Early Cutaneous T-cell Lymphoma Research Articles

HyBryte™ use in early-stage cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.

CD25 expression could be a prognostic marker of bexarotene monotherapy for cutaneous T-cell lymphomas.

Bexarotene is often administered to phototherapy-resistant early cutaneous T-cell lymphoma (CTCL) patients as one of the first-line therapies in real-world practice. Since bexarotene reduces the expression of CCR4 in CTCL cells and CCL22 to decrease serum CCL22 levels, bexarotene inhibits the migration of CTCL cells, as well as other CCR4+ cells, such as cytotoxic T cells and regulatory T cells, in the lesional skin of CTCL. In this report, the efficacy of bexarotene in 28 cases of CTCL, as well as its correlations with immunohistochemical profiles of tumour-infiltrating leucocytes (TILs), was retrospectively investigated. The overall response rate at 1 and 4months for the total cohort was 70.8% (95% CI, 50.6%-86.3%) and 47.8% (95% CI, 29.2%-67.0%), respectively. The disease control rate for the total cohort at 4months was 65.2% (95% CI, 44.8%-81.3%). The mean event-free survival for all patients was 4.1months (0.3-68.5months). In addition, the immunoreactive cells were calculated using digital microscopy, suggesting that the ratio of CD25+ cells among TILs was significantly increased in patients who responded to bexarotene (p=0.0209), whereas there were no significant differences in the ratios of CD8+ cells, granulysin+ cells, and Foxp3+ cells among TILs between responder and non-responder patients. Collectively, the ratio of CD25 expression among TILs might be a predictive biomarker for the efficacy of bexarotene.

TOX Expression in Mycosis Fungoides and Sezary Syndrome

Mycosis fungoides (MF) and Sezary syndrome (SS) are the two most common type of cutaneous T-cell lymphoma (CTCL). Currently, no markers can be clearly related to prognosis or to differential diagnosis between early stages and inflammatory benign diseases (IBD). The thymocyte selection-associated high mobility group box factor (TOX), has been proposed as a possible marker in differential diagnosis between early CTCL stages and IBD. Recently TOX has been related to prognosis. We aimed to investigate whether TOX may be a diagnostic or prognostic marker. MF and SS biopsies between 2010 and 2020 were retrieved. New tissues slides were stained with an anti-TOX antibody, (Clone NAN448B). On each slide, 5 fields were examined at high magnification (400×), to evaluate the percentage of marker-positivity in a quantitative way. Thirty-six patients (12 females and 24 males) and 48 biopsies were collected. Nine patients had multiple biopsies. TOX expression in MF/SS cases showed an increase from early to advanced phases. TOX was not regarded as a prognostic marker due to the absence of significant changes by comparing early MF cases with reactive conditions. TOX statistical significance increased in patients alive with disease and in those dead of disease (p = 0.013 and = 0.0005, respectively) as compared with patients in complete remission. Our results show that TOX should be regarded more as a prognostic than a diagnostic marker.

Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy.

Bexarotene is useful for both early and advanced cutaneous T-cell lymphoma (CTCL), and is sometimes applied to ultraviolet-tolerant early CTCL patients as one of the first-line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objectiveresponse rate (ORR) for the overall cohort was 65.5%. ORR of the 300mg/m2 cohort (conventional dose) was 76.2%, while that of the 150-300mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0months for all patients, 6.7months for the bexarotene conventional-dose cohort and 19.1months for the low-dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional-dose cohort and 12.5% for the low-dose with NBUVB cohort. Our present study suggests that low-dose bexarotene plus NBUVB therapy is well-tolerated and could be one of the optimal therapies for advanced CTCL.

Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma.

Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.

Investigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update

ABSTRACTIntroduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis.Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody.Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.

Single-Cell Profiling of Cutaneous T-Cell Lymphoma Reveals Underlying Heterogeneity Associated with Disease Progression.

