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Cutaneous T-Cell Lymphoma and Defective Apoptosis: Fas Pathway

Summary and Comment |
December 14, 2012

Cutaneous T-Cell Lymphoma and Defective Apoptosis: Fas Pathway

  1. Angelica Selim, MD

Some CTCL phenotypes were associated with resistance to apoptosis.

  1. Angelica Selim, MD

Apoptosis maintains cellular homeostasis and eliminates unneeded T cells. Fas, a transmembrane death receptor, induces apoptosis by activation of caspases after binding to the Fas ligand (FasL). Functional studies in cell lines of cutaneous T-cell lymphomas (CTCLs) point to resistance to apoptosis caused by disruption to the Fas apoptotic pathway. Investigators retrospectively studied protein expression in the Fas pathway in patients with mycosis fungoides (MF) or CD30+ lymphoproliferative disorders (CD30+ ds).

They analyzed 36 MF samples and 36 CD30+ d samples (22 lymphomatoid papulosis [LYP], 10 anaplastic large cell lymphomas [ALCLs], and 4 borderline cases). Immunohistochemical studies showed that most MF cases were FasL-negative; 64% were low in Fas, and 25% were high in Fas or FLICE-like inhibitory protein (cFLIP; a Fas pathway inhibitor). Cleaved or active caspases 3 and 8 were uncommon. All of the ALCLs were FasL-negative; 9 of 10 (90%) were also either Fas low or coexpressed Fas and cFLIP. Of the LyPs, 68howed a phenotype consistent with resistance to Fas pathway apoptosis. However, regressed LyP lesions were FasL-positive or Fas high/cFLIP low, indicating sensitivity to apoptosis. Downstream apoptotic findings in CD30+ d correlated with the upstream profile.

Comment

Defective apoptotic mechanisms may contribute to cutaneous T-cell lymphoma genesis and progression. Nearly all the mycosis fungoides cases showed evidence of apoptotic resistance, which may be why some targeted therapy does not work in these tumors and may point to new treatment targets (e.g., FLICE-like inhibitory protein in early MF). The status of upstream Fas pathway proteins (Fas, Fas ligand) and inhibitors (cFLIP) in CD30+ d correlated with regression or progression. This is an exciting and welcome finding, despite the small sample number and the limitation of retrospective study. We now have no marker to predict CD30+ d behavior. Larger studies with immunohistochemical staining in the Fas apoptotic pathway may confirm the predictive value of these factors using techniques available in most pathology laboratories.

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