Classic Dermatofibrosarcoma Protuberans Research Articles

Molecular Pathogenesis and Histological Variability of Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans (DFSP) is a kind of infrequent tumor of the soft tissues distinguished by its gradual proliferation and a preference for regional reoccurrence, despite its limited capacity for metastasis. At the molecular level, a significant majority of DFSP cases manifest the t (17;22) (q22; q13) chromosomal translocation, resulting in the fusion of the collagen type I alpha chain (COL1A1) gene and platelet-derived growth factor B chain (PDGFB) gene. This fusion results in PDGFB overexpression, consequently activating the PDGF Receptor-beta (PDGFR-β). The activated PDGFR-β serves as a central nexus for numerous intracellular signaling pathways, initiating cascades including Phosphatidylinositol 3-kinase (PI3K)/Akt, Mitogen-Activated Protein Kinase (MAPK)/extracellular signal-regulated kinase (ERK), and STATs pathways. These cascades collectively enhance DFSP cell growth, proliferation, and invasiveness. Histologically, DFSP tumors are predominantly fibroblastic and display distinct immune cell infiltration patterns in their microenvironment. Elevated expression of CD4+ naïve cells, CD4+ Th2 cells, CD8+ central memory T cells, B cells, and macrophages is evident, while levels of CD4+ central memory T cells and eosinophils are diminished. Immunohistochemical analyses further highlight that most DFSP cells exhibit positive cytoplasmic CD34 expression, whereas factor XIIIa and α-smooth muscle actin are notably absent. Clinically, DFSP presents in diverse subtypes, each characterized by its unique histological profile. Prominent subtypes encompass classic DFSP, fibrosarcomatous DFSP (FS-DFSP), pigmented DFSP, giant cell fibroblastoma, myxoid DFSP, atrophic DFSP, and the granular cell variant. This review aspires to deliver an exhaustive insight into DFSP, accentuating its molecular underpinnings and clinical presentation, with the ultimate goal of advancing our understanding and management of this distinct dermatological entity.

Establishment and characterization of NCC-DFSP4-C1: a novel cell line from a patient with dermatofibrosarcoma protuberans having the fibrosarcomatous transformation.

Dermatofibrosarcoma protuberans (DFSP) is a superficial low-grade sarcoma, genetically characterized by a fusion gene in collagen type I α (COL1A1) gene and platelet-derived growth factor subunit β (PDGFB). DFSP is locally aggressive and does not typically metastasize. However, DFSP with fibrosarcomatous transformation, which occurs in 7-16% of DFSP cases, demonstrates a poor prognosis than classic DFSP with a higher local recurrence rate and metastatic potential. Although imatinib, a PDGF receptor inhibitor, is a potent therapeutic agent for classic DFSP, it is less effective for DFSP with fibrosarcomatous transformation. The development of definitive chemotherapies for DFSP with fibrosarcomatous transformation is required. Patient-derived tumor cell lines are indispensable tools for preclinical research to discover novel therapeutic agents. However, only seven cell lines were derived from DFSP, out of which only two were established from DFSP with fibrosarcomatous transformation. Hence, in the present study, we established a novel DFSP cell line, NCC-DFSP4-C1, from a surgically resected DFSP tumor specimen with fibrosarcomatous transformation. NCC-DFSP4-C1 harbored an identical COL1A1-PDGFB fusion gene as its donor tumor. NCC-DFSP4-C1 cells retained the morphology of their donor tumor and demonstrated constant proliferation, spheroid formation, and invasion capability in vitro. By screening a drug library, we found that bortezomib and romidepsin demonstrated the strongest suppressive effects on the proliferation of NCC-DFSP4-C1 cells. In conclusion, we report a novel cell line of DFSP with fibrosarcomatous transformation, and demonstrate its utility in the development of novel therapeutic agents for DFSP.

Rare Variants of Dermatofibrosarcoma Protuberans: Clinical, Histologic, and Molecular Features and Diagnostic Pitfalls.

