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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.)

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.)

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.

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.

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.

Indeterminate fibrohistiocytic lesions of the skin share histological and immunohistochemical features of both benign fibrous histiocytoma/dermatofibroma and dermatofibrosarcoma protuberans (DFSP). Unlike dermatofibroma, DFSP harbors recurrent genetic aberrations resulting in the fusion of COL1A1 on chromosome 17 and PDGFB on chromosome 22. Because indeterminate fibrohistiocytic lesions share some features with DFSP, they were evaluated for the possible presence of COL1A1-PDGFB chimeric transcripts. Twelve formalin-fixed paraffin-embedded cases were examined for COL1A1-PDGFB chimeric transcripts using a previously validated sensitive multiplex reverse transcriptase-polymerase chain reaction assay. The median patient age was 52.5 years (33-70 years) with 9 females and 3 males. The most common site was the extremities (n = 8) followed by the trunk (n = 2) and the head and neck region (n = 2). All demonstrated the expected reactivity for both CD34 and factor XIIIa, and the majority focally infiltrated into subcutaneous fat. Of the 6 patients with follow-up, 2 had residual tumor excised, but no patient developed a recurrence. None of the tumors harbored COL1A1-PDGFB fusion transcripts identified by reverse transcriptase-polymerase chain reaction. Although indeterminate fibrohistiocytic lesions share some features with DFSP, the lack of COL1A1-PDGFB chimeric transcripts suggests that they are distinct entities.

Podoplanin, also recognized by the monoclonal antibody D2-40, is a mucin-type transmembrane glycoprotein that is highly expressed in lymphatics and in a range of vascular and nonvascular proliferations. Recently, podoplanin has been detected in fibrous histiocytomas (FHs) and proposed to represent a potentially useful marker in the diagnostic evaluation of this lesion. There is, however, limited data concerning podoplanin expression in FH and its morphological mimics. Cellular neurothekeomas (CNs) are rare cutaneous neoplasms of uncertain histogenesis that often morphologically mimic FH. In this study, we reviewed our experience with podoplanin expression in FH (n = 30), especially in comparison to CN (n = 15). In addition, we also immunostained a selected group of other mesenchymal lesions that may fall within the differential diagnosis of FH for podoplanin, including dermal nerve sheath myxoma (n = 2), dermatofibrosarcoma protuberans (N = 8), and plexiform fibrohistiocytic tumor (n = 2). Podoplanin expression was observed in a significant subset of FHs (26/30, 86.6%) and in all CNs (15/15, 100%), whereas DFSPs, dermal nerve sheath myxomas, and plexiform fibrohistiocytic tumors were all negative. To the best of our knowledge, this is the first report demonstrating podoplanin expression in CN. Expression of podoplanin in CN represents a potential pitfall in the use of this antibody for diagnostic evaluation of FH. However, podoplanin may be of value as an adjunct to morphological examination in assessment of problematic lesions falling within the differential diagnosis of FH and CN.

Pigmented dermatofibrosarcoma protuberans (DFSP; Bednar tumor) constitutes 5%-10% of all cases of DFSP and shows morphologic features that overlap with melanocytic and fibrous proliferations. We report 2 unusual cases of pigmented fibrous proliferations that demonstrate features of dermatofibromas and DFSP. The first case is that of a 19-year-old man with a 3-year history of a slowly growing pigmented lesion on the right arm. On clinical exam, the lesion was a 7-mm firm pigmented papulonodular lesion. The second case is that of a 31-year-old woman with a 4- to 5-year history of a slowly enlarging, asymptomatic "dark area" on the right buttock. On clinical exam, the lesion was a 2-cm darkly pigmented flat nodule. Morphologically, both lesions are primarily dermal proliferations of spindled cells admixed with pigmented dendritic melanocytes. The lesional cells trap collagen fibers at the periphery and there is basal cell hyperpigmentation. Adnexal structures are effaced, but significant trapping of subcutaneous fat is not present. By immunohistochemistry, both lesions show focal CD34 positivity but are negative for Factor XIIIa and melanocytic markers. Although overlap between standard dermatofibromas and DFSP is well documented in the literature, pigmented fibrous lesions with features of both entities are not well described.

