Conventional Dermatofibrosarcoma Protuberans Research Articles

PRAME expression in fibrosarcomatous dermatofibrosarcoma protuberans

PRAME (PReferentially expressed Antigen in MElanoma) was first identified as a malignant melanoma-specific antigen. Recently, a few cases of fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP) were shown to have positivity for PRAME, while conventional dermatofibrosarcoma protuberans (C-DFSP) was negative. Because PRAME may be of diagnostic utility in FS-DFSP and is raising expectations as a new immunotherapy target, we examined the positivity of PRAME in FS-DFSP. Twenty-one cases of FS-DFSP and age/sex/location-matched cases of C-DFSP as a control group were examined by immunohistochemistry for CD34 and PRAME. The results were then evaluated by H-score, which was objectively and semi-quantitatively calculated using the open-source bioimaging analysis software QuPath. The results revealed that the PRAME H-score in FS-DFSP was significantly higher than that in C-DFSP (p = 0.0137). As for CD34, the H-score in FS-DFSP was significantly lower than that in C-DFSP (p < 0.001). Using these two immunohistochemical analyses in combination, the sensitivity and specificity for the diagnosis of FS-DFSP were 86% and 90%, respectively. Double staining of CD34 and PRAME revealed that PRAME-positive and CD34-positive areas did not overlap. This is the largest study to examine PRAME expression in FS-DFSP, and it confirmed the usefulness of PRAME in diagnosing this condition.

ALK-rearranged, CD34-positive spindle cell neoplasms resembling dermatofibrosarcoma protuberans: a study of seven cases.

The majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D-negative CD34-positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK-rearrangements in DFSP and plaque-like CD34-positive dermal fibroma (P-LDF). We searched the archives of academic institutions for cases previously coded as DFSP and P-LDF. NGS-naïve or PDGFB-negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK-positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of "DFSP" and two "P-LDF" with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0-2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP-like cases and FLNA in P-LDF-like lesions. ALK FISH was positive in one (of two) cases previously labelled P-LDF. Methylome profiling of two (of three) ALK-rearranged DFSP-like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months). We describe a cohort of novel ALK-rearranged tumours with morphologic features similar to DFSP.

The role of next-generation sequencing in achieving diagnostic precision for dermatofibrosarcoma protuberans and its fibrosarcomatous variant.

e23531 Background: Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive skin and subcutaneous fibroblastic neoplasm, characterized by COL1A1:: PDGFB fusions and, less frequently, PDGFD fusions. Approximately 10-15% of DFSP cases progress to distant metastases, yet the genetic mechanisms behind this transformation to fibrosarcomatous DFSP (FS-DFSP) or metastatic development remain unclear. Reports of DFSP in deeper tissues suggest a broader occurrence than previously recognized. We hypothesize that conventional histopathology may not adequately identify certain DFSP variants, especially those in deep tissues, potentially missing critical opportunities for targeted therapy with FDA-approved tyrosine kinase inhibitors. Methods: We searched Caris’s database to identify solid tumors with PDGFB or PDGFD fusions, markers of DFSP or FS-DFSP. We reviewed histologic features and clinical information, along with exome sequencing and copy number amplifications. Significance was tested using Mann Whitney U and Fisher’s exact tests as appropriate. Results: We identified 59 cases with PDGFB or PDGFD fusions: 55 COL1A1:: PDGFB, 3 EMILIN2:: PDGFD, and 1 COL1A2:: PDGFB cases. Of these, 51 were primary specimens and 8 metastatic. The patients included 31 males and 28 females, with a median age of 49 years (range: 14-93). Primary tumors occurred mainly in the skin/subcutis or deep soft tissues (35 trunk, 9 head and neck, 7 lower extremity, 2 upper extremity), but 6 were found in visceral organs (4 uterus, 1 cervix, 1 lung). Histologically, 20 cases were conventional DFSP and 32 were FS-DFSP. Notably, 21 tumors (36%) had been initially misclassified; most of which had metastatic presentation, unusual histology, or atypical location. Tumor sequencing revealed a higher incidence of genetic changes in addition to the PDGFB/ PDGFD fusions: concurrent mutations were detected in 66% of FS-DFSP cases versus 25% of DFSP cases (p = 0.009). Moreover, tumor mutational burden was significantly higher in FS-DFSP than DFSP (p = 0.006). The most prevalent mutations were in the TERT promoter and NF1, found exclusively in FS-DFSP cases. Conclusions: Conventional histology commonly fails to recognize FS-DFSP, leading to missed opportunities for targeted therapy. This highlights the essential role of next-generation sequencing in achieving greater diagnostic accuracy for DFSP and its fibrosarcomatous variant. While no single gene mutation consistently differentiates DFSP from FS-DFSP, the occurrence of additional genetic alterations is notably more common in FS-DFSP cases.

