Dermatofibrosarcoma Protuberans

Etiology

Ninety percent of patients with DFSP, including those who develop the fibrosarcomatous variant (DFSP-FS), have the t(17;22)(q22;q13) translocation.[2] An alternative translocation involving the platelet-derived growth factor subunit B (PDGFB) gene on chromosome 22 may be present in patients without the t(17;22)(q22;q13) translocation. In certain instances, the progression from DFSP to DFSP-FS is associated with genomic gain affecting the PDGFB/COL1A1 fusion gene, although this occurrence is variable.

Furthermore, researchers have noted the occurrence of microsatellite instability, characterized by alterations in the number of repeated deoxyribonucleic acid (DNA) bases within microsatellites or short, repetitive DNA sequences compared to the inherited state. Subsequently, these instances of microsatellite instability are accompanied by the acquisition of tumor protein p53 (TP53) mutations, particularly in cases displaying features of high-grade sarcoma

Epidemiology

DFSP is a rare tumor, occurring at a rate of 0.8 to 4.5 cases per million persons annually and represents 1% to 6% of all soft tissue sarcomas and 18% of cutaneous soft tissue sarcomas—affecting both genders equally. Some studies report a slight predominance in med. While most commonly diagnosed in adults between the third and fifth decades, DFSP can manifest across all age groups. Children account for 6% of all cases of DFSP. This tumor may exhibit accelerated growth during pregnancy.[3] DFSP-FS accounts for 5% to 15% of all DFSPs, and the Bednar or pigmented variant represents fewer than 5% of all DFSP cases. DFSP, including the pigmented variant, is more common in Black individuals than White.[4] 

Pathophysiology

The t(17;22)(q22;q13) translocation results in the formation of supernumerary ring chromosomes from chromosome 22 and contains low-level amplified sequences from 17q22-qter and 22q10-q13.1.[4][5] Less commonly, a linear derivative of chromosome 22 may also be implicated.[6] The ring chromosomes and the translocated linear derivative of chromosome 22 harbor a fusion gene where PDGFB merges with the collagen type 1A1 (COL1A1) gene. The usually suppressed PDGFB now becomes activated by the COL1A1 promoter. This genetic rearrangement induces PDGFB upregulation, resulting in excessive platelet-derived growth factor (PDGF) production, continuous activation of the tyrosine kinase PDGFRB receptor, cellular proliferation, and tumor development.[7]

Histopathology

DFSP is poorly circumscribed and usually involves the dermis and subcutis, although rare cases can be limited to the dermis (see Image. Dermatofibrosarcoma Protruberans, Low-Power Field). Due to the possibility of distant metastasis and aggressive local invasion, DFSP is considered an intermediate tumor between a benign dermatofibroma and a frank fibrosarcoma. Transformation to a high-grade sarcoma is extremely rare. The overlying epidermis does not show any atypical histological features.[8] 

The spindle-shaped tumor cells of DFSP are arranged in a storiform or woven pattern, parallel to the epidermal surface, and have little pleomorphism and scant cytoplasm (see Image. Hematoxylin and Eosin Stain Dermatofibrosarcoma Protuberans). The cells are surrounded by collagenous stroma, sometimes associated with hyaline or myxoid changes. The characteristic honeycomb appearance results from irregular tentacle-like projections infiltrating the underlying subcutaneous tissue, traversing the septa and fat, leading to fat entrapment. DFSP typically extends into subcutaneous fat but seldom involves fascia, muscle, or bone unless recurrent or long-standing. Necrosis is uncommon. While mitoses are present, no significant mitotic activity is present, and atypical mitoses are rare. A mitotic count that reaches 10 mitoses per 10 high power field (HPF) and tumor size correlates with metastatic spread. About one-fifth of all DFSPs undergo fibrosarcomatous transformation, which appears as an expansive tumor with fascicular and herringbone patterns and atypical cytological features.[9][10]