Dermatofibrosarcoma protuberans (DFSP) is a dermal malignant mesenchymal tumor. Most variants are associated with a high risk of local recurrence and a low risk of metastasis. The classic histomorphology of this tumor is made up of uniform, spindle-shaped cells, arranged in a storiform pattern. Tumor cells characteristically infiltrate the underlying subcutis in a honeycomb pattern. Less common variants of DFSP have been identified: myxoid, pigmented, myoid, granular cell, sclerosing, atrophic, and fibrosarcomatous. Only the fibrosarcomatous variant has been shown to differ significantly from classic DFSP in terms of clinical outcome; fibrosarcomatous DFSP has been shown to be associated with a greater risk of local recurrence and metastatic potential than classic DFSP. However, the other variants may pose diagnostic difficulty as they resemble other types of spindle cell neoplasms, especially in small biopsy specimens. This article reviews the clinical, histologic, and molecular features of DFSP variants, as well as possible pitfalls in their diagnosis and how to resolve them.

Dermatofibrosarcoma protuberans of the face: A clinicopathologic and molecular study of 34 cases.

Dermatofibrosarcoma protuberans (DFSP) is one of the most common dermal sarcomas, but facial DFSP is rare. The clinicopathological characteristics of 34 facial DFSPs were reviewed. Additional immunostaining (CD34) and PDGFB/COL1A1-PDGFB fluorescence in situ hybridization (FISH) detection were performed. Patients were aged from 24 to 64 years (mean 42.9 years), with a male-to-female ratio of 4.7: 1. Morphologically, classic DFSP (25/34, 73.5%), pigmented DFSP (2/34, 5.9%), DFSP with myoid differentiation (1/34, 2.9%) and fibrosarcomatous DFSP (FS-DFSP) (6/34, 17.6%) were found. Moreover, myxoid degeneration was observed in three FS-DFSP cases (3/6, 50.0%). All 29 cases that underwent CD34 immunohistochemistry exhibited positive staining (100%). Genetically, PDGFB rearrangement/COL1A1-PDGFB fusion was detected in 94.1% (16/17) of patients. Regarding prognosis, the recurrence (83.3% vs. 59.1 %) and metastasis (33.3% vs. 0%) rates were higher in FS-DFSPs than that in ordinary DFSPs. All available surgical margins were positive before DFSPs recurrence. All patients with negative excision or re-excision margins were alive without evidence of disease (mean, 81.8months; median, 81months). Facial DFSP occurs predominantly in males, while FS-DFSPs are more likely to exhibit myxoid degeneration and a worse prognosis. Notably, negative surgical margin status determined a satisfactory prognosis.

PDGFB Rearrangements in Dermatofibrosarcoma Protuberans of the Vulva: A Study of 11 Cases Including Myxoid and Fibrosarcomatous Variants.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma that tends to arise in young to middle age adults and involve the trunk and proximal extremities. Rare examples of vulvar DFSP have been reported, including myxoid, myoid, and fibrosarcomatous variants, but detection of the characteristic t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion has not been evaluated in a large series of primary vulvar tumors. The clinical, morphologic, immunohistochemical, and molecular cytogenetic features of 11 cases were examined. Patient age ranged from 29 to 75 yr (mean, 46 yr; median, 43 yr). Seven tumors were purely classic DFSP, 1 was purely myxoid DFSP and the remaining 3 had varying quantities of fibrosarcomatous DFSP. All cases of classic DFSP had diffuse expression of CD34 and low-level p53 immunoreactivity. Myxoid variants had strong, but reduced expression of CD34. Fibrosarcomatous DFSP showed focal CD34 expression and increased p53 reactivity. Nine of 11 tumors (82%) had rearrangement of PDGFB by fluorescence in situ hybridization. The 2 nonrearranged tumors were a classic DFSP and a myxoid DFSP with fibrosarcomatous transformation. Follow-up was available for 9 patients (82%) and ranged from 1 to 108 mo (mean, 30 mo; median, 21 mo). Eight patients had tumors with positive margins, one of which developed local recurrence after no further therapy. No patient developed metastasis. The high frequency of PDGFB rearrangement in vulvar DFSP provides a useful exploit in diagnostically challenging cases and genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic tumors.

Review of the medical literature and assessment of current utilization patterns regarding the use of two common fluorescence in situ hybridization assays in the diagnosis of dermatofibrosarcoma protuberans and clear cell sarcoma.

