Comparative expression profile of CD10 and cyclin D1 in cutaneous histiocytofibroma and dermatofibrosarcoma.

Dermatofibrosarcoma protuberans (DFSP) and histiocytofibroma (HF) are two rare fibrohistiocytic tumors, with some overlapping pathologic features. Immunohistochemistry is very useful in these cases. CD34 is a commonly used marker. However, the increasing cases of CD34 negative DFSP make it pressing to test other immunohistochemical markers that could help in the differential diagnosis. DFSP is known to harbor COL1A1-PDGFB rearrangement. Tumors in the differential diagnosis of DFSP usually lack this molecular signature. Recent studies suggested the interaction of PDGFB and PDGF receptor b with various signaling pathways, including the Akt-mTOR pathway. Cyclin D1, one of the oncoproteins activated in this pathway, may represent a promising useful biomarker in the differential diagnosis. On the other hand, CD10 expression in specialized mesenchymal skin cells, and especially in fibrohistiocytic skin tumors has been reported, which raises the interest of using this biomarker in HF and DFSP. In this study, we aimed to compare the expression of CD10 and cyclin D1 in 15 cases of DFSP and 15 cases of HF and discuss their potential contribution in the differential diagnosis.

The Role of CD34 and D2-40 in the Differentiation of Dermatofibroma and Dermatofibrosarcoma Protuberans.

OBJECTIVE: Dermatofibroma (DF) is a benign fibrohistiocytic tumor whereas dermatofibrosarcoma protuberans (DFSP) has intermediate malignant potential. CD34 is the most commonly used antibody in differentiating these tumors. Various studies have stated the rates of D2-40 expression as 0-50% in DFSPs and 86-100% in DFs. Our aim in this study was to determine the expression of CD34 and D2-40 in DFs and DFSPs and the possible use of D2-40 in the differential diagnosis of these lesions. MATERIAL AND METHOD: This is a retrospective study including 30 DF and 15 DFSP cases which were reevaluated for epidermal changes, the presence of a transmission zone (Grenz zone), infiltration of soft tissues, infiltration pattern and histologic subtypes in addition to cellular pleomorphism, nuclear atypia, and necrosis. A manual immunohistochemistry procedure was performed with D2-40 and CD 34 antibodies using a representative paraffin block. RESULTS: The average age was 37.36 and 42.86 years in the DF and DFSP cases. The average diameter was 0.9 and 5.03 cm, respectively, for the DFs and DFSPs. There was a significant correlation between the two entities for sex, localization and diameter of the lesion. A significant difference was found between the positivity of CD34 and D2-40 in DFs and DFSPs. CONCLUSION: Additional immunohistochemical markers may be needed in DFs with CD34 positivity. Our results showed the additional helpful role of this marker in problematic cases.

Dermatofibrosarcoma Protuberans: An Immunomarker Study of 57 Cases That Included Putative Mesenchymal Stem Cell Markers.

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 PDGFRß 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.

Adaptive Immunity in Fibrosarcomatous Dermatofibrosarcoma Protuberans and Response to Imatinib Treatment.

Dermatofibrosarcoma protuberans (DFSP), although rare, is the most frequent skin sarcoma. Here, we focus on DFSP carrying the fibrosarcomatous transformation (FS-DFSP). FS-DFSP responds to imatinib (IM); however, tumor relapse often occurs. In a series of 21 pre- and post-treatment FS-DFSP samples, the present study explored the events that occur at the tumor site during IM therapy. Gene expression profile and immunohistochemistry analyses documented the occurrence of IM-induced senescence phenotype in the tumor cells and showed the accumulation of activated CD3+ T cells and CD163+CD14+ myeloid cells expressing the CD209 marker in post-therapy lesions. In post-IM specimens, the pathological response and tumor apoptosis were tightly associated with T-cell infiltration, thus suggesting the presence of an ongoing anti-tumor response, which was further confirmed by in vitro functional assays with CD3+ T cells isolated from an IM-responding FS-DFSP lesion. The integration of targeted therapies with immune therapies is currently under investigation to achieve longer tumor control. Our data outline the in situ immunological effects of IM and classify IM-treated FS-DFSP as potentially sensitive to immunotherapy, thus providing the rationale for further investigations of combination treatment for this soft-tissue sarcoma.

Superficial CD34-positive fibroblastic tumor: A new case from Japan.

