Search

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., (© 2024. The Author(s).)

Aims: 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)., Methods and Results: 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)., Conclusion: We describe a cohort of novel ALK-rearranged tumours with morphologic features similar to DFSP., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Cutaneous spindle cell neoplasms can be challenging to diagnose using routine histopathological techniques alone, and the growing repertoire of molecular studies can assist in diagnosis. We describe a cutaneous spindle cell neoplasm characterized by a COL3A1::PDGFRA rearrangement predicted to lead to constitutive activation of the PDGFRA kinase domain. The lesion shows some similarities to dermatofibrosarcoma protuberans and also benign and epithelioid fibrous histiocytomas but is distinct from these entities histopathologically and molecularly. This tumor is considered to represent an entity in the spectrum of PDGFR-driven cutaneous mesenchymal neoplasms., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma characterized by the COL1A1-PDGFB fusion gene. This study utilized single-cell RNA sequencing to dissect the cellular and molecular landscape of primary DFSP. Distinct DFSP cell clusters, exhibiting fibroblast-like traits, revealed variations in pathways associated with proliferation, inflammation and metabolism. Differential gene expression analysis during the differentiation from tumour stem cells to DFSP cells unveiled SMOC2, DCN and TGFBR3 as potential regulators of tumour invasion and immune infiltration through VEGF/TGF-β signalling modulation. Cellular communication analysis highlighted interactions within DFSP cell clusters and with endothelial cells, implicating molecules such as NAMPT, ANGPT2 and PTN in pathogenesis and treatment resistance. These findings offer insights into DFSP intratumour heterogeneity, elucidate molecular mechanisms underlying tumour behaviour, and suggest potential therapeutic targets., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dermatofibrosarcoma protuberans (DFSP) is characterized by collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusion. We present a case of fibrosarcomatous DFSP with lung metastasis in a 53-year-old man. Histologically, the primary and metastatic tumors were composed of high-grade fibrosarcomatous component with varying myxoid changes, while only a small focus of the classic DFSP element was identified in the primary lesion. No evidence of COL1A1-PDGFB fusion was identified by routine fluorescence in situ hybridization (FISH). Subsequent next-generation sequencing and COL1A1 break-apart FISH identified the fusion. In addition, coamplification of 12q15 and 12p13, along with CDKN2A/2B deletion, was confirmed to be limited to the fibrosarcomatous component. The current case is a novel FS-DFSP with cryptic COL1A1-PDGFB fusion. This is the first published example of DFSP harboring coamplification of 12q and 12p sequences. More importantly, the genetic aberrations restricted to the fibrosarcomatous component indicated a synergistic role of higher-grade progression., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunohistochemical staining can be of great utility in differentiating various cutaneous spindle cell neoplasms, particularly when the histomorphologic appearance of the lesions is inconclusive. Nuclear staining for ETS-related gene (ERG), a highly sensitive endothelial cell marker, has seldom been studied in the context of cutaneous spindle cell neoplasms. Little is known about its specificity for vascular differentiation. In this pilot study, immunohistochemical analysis for ERG was performed on 15 dermatofibromas (DF), 10 keloids, and 9 dermatofibrosarcoma protuberans (DFSP) tumors. Consistent nuclear expression of ERG was found in DF [100% (15/15) of the lesions demonstrated >50% labeling of tumor cells with moderate to strong intensity]. However, ERG expression was largely absent in DFSP [89% (8/9) of the lesions demonstrating <50% labeling staining, generally of mild intensity] and hypertrophic scars-keloids [80% (8/10) without expression]. On the basis of the results of this pilot study, immunohistochemical staining for ERG may prove useful in helping to differentiate DF from DFSP and hypertrophic scars in the context of partial biopsy sampling. If replicated in a larger number of samples, this finding could mitigate the use of costly sequencing panels and potentially avoid unnecessary reexcisions in certain contexts., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