Dermatofibrosarcoma protuberans (DFSP) is a tumor of intermediate malignancy, which in selected circumstances can pose difficulty in diagnosis. Clear cell sarcoma (CCS) is a very rare aggressive soft tissue sarcoma that can be difficult to distinguish histologically from melanoma. The current literature on t(17;22) COL1A1-PDGFB fluorescence in situ hybridization (FISH) assay in DFSP was reviewed. Also reviewed was the current literature on dual color break-apart EWSR1 FISH assay in CCS. Finally, the current utilization patterns of these tests was assessed in attendees of the American Society of Dermatopathology annual meeting (Chicago, 2016). The literature indicates that (17;22) COL1A1-PDGFB FISH assay has limited value for classic DFSP, where the diagnosis can be established by routine morphology and immunohistochemistry. Given the high specificity of the EWSR1 FISH assay and significant complexity in the diagnosis of CCS, this ancillary study is helpful in distinguishing CCS from melanoma. In attendees, t(17;22) COL1A1-PDGFB FISH testing for classic cases of DFSP is appropriately not being used by respondents. However, the literature sustains that it is useful in selected circumstances in which a definitive diagnosis is challenging. The majority of respondents are utilizing the EWSR1 FISH assay to distinguish CSS from melanoma as is supported by the literature.

Dermatofibrosarcoma protuberans: A clinical analysis

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor with a high incidence of misdiagnosis. DFSP has a high rate of recurrence but a low rate of metastasis. In the present study, retrospective analyses were performed on the clinical features, differential diagnosis and treatment of patients with DFSP to improve our understanding of the disease and allow more effective treatment measures to be implemented. The present study investigated the clinicopathological features of 70 pathologically confirmed cases of DFSP at the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between March 2012 and 2017. The primary endpoint was recurrence rate. Three cases were analyzed in detail. The results revealed that 7 of the 41 primary patients (follow-up at 2.7 years) had recurrence (17.1%), compared with 11 (37.9%) of the 29 recurrent patients (follow-up at 2.0 years, P=0.049). Of the 59 patients with DFSP (follow-up at 2.6 years), 12 had recurrence (20.3%) compared with 6 (54.6%) of the 11 patients with fibrosarcomatous DFSP (FS-DFSP; follow-up at 2.1 years, P=0.045). DFSP requires diagnosis by pathological examination, and surgical resection is the main treatment. DFSP demonstrated a high recurrence rate, with the degree of malignancy increasing following multiple recurrences. FS-DFSP had a higher risk of local recurrence and distant metastasis, and a higher degree of malignancy than classic DFSP. These data may be useful to guide clinicians to improve decisions in the treatment of patients with DFSP.

Dermatofibrosarcoma Protuberans of Distal Extremities and Acral Sites: A Clinicopathologic Analysis of 27 Cases.

Dermatofibrosarcoma protuberans (DFSP) of the distal extremities and acral sites are extremely rare and incompletely characterized. Twenty-seven DFSP occurring in these sites were retrieved from our collective archives and reevaluated. Tumors occurred in 16 males and 11 females. Median age at presentation was 42.5 years (range, 7 to 78 y). Lesions involved the foot (18 with 6 in the toes and 2 on the plantar foot), distal ankle (4), hand (4 with 2 in the thumbs), and wrist (1). All cases showed predominantly classic DFSP morphology and were diffusely CD34 positive. Myxoid change, melanin pigmented, and giant cell fibroblastoma foci were each present in 1 case, respectively. Fibrosarcomatous change was present in 3 cases. Fluorescent in situ hybridization demonstrated PDGFB gene rearrangement in 9 of 10 tested cases. Clinical follow-up was available in 21 cases (median, 36.1 mo; range, 1 to 152 mo) and revealed 4 local recurrences. Four patients underwent digital amputation for unresectable recurrent disease. An additional patient underwent multiple resections with positive margins and elected to receive imatinib mesylate therapy. After a 2-year course, the patient has no evidence of residual disease (40 mo). No metastases were documented in any of the cases studied. The natural history of DFSP of distal extremities and acral sites is similar to that of its counterparts elsewhere. A high index of suspicion, careful morphologic examination for key histologic features of DFSP, and in selected cases, molecular studies to identify the pathognomonic COL1A1-PDGFB gene fusion should facilitate the distinction of these rare, locally aggressive neoplasms from morphologic mimics that may arise in distal extremities and acral sites.

Clinical Features and Treatment of Dermatofibrosarcoma Protuberans Affecting the Vulva: A Literature Review.