Dermatofibrosarcoma protuberans (DFSP), a cutaneous fibrohistiocytic tumor of intermediate (borderline) malignancy, typically arises in the dermis and subsequently infiltrates the subcutaneous tissue. Very rarely DFSP may either arise within the subcutaneous fat without dermal involvement or show very extensive subcutaneous involvement with only minimal and clinically subtle dermal involvement. We present the clinicopathological features of 15 cases of DFSP showing exclusive or near-exclusive involvement of the subcutaneous fat. The differential diagnosis with other subcutaneous spindle cell neoplasms is emphasized. Awareness of this rare subset of DFSP should prevent its misdiagnosis as other less aggressive tumor types.

Dermatofibrosarcoma protuberans (DFSP) represents a locally aggressive mesenchymal neoplasm of skin and subcutis with characteristic clinicopathologic, immunohistochemical, and molecular findings. In addition to typical cases, morphologic variants such as pigmented, fibrosarcomatous, myofibroblastic, and granular cell DFSP have been described. Purely or predominantly myxoid DFSP is extremely rare, and may cause considerable diagnostic problems. Eight cases of predominantly myxoid DFSP were studied. Paraffin-embedded blocks and slides were retrieved from the files of the authors. Clinical data were obtained from the referring pathologists and dermatologists. Immunohistochemistry was performed using the ABC method, and three cases were studied by polymerase chain reaction technique. There were six male and two female patients (age range: 29 to 74 years). Locations included the inguinal area (three cases), thigh, upper arm, shoulder, abdominal wall, and back (one each). The patients were treated by wide excision as well as reexcision. Tumor size ranged from 1.5 to 12 cm. Histologically, a nodular growth with peripheral diffuse infiltration, as well as a diffusely infiltrating growth of relatively uniform spindled and stellated tumor cells containing slightly enlarged nuclei, was noted. Three cases were entirely myxoid, and in five cases more than 80% of the tumor area showed myxoid stromal changes. In two cases each, focal fibrosarcomatous and focal giant cell fibroblastoma-like changes were present. At least focally, hypocellular areas were evident in one case. Scattered enlarged tumor cells were seen in two cases. The mitotic rate ranged from 1 to 10 mitoses in 10 high-power fields. Numerous blood vessels with slightly fibrosed vessel walls were seen in seven cases. Immunohistochemically, tumor cells in all cases stained positively for CD34, and in one case each a focal expression of alpha-smooth muscle actin and epithelial membrane antigen (EMA) was noted. The remaining antibodies (CD99, CD31, S-100, Factor XIIIa) were all negative. Polymerase chain reaction technique showed in one case the characteristic COL1A1-PDGFB fusion gene. Follow-up information in seven cases (range: 2 months to 10 years; mean: 62 months; median: 48 months) revealed a local recurrence at 5 years. In conclusion, myxoid DFSP represents a very rare morphologic variant with characteristic changes that has to be distinguished from benign and malignant myxoid mesenchymal neoplasms as superficial angiomyxoma, superficial acral fibromyxoma, myxoid solitary fibrous tumor, myxoid perineurioma, low-grade myxofibrosarcoma, low-grade fibromyxoid sarcoma, myxoid liposarcoma, and myxoid synovial sarcoma.

The histologic distinction of dermatofibrosarcoma protuberans (DFSP) and dermatofibroma (DF) may be difficult, especially in the case of DF extending into the subcutaneous fat (deep DF). CD34 and Factor XIIIa staining is commonly used in separating DF from DFSP, but is not always helpful. HMGA1 and HMGA2 genes, members of the high mobility group protein family genes, encode proteins that act as architectural transcription factors and are frequently dysregulated in a variety of benign or locally aggressive mesenchymal tumors. In this study, we evaluated the immunoreactivity of HMGA1 and HMGA2 in a series of DF and DFSP to determine the possible utility for these markers in the differential diagnosis of these two entities. Immunohistochemical stains were performed on paraffin-embedded tissues from 22 cases of DF, including 14 cases of deep DF and 14 cases of DFSP, using antibodies against HMGA1 and HMGA2. CD34 and Factor XIIIa immunoreactivity was also evaluated in these lesions and compared with the results of HMGA immunostaining. Immunopositivity for both HMGA1 and HMGA2 was seen in 21of 22 (96%) DFs, but in only 3 (21%) and 1 (7%) of 14 DFSPs, respectively. While 100% of DFSP stained for CD34, 36% of DF also labeled for CD34. The immunoreactivity of HMGA1 and HMGA2 in DF was generally strong and diffuse, in contrast to weak and focal staining seen in DFSP. The proportion of cases with positive immunoreactivity for both markers was significantly higher in DF and in deep DF than in DFSP (P < 0.001). We conclude that HMGA1 and HMGA2 expression can be used to distinguish DF from DFSP with a degree of accuracy that is fully equivalent to that of Factor XIIIa and CD34.