We present a case of a 21-year-old female with a vague nontender mass in the lower inner quadrant of the left breast discovered incidentally on chest imaging following trauma. A breast ultrasound demonstrated an 8×6×8 mm irregular hyperechoic mass at the 7 o'clock position of the left breast, 9 cm from the nipple. The mass was graded Breast Imaging Reporting and Data System (BI-RADS) category 4 (suspicious finding). An ultrasound-guided biopsy of the mass showed a proliferation of monotonous spindled cells in a storiform pattern with tapered nuclei with infiltration into the adipose tissue. No normal breast elements were identified in the biopsy. Myofibroblastoma was the first differential diagnosis; however, the characteristic infiltrative pattern of the tumor mandated additional tests including fluorescence in situ hybridization to rule out a dermatofibrosarcoma protruberance (DFSP). Immunohistochemical staining showed positive staining for CD34, which can be positive in myofibroblastoma also. However, fluorescence in situ hybridization demonstrated a platelet-derived growth factor B (22q13.1) gene rearrangement confirming a diagnosis of DFSP. The patient underwent a wide local excision of the DFSP for definitive treatment. She is doing well with no recurrence reported so far, after 15 months of follow-up. Conventional DFSP does not metastasize but is prone to recurrence making wide margins imperative for definitive treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Immunohistochemistry for preferentially expressed antigen in melanoma (PRAME) has been studied in melanocytic lesions but not nonmelanoma skin cancers (NMSCs). This study evaluated PRAME expression in NMSCs and dermoepidermal junction (DEJ) melanocytes in the surrounding skin., Methods: Ninety-nine NMSCs were studied: 23 Merkel cell carcinomas (MCCs), 25 well to poorly differentiated squamous cell carcinomas (SCCs), 14 basal cell carcinomas (BCCs), five basosquamous carcinomas, four sebaceous carcinomas, ten atypical fibroxanthomas, 11 dermatofibrosarcoma protuberans, and seven leiomyosarcomas. Staining quality was considered low or high intensity. Staining quantity was reported as negative 0%, 1% to 24%, 25% to 50%, and >50%. DEJ melanocyte PRAME expression was recorded., Results: Forty-eight percent of NMSCs showed PRAME expression, mostly low intensity in fewer than 25% of cells. High-intensity expression was noted in one poorly differentiated SCC, six BCCs, and seven MCCs. Only MCCs showed expression in greater than 25% of tumor cells. Focal DEJ melanocytes expressed high-intensity PRAME in 18% of cases, most commonly SCCs (11/23)., Conclusions: PRAME is negative or expressed with low intensity in a small percentage of NMSCs, with the exception of some MCC showing high-intensity and diffuse staining. Focal DEJ melanocytes showed high-intensity PRAME reactivity in the skin surrounding some NMSCs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue sarcoma that originates from the dermis or subcutaneous tissue in the skin. While its prognosis is generally favorable, disease recurrence is relatively frequent. Because morbidity after repeated surgery may be significant, an optimized prediction of recurrence-free survival (RFS) has the potential to improve current management strategies. The purpose of this study was to investigate the prognostic value of the Ki-67 proliferation index with respect to RFS in patients with DFSP. We retrospectively analyzed data from 45 patients with DFSP. We calculated the Ki-67 proliferation index as the percentage of immunostained nuclei among the total number of tumor cell nuclei regardless of the intensity of immunostaining. We constructed univariate and multivariate Cox proportional hazards regression models to identify predictors of RFS. Among the 45 patients included in the study, 8 developed local recurrences and 2 had lung metastases (median follow-up: 95.0 months; range: 5.2-412.4 months). The RFS rates at 60, 120, and 240 months of follow-up were 83.8%, 76.2%, and 65.3%, respectively. The median Ki-67 proliferation index was 14%. Notably, we identified the Ki-67 proliferation index as the only independent predictor for RFS in multivariate Cox proportional hazards regression analysis (hazard ratio = 1.106, 95% confidence interval = 1.019-1.200, p = 0.016). In summary, our results highlight the potential usefulness of the Ki-67 proliferation index for facilitating the identification of patients with DFSP at higher risk of developing disease recurrences.

