Dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing soft tissue sarcoma that originates in the dermis, the middle layer of the skin, and is classified as an intermediate- to low-grade malignancy.^[1] It typically presents as a small, firm, reddish-brown plaque or nodule that expands gradually over time, often resembling a scar, pimple, or birthmark, and is most commonly found on the trunk, followed by the proximal extremities, with about 15% occurring on the head or neck.^[2][3] The tumor arises from fibroblastic cells and has a characteristic infiltrative growth pattern into the subcutaneous tissue, but it rarely metastasizes, with distant spread occurring in only about 5% of cases, primarily to the lungs.^[1] Epidemiologically, DFSP has an annual incidence of 0.8 to 4.5 cases per million people, affecting individuals of all ages but peaking between 30 and 50 years, with equal distribution between sexes and a higher prevalence in Black individuals.^[1][4] It accounts for approximately 1% of all soft tissue sarcomas, with about 6% of cases occurring in children, where it may mimic congenital lesions.^[1] The pathogenesis is driven by a recurrent genetic translocation, t(17;22)(q22;q13), which fuses the COL1A1 and PDGFB genes in over 90% of cases, leading to overproduction of platelet-derived growth factor beta (PDGF-β) that stimulates uncontrolled cell proliferation.^[1][2] This somatic mutation occurs sporadically in tumor cells and is not inherited, with no clear environmental risk factors identified beyond possible associations with prior trauma or sites of injury in some cases.^[2] Clinically, DFSP is often asymptomatic in its early stages, growing indolently for months to years before becoming protuberant or ulcerated, and variants such as the pigmented Bednar tumor or fibrosarcomatous DFSP (5-15% of cases) may exhibit more aggressive features like higher recurrence or metastasis risk.^[1] Diagnosis relies on biopsy showing spindle-shaped tumor cells in a storiform pattern, positive staining for CD34, and confirmation of the characteristic translocation via fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR).^[1] Treatment primarily involves wide surgical excision with 2-4 cm margins or Mohs micrographic surgery to achieve clear margins and minimize recurrence, which occurs in up to 50% of cases if inadequately resected; for advanced or metastatic disease, targeted therapy with imatinib, a tyrosine kinase inhibitor, yields response rates of about 65%.^[1] The prognosis is generally excellent, with a 10-year overall survival rate exceeding 99%, though vigilant follow-up is essential due to the tumor's propensity for local invasion into deeper tissues like fat, muscle, or bone if untreated.^[1][3]

Epidemiology

Incidence and prevalence

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma, with an incidence of 4.1 cases per million person-years in the United States based on Surveillance, Epidemiology, and End Results (SEER) program data from 2000 to 2010.^[5] More recent analyses of SEER data indicate a stable rate of approximately 4.6 cases per million person-years from 2000 to 2020, and 6.25 cases per million person-years in a 2024 study (SEER data, recent period).^[6][4] Globally, incidence rates are comparable, ranging from 3 cases per million in France to 4 to 5.3 cases per million in Scandinavian countries, with no substantial geographic variations beyond differences in diagnostic infrastructure and reporting.^[7] DFSP represents approximately 1% of all soft tissue sarcomas and less than 0.1% of all malignant neoplasms overall.^[7] This rarity underscores its position among cutaneous sarcomas; for context, it is less common than atypical fibroxanthoma, which exhibits an incidence of up to 2 to 3 cases per 100,000 in sun-exposed populations, primarily among older adults. A 2024 SEER analysis confirms ongoing stability in incidence rates without notable increases or declines through recent years.^[4] The tumor most frequently affects young to middle-aged adults, with peak incidence in the third to fourth decades of life.^[7]

Demographics and risk factors

Dermatofibrosarcoma protuberans (DFSP) most commonly affects individuals between the ages of 20 and 50 years, exhibiting a bimodal age distribution that includes rare occurrences in children and congenital presentations accounting for less than 10% of all cases.^[1] Approximately 6% of DFSP cases are diagnosed in patients under 16 years old, with congenital forms often presenting as firm plaques on the trunk or extremities at birth.^[1] DFSP occurs with equal distribution across genders, though some studies report slight variations, including a minor female predominance in recent U.S. data.^[1][5] DFSP occurs across racial groups without a strong overall disparity, but U.S.-based analyses show higher incidence rates among Black individuals, approximately double those in White populations (8.7 per million versus 4.5 per million).^[4] No strong genetic predisposition exists for DFSP, as the characteristic COL1A1-PDGFB fusion gene rearrangement is typically a somatic event rather than inherited.^[1] However, associations with prior trauma, including burn scars and surgical sites, are noted in 10-20% of cases, suggesting local injury as a potential trigger.^[7] Rare familial clusters have been reported, occasionally linked to the same gene rearrangement, but these do not indicate a hereditary pattern.^[1] Unlike other skin cancers such as melanoma or basal cell carcinoma, DFSP lacks major environmental risk factors like ultraviolet (UV) exposure.^[1] A 2025 literature review highlights possible hormonal influences, with accelerated tumor growth observed during pregnancy in multiple cases, potentially mediated by estrogen or other pregnancy-related hormones.^[8]