Dermatofibrosarcoma protuberans in pregnancy: a case series and review of the literature.

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma, which has been reported in pregnancy. This case series reports the clinical and histopathological findings of DFSP in pregnancy. Eighteen cases of DFSP, including six unreported cases and 12 cases from the literature, were identified. Age, anatomic location, tumor size, changes in tumor characteristics during pregnancy, histopathological features, and treatment were recorded. Follow-up data, when available, were noted. The average age of the cohort was 30.6years (range 19-38). Ten tumors (55.6%) were located on the trunk, four (22.2%) on the head and neck, three (16.7%) on the extremities, and one (5.6%) in the genitalia. Most tumors demonstrated features of conventional DFSP (12/18, 66.7%), while the remaining were identified as DFSP with fibrosarcomatous (FS) change (3/18, 16.7%), atrophic DFSP (2/18, 11.1%), and myxoid DFSP (1/18, 5.6%). Treatment was reported in 17 cases, at least nine of which were treated postpartum. Ten patients were treated with excision, while seven underwent Mohs micrographic surgery. Three patients recurred on follow-up, one with local recurrence and two with distant metastasis. DFSP can undergo enlargement or change in size or color in pregnancy, possibly mediated by hormones. While the majority of cases in this series represented conventional DFSP, unusual clinical and histopathological variants were also present. Treatment in most cases can be safely delayed until after delivery, but recurrent or very large tumors may require treatment prepartum. Close monitoring for recurrence or metastasis is advised.

PDGFB RNA in situ hybridization for the diagnosis of dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is a spindle cell neoplasm of the skin and superficial soft tissue with a tendency for locally aggressive behavior; metastatic potential coincides with fibrosarcomatous transformation. The vast majority of DFSPs harbor the t(17;22) translocation resulting in a COL1A1-PDGFB fusion that drives autocrine growth stimulation via PDGFB overexpression. Here, we examined the utility of PDGFB RNA chromogenic in situ hybridization (CISH) for the diagnosis of DFSP. A total of 337 tumors represented in whole tissue sections and tissue microarrays, including 37 cases of DFSP and 300 histologically similar spindle cell tumors, were subjected to PDGFB RNA CISH using commercially available probes. PDGFB overexpression was observed by light microscopy in 24 of 26 conventional DFSPs (92%) and 11 of 11 fibrosarcomatous DFSPs (100%). One of two DFSPs negative for PDGFB by RNA CISH was found to harbor an uncommon alternative rearrangement involving PDGFD. All examined cases of histologic mimics were negative for PDGFB overexpression; limited PDGFB expression, not reaching an empirical threshold of greater than 5 puncta or one aggregate of chromogen in more than 25% of cells, was observed in 7 of 300 mimics (2.3%), including desmoplastic melanoma, malignant peripheral nerve sheath tumor, angiosarcoma, and pleomorphic dermal sarcoma. Vascular PDGFB expression was seen in several tumor types. We conclude that PDGFB RNA CISH, with careful interpretation and the use of appropriate thresholds, may serve as a surrogate marker of PDGFB rearrangement and a useful ancillary tool for the diagnosis of DFSP.

Clinicopathological features of fibrosarcomatous dermatofibrosarcoma protuberans and the construction of a back-propagation neural network recognition model

BackgroundFibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP) is a form of tumor progression of dermatofibrosarcoma protuberans (DFSP) with an increased risk of metastasis and recurrence. Few studies have compared the clinicopathological features of FS-DFSP and conventional DFSP (C-DFSP).ObjectivesTo better understand the epidemiological and clinicopathological characteristics of FS-DFSP.MethodsWe conducted a cohort study of 221 patients diagnosed with DFSP and built a recognition model with a back-propagation (BP) neural network for FS-DFSP.ResultsTwenty-six patients with FS-DFSP and 195 patients with C-DFSP were included. There were no differences between FS-DFSP and C-DFSP regarding age at presentation, age at diagnosis, sex, size at diagnosis, size at presentation, and tumor growth. The negative ratio of CD34 in FS-DFSP (11.5%) was significantly lower than that in C-DFSP (5.1%) (P = 0.005). The average Ki-67 index of FS-DFSP (18.1%) cases was significantly higher than that of C-DFSP (8.1%) cases (P < 0.001). The classification accuracy of the BP neural network model training samples was 100%. The correct rates of classification and misdiagnosis were 84.1% and 15.9%.ConclusionsThe clinical manifestations of FS-DFSP and C-DFSP are similar but have large differences in immunohistochemistry. The classification accuracy and feasibility of the BP neural network model are high in FS-DFSP.