Cutaneous T-cell lymphomas (CTCL), encompassing a spectrum of T-cell lymphoproliferative disorders involving the skin, have collectively increased in incidence over the last 40 years. Sézary syndrome is an aggressive form of CTCL characterized by significant presence of malignant cells in both the blood and skin. The guarded prognosis for Sézary syndrome reflects a lack of reliably effective therapy, due, in part, to an incomplete understanding of disease pathogenesis. Using single-cell sequencing of RNA and the machine-learning reverse graph embedding approach in the Monocle package, we defined a model featuring distinct transcriptomic states within Sézary syndrome. Gene expression used to differentiate the unique transcriptional states were further used to develop a boosted tree classification for early versus late CTCL disease. Our analysis showed the involvement of FOXP3 + malignant T cells during clonal evolution, transitioning from FOXP3 + T cells to GATA3 + or IKZF2 + (HELIOS) tumor cells. Transcriptomic diversities in a clonal tumor can be used to predict disease stage, and we were able to characterize a gene signature that predicts disease stage with close to 80% accuracy. FOXP3 was found to be the most important factor to predict early disease in CTCL, along with another 19 genes used to predict CTCL stage. This work offers insight into the heterogeneity of Sézary syndrome, providing better understanding of the transcriptomic diversities within a clonal tumor. This transcriptional heterogeneity can predict tumor stage and thereby offer guidance for therapy.

Inhibition of the Integrin αVβ3 Improves the Immune and Anti-Lymphoma Effects of Bexarotene in Cutaneous T-Cell Lymphoma (CTCL)

Bexarotene (Bex) is an oral RXR agonist that is effective for the treatment of early and advanced-stage CTCL. However, Bex is associated with the unavoidable side effect of hypothyroidism in about 95% of pts, which is prophylactically managed with the administration of thyroid hormone (TH). Paradoxically, we found that physiological levels of TH increase the proliferation of CTCL by activating both the nuclear TRA receptor and the membrane integrin αVβ3 in these cells. Here, we determined the influence of TH replacement therapy on the anti-lymphoma activity of Bex, an unknown topic with clinical implications.Results: In standard culture conditions, Bex decreases the proliferation and viability of CTCL cell lines HuT78 and MJ. We conducted RNA-sequencing in HuT78 cells treated with Bex (vs. vehicle) to understand the mechanism/s underpinning these effects. We found that Bex regulates pathways related to “cell proliferation and differentiation” (e.g. REL, SCD, CCND1) and “immune system” (e.g. TBX21, IFNG, MX1) , which we independently validated. This suggests that Bex treatment could also impact anti-neoplastic immunity by increasing INF-gamma release from CTCL cells. We then conducted the same experiment culturing HuT78 and MJ in TH-depleted culture conditions and observed a higher effect of Bex in decreasing proliferation and viability; supporting the notion that Bex should not be administered with TH replacement. However, hypothyroidism is associated with marked immunosuppression that could favour CTCL progression and potentially affect the immune modulator effect of Bex that we described above.We thus determined the impact of TH replacement on the anti-lymphoma effect of Bex using a murine CTCL model. We implanted murine EL4 TCL cells in the hypodermis of immunocompetent C57BL/6 mice. Once tumors developed, mice were randomized into treatment with vehicle (Veh), Bex with no TH replacement (Bex) and Bex with TH replacement (BexT4+). TH replacement was done with oral administration of T4. We measured T4 in these mice plasma by RIA to assure that mice with T4 replacement reach physiological levels and those with no T4 develop hypothyroidism. Compared to Veh mice, the administration of Bex significantly decreased lymphoma growth in both conditions although slightly better in mice without T4 replacement (p<0.001 and p<0.01) for Bex and BexT4+, respectively). However, mice with Bex alone that developed hypothyroidism showed a significant decrease of CD8+CD44+ T-cells (p<0.05 vs. BexT4+) and increase of myeloid-derived suppressor cells in the tumor microenvironment and draining lymph nodes. Since infiltration of CD8+ cells decreases with CTCL progression, our data indicates that Bex treatment should be administered with T4 replacement to avoid a negative immune microenvironment.Considering the cellular effects of TH are exerted through TRA and integrin αVβ3 that can be independently modulated pharmacologically, we investigated whether integrin αVβ3 inhibition would be sufficient to blunt the TH-induced decrease on the antineoplastic efficacy of Bex. The lack of expression of integrin αVβ3 in normal T-cells offers a rationale for a selective effect on CTCL cells while sparing immune cells. In HuT78 and MJ cell lines, either αVβ3 silencing by siRNAs or pharmacologic inhibition with the clinical drug cilengitide avoided the decrease in the anti-CTCL effect of Bex upon TH supplementation. Moreover, gene expression analysis (RNA-seq and PCR) demonstrated that αVβ3 silencing induced higher (vs. Bex) up-regulation of “immune ” genes like TBX21 and INFG, or down-regulation of “proliferation” genes like REL and CCND1 .We thus tested if this mechanism can be therapeutically capitalized to improve Bex treatment in our CTCL murine model. We implanted 24 C57BL/6 mice with murine EL4 TCL cells and randomized them to vehicle (Veh), Bex with TH replacement in combination with cilengitide 40mg/kg (BexT4+Cil) or without cilengitide (BexT4+). At end of treatment, BexT4+Cil mice showed significantly smaller tumors compared with Veh and BexT4+ mice (p<0.001 and p<0.05, respectively). Importantly, the anti-tumoral immune response of CD8+CD44+ T-cells in the CTCL microenvironment and draining lymph nodes remained similar in BexT4+Cil vs. BexT4+ mice. Our data indicates that inhibition of the integrin αVβ3 is an effective strategy to improve Bex-based treatments in CTCL. DisclosuresCerchietti:Celgene: Research Funding; Lymphoma Research Foundation: Research Funding; Leukemia and Lymphoma Society: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment.

