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A 27-year-old man presented with a slow-growing, painless mass on the right anterior forearm of 4 years’ duration. Because of apparent rapid enlargement of the mass, he underwent surgical excision in a local clinic without histopathologic examination in June 1999. Recurrence of the tumor was noted in August 1999, when an excisional biopsy was performed. The pathologic diagnosis was giant cell tumor of the tendon sheath. In December 1999, he presented to our dermatology clinic with a local recurrence at the same site. He denied any history of trauma or any particular event preceding the initial appearance of the mass. On physical examination, there was a skin-colored subcutaneous nodule, about 1.5 cm in size, under the operative scar on the right anterior forearm (Fig. 1). We performed an excisional biopsy. The pathology showed features of osteosarcoma. No bony involvement was seen on X-ray or bone scan. Routine blood chemistry and blood count were normal. Figure 1. A subcutaneous nodule under the operative scar on the right forearm Download figure to PowerPoint A wide excision was performed. Postoperatively, the patient was given six courses of radiotherapy (7020 cGy, cumulative dose), followed by chemotherapy consisting of six cycles of epirubicin. Follow-up studies, including chest X-ray and bone scan, did not show any evidence of metastasis or recurrence. He is currently well without recurrence, 2 years after treatment for the malignancy. On histopathologic examination, the biopsy specimen from August 1999 exhibited a somewhat nodular pattern. It was moderately cellular and composed of sheets of polygonal mononuclear cells with oval nuclei, which blended with stromal collagen. Many multinucleated giant cells of the osteoclast type were scattered throughout the lesion (Fig. 2a and 2b). Foci of xanthomatous change were seen at the periphery. These findings were consistent with a giant cell tumor of the tendon sheath. The recurrent tumor in December 1999 was a pseudoencapsulated nodular lesion with infiltration at the borders, and was mainly located in the subcutis with involvement of the dermis. Prominent cartilaginous tumor elements appeared in the center of the lesion (Fig. 3a). Abundant stream-like tumor osteoid and ramifying bone formation were seen peripherally. The tumor was hypercellular and composed of irregular round or spindle cells with considerable pleomorphism and atypical mitoses (Fig. 3b). In addition, a varying number of giant cells with multiple bizarre nuclei or osteoclast-like giant cells were present in some areas. Figure 2. (a) The lesion was composed of mononuclear cells and scattered multinucleated giant cells in a collagenous stroma (hematoxylin and eosin, × 100). (b) Higher magnification of the lesion in (a), showing osteoclast-like giant cells with multiple, haphazardly distributed nuclei scattered among polygonal mononuclear cells (hematoxylin and eosin, × 200) Download figure to PowerPoint Figure 3. (a) Malignant cartilage formation (hematoxylin and eosin, × 200). (b) Atypical round or spindle cells with deposits of stream-like osteoid shown in the top part of the figure (hematoxylin and eosin, × 200) Download figure to PowerPoint The pathology specimen from the wide excision was largely identical to the previous biopsy, and the surgical margins were free of tumor involvement.

IL-17 has an important role in the immunopathogenesis of autoimmune diseases, and spleen tyrosine kinase (Syk) has been implicated as a critical molecule in the signaling pathways of various immunoreceptors. Chemokine (C-C motif) ligand 20 (CCL20) interacts with chemokine (C-C motif) receptor 6 to recruit IL-17-producing cells into the skin to promote progression of psoriasis. Herein we investigate how Syk regulates IL-17 signaling to affect CCL20 expression in primary human epidermal keratinocytes. We found that IL-17 can induce CCL20 expression and activate TAK, IKK, NF-κB, c-Jun N-terminal kinase, and Syk. Data of TAK inhibitor and Syk small interfering RNA (siRNA) indicate Syk being an upstream molecule of TAK in IL-17-elicited signaling. The promoter activity assay combined with site-directed mutagenesis showed that IL-17-elicited CCL20 upregulation is depending on the Syk-mediated NF-κB pathway. Immunoprecipitation also indicated the interaction of Syk with signal molecules of IL-17R, such as TRAF6 and Act1, under IL-17A stimulation. However, the essential signaling events including TRAF6 interaction with Act1 and TRAF6 polyubiquitination under IL-17A stimulation were diminished by Syk siRNA and pharmacologically inhibiting Syk. Taken together, we identify Syk as an upstream signaling molecule in IL-17A-induced Act1-TRAF6 interaction in keratinocytes, and inhibition of Syk can attenuate CCL20 production, which highlights Syk as a potential therapeutic target for inflammatory skin diseases such as psoriasis.

Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase, was initially identified as a crucial regulator in proximal immunoreceptor signaling. Additional studies have revealed its pleiotropic roles, and drugs targeting Syk are under development for inflammatory diseases. Syk expression in the skin has been detected, but its functions in the skin are still unknown. Here, we found that Syk phosphorylation and expression in primary human keratinocytes decreased gradually along with terminal differentiation. Human skin specimens showed similar in vivo patterns. Syk inhibitors or knockdown of Syk increased the expression of differentiation markers under in vitro differentiation models. Furthermore, EGFR activation prominently induced Syk phosphorylation, which could be inhibited by the EGFR inhibitor gefitinib or knockdown of EGFR. The Src inhibitor also partially attenuated EGF-induced phosphorylation of Syk. However, Syk inhibition suppressed EGF-induced phosphorylation of EGFR. Immunoprecipitation and confocal microscopy further revealed the increased molecular interaction between EGFR and Syk after EGF stimulation. This study unravels the role of Syk in EGFR-mediated signaling and reveals regulatory roles of Syk in keratinocyte differentiation, suggesting the clinical potential of topical or systemic Syk inhibitors in the treatment of skin diseases with aberrant differentiation.