Sarcomas currently represent 1% of adult malignancies and 15% of pediatric malignancies. To determine the prevalence of HER-2/neu overexpression by the histologic type and to identify a possible predictive role in patients with sarcoma, we performed a retrospective study on subjects with a biopsy-proven diagnosis of a soft tissue sarcoma. HER-2/neu overexpression was evaluated using immunohistochemistry (IHC) performed on paraffin-embedded specimens. An IHC score of 2+ or greater was considered positive for overexpression. Two hundred seventy-three patients with soft tissue sarcoma were identified (164 females, 109 males) with a mean age of 56 (range: 1-93). The most common tumors identified were malignant fibrous histiocytoma (MFH) (18.3%), dermatofibrosarcoma (DFS) (16.1%), leiomyosarcoma (13.2%) and carcinosarcomas (CS) (7.3%). Of the 273 specimens, 29 (10.6%) revealed HER-2/neu overexpression. CS, MFH, and DFS specimens showed the highest incidence of HER-2/neu overexpression (40%, 26%, and 18.2%, respectively). The incidence of HER-2/neu overexpression was found to be significantly higher in patients with a survival of less than 8 months (p = 0.035). This demonstrates that HER-2/neu overexpression is preferentially seen in certain soft tissue sarcomas, and when present is associated with a poorer prognosis in patients with sarcoma. Further studies would delineate whether HER-2/neu overexpression renders sarcomas chemoresistant and thus adversely affects outcome. In addition, there may be a role for Herceptin (trastuzumab) alone, or in combination with conventional therapy, in patients with CS, MHF, and DFS.

Only 18 cases of dermatofibrosarcoma protuberans (DFSP) of the vulva have been reported. This article describes the clinicopathologic and immunohistochemical findings of four additional vulvar DFSPs. The median patient age was 54 years (range, 36 to 69 years) and the most common clinical presentation was a slowly growing vulvar mass. The tumors occurred in the left paraclitoral area (1 case), right labium majus (1 case), left labium majus (1 case), and mons pubis (1 case). The tumor size, known in three cases, ranged from 1.2 to 5.0 cm in greatest dimension. Microscopically, the tumors were composed of bland spindle cells with oval or wavy nuclei arranged in a cartwheel pattern; in one case, fibrosarcomatous areas were apparent. CD34 immunostaining was positive in the three cases in which it was performed; positive staining was also seen in the area of fibrosarcoma. Estrogen and progesterone receptor immunostains were negative in three cases. Of the three patients who underwent surgery, one had tumor recurrences every 2 to 4 years for 18 to 20 years but has remained free of tumor in the 7 years since the last excision, one was free of tumor for 12 years before dying of an unrelated cause, and the other has been free of disease for 6 months. The fourth patient refused treatment and has persistent disease in the vulva. This study shows that the behavior of DFSP in the vulva is similar to its behavior in its more common locations.