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma.

Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.

Human Endogenous Retrovirus Expression in Primary Cutaneous T-Cell Lymphomas

Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most frequent cutaneous T-cell lymphomas (CTCL). Human endogenous retroviruses (HERVs) were reverse transcribed and integrated into primate chromosomal DNA, becoming noninfectious, although various stimuli may reactivate them. HERV expression seems to be impaired in several human diseases but limited data regarding CTCL are available. Objective: To evaluate the endogenous retroviral transcription profile in CTCL and their expression among disease clinical stages. Methods: Peripheral blood mononuclear cells from 42 MF/SS patients were analyzed. Total RNA was extracted and amplified with reverse transcription polymerase chain reaction. Results were compared with those obtained in a cohort of 20 healthy donors. Results: HERVs were significantly overexpressed in MF/SS patients compared with healthy donors. No differences were found between early and advanced CTCL stages. Conclusion: HERVs can act as promoters in MF/SS pathogenesis. It remains to link HERV hyperexpression to the outcome in CTCL patients.

Treatment options for primary cutaneous T-cell lymphoma

Primary cutaneous T-cell lymphoma (CTCL) represents a group of diseases characterized by the abnormal proliferation of lymphocytes derived from the skin,with mycosis fungoides (MF) as the most common type.The choice of treatment for CTCL is mainly based on the tumor-node-metastasis-blood (TNMB) classification and staging system for cutaneous lymphomas proposed by the International Society for Cutaneous Lymphomas (ISCL)-World Health Organization-European Organization for Research and Treatment of Cancer (EORTC) in 2007.Other factors to be considered should include the time to onset of action and duration of sustained remission,as well as tolerability,side effects,convenience and cost of treatment.Supportive and local therapies are recommended for early CTCL,while systemic chemotherapy,with or without immunomodulatory therapy,is recommended for advanced CTCL.Some specific cytokines,monoclonal antibodies,and fusion toxins have been tried to treat CTCL. Key words: Lymphoma, T-cell, cutaneous; Therapeutic uses

Cutaneous T cell lymphoma: update on treatment

Cutaneous T-cell lymphoma (CTCL) is a myeloproliferative disease with pronounced epidermotropism. The major subtypes of CTCL are mycosis fungoides and Sézary syndrome. Survival is dependent on the histological subtype and clinical stage. Early CTCL has a normal life expectancy, therefore early disease recognition and stage adapted treatment might help to ensure a good prognosis. This is a review of recent advances in CTCL treatment based on literature review. Skin targeted therapies are useful for patch and limited plaque disease with phototherapy as the cornerstone of such treatments. More advanced disease will benefit from systemic mono- or combined treatments including drug therapy, extracorporeal photopheresis, and radiotherapy. In practice combined treatments may reduce adverse events and improve response rates. For selected younger patients, stem cell transplantation seems a third-line option. The therapeutic spectrum for CTCL has been advanced during the last years, providing the opportunity of tailored treatment for patients.