Clinical presentation

Signs and symptoms

Dermatofibrosarcoma protuberans (DFSP) typically presents as a slow-growing, painless, indurated plaque or nodule on the skin, often with a skin-colored, reddish-brown, or violaceous hue.^[1] Initially, it may resemble a pimple, scar, or rough patch, feeling firm or rubbery to the touch, and lacks tenderness or pruritus in most cases.^[9] Over months to years, the lesion expands peripherally, potentially reaching several centimeters in diameter (up to 10 cm), and develops a protuberant appearance as it pushes through the overlying skin.^[1][10] As the tumor progresses, it may form multiple raised nodules, occasionally ulcerating or bleeding, with rare development of tenderness or itchiness.^[9] In advanced localized disease, large lesions can cause restricted mobility, particularly if located on the limbs or trunk, though systemic symptoms such as fever or weight loss are absent.^[11] The innocuous early appearance often leads to a diagnostic delay averaging 2 to 5 years, as patients and clinicians may overlook it or mistake it for benign conditions.^[12] Early recognition is emphasized in current guidelines to facilitate timely intervention.^[13] DFSP most commonly arises on the trunk.^[1]

Anatomic sites

Dermatofibrosarcoma protuberans most commonly arises on the trunk, accounting for 50-60% of cases, particularly involving the abdomen and chest regions.^[8] Extremities are affected in 20-30% of instances, with proximal locations more frequent than distal ones.^[8] Head and neck involvement occurs in 10-15% of cases, where the tumor's proximity to critical structures raises specific concerns for cosmetic outcomes and functional preservation in management.^[8] Lesions in the genital area or mucous membranes are uncommon, representing fewer than 5% of occurrences.^[8] In congenital presentations, DFSP typically manifests on the trunk or limbs.^[14] Pediatric cases show a higher proportion of extremity involvement relative to adults, often on the lower limbs or acral sites such as the legs.^[14] The tumor demonstrates site-specific growth patterns, characterized by tentacle-like infiltration into subcutaneous fat lobules, which facilitates more rapid radial expansion on the trunk due to the greater volume of subcutaneous tissue present there.^[15] This horizontal spread often results in an enlarging plaque-like lesion before deeper invasion becomes evident.^[1]

Pathogenesis

Etiology

The primary etiology of dermatofibrosarcoma protuberans (DFSP) remains unknown, with no established links to ultraviolet radiation or viral infections, unlike some other soft tissue sarcomas.^[7] In approximately 10-20% of cases, a history of local trauma, such as burns, surgical scars, or vaccination sites, precedes tumor development, potentially through mechanisms involving aberrant wound healing and fibroblastic proliferation.^[7][16] Hormonal influences have been hypothesized based on reports of accelerated tumor growth during pregnancy, observed in some cases and possibly mediated by estrogen or progesterone effects on cellular proliferation.^[17][18] No associations have been established with tobacco use, alcohol consumption, or occupational exposures, and recent reviews have dismissed chemical carcinogens as contributing factors.^[1][15]

Molecular mechanisms

Dermatofibrosarcoma protuberans (DFSP) is characterized by a hallmark chromosomal translocation t(17;22)(q22;q13) present in approximately 90% of cases, which generates the COL1A1-PDGFB fusion gene. This fusion places the platelet-derived growth factor beta (PDGFB) coding region under the transcriptional control of the collagen type I alpha 1 (COL1A1) promoter, resulting in constitutive overexpression of PDGFB. The fusion protein acts in an autocrine loop by binding to platelet-derived growth factor receptor beta (PDGFRβ) on tumor cells, activating downstream pathways including Ras-MAPK and PI3K-Akt, which drive uncontrolled proliferation and survival of fibroblasts.^[8][19] The aberrant PDGF signaling promotes the expansion of CD34-positive spindle cells, which infiltrate the dermis and subcutis in a characteristic storiform (cartwheel-like) pattern, underlying the tumor's locally aggressive behavior. Classic DFSP maintains a low mitotic rate due to the balanced activation of these pathways, contributing to its indolent, slow-growing clinical course over years.^[8][20] Transformation to the fibrosarcomatous variant (FS-DFSP), occurring in 5-15% of cases, involves additional genomic instability, such as TP53 mutations or homozygous deletions, alongside increased PDGFB gene copy numbers, which amplify signaling intensity, elevate mitotic activity, and heighten metastatic potential. Rare alternative fusions, including COL1A2-PDGFB and COL6A3-PDGFD, have been identified in a subset of DFSP cases and similarly activate PDGF-dependent pathways, though they are less common than the canonical COL1A1-PDGFB rearrangement.^[21][8]