Fibrosarcomatous pigmented dermatofibrosarcoma protuberans: A case report with review of the literature

Dermatofibrosarcoma protuberans (DFSP) is a relatively rare low-grade sarcoma that occasionally exhibits melanin-containing spindle cells within the tumor. Fibrosarcomatous DFSP (FS-DFSP) is a variant that is characterized by areas which are histopathologically indistinguishable from fibrosarcoma. In the present study, we describe a case of fibrosarcomatous pigmented DFSP and review the clinicopathological features of this extremely rare lesion. A 51-year-old male presented with a slow-growing nodular cutaneous mass in his left upper arm. Histopathologically, the resected tumor was comprised of pigmented DFSP in approximately 20% of the tumor, with the remaining area further covered by a fibrosarcomatous component. A review of the clinicopathological features of the five previously reported cases as well as the present case indicated that this lesion mainly affects middle-aged males and occurs mostly in the extremities. Melanin-containing spindle cells are present only in the conventional DFSP component. The prognosis appears to be poor; in the six cases reviewed, four demonstrated multiple metastases and three succumbed to the disease. Our analyses revealed that the presence of a fibrosarcomatous component in pigmented DFSP is associated with aggressive behavior; therefore, careful assessment for the presence of a fibrosarcomatous component is necessary in the diagnosis of this disease.

Dermatofibrosarcoma Protuberans With Unusual Sarcomatous Transformation: A Series of 4 Cases With Molecular Confirmation

Dermatofibrosarcoma protuberans (DFSP) is a superficial sarcoma of intermediate malignancy usually composed of monotonous short spindle cells with storiform architecture. The tumor cells are diffusely reactive for CD34 and characterized by a translocation involving chromosomes 17 and 22 or a supernumerary ring chromosome that results in the fusion of exon 2 of platelet-derived growth factor beta (PDGFβ; 22q13) to various exons of collagen type 1 alpha 1 (COL1A1; 17q22). In some tumors, fibrosarcomatous transformation can occur and is characterized by a monotonous spindle cell proliferation arranged in fascicles or a herringbone-type pattern. We report 4 DFSPs with unusual and pleomorphic sarcomatous transformation. They occurred on the back, scalp, shoulder, and forehead of women (ages 31,48, 48, and 27 year). In addition to areas of conventional DFSP that strongly expressed CD34, 2 cases showed pleomorphic areas mimicking undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma: 1 case had a patternless area and 1 case had combined round/spindled cells with myxoid areas. Reverse transcription--polymerase chain reaction was performed in 1 case, confirming the presence of a COL1A1-PDGFβ fusion transcript. The remaining three cases were found to be positive for a PDGFβ gene rearrangement by fluorescence in situ hybridization. This series illustrates that sarcomatous transformation in DFSP may occasionally display areas, which can mimic undifferentiated pleomorphic or unclassified sarcoma. Ancillary diagnostic testing may be helpful to confirm the diagnosis, especially in small biopsies.

A Case of Congenital Pigmented Dermatofibrosarcoma Protuberans (Bednar Tumor) in a Patient with Fanconi Anemia

Bednar tumor is a rare pigmented variation of dermatofibrosarcoma protuberans, present in 1 to 5% of all patients with dermatofibrosarcoma protuberans. No significant clinicopathologic differences exist between Bednar tumor and conventional dermatofibrosarcoma protuberans apart from the presence of scattered nonneoplastic pigmented dendritic cells in the former. Although most dermatofibrosarcoma protuberans occur in adults, they may be rarely present at birth. Fanconi anemia is a genetically heterogeneous chromosomal instability syndrome, characterized by multiple congenital anomalies, progressive bone marrow failure, and a predisposition to malignancy. We describe here a patient with Fanconi anemia who had a congenital Bednar tumor. To our knowledge, this is the first such patient described with both dermatofibrosarcoma protuberans and Fanconi anemia.

Transformed dermatofibrosarcoma protuberans: real time polymerase chain reaction detection of COL1A1–PDGFB fusion transcripts in sarcomatous areas

Background: Recent cytogenetic studies have shown that reciprocal translocation t (17;22)(q22;q13) and a supernumerary ring chromosome derived from the translocation r(17;22) are highly characteristic of dermatofibrosarcoma protuberans (DFSP). The chromosomal...

