Effects Of Narrow-Band Uvb Alone And In Combınatıon Wıth Isotretınoın On Apoptosıs And Its Clınıcal Implıcatıons In Early Stage Mycosıs Fungoıdes

INTRODUCTION: Mycosis fungoides, one of the most common subtypes of cutaneous T-cell lymphomas, is characterized by uncontrolled T cell proliferation, apoptosis resistance, and consequent chronic cutaneous inflammation. This study aims to show the effects of narrow-band UVB alone and narrow-band UVB + isotretinoin treatments on the expression of fas, fas ligand, BCL 2, STAT-3 and galectin-3 proteins which are responsible for apoptosis regulation, and also assess the relationship between this regulatory functions and clinical improvement
METHODS: The first group received narrow-band UVB alone and the other group received narrow-band UVB combined with 0,5 mg/kg/day oral isotretinoin. After 30 sessions of treatment, biopsies from the patient groups were examined immunohistochemically for the expression of fas, fas ligand, BCL 2, STAT-3 and galectin-3 protein.
RESULTS: In the narrow-band UVB only group, the intensity of epidermal BCL-2 staining was found to be increased in the post-treatment samples when compared to the pre-treatment. On the other hand, epidermal staining intensities and diffuseness for fas, fas- ligand, BCL-2, STAT-3, and galectin- 3, and also the intensities and diffuseness of epidermal lymphocyte staining and presence of epidermal cells were similar between pre and post-treatment samples within each group separately, and between the two treatment groups overall.
DISCUSSION AND CONCLUSION: Mycosis fungoides is a cutaneous T-cell lymphoma characterized by varying degrees of atypical lymphocyte infiltration in the papillary dermis. Phototherapy is accepted as an effective treatment approach for mycosis fungoides in that it exerts a suppressive effect against T-lymphocytes and Langerhans cells. Although narrow-band ultraviolet B phototherapy is frequently used especially in the treatment of early stage mycosis fungoides, in our study it did not result in significant changes in apoptotic markers. This may be due to the fact that apoptosis is not yet a prominent process in the early stage of the disease. In advanced stages of mycosis fungoides, other systemic treatment alternatives may be combined with phototherapy. There are many alternative drugs such as isotretinoin, bexarotene and vorinostat. Retinoids are vitamin A derivatives that regulate cell proliferation, differentiation and apoptosis. Isotretinoin, one of the first retinoids, was observed to show its clinical effects earlier when combined with narrow-band UVB, rather than being used alone. However, there was no difference between pre-treatment and post-treatment results in our narrow-band UVB only and isotretinoin + narrow-band UVB groups [p = 0.005]. Fas is an apoptosis-associated protein of lymphoid cells, and in mycosis fungoides, its expression decreases as the disease stage progresses. Narrow-band UV increases the expression of fas/fas-ligand, which has a strong inducing effect for apoptosis. [15]. Fas-directed apoptosis is inhibited by the antiapoptotic bcl-2 protein. The presence of bcl-2 expression leads to resistance development to apoptosis and is a negative prognostic factor. Our patients did not show a prominent bcl-2 expression was observed in patients, and a number of previous studies have shown that bcl-2 expression is decreased in these patients [16], implying that bcl-2 function is not pronounced in early-stage patients. Proapoptotic bax protein induces apoptosis by increasing the production of fas and suppressing bcl-2. Although increased bax expression following ultraviolet exposure and its role in intracellular signaling pathways in the pathogenesis of mycosis fungoides are well-established, bax levels were not found to be significant in our study [17]. STAT-3 activation was observed in malignant cells obtained from the skin and blood of patients with cutaneous T-cell lymphoma. STAT-3 positivity is rarely seen in early-stage mycosis fungoides lesions because most lymphocytes in this stage are inflammatory rather than neoplastic. We found that both cutaneous T-cell lymphoma patients and the control group showed positive keratinocyte staining for STAT-3 in the keratinocytes, revealing no significant difference between the patients and the control group [18].
STAT-3 positivity is an indicator of progression to advanced stages and this protein is one of the potential molecules that can be targeted in novel treatment strategies for patients in this stage. In our study, STAT-3 expression levels were similar between pre- and post-treatment samples in both groups, and between the two treatments groups. This may be attributable to the fact that STAT-3 expression is mostly observed in advanced stage patients and is not specific for malignant cells since STAT-3 is also present in proliferating keratinocytes. Galectin-3 is a lectin-binding beta-galactosidase and its expression is increased in various neoplastic cell types. It is functionally involved in epithelial cell proliferation, malignant transformation and metastasis. Galectin-3 expressing cells show resistance to apoptosis [19]. In our study, the median post-treatment galectin-3 staining levels were increased when compared to pre-treatment levels in both groups, the differences being statistically insignificant. This was thought to be due to the variations in cell surface glycosylation between individuals.