Estimation of serum and tissue level of interleukin-15 (IL-15) and IL-15 receptor alpha (IL-15Rα) in mycosis fungoides before and after phototherapy: An interventional cohort study.

BACKGROUND: Mycosis fungoides (MF) is a chronic, highly recurrent cutaneous T-cell lymphoma, whose pathogenesis has not yet been fully elucidated. Interleukin-15 was previously highlighted as a viability factor for cutaneous T-cell lymphoma with previous studies shedding light on its role in pathogenesis of MF and its plausibility as a potential therapeutic target. OBJECTIVE: This study was conducted to evaluate serum and tissue expression of IL-15 and IL-15Rα in early cases of MF (IA, IB, IIA) at baseline and following phototherapy. MATERIALS AND METHODS: Fourteen early MF cases were recruited. Samples were withdrawn prior to starting phototherapy treatment and following near complete clearance of the biopsied lesion or after a maximum of 36 sessions of phototherapy. Samples were assessed for change in expression of IL-15 and IL-15 Rα levels following treatment, whose levels were compared to healthy controls. RESULTS: Serum and tissue levels of IL-15 and IL-15Rα in early MF cases were significantly higher at baseline than their levels following phototherapy treatment and higher than healthy controls. However, they dropped significantly following treatment with no statistical difference between treated cases and controls, apart from serum IL-15Rα that remained significantly elevated than controls. CONCLUSION: Interleukin-15 and its receptor alpha appear to contribute to the pathogenesis of MF, being significantly elevated than healthy controls, which were normalized following phototherapy treatment, apart from serum IL-15Rα, which remained elevated. Controlling IL-15/IL-15Rα expression is a newly proposed mechanism of action of phototherapy in MF.

The role of macrophages in the pathogenesis of mycosis fungoides.

BACKGROUND: Macrophages are classified into classically activated (M1) and alternatively activated (M2) macrophages. Decrease in macrophage number in tumour tissue with treatment has been reported. AIM: The aim of this study was to determine whether treatment has an effect on the number of dermal M1 and M2 macrophages in patients with mycosis fungoides (MF). METHODS: In total, 21 patients (8 women, 13 men; age range 42-73 years) were included in this study. We determined markers for dermal M1 (inducible nitric oxide synthase and CD68) and M2 (markers: CD163 and CD206) macrophages using double immunohistochemistry to reduce the error rate, and then counted the cells. RESULTS: The number of dermal M1 cells was significantly lower pretreatment compared with post-treatment (P < 0.01). The numbers of dermal M2 cells were also numerically decreased by treatment. These results did not change significantly after exclusion of the patients who had recurrence (n = 2). There were no statistically significant differences between groups classified by stage, lesion type or treatment outcome. CONCLUSION: Macrophage numbers are decreased in MF after treatment of tumour tissue.

Bath-PUVA therapy decreases infiltrating CCR4-expressing tumor cells and regulatory T cells in patients with mycosis Fungoides.

BACKGROUND: Mycosis fungoides (MF) is a malignant lymphoma characterized by expansion of CD4(+) memory T-cell clones. Infiltrating cells express CCR4, which is attracted to CC chemokine ligands 17 and 22 (thymus and activation-regulated chemokine [TARC]/CCL17 and TARC/CCL22). Bath-psoralen plus ultraviolet A (PUVA) is effective against MF. In patients with psoriasis, bath-PUVA induces circulating regulatory T cells (Tregs), which suppress effector T cells. To understand the mechanisms in MF, we analyzed lesion-infiltrating cells before and after bath-PUVA therapy. PATIENTS AND METHODS: Thirteen patients with MF (12 stage IB, 1 stage III; mean age 69.2 years, range 35-87 years; 6 men, 7 women) were recruited. RESULTS: Immunohistochemical analysis revealed that lesion CCR4-positive (CCR4(+)) cells and Tregs significantly decreased from 105.1 ± 164.8 cells/10(-2) mm(2) to 31.4 ± 39.0 cells/10(-2) mm(2) and from 78.1 ± 67.8 cells/10(-2) mm(2) to 24.7 ± 25.0 cells/10(-2) mm(2), respectively. Serum TARC levels significantly correlated with infiltrating CD3(+) (r = 0.997), CCR4(+) (r = 0.991), and forkhead box P3-positive (Foxp3(+)) cells (r = 0.843). Circulating Tregs before bath-PUVA therapy were not significantly different from those in healthy volunteers. Bath-PUVA did not significantly change the percentage of circulating Tregs. CONCLUSIONS: Bath-PUVA decreased CCR4(+) cells and Tregs in MF lesions but did not induce circulating Tregs, which might suppress effector T cells. Direct effects through skin lesions might eliminate both pathogenetically relevant cells and Tregs. Systemic immunosuppression was not induced.

Broad band UVA: a possible reliable alternative to PUVA in the treatment of early-stage mycosis fungoides.