Dermatofibrosarcoma protuberans (DFSP) is a low-to-intermediate grade cutaneous neoplasm with a low propensity for metastasis and a high rate of local recurrence. It typically presents as a dermal plaque or nodule on the trunk, limbs, or head and neck region. Vulvar DFSP has also been described, although it is less common. To review the available literature and discuss the clinical course of DFSP affecting the vulva. We reviewed the existing English-language literature on DFSP of the vulva with respect to clinical presentation, diagnosis, treatment, and outcome. Thirty three case reports and series were included (n = 54 patients). Vulvar DFSP most commonly presents as a slowly enlarging tender or asymptomatic mass on the labia majora, with histological findings of classic DFSP. Most patients were treated with wide local excision. Three patients were treated with Mohs micrographic surgery, which may decrease local recurrence and seems well suited for use in vulvar DFSP. This literature review comprehensively reviews and describes the clinical presentation of vulvar DFSP and the treatment options for this rare vulvar neoplasm.

Subcutaneous dermatofibrosarcoma protuberans, a rare subtype with predilection for the head: A retrospective series of 18 cases

Dermatofibrosarcoma protuberans (DFSP) typically affects the dermis and subcutaneous tissue. The subcutaneous variant is rare. We sought to characterize the subcutaneous DFSP (SC-DFSP) variant and compare it with cutaneous DFSP (C-DFSP). This work was a retrospective study of DFSP treated in our institution. Of 124 cases of DFSP, 18 were SC-DFSP (14.5%). Except for the deep location, the pathologic and genetic features were indistinguishable from the C-DFSP variant. Histologically, of 18 SC-DFSP cases, 13 were classic DFSP, 3 fibrosarcomatous DFSP (FS-DFSP), 1 Bednar tumor, and 1 giant-cell fibroblastoma. All tumors expressed CD34 and the COL1A1-PDGFB fusion transcripts. In our series, higher proportions of SC-DFSP tumors (61%) than C-DFSP tumors (8.5%) were located on the head (P<.001). Of the 20 DFSP tumors on the head (16.1%), 11 were SC-DFSP and 9 were C-DFSP. In addition, half the SC-DFSP tumors affected muscle or periosteum, compared with a quarter of the C-DFSP tumors (P=.009). SC-DFSP needed a higher number of Mohs stages than did C-DFSP (P=.009). Median follow-up time was 63months, and 2 FS-DFSP tumors recurred (1 SC-DFSP, 1 C-DFSP). Limitations include the retrospective aspect of the study. Most DFSP tumors involving the head were subcutaneous and required more complex surgery. Dermatologists should be aware of this atypical presentation, especially in lesions involving the head.

Long-term results of treatment of advanced dermatofibrosarcoma protuberans (DFSP) with imatinib mesylate – The impact of fibrosarcomatous transformation

BackgroundDermatofibrosarcoma protuberans (DFSP) is rare, infiltrating dermal neoplasm, characterized by indolent growth and low probability of metastases. The first effective systemic therapy in DFSP introduced into clinical practice was imatinib, demonstrating high activity in advanced cases. The aim of the study was to perform an analysis of patients with advanced DFSP treated with imatinib, with or without surgery, in routine clinical practice with long-term follow-up. Patients and methodsWe analyzed the data of 31 Caucasian patients (14 male, 17 female; median age 56 years) with locally advanced/initially inoperable and/or metastatic DFSP who started therapy with imatinib at initial dose 800 mg daily between 12/2004 and 07/2014. All diagnoses were confirmed cytogenetically for the presence of specific COL1A1-PDGFB fusion. Median follow-up time was 5.3 years. ResultsMetastases were present in 15 cases (8 – lungs, 5 – soft tissue, 2 – lymph nodes). Fibrosarcomatous transformation (FS-DFSP) was confirmed in 16 patients (52%). 5-year progression-free survival (PFS) rate was 58% (median 6.8 years), 5-year overall survival (OS) rate was 64% (median time for OS was not reached). The shorter PFS and OS correlated with FS-DFSP and presence of metastatic disease. 5-year PFS rate was 93% for classic DFSP and 33% for FS-DFSP. The best overall responses were: 21 partial responses (68%, including 8 FS-DFSP, but the responses were shorter than for classic DFSP), 6 stable disease (19%) and 4 progressive diseases (13%). Thirteen patients (47%) underwent resection of residual disease and nine of them remained free of disease, although imatinib was discontinued. Median survival after progression on imatinib was 19 months, and longer survival were observed only in cases were rescue surgery/radiotherapy was possible. ConclusionsOur results indicate the long-term activity of imatinib in therapy of inoperable and/or metastatic cases of DFSP, including FS-DFSP. Some DFSP patients initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned resectable after imatinib therapy and this rational approach leading to complete remission maybe potentially curative.

Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients.

Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.

PDGFB rearrangement in dermatofibrosarcoma protuberans: correlation with clinicopathologic characteristics and clinical implications

Dermatofibrosarcoma protuberans (DFSP) is characterized genetically by the translocation t(17;22)(q22;q13), which creates a COL1A1/PDGFB fusion gene. The implications of this gene for the clinicopathologic features of the disease are not fully understood. Fifty-one cases of DFSP from 46 patients were reclassified as DFSP (n=29) and DFSP-fibrosarcomatous variant (DFSP-FS; n=22). Fluorescence in situ hybridization was performed using a dual-color break-apart probe to detect rearrangements involving PDGFB, and CD34 immunohistochemistry staining was done. The DFSP-FS was found in older patients, and the tumors were larger, with a smaller mean area of staining for CD34. PDGFB rearrangement was found in 45 cases (95.7%). The mean gene copy number was 3.82 (range 2.2-6.45) and was higher in DFSP-FS than in classic DFSP (4.54 vs. 3.47; P < .001). The PDGFB copy number showed a moderate positive correlation with the number of mitotic figures and tumor size. Patients undergoing wide excision or having no involvement of the resection margin had no relapses. These results suggest a role for COL1A1/PDGFB in sarcomatous change in DFSP over time. Detection of COL1A1/PDGFB rearrangement by fluorescence in situ hybridization is useful for confirmation of the diagnosis. Patients who present with metastatic DFSP-FS show less typical histologic findings and loss of CD34 staining, leaving PDGFB rearrangement as the preferred adjunctive method for diagnosis from small biopsies and for prediction of the value of imatinib therapy.

Atrophic dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP) is an uncommon malignant mesenchymal tumor that arises in the dermis and is characterised by latency in its initial detection. As a rare form, atrophic or morphea-like DFSP has been documented. Atrophic DFSP resemble other benign lesions such as morphea, idiopathic atrophoderma, atrophic scar, anetoderma or lipoatrophy. It behaves like classic DFSP. It commonly favours young to middle aged adults. It has a slow infiltrative growth and a high rate of local recurrence if not completely excised. Metastases are rare and occur after repeated local recurrence. Surgical excision is the best line of treatment. Long term follow up is required to detect recurrence. We report a case of atrophic DFSP in a 52-year-old female patient. Diagnosis was achieved according to clinical, histopathological and immunohistochemical findings. Tumor was surgically excised with safety margin and the patient is still under follow up. Atrophic DFSP is a rare variant of DFSP. It is a tumor of low to moderate grade malignancy. Surgical excision is the best line of management. Long term follow up is necessary.

Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials.

Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB). Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment. Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%. Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.

Dermatofibrosarcoma protuberans—a review of 10-year experience on wide local excision

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma of low to intermediate grade. Correct diagnosis is very often difficult to make on initial presentation. It is a locally destructive tumour which seldom metastasizes. Excision with an adequate margin is the recommended treatment. However, local recurrence is not uncommon with ranges from 4% to 21% in the literature. Medical records of all patients suffering from DFSP who received operation in our centre were reviewed. The age, gender, location of tumour and method of wound closure were described. Factors that may contribute to tumour recurrence were analysed. Between January 1997 and December 2007, 32 patients (20 men) with DFSP, age ranging between 15 and 78 years, were treated. The lesions (22, 69%) located on the trunk and the lesions (five, 15.5%) located on the extremities were resected with a 3-cm margin, while those located in the head and neck region (5, 15.5%) were excised with a 1.5-cm margin. Intra-operative frozen section was performed in all cases. Final histological examination showed 30 cases of classic DFSP and two cases of DFSP with fibrosarcomatous transformation (FS-DFSP). The positive margin rate was 3.2%. In all cases, tumour resection and reconstruction were performed in a single-stage operation. Adjuvant therapy was given to two cases of FS-DFSP and one case of involved resection margin. With a mean follow-up of 51 months, there was no local recurrence in the classic DFSP group, while the two patients with FS-DFSP developed local recurrence at post-operative 4 and 10 months, respectively. We echo the literature that wide local excision with clear margins is the recommended treatment for the classic DFSP. The achievement of low positive margin rate is crucial for a single-stage operation and to minimise the use of adjuvant therapy.

Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP)

10520 Background: DFSP is an infiltrative, low-grade, dermal tumor with propensity to recur locally and occasionally metastasize. Translocation between COL1A1 on chromosome 17 and PDGFB on chromosome 22, which results in transcriptional upregulation of PDGFB, is characteristic of DFSP. Autocrine/paracrine PDGFB-mediated activation of PDGFRB drives DFSP proliferation. Two distinct phase II trials of imatinib in patients (pts) with locally advanced or metastatic DFSP were conducted, 1 in North America (SWOG) with confirmed objective response rate and 1 in Europe (EORTC) with 14 week progression-free rate as primary end-points. Methods: Pts with locally advanced or metastatic DFSP were eligible. In the EORTC trial confirmation of t(17;22) by FISH was prospectively required for participation, imatinib was started at 400mg bid, surgery was undertaken after 14 weeks if feasible and response was assessed at 14 weeks. Full accrual was to be 44 pts in one step. In the SWOG trial confirmation of t(17;22) by RT-PCR was performed after enrollment, imatinib was started at 400mg daily and response was assessed every 8 weeks. Full accrual was to be 40 pts in 2 steps. Results: 16 pts were enrolled in EORTC and 8 pts enrolled in SWOG trial. The studies were closed early because of slow accrual and regulatory approval of imatinib in DFSP. Pts age ranged from 24 to 70 yrs, DFSP was located on head/neck, trunk and extremity in 7, 11 and 6 pts, respectively, ranged in size from 1.2–49 cm and was classic, pigmented and fibrosarcomatous DFSP in 13, 1 and 7 pts, respectively. One patient did not have DFSP on central review, lacked t(17;22) and thus was ineligible. Metastases were present in 7 pts involving lung in 6 pts. 11 pts (46%) had partial response, 9 pts had stable disease and 4 pts had progressive disease as best response. Median time to progression was 1.7 yrs. Response and progression-free at 1 yr rates were similar between studies. Imatinib was stopped in 11 pts for progression, 1 pt for toxicity, 2 pts resected free of gross disease and 1 pt withdrew. Conclusions: Imatinib is active in DFSP harboring t(17;22) with an objective response rate approaching 50% and is active in fibrosarcomatous DFSP. Response rates and time to progression did not appear to differ between pts taking 400 mg daily versus 400 mg bid. [Table: see text]

The Prognostic Significance of Fibrosarcomatous Transformation in Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans (DFSP) is a superficial tumor characterized by high rates of local recurrence and a small risk of metastasis. Fibrosarcomatous (FS) areas rarely arise in DFSP, and considerable controversy exists as to whether these tumors have a higher risk of metastasis than the typical DFSP. The aim of this study was to reappraise the prognostic significance of FS changes in DFSP by analyzing 41 patients from the consultation files of our institution. The study included 23 females and 18 males, with a median age of 48 years (range, 16-100 years). Eighteen lesions were located on the trunk, 16 on the extremities, and 7 on the head/neck region. All tumors were treated with local excision, and the surgical margins were considered positive for tumor in 22 of 39 cases (56%). Fibrosarcomas arose de novo in 38 cases and as a recurrence in 3 cases. All tumors involved the dermis and subcutis, and the FS component comprised 5% to 95% of the tumor area (median, 60%). Mitotic rates of the FS component (median, 20 mitoses/10 high-power fields [HPFs]; range, 5-48/10 HPFs) were considerably higher than those of the neighboring DFSP component (0-2 mitoses/10 HPFs). Immunohistochemical analyses showed that CD34 expression was stronger and more extensive in the DFSP component (97% positive; median intensity, 3+) than in the FS component (81% positive; median intensity, 2+). The MIB-1 labeling index was higher in the FS areas (median, 20%; range, 5%-45%) than in the DFSP areas (<3%). Expression of p53 was present in 92% of the FS areas and in only 3% of adjacent DFSP areas. Follow-up data revealed that 8 patients had local recurrences, 4 patients (10%) had metastases, and 2 patients died of disease. None of the variables evaluated, including margin status, FS proportion, and mitotic count, correlated with disease progression. We demonstrate that FS change in DFSP is a form of tumor progression that carries an increased risk of metastasis over classic DFSP and is associated with gains of p53 mutations and increased proliferative activity.