Background: Cellular dermatofibromas (CDFs) and dermatofibrosarcoma protuberans (DFSP) can be challenging to differentiate from one another. Morphologically, both entities commonly extend into the subcutis, exhibit high cellularity with limited cytologic atypia and have a mixed fascicular-to-storiform growth pattern. We sought to evaluate the significance of fat necrosis with an associated lymphocytic infiltrate as a histopathologic clue for distinguishing CDFs from DFSP., Methods: We identified cases in our pathology database with a primary diagnosis of CDF or DFSP. Punch or excisional biopsy specimens with extension into the subcutis were selected. Previously biopsied lesions and specimens that did not interact with the subcutis were excluded. Histopathologic features were evaluated in hematoxylin and eosin stained sections., Results: Fat necrosis with lymphocytic infiltrate was present in 20/20 cases of CDF. None of the 20 DFSP cases had fat necrosis with lymphocytic infiltrate although 4/20 had fat necrosis alone., Conclusions: Fat necrosis with associated lymphocytic response can aid in the distinction between CDF and DFSP., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transducin-like enhancer of split 1 (TLE1) belongs to the Groucho/TLE/Grg family. It functions as a transcriptional corepressor and is widely used as a biomarker of synovial sarcoma (SS). Within the skin, atypical fibroxanthoma (AFX) and dermatofibrosarcoma protuberans (DFSP) often enter the histopathologic differential diagnosis. TLE1 expression has not been evaluated in these neoplasms. We examined archived tissues sections from the surgical pathology files from 10 adult patients diagnosed with AFX and 10 adult patients diagnosed with DFSP. We found nuclear staining in 10 of 10 AFX and 2 of 10 DFSP. We also noticed three patterns of staining in AFX: predominantly spindle component, predominantly epithelioid component, or mixed pattern of both epithelioid and spindle components. The group with the predominantly spindle pattern expressed the strongest nuclear TLE1 staining. In the DFSP group, one lesion demonstrated staining of epithelioid cells, with strong, diffuse nuclear TLE 1 expression, and the second lesion stained only the spindled cells, with weak nuclear TLE1 marking. In conclusion, TLE1, while a sensitive marker for SS, is not specific. A wide range of cutaneous spindle cell neoplasms also express TLE1. AFX and DFSP should be added to this list. TLE1 might be added to a diagnostic panel in this differential diagnosis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present a case series of atrophic dermatofibrosarcoma protuberans (DFSP) to further characterise its clinical and pathological features. Sixteen cases were enrolled in the study. There were five males and 11 females with a median age of 28 years. The vast majority occurred in the trunk (12/16, 75%), whereas a minority involved the upper limb or limb gird (2/16, 12.5%), and head and neck region (2/16, 12.5%). The most common presentation was a depressed plaque-like lesion with a greyish-red to purplish-blue colour. Histologically, the lesion was dermal-based consisting of monomorphous spindle cells arranged in parallel fascicles with focal areas displaying storiform architecture. In addition, one case showed remarkable hyalinisation of the matrix, two cases contained scattered pigmented dendritic cells and one case had admixed giant cell fibroblastoma-like component, respectively. The diagnosis was confirmed by immunohistochemical study, and by further fluorescence in situ hybridisation analysis in six cases. Follow-up thus far has revealed a relatively low rate of local recurrence (1/10, 10%). Familiarity with the distinctive clinical and pathological features of atrophic DFSP helps avoid misdiagnosis. Like a classical DFSP, morphological variants can also occur in an atrophic DFSP, including pigmented, sclerosing and hybrid subtypes, albeit rare., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Opinion Statement: Cutaneous sarcoma is a group of malignant mesenchymal tumors primarily involving the dermis, and it is characterized by extreme clinicopathological heterogeneity. Although its occurrence rate is rare, dermatofibrosarcoma protuberans (DFSP) is one of the most common types of dermal sarcoma. DFSP grows slowly and tends to relapse locally after inadequate resection. There are various histological variants of DFSP tumors and it often mimics benign lesions such as dermatofibroma and scar, which make accurate diagnosis difficult and delayed, and some cases progress to the stage where the tumor is unresectable. Recent advancements in cancer genetics and molecular biology methods have elucidated the COL1A1-PDGFB fusion gene, some novel fusion gene variants and pathways related to DFSP pathogenesis that have resulted in the evolution of cutaneous sarcoma diagnosis and treatment. For example, some clinical studies have confirmed the efficacy of imatinib methylate, an αPDGFR-targeted therapy for unresectable or metastatic DFSP. The present review summarizes recent updates in DFSP research, diagnostics, and treatment.

Background: In humans, there are four known proton-sensing G-Protein-coupled receptors (pH-GPCRs): GPR4 (GPR19), TDAG8 (GPR65, T-cell death-associated gene 8), OGR1 (GPR68, ovarian cancer GPCR1) and G2A (GPR132, G2 accumulation protein). They are known to be involved in sensing changes of extracellular proton concentrations in the acidic microenvironment of tumors, which leads to altered cell proliferation, migration, metastasis, immune cell function and inflammation. However, little is known about the expression of pH-GPCRs in the skin and especially skin cancers., Aim: We studied the expression of pH-GPCRs in selected skin cancers, that is Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS)., Methods: We did immunohistochemistry and immunofluorescence to analyse the expression of GPR4, TDAG8, OGR1 and G2A using paraffin-embedded tissue samples (n = 4, exceptions: PDS GPR4/GPR65 n = 5, AFX GPR132 n = 3) from patients suffering from MCC, DFSP, AFX and PDS., Results: (a) GPR4 was expressed on all AFX and PDS specimens. All AFX and MCC showed a positive expression of G2A. All PDS exhibited a strong positive expression of G2A. (b) MCCs neither expressed GPR4 nor TDAG8. All DFSP showed no expression of TDAG8. (c) For any other combination of GPCR and skin disease, we found positive/negative mixed results., Conclusions: These are the first results on pH-GPCRs in selected skin cancers. We provide evidence that these GPCRs are differentially expressed on the various types of skin cancers and that they can potentially be addressed as a therapeutic target in extensive disease., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In 1924, Darier and Ferrand described Dermatofibrosarcoma Protuberans as a progressive and recurring dermatofibroma. It is a locally aggressive sarcoma originating from dermal and subdermal tissue of the skin. It usually begins as a small plaque that grows over a period and later manifests as multiple small subcutaneous nodules. It is more commonly found in females as compared to males and typically occurs in between 2nd and 5th decades of life. Most frequently involved regions of the body are torso and proximal ends of extremities and very rarely head and neck region is the site of involvement. The mainstay of treatment of this entity is surgery. The rate of recurrence of this disease is very high in about 50% of the cases and it may also express rare distant metastasis. It is a radiosensitive tumour and radiation may play a role in reducing risk of recurrence. We present a case of a 35 years old male with recurrent Dermatofibrosarcoma Protuberans of right parotid gland.