Diagnosis

Clinical evaluation

Clinical evaluation of dermatofibrosarcoma protuberans (DFSP) begins with a detailed patient history and physical examination to assess for features suggestive of this rare soft tissue sarcoma. Patients often report a slowly enlarging cutaneous lesion present for months to years, typically exceeding one year in duration, with a history of preceding trauma, scarring, or tattoos in some cases; the lesion is usually asymptomatic and painless unless it ulcerates or enlarges significantly.^[1] During physical examination, the lesion appears as a firm, indurated plaque that may have a violaceous or red-brown hue, often with telangiectasias, and demonstrates tethering to the underlying dermis or deeper structures, progressing from a flat or slightly raised morphology to protuberant nodules.^[1] DFSP most commonly arises on the trunk, which aids in contextualizing the presentation in young adults.^[1] The differential diagnosis for suspected DFSP includes several benign and malignant entities that mimic its indolent growth. Dermatofibroma presents as a harder, stable nodule without progressive enlargement, often with a dimple sign on lateral compression.^[1] Keloids are distinguished by a clear history of preceding injury and a more hypertrophic, scar-like appearance without deep tethering.^[1] Leiomyomas, in contrast, are typically painful on palpation or exposure to cold, unlike the painless nature of DFSP.^[1] Misdiagnosis is frequent due to DFSP's resemblance to benign lesions, leading to diagnostic delays and inadequate initial interventions in a substantial proportion of cases. Over 50% of patients experience misdiagnosis, commonly as cysts, lipomas, or scars, resulting in unplanned excisions without appropriate margins that complicate subsequent management.^[22] The median diagnostic delay is approximately 3 to 5 years from lesion onset, with some cases extending longer, often attributed to the tumor's slow growth and initial innocuous appearance.^[22] A 2019 patient survey highlighted that such delays correlate with larger lesion sizes at definitive diagnosis, averaging 4.4 to 4.9 cm.^[22] Biopsy is recommended for any persistent, indurated plaque greater than 1 cm in young adults, particularly when atypical features such as progressive growth or tethering are present, to confirm suspicion and guide treatment.^[1] Core needle or incisional biopsy is preferred to obtain adequate tissue while minimizing sampling error in these low-grade but locally invasive tumors.^[1]

Histopathology and immunohistochemistry

Histopathology of dermatofibrosarcoma protuberans (DFSP) is characterized by a poorly circumscribed proliferation of uniform, monomorphic spindle cells arranged in a storiform or cartwheel pattern, extending from the dermis into the subcutis. These cells exhibit elongated nuclei with minimal atypia, scant eosinophilic cytoplasm, and are embedded in a delicate collagenous stroma. The tumor infiltrates the subcutaneous adipose tissue in a distinctive honeycomb pattern, with thin, branching extensions trapping individual fat cells.^[1][23] Mitotic activity in classic DFSP is low, typically fewer than 5 mitoses per 10 high-power fields, with rare atypical forms. Necrosis is absent in conventional cases, though it may appear in transformed variants. The overall architecture reflects a low-grade fibroblastic neoplasm with a propensity for local extension rather than deep invasion.^[1][23] Immunohistochemistry plays a crucial role in confirming the diagnosis. Tumor cells show strong, diffuse positivity for CD34 in over 90% of cases, highlighting the fibroblastic origin and aiding differentiation from mimics. Factor XIIIa staining is negative, contrasting with its positivity in dermatofibromas. DFSP is also negative for S100 protein, desmin, and smooth muscle actin, which helps exclude neural, myogenic, or melanocytic tumors.^[1][23] The 2025 NCCN Clinical Practice Guidelines recommend CD34 as a primary screening immunohistochemical marker for suspected DFSP, followed by molecular confirmation of the characteristic gene fusion if histology is equivocal.^[13] Grading of DFSP is based on the extent of solid spindle cell areas; classic cases with less than 5% such components are classified as low-grade, while greater involvement signifies intermediate-grade risk with increased metastatic potential.^[23]