History and Physical

DFSP typically manifests as an asymptomatic, skin-colored to red-brown firm plaque, eventually progressing to multiple raised nodules with a violaceous to red-brown hue (see Image. Dermatofibrosarcoma Protuberans). The pigmented variant often presents with irregular brown pigmentation, and the atrophic variant appears as a violaceous plaque resembling morphea or scar tissue. Lesions exhibit slow growth over months to years, occasionally resembling keloids or dermatofibromas, leading to misdiagnosis, particularly in the early stages. As the tumor progresses, it may reach several centimeters in diameter, potentially accompanied by telangiectasia in the surrounding or overlying skin. The tumor is typically fixed to the dermis but can freely move in relation to underlying structures. Later in the disease, the tumor may become fixed to underlying structures. Rarely, DFSP can arise from preexisting scars or tattoos. As lesions enlarge, some may ulcerate and become painful. Nearly 50% of lesions are on the trunk, followed by 35% on the extremities, and 15% on the head and neck.[11] 

Evaluation

Healthcare professionals should consider DFSP in individuals presenting with a slow-growing cutaneous nodule. Dermoscopy is the initial assessment tool, offering suggestive but not conclusive evidence. A core needle or excisional biopsy provides a definitive diagnosis. Patients should undergo a comprehensive history and physical examination, including an assessment of lymph nodes and a complete skin examination. Those with a prior treatment history may undergo a fine needle aspiration.

Typically, examining a hematoxylin and eosin-stained specimen by light microscopy can diagnose DFSP. In some cases, clinicians may find distinguishing DFSP from other neoplasms like dermatofibroma, fibrosarcoma, leiomyosarcoma, undifferentiated or unclassified soft tissue sarcoma, or atypical fibroxanthoma challenging. All cases of suspected DFSP should undergo confirmatory immunohistochemistry testing. DFSP stains positive for CD34 in 80% to 100% of cases (see Image. Cellular Dermatofibroma). Hyaluronate and vimentin are typically also positive. DFSP stains negative for factor XIIIa, smooth muscle actin, desmin, S100 proteins, and keratins.

Molecular testing using reverse transcription polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) to detect the t(17;22)(q22;q13) translocation is available. Both have a similar specificity of 100%, but FISH is more sensitive than RT-PCR for detecting the PDGFB/COL1A1 transcript at 90% versus 72%, respectively. Molecular testing is necessary when the diagnosis is unclear or to predict the likelihood of response to treatment with a tyrosine kinase inhibitor.

Because most cases of DFSP are superficial, clinicians can assess the extent of tumor and lymph node involvement by physical examination. Imaging is not a routine part of the diagnostic process. Occasionally, imaging may be helpful for large or recurrent tumors if the clinician suspects bone invasion or needs to define the extent of the disease. Magnetic resonance imaging is the imaging modality of choice.[12][13][14][15] Computed tomography (CT) is only helpful if underlying bone involvement or lung metastases are suspected. The lung is the most common site of metastasis via hematogenous spread, and regional lymph nodes are rarely involved. Due to the unlikely occurrence of lymphatic and hematogenous dissemination, an extensive staging workup is not generally necessary. Some authors suggest obtaining a radiograph or CT scan of the lungs before treatment, though the National Comprehensive Cancer Network does not make specific recommendations regarding a staging evaluation.[16][17]

Treatment / Management

The initial treatment for localized DFSP is surgical resection with negative margins.[18] The size and location of the tumor determine the best surgical approach. Regional lymph node dissection is unnecessary, given the low risk of metastasis. The risk of inadequate initial resection is high due to the delay in diagnosis and the tumor's ability to invade surrounding tissues. Nearly 50% of patients will experience local recurrence with simple excision. Recurrent tumors are more likely to invade fascia, muscle, or bone and result in distant metastases.[19][20] For these reasons, pathological negative margins are necessary. 

Wide Local Excision

Wide local excision (WLE) is an option for resection. The resection margins are essential in determining the risk of local recurrence. Tentacle-like tumor projections can extend beyond 3 cm of the primary tumor. Results from one study reveal the local recurrence in patients with a resection margin less than 3 cm is 47% compared to 7% in patients with margins of 3 to 5 cm.[20][21][22] The NCCN recommends margins of 2 to 4 cm with clear pathologic margins when clinically feasible.(B2)