Background and Objectives: Dermatofibrosarcoma protuberans (DFSP) is a relatively rare skin tumor. Clinical observations indicated that DFSP has a more aggressive behavior during pregnancy, which suggest there might be a hormonal influence on this tumor. We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) in DFSP patients., Methods: In our present case series, patients with histopathological-confirmed DFSP at a single institution were identified. The clinical, pathological, and immunohistochemical data were gathered for each patient. Expression of ER and PR were determined on formalin-fixed, paraffin-embedded tissue sections using immunohistochemistry. Some objective clinical and pathological indicators were then selected to compare between ER and PR status., Results: Immunoreactivity revealed none of these tumors stained positively for ER, while eight tumors (28.6%) stained positively for PR. There was a statistically significant difference in the distribution of tumor location between the PR-positive/negative groups., Conclusions: This finding suggests that progesterone may have potential effects in growth of DFSPs. Further studies are needed to fully address this question., (© 2018 Wiley Periodicals, Inc.)

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare low grade tumor with a locally aggressive behavior and low metastatic potential., Objectives: To evaluate the factors that are associated with relapse in DFSP. Methods Retrospective analysis of medical records from 61 patients with dermatofibrosarcoma. Fluorescence in situ hybridization was used to detect translocations., Results: Of 61 patients, 6 experienced a relapse. No patient with resection margins greater than 3 cm had a recurrence. One relapse was observed in a patient treated with at least 2 cm margins and 4 relapses occurred in 16 patients whose margins were below 2 cm (P = 0.018). The frequency of translocations was 77.8%. The recurrence rate was lower in patients with translocation, but this difference was not significant. Immunohistochemical markers did not correlate with recurrence rates, but greater FasL expression was associated with recurrence in patients with margins smaller than 3 cm., Conclusions: Surgical margins smaller than than 2 cm are related to higher recurrences in dermatofibrosarcomas. In this analysis a 2 cm margin was acceptable for treatment. Between all the immunohistochemical markers analyzed, only FasL was associated with a higher recurrence rate in patients with margins smaller than 3 cm., (© 2018 Wiley Periodicals, Inc.)

Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma with a superficial location that has been suggested to potentially be a type of mesenchymal stem cell tumor. We studied the expression of various immunomarkers, including putative stem cell markers, in a series of 57 DFSPs including variants, and 12 dermatofibromas (DFs). CD105, a mesenchymal stem cell marker, was weakly expressed in 24 DFSPs, whereas other stem cell markers, including CD133, ALK-1, and Oct3/4, were completely negative in all samples. The expression rates of CD105 and CD34 were significantly higher in DFSP (42% and 93%) than in DF (0% and 17%), and CD10 and D2-40 were significantly lower in DFSP (40% and 3.5%) than in DF (100% and 33%), respectively. CD99, CD117, PDGFB, and PDGFRβ expression was comparable between the groups. CD105 mesenchymal cells were not observed in non-neoplastic dermis. In summary, we did not obtain sufficient immunohistochemical evidence to support the DFSP as a cutaneous mesenchymal stem cell tumor. CD34 alone was the most consistent marker of DFSP, irrespective of its variants. Because CD34 non-neoplastic mesenchymal cells were distributed in a location similar to that of DFSP, we suggest that DFSP might have originated from CD34 mesenchymal cells in the dermis.

Background/aim: Dermatofibrosarcoma protuberance (DFSP) is a fibrohistiocytic tumor of intermediate malignancy characterized by slow infiltrative growth and a high tendency to recur locally. Periostin is involved in modulating cell function and inducing the production of proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) from tumor-associated macrophages (TAMs) to promote fibrosis and tumor growth. This study aimed to examine the cancer stroma of DFSP, focusing on TAMs-related proteins and MMPs., Patients and Methods: Using immunohistochemical staining and DNA microarray database, we evaluated periostin, CD163, CD206, MMP1 and MMP12 in 10 cases of DFSP and dermatofibroma., Results: Dense deposits of periostin as well as a substantial number of CD163 + TAMs were detected at the peripheral areas of DFSP. Moreover, MMP1 and MMP12, that were selected by using a DNA microarray database of monocyte-derived macrophages, were observed in the TAMs-detected area., Conclusion: Increased levels of MMP1 and MMP12 on TAMs in the peripheral areas of DFSP might contribute to local invasion., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Dermatofibrosarcoma protuberans (DFSP) is an uncommon intermediate-grade soft tissue sarcoma. The tumor is found preferentially on the trunk, whereas the head and neck region are affected in only 10% to 15% of cases. We report the case of a 44-year-old woman with a 5-month history of an asymptomatic, firm, yellow nodule in the mucosa of the right cheek measuring 2.5 cm. The clinical diagnosis was lipoma and an excisional biopsy was obtained. Histopathological analysis revealed a proliferation of spindle-shaped mesenchymal cells arranged in interlacing fascicles amidst fibrous stroma. Low mitotic activity (2 mitoses per field) and deep cell infiltration into adipose tissue were observed. These features led to the histopathological diagnosis of a malignant low-grade mesenchymal cell tumor. Immunohistochemical analysis revealed negative staining for α-SMA, S-100, and Bcl-2, but positive staining for Ki-67 (18%) and strong and diffuse staining for CD34. These findings were compatible with the diagnosis of DFSP. Only two cases of DFSP in the oral cavity, both involving the cheek mucosa, have been described so far, highlighting the rarity of the present case.