Imaging and molecular testing

Magnetic resonance imaging (MRI) is the preferred modality for preoperative assessment of dermatofibrosarcoma protuberans (DFSP) to delineate tumor extent, as it reveals a dermal and subcutaneous mass that often appears isointense on T1-weighted images and hyperintense on T2-weighted images, with characteristic linear, tentacle-like strands extending into the subcutaneous fat.^[20] These T2-hyperintense extensions help visualize infiltration beyond clinically apparent margins, aiding surgical planning.^[24] Ultrasound is useful for evaluating superficial DFSP lesions, typically showing a well-marginated, hypoechoic subcutaneous mass with a slightly lobulated border.^[20] Positron emission tomography-computed tomography (PET-CT) is rarely employed due to DFSP's low metabolic activity, resulting in minimal fluorodeoxyglucose (FDG) uptake, though it may assist in detecting rare metastases in aggressive variants.^[25] Molecular testing confirms DFSP through detection of the COL1A1-PDGFB gene fusion, present in most cases; fluorescence in situ hybridization (FISH) targeting this rearrangement demonstrates 94-95% sensitivity and is routinely used for diagnosis.^[26] In equivocal or atypical cases, such as fibrosarcomatous DFSP, reverse transcription polymerase chain reaction (RT-PCR) identifies fusion transcripts with high accuracy, detecting the rearrangement in nearly all informative samples.^[27] Sentinel lymph node biopsy is not routinely recommended for DFSP, given the low rate of nodal metastasis (less than 5%), though it may be considered in cases with fibrosarcomatous transformation.^[15]

Histological variants

Common variants

Dermatofibrosarcoma protuberans (DFSP) exhibits several histological variants that are generally less aggressive than the classic form, characterized by a storiform pattern of spindle cells infiltrating the dermis and subcutis, though these subtypes display distinct morphological features while retaining similar low-grade behavior and the characteristic COL1A1-PDGFB gene fusion.^[28] These variants often pose diagnostic challenges due to their atypical appearances but do not significantly alter prognosis when managed appropriately.^[29] The Bednar tumor, or pigmented variant, accounts for approximately 1-5% of DFSP cases and is distinguished by the presence of melanin-laden dendritic cells interspersed among the spindle cells, imparting a dark blue to black coloration clinically.^[30][31] These pigmented cells are typically scattered within the otherwise uniform storiform architecture, and the variant shares the same t(17;22) chromosomal translocation resulting in the COL1A1-PDGFB fusion as classic DFSP.^[32] Importantly, the Bednar tumor demonstrates no significant prognostic difference from the standard subtype, with comparable low metastatic potential.^[33] Myxoid DFSP features a mucin-rich, hypocellular stroma with spindle and stellate cells arranged in a haphazard pattern, often with prominent thin-walled vessels, which can mimic benign entities like cutaneous myxoma despite strong CD34 positivity.^[34][35] This variant tends to occur in older patients and is frequently located on the trunk, presenting as a slowly enlarging plaque or nodule.^[36] The myxoid change does not confer a worse prognosis, maintaining the low-grade nature of DFSP.^[37] Giant cell fibroblastoma represents a pediatric form of DFSP, comprising less than 10% of cases and primarily affecting children under 10 years of age, with pseudoangiomatous spaces lined by multinucleated giant cells amid a spindle cell proliferation.^[38][2] It shares the identical COL1A1-PDGFB fusion and CD34 expression with DFSP, often arising on the trunk or proximal extremities.^[39] Although prognosis remains favorable, this variant exhibits a higher local recurrence rate, approaching 50% in some series, necessitating vigilant follow-up.^[40] Atrophic and sclerosing variants are rare subtypes that present with subtle clinical features, often as plaque-like or depressed lesions mimicking scars or atrophic conditions.^[41] The atrophic form, more commonly reported in children, shows thinned dermal involvement with sparse spindle cells and reduced cellularity.^[42] In contrast, the sclerosing variant displays dense collagen bundles interspersed with atypical fibroblasts, potentially resembling sclerotic fibroma or lichen sclerosus on partial biopsy.^[43] A 2024 review highlights these as low-grade entities without prognostic implications beyond the classic DFSP, emphasizing the role of molecular confirmation for diagnosis.^[15]

