranges between 0.5 and 1:100,000, thus it is the most common cutaneous sarcoma. Although DFSP can present at birth or in children, most patients are middle-aged adults. There does not seem to be a gender or racial predilection for the tumor, however, the pigmented variant (Bednar's tumor) is more common in black patients.
Etiology and Pathogenesis
The histogenesis of DFSP is uncertain: fibrohistiocytic, purely fibroblastic, and neural-related differentiation have all been hypothesized. At the molecular level, DFSP is characterized cytogenetically by a reciprocal translocation t(17;22) (q22;q13), or more frequently, a supernumerary ring chromosome composed of hybrid material derived from t(17;22).2 The translocated chromosome and the supernumerary rings contain the same molecular genetic rearrangements. The t(17;22) translocation fuses the gene PDGFB on chromosome 22 with the strongly expressed collagen 1 alpha 1 (COL1A1) gene on chromosome 17. The PDFGB gene encodes the β chain of the PDGF, a ligand for the cell-surface receptor tyrosine kinase PDGFR (both PDGFRβ and PDFRα). PDGFβ is a growth factor that acts as a potent mitogen for a variety of connective tissue cells. The formation of the COL1A1-PFGFB fusion gene results in constitutive production of COL1A1-PDGFβ protein. After translation the COL1A1-PDGFβ fusion undergoes posttranslational processing to form functional PDGFβ. Thus, the production of PDGFβ can lead to autocrine stimulation of the tumor's own PDGFR, promoting tumor growth and survival. These observations suggest that deregulated expression of PDGFβ, with concomitant autocrine stimulation of PDGFR, is the critical molecular event in the pathogenesis of DFSP. Notably, both fibrosarcomatous transformation of DFSP and some cases of superficial fibrosarcoma (which actually may represent fibrosarcomatous transformed DFSP) have been shown to harbor these fusion transcripts, suggesting a close affinity between DFSP and fibrosarcoma.
In some patients, there is a history of previous trauma; in this regard it should be noted that DFSP has also been described as arising in scars, including surgical, burn, and vaccination sites.
DFSP is a slow-growing lesion that often presents on the trunk and proximal extremities, less frequently on the head and neck of patients. Due to its indolent onset, the patient may present rather late when the tumor is already several centimeters in size. The tumor is often misdiagnosed as a simple scar, keloid, or cyst (Box 125-1). Even when allowed to grow for many years, the tumor usually remains asymptomatic.
Box 125-1 Differential Diagnoses of DFSP, AFX, and ES ||Download (.pdf)
Box 125-1 Differential Diagnoses of DFSP, AFX, and ES
- Classic presentation
- Keloid/hypertrophic scar
- Fibrous histiocytoma
- Nodular melanoma (Bednar variant)
- Atrophic presentation
- Lichen sclerosis
- Morpheaform basal cell carcinoma
- Squamous cell carcinoma
- Basal cell carcinoma
- Amelanotic malignant melanoma
- Granuloma annulare
- Rheumatoid nodule
- Dupuytren contracture
- Infectious ulcer
The clinical presentation of DFSP is variable. The most common presentation is a firm, indurated plaque, often skin-colored with red–brown exophytic nodules (Fig. 125-1A). Purely plaque-like DFSP never developing nodules or tumors consisting of only a single nodule are rare. Initially the tumor is freely moveable; subsequently, however, larger adherent tumors evolve. At this stage the overlying epidermis may be thinned and telangiectases appear. Bleeding and ulceration are uncommon. DFSP may less frequently present as a nonprotuberant, atrophic (Fig. 125-1B), violaceous lesion resembling morphea or a sclerosing basal cell carcinoma; this form is more common in childhood. The pigmented variant of DFSP is termed Bednar tumor.
A. Dermatofibrosarcoma protuberans (DFSP) presenting as reddish brown confluent flat nodules. B. Atrophic variant of DFSP.
Giant cell fibroblastoma is considered a variant of DSFP, i.e., the juvenile variant of DFSP. Giant cell fibroblastoma typically presents as a dermal or subcutaneous mass, which most frequently involves the trunk, thigh, or inguinal region. It presents much earlier in life than the typical DFSP, often within the first decade, although occurrences in adults have been reported.
Histopathology and Immunohistochemistry
DFSP is a dermal proliferation of monomorphous, slender, or slightly plump spindle cells with little pleomorphism arranged in a storiform pattern (Figs. 125-2A and 125-2B). The epidermis is usually uninvolved. The proliferation commonly infiltrates the subcutaneous fat along the fibrous septa, isolating adipocytes to form lucencies (“honeycomb” pattern). The periphery of the tumor is poorly defined, rendering histological control of the surgical margins difficult. In contrast to dermatofibroma, the tumor is much more cellular and usually does not have mature collagen interspersed between fascicles of spindle cells. Mitoses are present; a high mitotic rate may correlate with an impaired prognosis.