p38 mitogen-activated protein kinase (MAPK) activity has been reported to either promote or suppress cell death, which depends on cell type and stimulus. Our previous report indicates that p38 exerts a protective role in tumor necrosis factor (TNF)-α-induced cell death in L929 fibroblastoma cells. However, key molecules regulating p38 activation remain unclear. Here, we show that ectopic expression of scaffold protein receptor for activated C kinase 1 (RACK1) suppressed TNF-α-induced cell death in L929 cells, which was associated with enhanced p38 activation. Knockdown of endogenous RACK1 expression exhibited opposite effects. The protective role of RACK1 in TNF-α-induced cell death diminished upon blockade of p38 activation. Therefore, RACK1 antagonizes TNF-α-induced cell death through, at least partially, augmenting p38 activation. Further exploration revealed that RACK1 directly bound to MKK3/6 and enhanced the kinase activity of MKK3/6 without affecting MKK3/6 phosphorylation. Similar effects of RACK1 were also observed in primary murine hepatocytes, another cell type sensitive to TNF-α-induced cell death. Taken together, our data suggest that RACK1 is a key factor involved in p38 activation as well as TNF-α-induced cell death.

Giant cell fibroblastoma (GCF) is a rare pediatric soft tissue tumor, which exists on a spectrum with dermatofibrosarcoma protuberans (DFSP). Histologic features are well established for these entities; however, cytologic findings have not been well characterized. We report for the first time a case of GCF, confirmed by cytogenetics, with mixed DFSP features. In this case of an 8-month-old boy, a fine needle aspiration specimen showed a low-grade spindle cell tumor, with oval to spindled cells dispersed singly and in patternless groups, and with occasional giant cells. Subsequent histologic features were consistent with GCF, which is an uncommon, CD34 positive, soft tissue neoplasm with a distinct molecular aberration. This case emphasizes the differential diagnosis in pediatric soft tissue tumors and stresses the unique features of GCF., (© 2014 Wiley Periodicals, Inc.)

L929 fibroblastoma cells (L929-A) and L929 fibrosarcoma cells (L929-N) are different cell lines that are commonly used to study the cytotoxicity of tumor necrosis factor alpha (TNFα). TNFα has been reported to induce necrosis in both of these cell lines. However, comparing the TNFα-induced cell death in these two cell lines, we found that, unlike the L929-N cells that show typical RIP3-dependent necrosis, TNFα-induced cell death in L929-A cells is pan-caspase inhibitor Z-VAD-FMK (Z-VAD)-sensitive, which does not depend on RIP3. We also confirmed that the cell death signal in the L929-A cells was initiated through cytosol-preassembled ripoptosome and that the knockdown of either Caspase-8 or RIP1 protein blocked cell death. Compared with the L929-N cells, the L929-A cell line had lower levels of constitutive and inducible TNFα autocrine production, and the pan-caspase inhibitors Z-VAD or Q-VD did not kill the L929-A cells as they affect the L929-N cells. Moreover, the L929-A cells expressed less RIP3 protein than the L929-N cells; therefore, TNFα failed to induce RIP3-dependent necroptosis. In addition, the ripoptosome-mediated cell death signal was transduced to the mitochondria through Caspase-8-mediated and RIP1 kinase activity-dependent Bid cleavage. The RIP1 kinase inhibitor Necrostatin-1 (Nec-1) or Caspase-8 knockdown completely blocked Bid cleavage, and the knockdown of Bid or Bax/Bak prevented TNFα-induced cell death in the L929-A cells. Although the activation of Bax/Bak decreased the mitochondrial membrane potential, the levels of mitochondrial intermembrane space proteins, including cytochrome-c (cyt-C) and Smac, declined, and western blotting and immunofluorescence staining analysis did not determine whether these proteins were redistributed to the cytosol. In addition, the mitochondrial outer membrane protein Tom20 was also reduced, indicating that the reduced mitochondria proteins may be induced by the reduced mitochondria numbers. No efficient cyt-C release was observed; therefore, the limited activation and cleavage of downstream caspases, including Caspase-9, Caspase-7, Caspase-6 and Caspase-3, was insufficient to kill the cells. The Caspase-9, Caspase-6 and Caspase-3/7 inhibitors or Caspase-9 and -3 knockdown also failed to block cell death, and the overexpression of Bcl-2 also did not abrogate cell death. Moreover, the dead cells showed necrotic-like but not apoptotic characteristics under transmission electronmicroscopy, and these features were significantly different from mitochondrial apoptosis, indicating that the effector caspases were not the executioners of cell death. These new discoveries show that TNFα-induced cell death in L929-A cells is different than typical RIP3-dependent necrosis and Caspase-8/Caspase-3-mediated apoptosis. These results highlight that caution is necessary when using different L929 cells as a model to investigate TNFα-induced cell death.