Aggressive variants

Fibrosarcomatous dermatofibrosarcoma protuberans (DFSP-FS) represents the primary aggressive variant of DFSP, occurring in approximately 10-15% of cases and characterized by areas of sarcomatous transformation comprising more than 10% of the tumor.^[44] These areas feature fascicles of spindle cells arranged in a herringbone pattern, with increased cellularity, cytologic atypia, and elevated mitotic activity exceeding 10 mitoses per 10 high-power fields.^[15] This transformation typically arises from classic DFSP through genetic alterations, including TP53 mutations that contribute to tumor progression and p53 protein overexpression.^[44][15] DFSP-FS exhibits a more aggressive clinical course than classic DFSP, with a notably higher risk of metastasis estimated at 15-20%, primarily to the lungs, soft tissues, and bones, alongside increased local recurrence rates.^[44] The 2025 NCCN guidelines classify DFSP-FS as a high-risk variant due to this elevated metastatic potential (ranging 10-23.5% in reviewed cases) and recommend multidisciplinary evaluation, preference for margin-controlled techniques like Mohs micrographic surgery, and consideration of wider excision margins (≥2-3 cm) to achieve negative margins and mitigate recurrence.^[45] Cases of radiation-induced DFSP-FS are exceptionally rare, with reports limited to isolated instances of high-grade transformation developing within irradiated fields years after therapy.^[46] Immunohistochemically, DFSP-FS lacks distinct markers differentiating it from classic DFSP beyond frequent diminution or loss of CD34 expression in transformed areas; however, proliferation marker Ki-67 is markedly increased, with average indices around 18% compared to 8% in non-transformed cases, reflecting heightened cellular turnover.^[44][47] Like classic DFSP, DFSP-FS harbors the characteristic COL1A1-PDGFB gene fusion driving oncogenesis.^[15]

Treatment

Surgical approaches

Surgical resection remains the cornerstone of treatment for localized dermatofibrosarcoma protuberans (DFSP), with the goal of achieving complete excision to minimize the risk of local recurrence due to the tumor's infiltrative growth pattern.^[15] For classic DFSP, wide excision with 2-3 cm margins of normal tissue, extending through the underlying fascia, is recommended to ensure clearance of microscopic extensions, as narrower margins increase the likelihood of incomplete resection.^[48] This approach has demonstrated clearance rates exceeding 84% when margins of at least 3 cm are utilized.^[15] Wide local excision (WLE) serves as the standard surgical method for most anatomical sites, particularly the trunk and extremities, where tissue availability allows for adequate margins without excessive functional compromise.^[49] For larger defects resulting from excision, reconstruction often involves local flaps or skin grafts to restore contour and function, especially in cosmetically sensitive areas.^[50] Intraoperative frozen section analysis has limited utility in DFSP surgery owing to the tumor's subtle infiltrative margins, which can lead to false negatives and subsequent positive permanent sections.^[51] A meta-analysis reported incomplete excision rates of up to 77% following WLE, underscoring the importance of thorough pathological evaluation to guide any necessary re-excision.^[52] For challenging locations such as the head and neck or tumors involving large surface areas, a multidisciplinary approach involving dermatologic surgeons, plastic surgeons, and oncologists is essential to balance oncologic safety with preservation of critical structures.^[53] Adjuvant radiation therapy may be considered in cases of close or positive margins to further reduce recurrence risk.^[15]

Mohs micrographic surgery

Mohs micrographic surgery (MMS) is a specialized technique particularly suited for treating dermatofibrosarcoma protuberans (DFSP) due to the tumor's irregular, tentacle-like subcutaneous extensions that can extend far beyond clinically visible margins. The procedure involves sequential layer-by-layer excision of the tumor with immediate microscopic examination of the 100% of the surgical margins using horizontal sections, allowing for precise mapping and removal of residual disease while maximizing tissue conservation. This approach is especially advantageous for lesions on the face or acral sites, where preserving healthy tissue is critical to maintain function and cosmesis.^[54] In DFSP cases, the technique is enhanced by the use of CD34 immunostaining on frozen sections to improve detection of tumor cells, which often show diffuse positivity for this marker, aiding in differentiation from surrounding normal tissue and identification of subtle subcutaneous infiltrations. Initial excision typically employs 1-2 cm margins, followed by additional layers as needed based on microscopic findings. Recent studies, including a 2025 prospective cohort of 223 patients treated with fixed MMS incorporating CD34 and molecular confirmation, demonstrate high efficacy, with 87.9% of cases cleared in a single stage.^[55][56] MMS achieves recurrence rates below 2%, significantly lower than traditional methods, as evidenced by a 0.4% rate (1 recurrence in 223 cases) in the aforementioned 2025 French cohort with long-term follow-up exceeding 85 months, and a 1% rate reported in a comprehensive 2025 review of MMS outcomes. These results underscore MMS as the preferred surgical option for DFSP, particularly for primary tumors, due to its superior margin control.^[56][57] Despite its benefits, MMS has limitations, including its time-intensive nature and logistical challenges, making it less practical for very large lesions or those on the trunk where extensive excision may be required. In such scenarios, the procedure's duration and need for specialized pathology support can complicate feasibility.^[54]