Low Herpesvirus Entry Mediator (HVEM) Expression on Dermal Fibroblasts Contributes to a Th2-Dominant Microenvironment in Advanced Cutaneous T-Cell Lymphoma

LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a ligand for HVEM. LIGHT-HVEM interactions are important in T helper type 1 (Th1) immune responses. In some cases with early stages of cutaneous T cell lymphoma (CTCL), IL-2, IFN-γ, and Th1 chemokines are expressed in lesional skin, while IL-4, IL-5, and Th2 chemokines are dominant in advanced CTCL. In this study, we investigated roles of LIGHT and HVEM in the microenvironment of CTCL. LIGHT enhanced production of Th1 chemokines, such as CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, from IFN-γ-treated dermal fibroblasts via phosphorylation of inhibitor κBα. Messenger RNA levels of these chemokines were increased in lesional skin of early CTCL. Interestingly, while LIGHT expression in CTCL skin correlated with disease progression, HVEM expression was significantly decreased in advanced CTCL skin. HVEM was detected in dermal fibroblasts in early CTCL skin, but not in advanced CTCL skin in situ. These results suggest that low HVEM expression on dermal fibroblasts in advanced CTCL skin attenuates expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment as disease progresses.

Predictors of complete responses with denileukin diftitox in cutaneous T‐cell lymphoma

The clinical course of cutaneous T-cell lymphoma (CTCL) is typically chronic, often progressive, and variably response to existing therapeutic interventions. To date, few controlled clinical trials demonstrate durable complete responses (CR) in advanced-stage patients. Denileukin diftitox (DD) is a recombinant fusion protein targeting the interleukin-2 receptor of malignant cells. Of 263 relapsed and refractory CTCL patients treated with denileukin diftitox in three prospective, randomized Phase II and III clinical trials, 24 (9.1%) patients attained a durable complete response lasting beyond 3.6 years. This study evaluated the characteristics of the complete responders in these trials. CR patients had received a mean of 3.6 prior therapies. There was no difference in the frequency of CR based on stage of disease, dose of DD (9 vs. 18 μg/kg/day) (P = 0.646) or between CD25-positive and CD25-negative patients (P = 1.00). Response durations were 57-1,325+ days in the CD25-positive group and 190-400+ days in the CD25-negative group. These studies demonstrate that DD therapy resulted in durable complete responses in a subset of patients with early and advanced CTCL and CD25-positive and CD25-negative disease.

The EORTC Cutaneous T-Cell Lymphoma (CTCL) Platform

AbstractAbstract 4896 Background:Primary Cutaneous T-cell Lymphomas (CTCLs) are a heterogenous group of lymphomas, as outlined in the WHO classification. Due to the rarity of CTCL, very few prospective randomized trials have been performed for this disease. EORTC consensus recommendations for the treatment of early CTCL have been published, but treatment of advanced stage disease remains largely empirical, based on small non-randomized, uncontrolled studies with uncertain response data and limited chances to affect clinical practice. Methods:The CTCL platform has been designed by the EORTC Cutaneous Lymphoma Task Force to address critical unadressed questions to move forward the standards of care of CTCL in advanced stage disease. It was built following a sequential approach. Following a European consensus defining the key clincial questions to improve disease control in CTCL, ideas regarding the biology of the disease and all possible emerging targets which may lead to a better understanding of the disease were explored. The candidate targets were selected and prioritized by their scientific and clinical relevance. The maturity and relevance of agents in development to tackle these pathways and targets were analyzed. Methodologically and statistically robust clinical trials were designed to allow the enrollment of patients through the evolution of their disease. Endpoints and translational research programs that could address and help identify mechanisms of action and clinical efficacy were also evaluated as to feasibility and scientific relevance. This comprehensive process lead to the design of early phase randomized trials on solid scientific grounds with the use of innovative drugs. Study protocol 21081 is a multicenter, randomized, open-label, phase III study and is suitable for patients who have not previously had other intravenous chemotherapy, and are therefore relatively treatment-naïve. The accrual goal is 105 patients. The objective of this trial is to test the hypothesis that lenalidomide is able to increase progression free survival in patients achieving a complete (CR) or partial (PR) response after standardized debulking treatment. A sister protocol, 21082, is addressed to patients who have had previous chemotherapy. Patients in that study will be treated with the histone deacetylase inhibitor vorinostat, with or without the addition of the proteosome inhibitor bortezomib. The primary objective of this trial will be to determine if the combination of bortezomib plus vorinostat is more effective than a histone deacetylase inhibitor alone in terms of prolonging progression free survival.The presentation will address details of the disease biology which gave rise to these trials and the selection of innovative agents, the procedures of the strategy adopted and the challenges of designing methodologically valid trials addressing this rare disease. Disclosures:Ortiz-Romero: MSD: Consultancy; Ferrer: Honoraria.

