Lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL) comprise a spectrum of CD30+ lymphoproliferative disease with overlapping morphology and clinical behavior. The border between LyP and ALCL is often difficult to establish. Moreover, secondary skin lesions of systemic ALCL closely resemble pcALCL and confer a poor prognosis. Thus, it is important to develop new criteria to make these distinctions. This study uses tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF-1) and cutaneous lymphocyte antigen (CLA) in differentiating CD30-positive lymphoproliferations involving the skin. TRAF-1 is involved in the intracellular signal transduction of TNFR family members without a death domain. TRAF-1 is expressed mainly in activated lymphocytes and strongly induced by NF-kB. CLA is an E-selectin ligand that facilitates adhesion of T lymphocytes to cutaneous vascular endothelium, initiating egress of T lymphocytes to the skin from the systemic circulation. After obtaining SRC and IRB approval, formalin-fixed, paraffin-embedded biopsy specimens from confirmed cutaneous and systemic CD30+ lymphomas were selected from the pathology department of Moffitt Cancer database, 2000–2007. The selected cases included 13 LyP, 9 primary cutaneous ALCL, and 8 systemic ALCL. All cases were stained with TRAF-1 (Imgenex IMG 5757) and CLA (HECA 452) using manufacturer’s protocols. Manual morphometry of 500 lymphocytes counted under high power view (40x HPF) and virtual flow cytometry were performed to quantitate the degree of antibody expression. Antigen expression was scored as negative (less than 5%), weak positive (5 to 50%), intermediate positive (50–80%) and strong positive (80–100%). TRAF-1 was expressed by > 5% of CD30+ large atypical cells in 12 out of 13 LyP cases and in all nine pcALCL. TRAF-1 expression was virtually absent in systemic ALCL with or without skin manifestations. There was no significant difference of TRAF-1 staining between LyP and pcALCL (p>0.05), but significant significant differences betweeen LyP and systemic ALCL (p<0.01), and between pcALCL vs systemic ALCL (p <0.001). Tumor cells of all cases of systemic ALCL case were negative for TRAF-1 (p= 0.0003). CLA expression showed significant differences between LyP and pcALCL (p<0.05) as well as LyP and systemic ALCL (p<0.001), and insignificant differences between pcALCL and systemic ALCL( p>0.05). Mean expression of TRAF-1 was 25% in LyP vs 32% in pcALCL and 0.87% in systemic ALCL. CLA had a mean of 52% for LyP, 28.5% for pcALCL and 6.5% for systemic ALCL. In conclusion, (1) there is significant differential expression of TRAF-1 and CLA in LyP, (2) pcALCL and systemic ALCL. CLA can differentiate LyP from pcALCL. Strong TRAF-1 expression is almost restricted to CD30+ cells in LyP and intermediate to high expression in primary cutaneous ALCL. Systemic ALCL is uniformly negative for TRAF-1. This study indicates potential utility of TRAF-1 and CLA expression data in separating systemic from pcCD30-positive lymphoproliferative disorders.

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