Adjuvant radiation therapy

Adjuvant radiation therapy is employed in the management of dermatofibrosarcoma protuberans (DFSP) primarily to enhance local control following surgical resection when complete excision with adequate margins is not achievable. It is indicated for cases with positive or close surgical margins (less than 1 cm if Mohs micrographic surgery was not performed), tumors in high-risk anatomic sites such as the head and neck where wide excision may cause significant morbidity, or the more aggressive fibrosarcomatous (FS) variant, which carries an elevated risk of local recurrence. According to the National Comprehensive Cancer Network (NCCN) guidelines version 1.2025, adjuvant radiation is not recommended routinely for tumors with negative margins after margin-controlled surgery.^[1] The standard radiation dose for adjuvant therapy in DFSP ranges from 50 to 60 Gy, delivered in conventional fractions of 1.8 to 2 Gy per day over 5 to 6 weeks. This dosing regimen aims to sterilize microscopic residual disease while minimizing toxicity to surrounding tissues. Surgical margins are typically referenced to define the clinical target volume, extending 3 to 5 cm beyond the resection bed when feasible.^[58] Clinical outcomes demonstrate that adjuvant radiation significantly improves local control, particularly in incomplete resections. A seminal 2016 systematic review and meta-analysis of 12 studies involving 167 patients treated with surgery plus adjuvant radiation reported a pooled local recurrence rate of 11.74% (95% CI: 7.4–17.38%), with rates dropping to 14.23% for positive or close margins and 0% for negative margins. Without radiation, recurrence rates after inadequate surgery can exceed 20%, and adjuvant therapy reduces this risk to less than 5% in high-risk incomplete resection cases, though it does not confer a survival benefit given DFSP's low metastatic potential. A 2024 review of postoperative radiotherapy corroborated these findings, emphasizing improved local control without impacting overall survival in a cohort of over 100 cases.^[59][60] Techniques for delivery include external beam radiation therapy (EBRT), often using intensity-modulated radiation therapy (IMRT) for precise targeting in complex sites, or electron beam therapy for superficial lesions to spare underlying structures. Common side effects are generally mild and include skin fibrosis, telangiectasia, and lymphedema, with rare instances of secondary malignancies occurring years later due to radiation exposure. Long-term follow-up is essential to monitor for these effects.^[61][62]

Systemic targeted therapy

Systemic targeted therapy plays a crucial role in managing unresectable, locally advanced, or metastatic dermatofibrosarcoma protuberans (DFSP), particularly in cases driven by the characteristic COL1A1-PDGFB gene fusion. Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor, is the established first-line agent for PDGFB fusion-positive advanced disease, targeting the constitutively activated platelet-derived growth factor receptor beta (PDGFRβ) resulting from the fusion.^[37] This mechanism disrupts aberrant signaling that promotes tumor proliferation, leading to tumor regression in responsive cases.^[63] Clinical response rates to imatinib range from 50% to 80%, with objective response rates (complete or partial) typically around 60% across studies.^[37] Standard dosing starts at 400 mg daily, escalating to 800 mg if tolerated and needed for optimal response, with no significant efficacy difference between doses in systematic analyses.^[64] A 2019 systematic review of nine studies involving 152 patients reported a 60.5% overall response rate (5.2% complete, 55.2% partial), 27.6% stable disease, and 9.2% progression, confirming imatinib's reliability in advanced DFSP.^[64] Long-term outcomes demonstrate durable control, with a 2017 multicenter study of 31 patients showing a median progression-free survival (PFS) of 6.8 years and a 5-year PFS rate of 58%, though lower (33%) in fibrosarcomatous variants.^[65] For imatinib-resistant disease, alternative multi-targeted tyrosine kinase inhibitors such as sunitinib or pazopanib offer second-line options, albeit with more limited efficacy. Sunitinib, dosed at 37.5 mg daily continuously, achieved a 40% objective response rate and 73.3% disease control in a series of 30 imatinib-refractory patients, with a median PFS of 19 months.^[66] Pazopanib, typically at 800 mg daily, has shown partial responses in about 22% of resistant cases in small cohorts, primarily stabilizing disease rather than inducing regression.^[67] Traditional cytotoxic chemotherapy, including doxorubicin-based regimens, demonstrates low efficacy in DFSP, with response rates under 20% and no established role in standard management due to the tumor's relative chemoresistance.^[57] Neoadjuvant imatinib is particularly valuable for borderline resectable tumors, often achieving 20-37% size reduction after 2-3 months of therapy, thereby enabling curative surgery while minimizing morbidity.^[68] In one series, 60% of treated patients proceeded to resection post-imatinib, with many maintaining long-term remission after discontinuation.^[64] Adverse effects are generally manageable, with edema, fatigue, and nausea most common, though severe events occur in about 15% of cases.^[64]