Análisis comparativo de la expresión de moléculas de adhesión celular en linfomas cutáneos (micosis fungoide/síndrome de Sézary) y dermatosis inflamatorias mediadas por células T

Introduction Cell adhesion molecules play a pivotal role in the establishment of T-cell populations in the skin. In this study, we quantify the expression of cell adhesion molecules in patients with cutaneous T-cell lymphoma (CTCL) and compare it with the expression found in other skin diseases. Material and methods Frozen material was obtained from 42 patients in 5 different groups: early CTCL, comprising patients with patch- and plaque-stage of mycosis fungoides ( n=11); advanced CTCL ( n=7), comprising patients with mycosis fungoides ( n=3) and Sézary syndrome ( n=4); inflammatory skin disease ( n=12), comprising patients with psoriasis ( n=9) and atopic dermatitis ( n=3); chronic skin diseases with persistent plaques that do not fulfil the histological criteria for mycosis fungoides (pre-CTCL) ( n=8); and healthy volunteers ( n=4). Expression of the following cell adhesion molecules was analyzed: lymphocyte function-associated antigen 1, intercellular adhesion molecule 1 (ICAM-1), ICAM-3, cutaneous lymphocyte-associated antigen, E-selectin, very late antigen 4, vascular cell adhesion molecule 1, alphaEbeta7 integrin, and E-cadherin. Results The immunohistochemical analyses used here revealed statistically significant differences between CTCL and other skin diseases but not between early and advanced CTCL. The expression of alphaEbeta7 integrin and ICAM-3 in the epidermis per high-power field (400× magnification) allowed the different groups to be distinguished from each other, except for advanced CTCL and pre-CTCL. There were statistically significant differences between advanced CTCL and pre-CTCL in terms of the expression of E-selectin at 400× magnification and the expression of ICAM-1 in a honeycomb pattern in epidermal keratinocytes. Conclusions The expression of cell adhesion molecules involved in the adhesion and migration of lymphocytes in the skin does not differ significantly between initial and advanced stages of CTCL.

Extragenital lichen sclerosus et atrophicus mimicking cutaneous T‐cell lymphoma: report of a case

Early lesions of lichen sclerosus et atrophicus (LSA) may present as a mild lichenoid tissue reaction, occasionally together with basilar epidermotropism, mimicking early cutaneous T-cell lymphoma, mycosis fungoides (MF) variant. We report a case of extragenital LSA in which both histological patterns were present in the same clinically homogenous and stable lesion. A 27-year-old man presented with a history of white atrophic plaques on the trunk. A biopsy of an abdominal lesion revealed epidermal thinning, a superficial perivascular lymphoid cell infiltrate with focal epidermotropism, mild nuclear atypia and perinuclear halos. Immunophenotyping showed decreased CD5 and CD7, with a slight predominance of CD8-positive T-lymphocytes. All these changes were suggestive of MF. However, a repeat biopsy 3 months later from the same stable plaque revealed features diagnostic of LSA. LSA mimicking early MF histologically has been reported in genital skin. Conversely, MF may clinically and histopathologically resemble LSA. With gene rearrangement studies, clonal proliferation may not be detected in early MF but has been reported to occur in LSA. Awareness of the histopathologic spectrum of LSA within a stable plaque is important to avoid a potential diagnostic pitfall, and should prompt a repeat biopsy.

Comparative Analysis of the Expression of Cell Adhesion Molecules in Cutaneous T-Cell Lymphomas (Mycosis Fungoides/Sézary Syndrome) and Inflammatory Skin Diseases