Bednár tumor associated with dermal melanocytosis: melanocytic colonization or neuroectodermal multidirectional differentiation?

Neuroectodermal differentiation or melanocytic colonization are the opposing theories of histogenesis for the Bednár tumor or pigmented dermatofibrosarcoma protuberans (DFSP). A 31-year-old African-American woman presented with a 2-cm blue-black shoulder nodule of 1-year duration. Punch biopsy revealed a CD34+, Factor XIIIa-DFSP, harboring numerous, pigmented spindle S100+, Mart-1+ and HMB-45+ cells. Subsequent wide excision demonstrated pigmented dendritic and spindled cells widely scattered throughout the dermis of the 3-cm excisional margins and punch biopsy specimens of normal skin from both shoulders. This latter process was interpreted as dermal melanocytosis (nevus of Ito). The dermal pigmented spindle cells were Mart-1+ and CD34-, and were associated with non-pigmented CD34+, cytologically banal spindle cells, which were more numerous in the excisional margins than the contralateral shoulder. Reported herein is a singular case of Bednár tumor associated with dermal melanocytosis. Although the coexistence of these processes implicates colonization of the DFSP by constituent dermal melanocytes, the mixed immunophenotype (CD34+ or Mart-1+ cells) of dispersed dermal spindle cells hints at the possibility of a common cell of origin: the putative neuromesenchymal cell. In effect, the Bednár tumor could represent one part of a spectrum of neural crest-derived dermal tumors that includes dermal melanocytosis, cellular blue nevus and conventional DFSP.

Expression of COL1A1-PDGFB fusion transcripts in superficial adult fibrosarcoma suggests a close relationship to dermatofibrosarcoma protuberans.

The diagnosis of fibrosarcoma has become relatively rare since the recognition and definition of certain adult spindle-cell sarcomas, such as monophasic synovial sarcoma, malignant peripheral nerve sheath tumour (MPNST), and malignant fibrous histiocytoma (MFH). Although most adult fibrosarcomas occur within intra- or inter-muscular fibrous tissues, some originate from superficial soft tissues (superficially located adult fibrosarcomas) (SAFs). Recently, the COL1A1-PDGFB chimeric gene resulting from a reciprocal translocation, t(17;22), and/or a supernumerary ring chromosome, r(17;22), has been identified, not only in conventional dermatofibrosarcoma protuberans (DFSP) but also in areas of DFSP with progression to fibrosarcoma (so-called fibrosarcomatous transformation) (FS-DFSP). Since many SAFs are clinically and histologically similar to DFSP or FS-DFSP, this study postulated that the two groups may be interrelated histogenetically. To test this hypothesis, a reverse transcription-polymerase chain reaction (RT-PCR) assay was conducted to determine whether COL1A1-PDGFB fusion transcripts could be detected in six cases of SAF, using archival formalin-fixed, paraffin-embedded tissues. COL1A1-PDGFB fusion transcripts were detected in four of six SAFs, whereas no such fusion transcripts could be amplified in five deep-seated fibrosarcomas, eight congenital/infantile fibrosarcomas or 28 other spindle-cell tumours and tumour-like lesions. These results show that at least some cases of SAF are genetically similar to DFSP and FS-DFSP, suggesting that some SAFs originate from DFSP or involve similar pathogenetic mechanisms.

COL1A1-PDGFB Fusion Transcripts in Fibrosarcomatous Areas of Six Dermatofibrosarcomas Protuberans

The fibrosarcomatous transformation of dermatofibrosarcoma protuberans (DFSP) has been considered for some time to be associated with an adverse clinical outcome. However, the molecular and cellular mechanism underlying the tumor progression remains undetermined. As the chimeric gene, COL1A1-PDGFB, has been proposed to play an important role in the histogenesis of DFSP, we conducted a reverse transcription-polymerase chain reaction assay to ascertain whether the COL1A1-PDGFB fusion transcripts can be detected in both conventional DFSP and fibrosarcomatous components of DFSP with fibrosarcomatous areas (DFSP-FS), using a simple method of microdissection on sections of archival formalin-fixed, paraffin-embedded tumor specimens from six DFSP-FS cases. The COL1A1-PDGFB fusion transcripts could be detected in FS areas in five of the six cases, whereas conventional DFSP areas of all cases expressed the chimeric mRNA. A subsequent sequence analysis of the polymerase chain reaction products confirmed that the detected messages were derived from identical gene fusions in the two different components of each of the five cases. Our results verify that the COL1A1-PDGFB fusion transcripts are preserved in the FS areas of most DFSP-FSs. The expression of the fusion transcripts in both conventional DFSP and FS areas of DFSP-FS supports a common histogenesis of the two components.