Prognosis

Recurrence rates

Local recurrence rates for dermatofibrosarcoma protuberans (DFSP) following adequate surgical excision with wide margins (typically 2-3 cm) are generally low, ranging from 10% to 15% in classic cases.^[69] However, rates increase significantly to 20-50% in fibrosarcomatous (FS) variants or when narrower margins or positive surgical margins are achieved, with one meta-analysis reporting a 29.8% recurrence rate for FS-DFSP compared to 13.7% for classic DFSP.^[57][70] The median time to local recurrence is typically 1 to 3 years post-treatment, though long-term follow-up data indicate that late recurrences beyond 5 years occur in a small subset of cases, emphasizing the need for extended surveillance.^[71][72] Key risk factors for recurrence include positive microscopic margins, tumors located on the trunk, and presentation in pediatric patients, where diagnostic delays and infiltrative growth patterns may contribute to incomplete excision.^[71][73][74] Post-treatment monitoring is recommended with clinical examinations every 6 months for the first 3 to 5 years, followed by annual evaluations, and MRI imaging for high-risk cases (e.g., positive margins or FS variant) during this initial period to detect subclinical recurrences early.^[1][57] In classic DFSP, local recurrences do not significantly impact overall survival, which remains excellent at exceeding 99% at 10 years due to the tumor's low metastatic potential.^[1]

Metastatic disease

Dermatofibrosarcoma protuberans (DFSP) is characterized by a low risk of distant metastasis, occurring in less than 5% of classic cases and approximately 15% in those with fibrosarcomatous transformation (DFSP-FS).^[75] The overall metastasis rate across DFSP variants is estimated at 1-4%.^[1] A systematic review of retrospective studies confirmed a higher metastatic potential in DFSP-FS compared to classic DFSP, with relative risk elevated up to 5.5-fold.^[57] Metastasis in DFSP occurs primarily via the hematogenous route, with lymphatic spread being rare.^[37] The lungs represent the most common site of distant spread, followed by regional lymph nodes and bone. Risk factors for metastasis include fibrosarcomatous transformation and larger primary tumor size greater than 5 cm, which is associated with increased metastatic development.^[76] Management of metastatic DFSP depends on the extent and location of disease. Solitary metastases are typically treated with surgical resection when feasible, aiming for complete removal. For multifocal, unresectable, or advanced metastatic disease, systemic targeted therapy with imatinib is the preferred approach, particularly in tumors harboring COL1A1-PDGFB fusions, yielding partial responses in over 50% of cases. Median survival following metastasis diagnosis ranges from 3 to 5 years, with favorable outcomes even in node-positive or distant cases when treated aggressively.^[77] Due to the low overall metastatic risk, routine staging scans such as chest CT or PET are not recommended for all DFSP patients; imaging is reserved for those with high-risk features like large tumors or FS transformation.^[25]

Considerations in pregnancy

Dermatofibrosarcoma protuberans (DFSP) typically exhibits slow growth, but during pregnancy, it can demonstrate accelerated enlargement or changes in size and color in a subset of cases, potentially influenced by hormonal factors such as estrogen and progesterone.^[78] This rapid progression is rare, with literature documenting approximately 14-18 reported instances of hormone-associated growth alterations across case series and reviews.^[79] Diagnosis is frequently delayed due to the tumor's indolent nature and attribution of changes to normal pregnancy-related skin modifications, often extending the interval from symptom onset to confirmation by several months.^[1] Surgical management remains the cornerstone of treatment for DFSP in pregnant patients, with wide local excision or Mohs micrographic surgery recommended when feasible. Excision is generally considered safe during the second and third trimesters to minimize risks associated with anesthesia and procedural stress, while first-trimester interventions are avoided if possible to reduce potential teratogenic effects.^[80] A 2021 case series reviewing 18 instances of DFSP diagnosed or managed during pregnancy reported no adverse fetal outcomes following prepartum surgical interventions in select cases, supporting the viability of this approach for symptomatic or rapidly progressing lesions.^[78] For most patients, however, definitive surgery can be deferred until postpartum to prioritize maternal-fetal stability. Systemic therapies like imatinib, a tyrosine kinase inhibitor effective against DFSP harboring COL1A1-PDGFB fusions, are contraindicated during pregnancy due to its teratogenic potential, including risks of fetal malformations observed in animal studies and human case reports.^[81] Close monitoring with serial ultrasounds for both tumor progression and fetal well-being is advised, alongside deferral of radiation therapy, which is rarely indicated for DFSP but poses significant risks to the developing fetus if used.^[1] Congenital DFSP, a distinct entity presenting as plaques or nodules at birth, differs from pregnancy-associated cases and requires separate consideration in neonatal management, often involving early surgical intervention to prevent local invasion.^[82]

