The Fas apoptotic pathway in cutaneous T-cell lymphomas: Frequent expression of phenotypes associated with resistance to apoptosis

Background: Low proliferation rates, sparse apoptotic cells, and resistance to chemotherapeutic agents suggest that defective apoptotic mechanisms may be important in the pathogenesis and progression of cutaneous T-cell lymphomas (CTCLs). Functional studies of CTCL cell lines and leukemic cells further support abnormal expression of Fas apoptotic pathway proteins as a mechanism for resistance to apoptosis. Objective: We sought to compare the Fas apoptotic pathway protein expression of mycosis fungoides (MF) with CD30⁺ lymphoproliferative disorders (CD30⁺d) in the context of insights gained from functional studies of CTCL cells. Methods: We conducted immunohistochemical analysis of 36 MF and 36 CD30⁺d skin biopsy specimens with antibodies against Fas, Fas ligand, FLICE-like inhibitory protein, Fas-associated death domain, and total and cleaved caspases 8 and 3. Results: Almost all MF lesions (94%) were Fas ligand-negative. In all, 64% of MF lesions were Fas low. An additional 25% of MF lesions were both Fas high and FLICE-like inhibitory protein high (Fas pathway inhibitor). Altogether, this equated to a phenotype predictive of apoptotic resistance in 89% of MF samples. In 9 of 10 cases of CD30⁺d, the apoptotic phenotype predictive of sensitivity/resistance correlated with signs of regression/progression, respectively. Limitations: The study is limited by its retrospective design. Discussion: Our in situ analysis of MF and CD30⁺d tissue samples correlates well with previous functional studies of CTCL cell lines and leukemic blood. Our data strengthen the hypothesis that abnormal expression of upstream Fas pathway factors (Fas, Fas ligand) and the inhibitor FLICE-like inhibitory protein contributes to defective apoptosis in CTCLs.