Mohs Micrographic Surgery

Mohs micrographic surgery (MMS) involves the progressive horizontal slicing of tissue during resection, coupled with immediate microscopic evaluation via frozen section analysis. Microscopic evaluation includes prompt immunostaining for CD34 until achieving a clear margin. Real-time microscopic examination of margins reduces the likelihood of positive margins. Some studies propose that MMS may result in lower local recurrence rates than WLE for DFSP. Notably, DFSP treated with WLE exhibits a recurrence rate of approximately 7.3%, contrasting with the 1% recurrence rate observed with MMS treatment.[23][24] However, randomized trials and comprehensive long-term data are required to confirm these findings. A significant benefit of MMS is the smaller required lateral margins, resulting in more minor wounds and less complex reconstruction. MMS is a good option for cosmetically sensitive areas, where achieving narrow margins is preferable. (B2)

Radiation Therapy

DFSP is radiosensitive tumor. Radiation therapy is rarely used alone in the treatment of DFSP. 

Current NCCN guidelines recommend the use of adjuvant radiation in the following settings:

• Positive margins after surgical resection
• Negative margins, with the closest margin being less than 1 cm in patients who did not undergo MMS
• For recurrent or metastatic disease when surgical excision is not feasible [25]

The doses of radiation range from 50 to 70 Gy and typically extend 3 to 5 cm beyond the surgical margin when feasible.[26]

Molecularly Targeted Therapy

Imatinib inhibits the PDGF receptor and other receptor tyrosine kinases such as c-KIT. Imatinib has the United States Food and Drug Administration (FDA) approval for unresectable, recurrent, or metastatic DFSP.[27] Imatinib competitively inhibits adenosine triphosphate (ATP) binding to the PDGFB receptor, slowing down kinase activity, limiting tumor growth, and promoting apoptosis. Patients with the t(17;22)(q22;q13) translocation show a more significant response to imatinib, and thus, screening for this translocation should be performed before initiating therapy. Further studies are necessary to see if patients without the translocation will benefit from imatinib.(A1)

Adverse effects associated with imatinib include gastrointestinal upset, edema, fatigue, anemia, and rash. Most patients with DFSP with translocation respond favorably to imatinib therapy, with studies suggesting a response rate of approximately 65%. The duration of therapy varies. Some sources recommend 6 months of therapy, which may be extended.[28][29] Additional research is necessary to determine the potential integration of imatinib into the surgical approach for localized DFSP. 

Posttreatment Surveillance

Patients should participate in regular self-examination, and the primary site should be examined every 6 months for 3 to 5 years. Lifelong examination annually follows. Radiographic surveillance, blood counts, and liver function testing are necessary only if symptoms dictate. Metastatic lesions are most likely to occur with recurrent lesions that have progressed for many years and when a fibrosarcomatous component is present. Some authors recommend limiting follow-up imaging examinations to those with recurrent DFSP or DFSP-FS. 

Differential Diagnosis

The following list contains the differential diagnoses for DFSP:

• Cellular fibrous histiocytoma
• Solitary fibrous tumor
• Spindle cell lipoma
• Angiosarcoma
• Peripheral nerve sheath tumors
• Spindle cell melanoma
• Angiomyxoma
• Myxoid sarcoma
• Synovial sarcoma
• Sarcomatoid carcinoma 
• Cutaneous melanoma
• Dermatofibroma
• Dermatologic metastatic carcinoma
• Epidermal inclusion cyst
• Keloid
• Morphea [17]

Prognosis

The prognosis for DFSP is generally favorable, with a 10-year survival rate of 99.1%. However, patients with metastatic disease typically survive approximately 2 years post-diagnosis. The overall risk for the development of metastatic disease is 5%, including 1% with regional lymph node metastasis and 4% with distant metastasis. While metastasis remains uncommon, local recurrence poses a more prevalent concern for morbidity. Features that increase the risk of a poor prognosis are patients older than 50, DFSP-FS, a high mitotic index, and increased cellularity.[30] A wider surgical excision improves the overall prognosis.  

Complications

Complications of DFSP primarily stem from the extent of the surgical defect and issues linked to local recurrence. Common complications include wound-related problems such as infections, challenges in covering the defect necessitating skin grafting or complex plastic surgery procedures, contractures, keloid formation, and suboptimal cosmesis. Employing MMS aids in mitigating these complications. Death is an uncommon but possible complication in patients who develop metastatic disease.