Fusion of COL1A1 exon 29 with PDGFB exon 2 in a der(22)t(17;22) in a pediatric giant cell fibroblastoma with a pigmented Bednar tumor component. Evidence for age-related chromosomal pattern in dermatofibrosarcoma protuberans and related tumors

In contrast with classic dermatofibrosarcoma protuberans (DP), genetic information about the juvenile or pigmented variant forms of DP, so-called giant cell fibroblastoma (GCF) and Bednar tumor (BT), is limited. In the sole karyotyped case of BT a supernumerary ring containing chromosomes 17 and 22 sequences, similar to DP rings, was reported, whereas in three GCF cases, t(17;22) or der(22)t(17;22) with COL1A1-PDGFB fusion involving exons 11, 40, and 47, respectively, have been described. Here, we report the first cytogenetic and molecular analysis of a tumor from a 5-year-old child that contained both GCF and BT components. The karyotype and molecular analyses confirmed the common histogenetic origin between DP, GCF, and BT in showing the presence of a der(22)t(17;22) fusing the COL1A1 exon 29 to PDGFB exon 2. Because COL1A1 exon 29 has been involved previously in gene fusion with PDGFB exon 2 in several cases of adult or infantile DP presenting either t(17;22) or ring chromosomes, our results support the concept that DP, GCF, and BT are morphologic variants of a same entity, rather than distinct tumors. Of interest, our findings give prominence to the relation between patient age and the chromosomal rearrangement pattern in DP and related tumors. Whereas only a few adult DP cases presented with translocations, all the infantile cases, either DP, GCF, or mixed BT-GCF, as shown here, contained translocation derivatives but not ring chromosomes. All the ring chromosomes were observed in adult cases. With respect to cytogenetic studies, DP, GCF, and BT appear to be a unique model for age-related chromosomal rearrangement progression.

Dermatofibrosarcoma protuberans

Despite optimal surgical therapy for patients with dermatofibrosarcoma protuberans (DFSP), some patients still continue to develop local recurrence. The authors' objective was to identify and analyze clinicopathologic factors for disease free survival in a large group of patients who were followed prospectively at a single institution. Prospectively collected data and pathology slides were available for review from 159 patients with primary or recurrent DFSP who underwent treatment between July 1950 and July 1998. The study group was comprised of patients with either the "classic" form of DFSP or the fibrosarcomatous "high grade" variant of DFSP (FS-DFSP). Patient, tumor, pathologic, and treatment factors were analyzed using the log rank test for univariate influence and Cox regression analysis for multivariate influence. Local recurrence free survival was determined by the Kaplan-Meier actuarial method. Of the 159 patients who comprised the current study group, 134 (84%) had the classic form of DFSP. The FS-DFSP variant was found in the remaining 25 patients (16%). The overall 5-year local recurrence free survival rate was 75%, with a median follow-up of 4. 75 years. The 5-year recurrence free survival rate for each group was 81% and 28%, respectively. On univariate analysis, age > 50 years, very close (< 1 mm) to positive microscopic margins, FS-DFSP variant, high mitotic rate, and increased cellularity were unfavorable prognostic factors. Multivariate analysis determined very close (< 1 mm) to positive microscopic margins and FS-DFSP variant to be independent adverse prognostic factors. For the 34 patients who developed a recurrence after surgical resection (21%), the median time to local recurrence was 32 months. Of the patients in this group, two died from metastatic disease. The prognosis after surgical resection with negative and sometimes positive microscopic margins for patients with DFSP is very good. However, increased age, high mitotic index, and increased cellularity are predictors of poor clinical outcome. The FS-DFSP variant represents a much more aggressive tumor with metastatic potential. Patients who are treated with curative intent for FS-DFSP should undergo aggressive attempts at complete surgical resection. Patients with recurrent classic DFSP without evidence of adverse prognostic features may benefit from conservative management, especially in the setting of potentially unresectable disease.