A 48-year-old Japanese woman presented with a painless, slow-growing, brown nodule of 15 mm in diameter on the left thigh. She noticed the nodule a few years before the first presentation to our hospital. She underwent total resection of the nodule. On histopathological examination, a relatively well-defined tumor with infiltrative growth was located in the dermis and extended into the subcutis. The tumor was composed of spindle to polygonal cells with pleomorphic nuclei arranged in a sheet-like or fascicular pattern. Tumor cells with granular cytoplasm were also scattered. Immunohistochemical examination revealed that the tumor cells were strongly positive for CD34. The fusion transcripts of the collagen type 1 alpha 1 platelet-derived growth factor beta chain were not detected. After excluding other fibroblastic tumors through histopathological and immunohistochemical examinations, a diagnosis of superficial CD34-positive fibroblastic tumor (SCPFT) was made. SCPFT is a recently proposed fibroblastic tumor that is characterized by striking pleomorphism, granular cytoplasm, low mitotic rate and diffuse CD34 expression. Only two reports with 20 cases have been reported so far. The present case is the first that corresponds to SCPFT in Japan.

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP).

PURPOSE: To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology. EXPERIMENTAL DESIGN: Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFB was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis. RESULTS: All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 partial response, 1 stable disease, and 1 progressive disease. Median progression-free survival was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most upregulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed upregulation in genes involved in antigen processing and presentation, natural killer-mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected. CONCLUSIONS: All metastatic cases were fibrosarcomatous. Most patients responded to IM, but PFS was shorter than reported in published series which included both DFSP and FS-DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of naïve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.

[Myxoid dermatofibrosarcoma protuberans: a clinicopathologic analysis of 16 cases].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of myxoid dermafibrosarcoma protuberans (DFSP). METHODS: The clinical and pathologic features of 16 cases of myxoid DFSP were reviewed. RESULTS: There were altogether 15 males and 1 female. The age of the patients ranged from 11 to 73 years (mean = 47 years and median = 48 years). The commonest site of involvement was trunk (number = 11), followed by shoulder (number = 2), head and neck (number = 2), and extremity (number = 1). Similar to conventional DFSP, most patients presented with a slowly enlarging subcutaneous nodule which showed a rapid recent growth in some cases. Amongst the 16 cases studied, 12 occurred de novo and 4 represented local recurrence. The tumors ranged from 2 to 10 cm in greatest dimension (mean = 5 cm and median = 4 cm). Histologically, they were poorly circumscribed and located in the dermis, with focal infiltration into the underlying subcutaneous tissue. Seven cases were purely myxoid and composed of spindly and stellate cells with delicate arborizing vascular meshwork. The remaining 9 cases were predominantly myxoid (> 50%), with 5 cases containing cellular areas resembling conventional DFSP and 4 cases showing fibrosarcomatous transformation. In addition, foci of giant cell fibroblastoma-like areas were noted in 1 case. Immunohistochemical study showed that the tumors cells were positive for CD34. The staining was weak in the myxoid areas, as compared with conventional DFSP. Of the 4 recurrent cases, one patient developed lung metastases. CONCLUSIONS: Myxoid DFSP represents a rare variant of DFSP and may pose important diagnostic pitfalls. It is especially so if the tumor purely consists of myxoid element. Familiarity with the histologic features helps to avoid misdiagnosis.

Cutaneous CD34+ spindle cell neoplasms: Histopathologic features distinguish spindle cell lipoma, solitary fibrous tumor, and dermatofibrosarcoma protuberans.

Spindle cell lipoma (SCL), dermatofibrosarcoma protuberans (DFSP), and solitary fibrous tumors (SFT) are cutaneous CD34+ spindle cell tumors that may exhibit histopathologic and immunophenotypic overlap. We sought ways to reliably distinguish among these lesions even in small or superficial biopsies. Ten morphologic characteristics were analyzed in a group of 5 SCLs, 6 cutaneous SFTs, and 12 DFSPs. SFT and DFSP exhibited extensive histopathologic overlap in small or partial biopsies. However, adnexal entrapment, defined as diffuse proliferation of tumor cells around pilosebaceous and eccrine structures with minimal disruption or expansion of the dermis, was a feature seen in 10 of the 12 DFSPs and in none of the SFTs or SCLs. Even when only superficial portions of a lesion were present, this feature was identifiable. Spindle cell lipomas posed little diagnostic difficulty, in part because excisional biopsies were performed in all cases of SCL. The number of samples included in the study is relatively small, in part due to the rarity of cutaneous solitary fibrous tumors. We conclude that careful attention to these histopathologic features enables reliable distinction among these tumors.

Human leucocyte antigen class I and class II antigen expression in malignant fibrous histiocytoma, fibrosarcoma and dermatofibrosarcoma protuberans is significantly downregulated.