History

Discovery

Dermatofibrosarcoma protuberans (DFSP) was first reported in the medical literature in 1890 by Robert W. Taylor, who described a cutaneous sarcoma resembling a keloid in a single case, noting its firm, plaque-like appearance on the skin. This initial observation laid the groundwork for recognizing the tumor's distinctive clinical features, though it was not yet identified as a separate entity. Subsequent reports in the early 20th century began to highlight its recurrent and progressive nature, but classification remained inconsistent due to similarities with other dermal fibrotic lesions. In 1924, Jean Darier and Marcel Ferrand provided the first detailed clinical and pathological description of DFSP as a distinct condition, terming it "progressive and recurrent dermatofibroma" or "dermatofibrosarcomes progressifs et récidivants."^[83] They analyzed multiple cases, emphasizing the tumor's slow growth, tendency to recur after excision, and infiltrative dermal involvement, which differentiated it from more benign fibromas. This work marked a pivotal step in establishing DFSP's unique identity, although early pathologists often confused it with dermatofibroma owing to overlapping histological patterns of spindle cell proliferation in the dermis.^[15] The term "dermatofibrosarcoma protuberans" was coined in 1925 by Erich Hoffmann, who added "protuberans" to reflect the tumor's characteristic bulging or protuberant nodules that develop over time, often after years of indolent plaque formation.^[84] Hoffmann's contribution refined the nomenclature to capture this protuberant evolution, distinguishing it further from flat or non-protruding fibrotic conditions. By the mid-20th century, case series in the 1950s, such as those by Pack and Tabah in 1951, underscored DFSP's local aggressiveness and high recurrence rates following incomplete excision, prompting greater awareness of its infiltrative subcutaneous extension.^[85] The seminal 1962 study by Howard B. Taylor and Elson B. Helwig analyzed 115 cases, confirming DFSP as a low-grade sarcoma originating from dermal fibroblasts, distinct from more aggressive fibrosarcomas due to its rare metastatic potential and emphasis on wide local recurrence.^[86] This comprehensive review solidified DFSP's clinicopathologic profile, highlighting antecedent trauma in about 16% of cases and reinforcing the need for thorough surgical margins to mitigate its persistent local behavior.

Major advancements

A pivotal advancement in the 1990s was the identification of the t(17;22)(q22;q13) chromosomal translocation in DFSP, reported by Simon et al. in 1997, which fuses the COL1A1 and PDGFB genes and enables precise molecular diagnosis through detection of the resulting fusion transcript.^[87] This discovery provided a genetic hallmark for distinguishing DFSP from other spindle cell tumors and laid the foundation for targeted therapies exploiting the PDGFB pathway.^[88] In the 2000s, the adaptation of Mohs micrographic surgery for DFSP and related sarcomas emerged as a key refinement, allowing tissue-sparing excisions with complete margin control and reducing recurrence through histologic verification during surgery.^[89] Concurrently, imatinib mesylate gained FDA approval in 2006 for unresectable, recurrent, or metastatic DFSP, driven by its inhibition of the PDGFB-COL1A1 fusion protein, which demonstrated objective response rates of up to 50% in clinical trials.^[90] From the 2010s to the 2020s, the National Comprehensive Cancer Network (NCCN) guidelines for DFSP evolved to incorporate multidisciplinary approaches, emphasizing wide local excision or Mohs surgery for localized disease, neoadjuvant imatinib for borderline resectable cases, and surveillance protocols tailored to risk factors like fibrosarcomatous transformation.^[91] Recent reviews between 2023 and 2025 have refined fibrosarcomatous (FS) variant grading, highlighting its higher mitotic activity and p53 expression as predictors of aggressive behavior, while underscoring expanded roles for targeted therapies like imatinib and emerging tyrosine kinase inhibitors in managing FS-DFSP.^[37][75] In 2025, the NCCN guidelines (Version 1.2025) reaffirmed surgical excision with negative margins as primary treatment to minimize recurrence, alongside updates on clinical trials exploring novel targeted therapies and genomic profiling revealing a broader spectrum of fusions, such as those involving PDGFD.^[92][93] These developments have markedly improved outcomes, shifting recurrence rates from approximately 50% with pre-1990 wide local excisions to less than 10% using modern 2-3 cm margins combined with imatinib for high-risk cases.^[94][95]