Objective: To investigate the clinical pathological features, diagnosis and differential diagnosis of pigmented dermatofibrosarcoma protuberance (PDFSP)., Methods: The clinical history, histopathological features, immunohistochemical characteristics, treatment and prognosis were analyzed in seven cases of PDFSP. Fluorescence in situ hybridization (FISH) was used to detect the expression of COL1A1/PDGFB fusion gene, and related literature was reviewed., Results: The median age of the seven patients (4 females, 3 males) was 47 years with the tumors involving mostly the trunk (four cases). Histologically, PDFSP showed a cellular lesion composed of spindle cells arranged in short fascicles that form a distinct storiform pattern, and the pigmented bipolar or multipolar dendritic cells were present with tentacle like processes emanating from a nucleus containing zone. One case showed fibrosarcomatous change. The pigment was tinctorially similar to melanin. The spindle cells were positive for CD34 and vimentin, but negative for HMB45, Melan A, S-100, desmin, CD68 or α-SMA. HMB45, Melan A, S-100 and vimentin were expressed in the melanin containing cells in 4, 4, 5 and 7 cases, respectively. The labeling index of Ki-67 was 1%-8%. Among the 4 cases successfully examined by FISH, 3 showed t(17;22)(q21;q13) which suggested COL1A1/PDGFB fusion gene. Three patients were treated by wide local excision and four were treated by simple surgical excision. Two patients developed recurrences during the follow-up period of 12 to 123 months. Of those treated by wide local excision, none developed recurrence. No patient died in the follow-up period., Conclusions: PDFSP is a rare pigmented variant of DFSP and an intermediate grade malignant tumor. The orgin of the tumor cells is still controversial. Surgical pathologists and dermatopathologists need to be aware of the prototypical histological appearance of PDFSP as there is a risk of misdiagonsing it as either pigmented tumors associated with neurocutaneous syndromes or a highly malignant melanocytic neoplasm.

Objective: To investigate the clinical pathological features of fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP)., Methods: The clinical history, histopathological features and immunohistochemical characteristics were analyzed in twelve cases of FS-DFSP from January 1997 to February 2011, and related literature were reviewed., Results: Age of the patients (2 females, 10 males) at diagnosis ranged from 41 to 70 years (mean 53 years). Among the 12 cases of FS-DFSP, 9 cases aroused in recurrent ordinary DFSP. Histologically, FS areas in FS-DFSP were characterized by a fascicular and highly cellular histology, frequently showing a characteristic herringbone pattern. FS-DFSP showed diminishment of CD34 staining in FS areas. The labeling index of Ki-67 was much higher in the FS areas (10%-40%) than that in the conventional DFSP areas (2%-5%). All the patients were treated by operation with local excision or wide excision. Postoperative radiotherapy and chemotherapy was administered in two cases respectively. Follow-up information in 9 of 12 patients (9 to 86 months) revealed local recurrence in 6 patients. Distant metastases were seen in two patients. One patient was died in the follow up period., Conclusions: FS-DFSP is a rare and unique subtype of DFSP and is associated with significant elevated risk of both local and distance metastasis, usually followed by poor outcome. Compared to ordinary DFSP as a borderline neoplasm, FS-DFSP should be considered as a malignant tumor.

Background: Dermatofibrosarcoma protuberans (DFSP) was recently shown to express nestin, a marker that has been associated with poorer prognosis when present in high levels in certain tumors. The objective of this study is to explore the association between high nestin expression and deep invasion., Methods: We performed a retrospective, observational study in which we evaluated the degree of nestin expression in 71 DFSP. The odds of fascial involvement was calculated before and after adjusting for the following confounders: age, sex, tumor size, time to diagnosis, tumor site, the presence of fibrosarcomatous areas, pleomorphism, number of mitotic figures and predominant histopathologic pattern. We also calculated the Spearman Rho correlation coefficient between nestin staining intensity and depth of invasion., Results: Nestin immunopositivity was found in 98.6% of the tumors, and high expression levels were significantly associated with invasion of the fascia. The odds of fascial involvement in tumors with strong nestin staining was 6.56 (p = 0.001) before adjustment for confounders and 14.86 after adjustment (p = 0.007). The Spearman rho correlation coefficient between nestin expression and deep invasion was 0.287 (p = 0.015)., Conclusion: High inmunohistochemical nestin expression appears to be associated with deeper invasion in DFSP., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To study the clinicopathologic characteristics of cellular fibrous histiocytoma (CFH) with emphasis on diagnosis and differential diagnosis., Methods: Clinical and pathologic features were reviewed in 27 cases of CFH (encountered during the period from 2008 to 2012) along with outcome analysis. Immunophenotyping was performed with EnVision method., Results: The patients included 13 males and 14 females. The age at presentation ranged from 15 to 61 years (mean, 34 years; median, 32 years). The tumor occurred in the extremities (n = 14), head and neck (n = 7), and trunk (n = 6). Histologically, the tumors were located in the dermis. Some cases showed wedge like extension into the subcutaneous adipose tissue. On high power, they consisted of dense fibroblasts and myofibroblasts. Other cell components such as psammoma-like histiocytes, hemosiderin-containing macrophages or touton-type giant cells were rare. The spindled tumor cells were arranged mostly in intersecting fascicles. Focal storiform architecture was not uncommon. In addition, a few cases showed prominent hemangiopericytoma-like pattern. There was no prominent cellular atypia but increased mitotic figures were not difficult to find. Two cases exhibited necrosis. By immunohistochemistry, the tumor cells showed variable expression of alpha smooth muscle actin. CD34 positive cells were present in some cases, but were distributed mostly in the periphery or bottom of the lesions. They were all negative for desmin, h-caldesmon, S-100 protein and cytokeratin. Follow-up in 19 cases revealed local recurrences in 5 cases and bilateral pulmonary metastases in 1 case after repeated recurrences., Conclusions: CFH is a cellular form of benign fibrous histiocytoma which has a risk for local recurrence after incomplete excision. Distant metastasis can occur in rare examples. However, there were no morphological parameters predicting the risk of recurrence or metastasis. Increased awareness of the clinocopathological features and immunophenotypes of CFH is helpful in avoiding misdiagnosing the disease as malignant tumors, especially dermatofibrosarcoma protuberans.