BACKGROUND: Abnormalities in the expression of human leucocyte antigens (HLA) by tumour cells impair cellular immune responses promoting immune evasion and tumour survival. To date, studies analysing HLA class I and class II expression levels in malignant fibrous histiocytomas, fibrosarcomas and dermatofibrosarcoma protuberans are limited. AIMS: Therefore, we investigated the in vivo expression profile of HLA class I and class II antigens in 99 malignant fibrous histiocytomas, 20 fibrosarcomas and 34 dermatofibrosarcoma protuberans from different anatomical sites. MATERIAL AND METHODS: Immunohistochemistry using monoclonal antibodies to HLA class I and class II antigens was used to define the expression levels of these antigens on respective tumour samples. RESULTS: Frequent loss or downregulation of HLA class I and class II expression in malignant fibrous tumours was observed for the different types of tumours examined. DISCUSSION: The data presented suggest for the first time a high frequency of HLA class I and class II abnormalities in malignant fibrous histiocytomas, fibrosarcomas and dermatofibrosarcoma protuberans in vivo. CONCLUSION: This information might be useful in the practical and clinical design of tumour vaccination strategies.

Dermatofibrosarcoma protuberans and giant cell fibroblastoma exhibit CD99 positivity.

According to most authors, dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) represent the adult and juvenile forms, respectively, of the same disease entity, as evidenced by similar morphology, an identical chromosomal translocation, and CD34 positivity. It has been shown that DFSP and nuchal-type fibroma (NTF) (which is also CD34-positive) are related lesions, and that there might possibly be a continuum between the two. In addition, NTF exhibits CD99 positivity. It was therefore, hypothesized that both DFSP and GCF would show similar immunopositivity for CD99. Archives of pathology at several institutions were searched for DFSP and GCF tissue blocks. A total of 29 DFSP and 5 GCF were analyzed by immunohistochemistry for expression of CD99. Twenty-three of 29 DFSP (79%) and 2 of 5 GCP (40%) expressed CD99. Comparison of CD99 and CD34 showed that the non-tumoral periphery of DFSP was less probable to be CD99 positive, but this finding was not statistically significant.

Apolipoprotein D in CD34-positive and CD34-negative cutaneous neoplasms: a useful marker in differentiating superficial acral fibromyxoma from dermatofibrosarcoma protuberans.

More recent techniques to characterize the genetic profile of soft-tissue tumors include the use of gene arrays. Using this technique, Apolipoprotein D (Apo D), a 33-kDa glycoprotein component of high-density lipoprotein, has been found to be highly expressed in dermatofibrosarcoma protuberans. To corroborate these results, we sought to ascertain the utility of Apo D by investigating its sensitivity and specificity in a variety of CD34-positive and CD34-negative cutaneous neoplasms including superficial acral fibromyxoma, sclerotic fibromas, and cellular dermatofibromas. Of interest, we found absence of Apo D expression in all four cases of superficial acral fibromyxoma. Of the remaining CD34-positive lesions, Apo D expression was noted in 35/36 (97%) cases of dermatofibrosarcoma protuberans, 3/5 (60%) giant-cell fibroblastomas, 4/4 (100%) sclerotic fibromas, 8/8 (100%) neurofibromas, and 1/1 (100%) solitary fibrous tumor. Of the CD34-negative lesions, Apo D expression was noted in 2/22 (9%) regular dermatofibroma, 23/45 (51%) cellular dermatofibroma, 10/10 (100%) malignant fibrous histiocytoma, 9/10 (90%) atypical fibroxanthoma, 7/8 (86%) cellular neurothekeoma, 9/9 (100%) malignant melanoma, 8/8 (100%) melanocytic nevi (100%), 0/2 superficial angiomyxoma, 0/15 fibromatosis, 0/1 nodular fasciitis, and 1/2 (50%) desmoplastic fibroblastomas. In summary, our findings indicate that Apo D expression is not specific to dermatofibrosarcoma protuberans. Its principal use as an immunohistochemical adjunct lies in its utility in differentiating superficial acral fibromyxoma from dermatofibrosarcoma protuberans. Although strong positive staining of Apo D in a markedly atypical fibrohistiocytic lesion is suggestive of atypical fibroxanthoma and/or malignant fibrous histiocytoma, further studies with the inclusion of other atypical spindled cell neoplasms are required to conclusively prove the same.

Myxoid dermatofibrosarcoma protuberans: clinicopathologic, immunohistochemical, and molecular analysis of eight cases.

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.

Expression of the CD10 antigen (neutral endopeptidase) by mesenchymal tumors of the skin.