Recent data indicate that reduced expression of the 17-kD protein encoded by the nm23 gene may be important in the pathogenesis of several types of human tumors. Immunohistochemistry was performed using a murine monoclonal antibody, NCL-nm23 (Novocastra, 1:150 dilution) to investigate nm23 protein immunoreactivity in a group of locally aggressive cutaneous fibrohistiocytic tumors; dermatofibrosarcoma protuberans (DFSP) (n = 14) and atypical fibroxanthoma (AFX) (n = 7). Cases of dermatofibroma (DF) (n = 17) formed the benign control group. Comparison with p53 protein immunoreactivity in the same cases studied previously was made. Strong immunohistological expression of the nm23 protein was seen in most of the cases of DF (n = 15; 88%) in the form of strong cytoplasmic immunolabelling without nuclear staining. However, strong nm23 immunoreactivity was observed in only a minority of the cases of DFSP (n = 5; 36%) and AFX (n = 2; 29%). Statistically significant differences in nm23 immunoreactivity were found between DFSP and DF (p = 0.008, chi 2 test with continuity correction) and between AFX and DF (p = 0.015; chi 2 test with continuity correction). No significant difference was seen between DFSP and AFX (p = 0.87, chi 2 test with continuity correction). There was inverse correlation between nm23 and p53 immunoreactivity (r = 0.331; r2 = 0.109; p = 0.046; simple regression analysis). In summary, nm23 protein immunoreactivity is reduced in DFSP and AFX but not in dermatofibroma suggesting that reduced expression of the protein may be important in influencing the behavior of fibrohistiocytic tumors, although this is not well characterised. nm23 protein expression is also found to be inversely related to p53 immunohistological expression in these tumors.

Abnormal expression of the 53 kDa nuclear phosphoprotein produced by the p53 gene is observed in many human cancers. p53 nuclear immunoreactivity is found commonly in tumor cells. Immunohistochemistry was performed using a monoclonal antibody, DO-7 (DAKO, Denmark; cat. no. M7001; 1:100 dilution), to investigate p53 protein immunoreactivity in a group of cutaneous fibrohistiocytic tumors that are known to be locally aggressive. The study group consisted of dermatofibrosarcoma protuberans (DFSP) (n = 14) and atypical fibroxanthoma (AFX) (n = 7). Cases of dermatofibroma (DF) (n = 16) formed the benign control group. Intense nuclear immunostaining for p53 protein was observed in 71% of DFSP and 86% of AFX. None of the dermatofibromas showed strong p53 nuclear immunostaining. Statistical analyses revealed significant differences in p53 immunoreactivity between DFSP and DF (P = 0.0001, chi 2 test) and between AFX and DF (P = 0.0001, chi 2 test). In conclusion, increased p53 protein immunoreactivity is found in DFSP and AFX but not in DF. These differences in p53 immunoreactivity suggest that increased expression of the protein may be important in the pathogenesis of the more aggressive group of fibrohistiocytic tumors.

We studied the immunolocalization of the extracellular matrix glycoprotein tenascin in a series of 24 cutaneous fibrohistiocytic tumors, including seven benign lesions (benign fibrous histiocytoma/dermatofibroma), six intermediate malignancy lesions (dermatofibrosarcoma protuberans), and 11 malignant lesions (three atypical fibroxantomas and eight malignant fibrous histiocytomas). The results of the immunohistochemical staining were evaluated semiquantitatively. All lesions expressed tenascin in the extracellular matrix, with some differences in the distribution of the immunoreactivity. In benign fibrous histiocytoma and in dermatofibrosarcoma protuberans, there was a homogeneous, intense, and diffuse staining of the extracellular matrix (++); the only exception was the homogenized, sclerotic collagen present in late, regressing benign fibrous histiocytoma, which showed a weak and patchy reactivity (+). In atypical fibroxantomas and in malignant fibrous histiocytomas, there was an irregular distribution of the positivity within the tumor matrix (+). Prominent staining of the cytoplasm of several neoplastic cells was observed in atypical fibroxantoma and malignant fibrous histiocytoma (++), focal cytoplasmic staining of scattered cells was found in dermatofibrosarcoma protuberans (+), and cytoplasmic staining was absent from benign fibrous histiocytoma (-). These findings indicate a relationship between cytoplasmic and extracellular matrix expression of tenascin in these lesions, with an increase in cytoplasmic staining and a decrease in extracellular matrix staining in the malignant forms. Based on these different staining patterns, tenascin immunolocalization could furnish some help in the differential diagnosis among benign, intermediate malignancy, and malignant cutaneous fibrohistiocytic tumors. Moreover, the intense tenascin staining at the edge of the lesion could be helpful in defining its extent and therefore provide an additional criterion to evaluate the radicality of the surgical procedure.