UVA1 phototherapy was found to induce marked improvement in skin lesions of patients with stages IA and IB mycosis fungoides (MF). Broad band UVA (BB-UVA) is composed of 80.1% UVA1, with similar mechanisms of action. Our aim was to evaluate the efficacy of BB-UVA in the treatment of early-stage MF. Thirty patients with early stage MF were included. They were divided into two equal groups receiving either BB-UVA at 20 J/cm2/ session or PUVA three times/week for 40 sessions. Clinical and histopathological evaluations were performed before and after therapy in addition to immunohistochemical measurement of CD4+ cells and Bcl-2. Patients were followed up for an average duration of 36 months. Comparable clinical and histopathological improvement was noted in MF patients in both groups. Clinical improvement graded 'Excellent' was achieved in 33% of patients in the BB-UVA versus 13.3% in the psoralen and UVA (PUVA) group. Long-term follow-up indicated superiority of BB-UVA over PUVA. BB-UVA group showed a more rapid clearance rate, shorter time to achieve complete clearance, a longer disease-free interval and lower relapse rate. The use of BB-UVA in the treatment of early-stage MF is comparable or even superior to PUVA regarding efficacy and remission periods.

CD8-positive granulomatous mycosis fungoides: a case report with review of the literature.

Granulomatous mycosis fungoides (GMF) represents an uncommon variant of mycosis fungoides (MF) characterized by the presence of an associated granulomatous reaction. Most cases of GMF are CD4 positive, and CD8 positive cases are extremely rare. Herein, we report a case of CD8-positive GMF. A 75-year-old Japanese woman presented with brownish maculae on the trunk and upper and lower extremities. She had been diagnosed with MF, and most of the eruption improved by psoralen ultraviolet A therapy. However, the eruption relapsed and gradually expanded 5 months prior to her visit to our hospital. Histopathology showed an atypical lymphocytic infiltrate in the dermis accompanied by granulomatous reaction with multinucleated giant cells. Epidermotropism was evident and elastophagocytosis was also found. Immunohistochemically, the atypical lymphocytes expressed betaF1, CD3 and CD8, and some of the atypical lymphocytes were also T cell intracellular antigen-1 positive. These findings were consistent with CD8-positive GMF. The dermatopathological diagnosis of GMF is challenging in some cases because of the prominent secondary granulomatous reaction. Therefore, when dermatopathologists diagnose granulomatous skin lesions, GMF should also be considered. In addition, the prognosis of GMF, especially CD8-positive GMF, is still controversial. Additional studies are required to clarify the clinicopathological features of CD8-positive GMF.

Bcl-2 expression in mycosis fungoides before and after PUVA therapy.

PUVA is the first therapeutic choice in early stages of mycosis fungoides (MF). In this study the effect of PUVA on bcl-2 expression in MF was assessed in 15 patients (three stage Ia and 12 stage Ib) and 10 controls. Two biopsies were taken from each patient before and after 24 sessions of PUVA therapy. Histopathological assessment and immunohistochemical staining for bcl-2 was performed and showed positive bcl-2 staining of lymphocytes in 53% of MF cases (8/15) before PUVA, with no statistically significant difference in the bcl-2 level before and after PUVA therapy (P value 0.3). A statistically significant difference was found in the bcl-2 level between control samples and MF patients' biopsies before (P value 0.02) and after PUVA therapy (P value 0.011). In conclusion, a lack of decline in the bcl-2 level and the absence of clinical or histopathological correlation with the bcl-2 level before and after PUVA therapy in MF patients suggest that PUVA-induced apoptosis in MF cases may occur through pathways other than bcl-2 inhibition.

CCR4 Expression by atypical T cells in systemic pilotropic lymphoma: its behavior under treatment with interferon gamma, topical PUVA and systemic retinoid.

We describe an 88-year-old Japanese patient with pilotropic T cell lymphoma involving the peripheral blood as well as lymph nodes. This patient presented with multiple red follicular papules, confluent, infiltrated erythematous plaques and nodules. Moreover, he was conspicuous for the presence of total alopecia of the scalp and eyebrows. Histopathologically, the lesional skin showed dense follicular and perifollicular infiltrates of atypical lymphocytes. The flow cytometry disclosed the presence of weakly CD4+ CCR4+ cell populations that would not be detected in the peripheral blood from healthy controls. The patient responded well to topical PUVA and systemic etretinate (retinoid-PUVA) and intravenous IFN-gamma. Parallel with the decrease in atypical cells in the peripheral blood, the percentage of weakly CD4+ CCR4+ T cells declined. However, about 1 week after we discontinued this treatment because of the side effects, the lymph node swelling became prominent, and, 4 weeks later, the patient died before restarting any specific chemotherapy.

Cutaneous necrosis associated with the antiphospholipid syndrome and mycosis fungoides.

The development of extensive cutaneous necrosis in a patient with tumour-stage mycosis fungoides is described. Skin biopsies showed a lymphomatous infiltrate, and thrombosis of dermal blood vessels. Investigation revealed the presence of anticardiolipin antibodies, a lupus anticoagulant, and low free protein S, which contributed to a prothrombotic state. Antiphospholipid antibodies have been detected in non-Hodgkin's lymphoma, but clinical manifestations are uncommon. Such autoantibodies may be produced by neoplastic lymphoid cells. The frequency with which antiphospholipid antibodies occur in mycosis fungoides is currently unknown.