A and B. Dermatofibrosarcoma protuberans showing fibroblastic spindle cells that are arranged in interlacing fascicles. These intersect and bend at acute angles, producing a starburst (storiform) pattern. C and D. Strong expression of CD34 of the tumor cells. Magnification: A and C, 10×; B and D, 20×.
Variable histologic patterns described include myxoid, neuroid, fibrosarcomatous, and granular cell types. The tumor may be relatively monomorphous or may show combinations of various patterns within the original tumor or in the recurrences. The Bednar tumor is rich in melanocytes. Giant cell fibroblastoma is characterized by giant cells, irregular vascular-like space partially ligned by giant cells as well as myxoid to collagenous areas with elongated to stellated cells. Some lesions show overlap between giant cell fibroblastoma and DFSP. The fibrosarcomatous dedifferentiation appears histologically as cellular tumor zones with a fascicular growth pattern, cellular atypia, and numerous mitoses. These atypical cells are arranged in long fascicles in a herringbone (fibrosarcoma-like) pattern; this transformation appears to be related to mutations in the p53 pathway.
A very sensitive, although nonspecific, marker for DFSP is CD34.3 DFSP cells label diffusely and strongly with antibodies to CD34 (Figs. 125-2C and 125-2D) and vimentin; however, CD34 positivity may be lost in nodular regions; particularly the fibrosarcomatous dedifferentiated cellular zones can be negative for CD34. The low-affinity nerve growth factor receptor p75 has been reported positive in DFSP cells. Scattered Factor XIIIa positive cells may be present. Tenascin is negative at the dermoepidermal zone in DFSP. DFSP cells are negative for S100 protein, smooth muscle actin (SMA), desmin, keratins, and epithelial membrane antigen (EMA). In contrast to dermatofibroma, stromelysin 3 is not expressed in DFSP.
Clinical Course, Prognosis and Treatment
DFSP is a low-grade malignant tumor, often infiltrating diffusely through the dermis and into the subcutaneous fat but seldom metastasizing. Increased age, high mitotic index, and increased cellularity are predictors of poor clinical outcome. Approximately 30%–50% of DFSPs recur locally after simple excision. Local recurrences even after wide excision with 1–3-cm margins to the fascia or periosteum are common. Best results can be achieved by means of micrographic controlled surgery (Mohs micrographic surgery) for tumor extirpation. However, it should be kept in mind that by use of frozen sections the histomorphology is not as good as by use of formalin-fixed paraffin embedded sections—in some cases impede correct diagnosis. Metastases of DFSP are extremely rare, usually occurring in the setting of multiply recurrent tumors and tumor progression to fibrosarcoma. Metastases to the lung are most common, with nodal disease the next most common site of spread. Metastatic disease portends a poor prognosis. It has been suggested that tumors with fibrosarcomatous change may have a higher risk of recurrence or metastases. It is estimated that there is a 5% transformation rate from DFSP to conventional fibrosarcoma. The true impact of fibrosarcomatous changes seen within a DFSP remains uncertain.
Standard management of localized disease is complete local surgical resection. With standard excision, margins of 1–3 cm may be necessary to achieve clear margins. However, local recurrence rates are high (13%–52%), especially in fibrosarcomatous DFSP. Risk of local recurrence decreases with increasing surgical margins. Pathologic examination of margins during surgery is helpful in delineating the extent of the tumor. Multiple case series have shown Mohs micrographic surgery to be an extremely effective method of resection of DFSP, with an extremely low rate of local recurrence. As a result, Mohs micrographic surgery represents the preferred surgical approach of many practitioners.
The role of radiotherapy remains unclear. Radiotherapy in the adjuvant setting following surgery is a treatment option particularly when margins are positive or close after maximal resection, if there is concern about the adequacy of negative margins, or if the achievement of wide margins would result in a functional or cosmetic defect.
Targeting the PDGF receptor signaling by receptor TKI, such imatinib or nilotinib, has demonstrated remarkable clinical success in the setting of advanced, unresectable primary tumors or metastatic disease.4 These TKI are competitive antagonists of the adenosine triphosphate (ATP)-binding site, blocking the transfer of phosphate groups from ATP to tyrosine kinase residues of the substrates. This causes interruption of the downstream signaling process that leads to cell proliferation. The clinical activity of imatinib in patients with metastatic or locally advanced, unresectable DFSP was initially documented in case reports. The first published larger series of DFSP patients treated with imatinib confirmed the clinical activity with eight of eight patients with locally advanced disease obtained a clinical response. Four of these had a complete response; the other four patients were rendered free of disease after surgery following a partial response. Since 2007, imatinib has been approved in the United States and in the European Union for use in adult patients who have unresectable, recurrent, and/or metastatic DFSP and are no primary candidates for surgery. However, these observations raise the possibility of using PDGFR-specific TKI in the neoadjuvant setting in cases where surgery is associated with significant morbidity.2 Clinical trials are needed to determine whether neoadjuvant use of such TKI to reduce tumor burden and facilitate resection, as well as adjuvant use following complete surgery, particularly in fibrosarcomatous DFSP, can improve patient outcome. Several studies in the United States and in Europe are ongoing in these clinical settings.