Approximately 50% of patients with localized soft tissue sarcomas will develop recurrent disease after complete surgical resection, requiring alternative means of treatment. Conventional chemotherapy comprising of doxorubicin and ifosfamide has shown benefit in advanced disease, however, there remains a clear need for more effective, less toxic, therapies for the treatment of this heterogeneous group of mesenchymal malignancies. Recently, greater emphasis has been placed on the underlying biology of individual sarcoma subtypes, with the development and evaluation of novel therapies both in common and in rare subtypes. In addition, there is a greater specificity in the selection of chemotherapy agents based on activity in individual histological subtypes. Despite these advances the management of sarcoma, and in particular of rare subtypes, remains a major challenge. Some histological subtypes are resistant to conventional chemotherapy and patients with these diseases should be offered participation in early phase clinical trials of novel drugs.

Molecular techniques are increasingly important in the practice of surgical pathology. In soft tissue tumors, there are a number of tumors with recurring cytogenetic abnormalities. Knowledge of these abnormalities has furthered our understanding of these tumors and has also allowed development of molecular techniques to aid in the diagnosis. This review will focus on mesenchymal tumors with specific cytogenetic abnormalities that may present as a superficial tumor of the dermis or subcutis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Fibroblast growth factors (FGFs) and their receptors (FGFRs) control a wide range of biological functions; however, their involvement in the pathogenesis of dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) is currently unknown. In this study, we first confirmed the histological diagnosis by detecting fusion COL1A1-PDGFB transcripts in DFSP, and examined the expression of all FGFRs (FGFR1-4), some of their ligands (FGF1, 2, 9), and forkhead box N1 (FOXN1) as a downstream target of FGFR3 in DF and DFSP by immunohistochemical analysis. Although we failed to detect the expression of FGF1 and FGF9 as specific ligands for FGFR3 in DF, overexpression of FGFR3 and FOXN1 was observed in the epidermal regions of DF, suggesting that the epidermal regions of DF were similar to seborrhoeic keratosis both in terms of histological features and the activation of FGFR3/FOXN1. In addition, strong expression of FGF2 and FGFR4 was observed in the tumor lesions of DF. Expression patterns of FGFR3/FOXN1 and FGF2/FGFR4 in DF were in contrast with those of DFSP. The activation of FGFR signaling pathways may be not only relevant to the pathogenesis of DF, but also very useful in the differential diagnosis of DF and DFSP.

Important advances in fibroblastic and fibrohistiocytic tumors relevant to dermatologists and dermatopathologists include (1) recognition that myxofibrosarcoma is a distinct entity that frequently arises in skin; (2) CD10 is sensitive but not specific atypical fibroxanthoma; (3) neurothekeomas lacking S100 expression are probably fibrohistiocytic/fibroblastic tumors, whereas S100+ myxoid variants are better classified as nerve sheath myxomas; (4) the recognition of a primary cutaneous variant of solitary fibrous tumor; (5) thelimitations of b-catenin immunohistochemistry in desmoid tumors; and (6) the prognostic utility of clinical and histopathologic variables in dermatofibrosarcoma protuberans, and the effects of imatinib mesylate therapy., (Copyright © 2012. Published by Elsevier Inc.)

Subsets of cutaneous soft tissue tumors present morphologic features which are diagnostically challenging in part because of their ability to obscure the ultimate nature of the underlying neoplastic process. This review discusses entities, which in the authors' experience, present such challenges. The clinical, histologic, immunohistochemical, and where appropriate, molecular features of these entities are discussed along with their prognosis and differential diagnosis.