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<b>Background:</b> Recent cytogenetic studies have shown that reciprocal translocation t (17;22)(q22;q13) and a supernumerary ring chromosome derived from the translocation r(17;22) are highly characteristic of dermatofibrosarcoma protuberans (DFSP). The chromosomal rearrangements fuse the collagen type Iα1 (COL1A1) and the platelet-derived growth factor B-chain (PDGFB) genes. The COL1A1–PDGFB fusion transcript has been shown not only in conventional DFSP but also in a small series of DFSP with fibrosarcomatons areas (DFSP-FS) using reverse transcriptase-based conventional polymerase chain reaction. Nothing is known about the status of the COL1A1–PDGFB chimaeric gene in the pleomorphic areas of DFSP-PleoSarc (formerly known as DFSP-malignant fibrous sarcoma). <b>Aims:</b> To show the COL1A1–PDGFB fusion transcript in transformed malignant fibrous histiocytoma. <b>Method:</b> A real-time polymerase chain reaction assay for the COL1A1–PDGFB fusion transcript in a series of DFSP containing sarcoma was conducted to determine whether the chimaeric gene could be identified in both components of DFSP-FS and DFSP-PleoSarc. Eight cases were analysed. <b>Results:</b> In seven cases, transcriptable RNA was detected, and in these cases, translocations were found between COL1A1 and PDGFB genes involving exons 27, 32, 34, 40 and 47 of the COL1A1 gene and exon 2 of the PDGFB gene. <b>Conclusions:</b> From a diagnostic aspect, this assay can be particularly useful in confirming the diagnosis of sarcomatous DFSP. On the other hand, the COL1A1–PDGFB fusion gene was shown in three cases of DFSP containing pleomorphic sarcoma, which supports the theory of the common histogenesis.

Pigmented dermatofibrosarcoma protuberans (Bednar tumour): melanocytic colonization or neuroectodermal differentiation? A clinicopathological and immunohistochemical study

Approximately 5% of cases of dermatofibrosarcoma protuberans contain dendritic melanocytes; such lesions are often known as Bednar tumours. These neoplasms have received little attention in the literature but seem to show no great clinicopathological differences from conventional dermatofibrosarcoma protuberans except for the presence of melanocytes. The existence of such tumours, combined with ultrastructural evidence, has led some leading authors to regard them all as being of neuroectodermal origin. Seven examples of the pigmented variant are presented herein, of which six have been studied immunohistochemically and one has been examined ultrastructurally. Except for the presence of melanocytes in each tumour, no evidence of neuroectodermal (in particular perineural fibroblastic) differentiation has been demonstrated. The histogenesis of dermatofibrosarcoma protuberans and its pigmented variant is discussed. The possibility that the pigmentation may simply reflect secondary melanocyte colonization from the epidermis should be considered.

Pigmented dermatofibrosarcoma protuberans (Bednar tumor). A pathologic, ultrastructural, and immunohistochemical study.

Described by Bednar as a "storiform neurofibroma," pigmented dermatofibrosarcoma protuberans is a rare neoplasm accounting for approximately 1-5% of all cases of dermatofibrosarcoma protuberans (DFSP). The lesion commonly presents as an exophytic, multinodular neoplasm of the dermis or subcutaneous tissue. It occurs predominantly in blacks. The majority are located on the trunk, and the remainder are more or less equally distributed in the upper and the lower extremities and the head and neck. Microscopically the lesion is characterized by spindled cells arranged in a tight storiform pattern and admixed with a small population of melanin-containing dendritic cells. The dendritic cells are the primary feature distinguishing this lesion from conventional DFSP. Three cell populations are identifiable by electron microscopy. The majority of cells resemble fibroblasts. A second population of cells exhibits long slender cell processes partially or completely invested by basal lamina. The third population of cells, also invested by basal lamina, contains both melanosomes and premelanosomes. The histogenesis of this neoplasm remains controversial. Although Bednar considered these lesions as variants of neurofibroma, S-100 protein could not be identified, and this finding contrasts significantly from the description of conventional neurofibroma, which almost always contains this antigen. Follow-up information available in nine cases indicates that this lesion may recur locally. Although distant metastases were not observed in our material, complete excision in conjunction with close follow-up care is indicated for this neoplasm of probable intermediate malignant potential.