Introduction Cell adhesion molecules play a pivotal role in the establishment of T-cell populations in the skin. In this study, we quantify the expression of cell adhesion molecules in patients with cutaneous T-cell lymphoma (CTCL) and compare it with the expression found in other skin diseases. Material and methods Frozen material was obtained from 42 patients in 5 different groups: early CTCL, comprising patients with patch- and plaque-stage mycosis fungoides (n=11); advanced CTCL (n=7), comprising patients with mycosis fungoides (n=3) and Sézary syndrome (n=4); inflammatory skin disease (n=12), comprising patients with psoriasis (n=9) and atopic dermatitis (n=3); chronic skin diseases with persistent plaques that do not fulfil the histological criteria for mycosis fungoides (pre-CTCL) (n=8); and healthy volunteers (n=4). Expression of the following cell adhesion molecules was analyzed: lymphocyte function-associated antigen 1, intercellular adhesion molecule 1 (ICAM-1), ICAM-3, cutaneous lymphocyte-associated antigen, E-selectin, very late antigen 4, vascular cell adhesion molecule 1, αEβ7 integrin, and E-cadherin. Results The immunohistochemical analyses used here revealed statistically significant differences between CTCL and other skin diseases but not between early and advanced CTCL. The expression of αEβ7 integrin and ICAM-3 in the epidermis per high-power field (400× magnification) allowed the different groups to be distinguished from each other, except for advanced CTCL and pre-CTCL. There were statistically significant differences between advanced CTCL and pre-CTCL in terms of the expression of E-selectin at 400× magnification and the expression of ICAM-1 in a honeycomb pattern in epidermal keratinocytes. Conclusions The expression of cell adhesion molecules involved in the adhesion and migration of lymphocytes in the skin does not differ significantly between initial and advanced stages of CTCL.

Skin-homing CD8+ T lymphocytes Show Preferential Growth in vitro and Suppress CD4+ T-cell Proliferation in Patients with Early Stages of Cutaneous T-cell Lymphoma

A total of 27 T-lymphocyte cell strains were established from skin biopsies of 24 patients with various stages of cutaneous T-cell lymphoma (CTCL) by addition of the T-cell growth factors interleukin (IL)-2 and IL-4. Cellular proliferation and phenotypic changes were measured over 3 months in culture, and T-cell clones were studied using T-cell receptor-? re-arrangement techniques. An average outgrowth of 134 million T-lymphocytes from a 4-mm skin biopsy was observed over 2 months. Initially, most T-cells expressed the CD4+ phenotype. In 17 cell strains from patients with early CTCL a statistically significant predominance of CD8+ T-lymphocytes developed over 8-weeks' culture, indicating that CD8+ T-cells controlled the growth of CD4+ T cells, whereas CD4+ T-cells were predominant in cell strains from advanced CTCL (p <0.05). TCR-? re-arrangement studies revealed, on average, 12 T-cell clones per cell strain, which was reduced over time to 6 T-cell clones per cell strain. Lymphocytes from peripheral blood could kill lymphocytes from an autologous cell strain, suggesting the presence of autoreactive cytotoxic T-cells. Our study suggests how skin-homing CD8+ T-lymphocytes from patients with early stage CTCL can suppress the in vitro growth of skin-homing CD4+ T-lymphocytes, indicating immune surveillance.

Narrow band UVB (311 nm), psoralen UVB (311 nm) and PUVA therapy in the treatment of early‐stage mycosis fungoides: a right–left comparative study

Psoralen ultraviolet A (PUVA) is a widely used first-line therapy for treatment of early cutaneous T-cell lymphoma. Narrow band UVB (UVB-NB) (311 nm) has been recently introduced as another effective line of treatment. It is postulated that the efficacy of UVB-NB could be enhanced by addition of psoralen. The aim of the present work was to compare the clinical and histopathologic efficacy of PUVA and UVB-NB in the treatment of early-stage MF (stages IA, IB and IIA), and to evaluate whether psoralen adds to the efficacy of UVB-NB or not. Twenty patients (stage IA, IB or IIA) were divided into two equal groups: group I received UVB-NB on the right body half vs. PUVA on the left side of the body for 48 sessions, and group II received PUVB-NB on the right side of the body vs. PUVA on the left side for 36 sessions. The sessions were administered three times weekly. In group I, almost equal results were obtained on both sides, i.e., UVB-NB and PUVA were equally effective in the treatment of early stages of MF, both clinically and histopathologically. In group II, PUVB-NB was found to be as effective as conventional PUVA in the treatment of early-stage mycosis fungoides, also on both clinical and histopathological grounds. UVB-NB phototherapy should be included among the initial therapeutic options of mycosis fungoides in view of its efficacy, convenience, and likelihood of fewer long-term adverse effects. Addition of psoralen does not seem to enhance its therapeutic efficacy.