Background: Cellular benign fibrous histiocytoma (CBFH) represents a morphologic variant of cutaneous fibrous histiocytoma (FH). Because of its relative monomorphism and frequent fascicularity, CBFH can easily be mistaken for a malignancy. In fact, CD34, often used to distinguish CBFH from dermatofibrosarcoma protuberans (DFSP), can also be positive. To add to the confusion, desmin positivity may also be observed in a subset of CBFH. Desmin and CD34 expression often cause interpretative difficulty which may lead to misdiagnosis. Our aim was to examine the incidence of desmin and CD34 expression in CBFH., Methods: One hundred consecutive cases of morphologically typical CBFH were retrieved from consultation files. Clinicopathologic and immunohistochemical features were evaluated., Results: SMA positivity was found in tumor cells in 93 of 100 cases (93%). Desmin positivity was found in 32 of 100 cases (32%). CD34 was positive in 6 of 100 cases (6%). There was no evident correlation between immunophenotype and anatomic site or other clinical variables., Conclusion: Frequent desmin (32%) and occasional CD34 (6%) expression are encountered in CBFH. Desmin positivity can be explained on the basis of myofibroblastic differentiation. The occasional CD34 positivity in a subset of CBFH should not be a deterrent from making the correct pathologic diagnosis, based on characteristic morphologic features., (Copyright © 2012 John Wiley & Sons A/S.)

Background: Loss of insulin-like growth factor-binding protein 7 (IGFBP7) has been found to be a critical step in the development of melanoma and colon cancer. To our knowledge, immunostaining of IGFBP7 in various dermatofibrosarcoma protuberans (DFSP) and dermatofibroma (DF) has not been studied before., Objectives: To assess the immunostaining of IGFBP7 in DFSPs and DFs and to ascertain whether IGFBP7 is superior to antibodies traditionally used in differentiating DFs from DFSPs., Methods: Immunohistochemical staining was performed on 28 cases of DFSP and 30 cases of DF, using antibodies to IGFBP7, CD34, factor XIIIa (FXIIIa), CD10 and stromelysin-3 (ST-3)., Results: Six of 28 (21.4%) DFSP samples were positive for IGFBP7, whereas 28 of 30 (93.3%) DF samples were positive. CD34 was positive in 26 of 28 (92.9%) cases of DFSP and 4 of 30 (13.3%) cases of DF. FXIIIa staining was positive in 4 of 28 (14.3%) cases of DFSP and 28 of 30 (93.3%) cases of DF. CD10 staining was positive in 12 of 28 (42.9%) cases of DFSP and ST-3 staining was positive in 7 of 28 (25.0%) cases of DFSP. The preferential IGFP7 staining of DFSPs in comparison with DFs was statistically significant (P < 0.01)., Conclusions: We confirmed that IGFBP7 is a negative immunohistochemical marker for DFSPs and the combination with CD34, FXIIIa and ST-3 immunostaining could make the distinction more reliable., (© 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.)

Background: Atypical fibroxanthoma (AFX) is a distinctive clinicopathologic entity presenting on sun-damaged skin of the elderly. Its behavior is benign if strict diagnostic criteria are applied. Tumors showing invasion of deeper structures or perineural/lymphovascular invasion are best regarded as undifferentiated pleomorphic sarcoma of the skin. The diagnosis requires immunohistochemical studies to exclude melanoma, squamous cell carcinoma, angiosarcoma and leiomyosarcoma., Methods: Two AFX and one undifferentiated pleomorphic sarcoma showing aberrant expression of Melan-A were identified. Clinical data were obtained and histopathological features, immunohistochemical profile and electron microscopy were assessed., Results: All tumors arose on sun-damaged skin of elderly males. Two AFX showed pushing growth into superficial subcutis only. The undifferentiated pleomorphic sarcoma was characterized by infiltrative growth into galea as well as perineural invasion. Multifocal expression of Melan-A and MART-1 was largely limited to tumor giant cells in the absence of S100 or HMB-45 labeling. No melanosomes or premelanosomes were identified by electron microscopy., Conclusions: Aberrant expression of Melan-A and MART-1 in AFX and undifferentiated pleomorphic sarcoma of the skin represents an important diagnostic pitfall with potential for misdiagnosis as melanoma., (Copyright © 2011 John Wiley & Sons A/S.)

An 8-year-old boy was admitted for excision of a putative 'blue nevus' on the left foot. Histological examination and immunohistochemistry revealed a Bednar tumour, the pigmented variant of dermatofibrosarcoma protuberans. Surgical options considered by a multidisciplinary team included wide local excision, Mohs micrographic surgery or a staged excision with examination of several histological sections. The third alternative procedure was chosen after consideration of tumour and patient factors to achieve the best possible clinical, cosmetic and functional outcome. After the final surgical procedure with resection of the third metatarsal bone, all peripheral margins were free of tumour, and the interdigital space was reconstructed with a pedicled pulpa flap. Three years after surgery, there was no tumour recurrence, and further long-term follow-up for this patient will be provided., (Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor of cutaneous origin of intermediate grade malignant potential. The incidence of DFSP is 0.1% of all cancers and 1% of all soft tissue sarcomas. We present the case of a 65years old female with a palpable, painful mass on the right thigh. A surgical excision of the lesion was done and the histopathology, as well as the immunohistochemical analysis with CD-34, confirmed the diagnosis of DFSP. Two years later, the patient is free of disease and no local recurrences or metastases have been found. Wide radical excision is the preferred surgical method for therapy of DFSP without distant metastasis. Furthermore, DFSP resists to conventional chemotherapy and radiation therapy, while, in cases of metastasis, therapy depends on cytogenesis and molecular biology of the tumor, so new therapeutic strategies are under research.