BACKGROUND: The CD10 (or CALLA) antigen is a neutral endopeptidase expressed by a variety of non-hemopoietic cells, including fibroblasts in various tissues. So far little or conflicting data exist concerning the expression of CD10 in normal and pathologic skin. METHODS: We investigated the immunohistochemical expression of the CD10 antigen on formalin-fixed, paraffin-embedded tissue specimens of normal skin and 162 cutaneous proliferative lesions, mostly mesenchymal tumors. RESULTS: In normal skin CD10 immunoreactivity was found in periadnexal mesenchymal cells. In skin tumors, CD10+ cells were found mainly in dermatofibromas and, to a lesser extent, in Dermatofibrosarcoma protuberans and neurofibromas. Metastatic (and to a lesser extent primary) melanomas also occasionally expressed CD10. CONCLUSION: Our results show that the CD10 antigen is expressed by mesenchymal cells of normal human dermis, presumably encompassing a subset of CD34+ dermal dendrocytes and/or periadnexal fibroblasts. The CD10 antigen could be used as an adjunct to the diagnosis of some spindle-cell cutaneous tumors such as dermatofibromas and Dermatofibrosarcoma protuberans, but its value as a single marker is rather limited. The possible role of CD10 as a progression marker in melanoma is interesting and merits further study.

Sarcomas arising in dermatofibrosarcoma protuberans: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up.

There is a prevailing view that sarcomas arising in dermatofibrosarcoma protuberans (DFSP) have a higher risk of metastasis than ordinary DFSP, but these data are based on cases with variable and often suboptimal treatment. There has not been a large study of sarcomas arising in DFSP in which all cases were treated by wide local excision, thereby arguably altering outcome. Clinicopathologic features of 18 cases of sarcomas arising in DFSP treated by wide local excision and having follow up of at least 5 years were analyzed. An estimate of the proportion of sarcoma and DFSP was made. The number of mitotic figures and degree of CD34 immunoreactivity were assessed in each case. The cohort included 13 females and 5 males (age, 23-87 yrs; median, 47 yrs). The tumors involved the trunk (7), scalp (4), extremities (4), and inguinal region (3), and ranged from 1.5 to 7 cm (median, 4 cm). Sarcoma occurred de novo in 15 cases and in a recurrence in three. Sarcomas resembled fibrosarcoma (17) or malignant fibrous histiocytoma (1) and occupied between 20% and 80% of the tumor (median, 60%). Mitotic activity ranged from 2 to 16 per 10 high-power field (HPF; median 7 per 10 HPF) in the sarcomatous component and 0 to 3 per 10 HPF (median, 1 per 10 HPF) in the DFSP component. All tumors expressed CD34 in the DFSP component but only nine (50%) in the sarcomatous component. All patients were treated by wide local excision with negative margins; three additionally received radiation. Four patients (22%) developed recurrences, but none developed metastasis during the follow-up period of 62 months to 17 years (median, 81.5 mos). In contrast to earlier studies, we demonstrate that patients with sarcomas arising in DFSP do not have an increased risk of distant metastasis within a 5-year follow-up period, provided they are treated by wide local excision with negative margins. This probably reflects the fact that wide local excision results in eradication of local tumor, thereby eliminating the source for subsequent dissemination. However, we cannot completely exclude the possibility that tumors in which clear margins are achieved represent a less aggressive subset, as has been suggested for high-grade extremity sarcomas. Previous studies showing increased metastasis for sarcomas arising in DFSP should be re-evaluated to determine if, with treatment stratification, metastatic rate varies.

Dermatofibrosarcoma protuberans of the vulva: a case report and review of the literature.

OBJECTIVE: The purpose of this study is to describe the management of a patient with dermatofibrosarcoma protuberans (DFSP) of the vulva and to review the literature. METHODS: A 39-year-old was referred by a district hospital for incomplete excision of a vulval mass. The lesion involved the left labium major and measured 8 x 12 cm. The lesion was reexcised with a 3-cm margin of normal skin. RESULTS: The patient made an uneventful postoperative recovery. Histology confirmed a diagnosis of DFSP with clear margins. Immunohistochemistry was positive for CD34 glycoprotein. CONCLUSIONS: DFSP of the vulva is a rare fibrous tumor of intermediate grade malignancy, with a tendency for local recurrence. However, it rarely metastasizes. Management should be multidisciplinary and Mohs' micrographic surgery is generally advocated to ensure precise margin control. Survival rates range from 91 to 100%, and local recurrence rates of 20 to 49% have been reported. Therefore close follow-up is recommended.

A pediatric case of dermatofibrosarcoma protuberans: an immunohistochemical study.

Dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor of intermediate malignancy that usually occurs in early or mid-adult life as a nodular cutaneous mass. DFSP has rarely been reported during childhood or at birth. We report a case of childhood DFSP that illustrates the usefulness of immunohistochemical analysis in the differential diagnosis between DFSP and other fibrohistiocytic proliferations occurring in the skin. A prompt and correct diagnosis is very important in order to ensure appropriate treatment and to prevent local recurrences.