Liisa Väkevä

European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – Update 2017

In order to provide a common standard for the treatment of mycosis fungoides (MF) and Sézary syndrome (SS), the European Organisation for Research and Treatment of Cancer-Cutaneous Lymphoma Task Force (EORTC-CLTF) published in 2006 its consensus recommendations for the stage-adapted selection of management options for these neoplasms. Since then, the understanding of the pathophysiology and epidemiology of MF/SS has advanced, the staging system has been revised, new outcome data have been published and novel treatment options have been introduced. The purpose of the present document is to update the original recommendations bearing in mind that there are still only a limited number of controlled studies to support treatment decisions for MF/SS and that often treatment is determined by institutional experience and availability. This consensus on treatment recommendations was established among the authors through a series of consecutive consultations in writing and a round of discussion. Recommended treatment options are presented according to disease stage, whenever possible categorised into first- and second-line options and supported with levels of evidence as devised by the Oxford Centre for Evidence-Based Medicine (OCEBM). Skin-directed therapies are still the most appropriate option for early-stage MF, and most patients can look forward to a normal life expectancy. For patients with advanced disease, prognosis is still grim, and only for a highly selected subset of patients, prolonged survival can be achieved with allogeneic stem cell transplantation (alloSCT). There is a high need for the development and investigation in controlled clinical trials of treatment options that are based on our increasing understanding of the molecular pathology of MF/SS.

Proapoptotic and antiapoptotic markers in cutaneous T-cell lymphoma skin infiltrates and lymphomatoid papulosis

Background In cutaneous T‐cell lymphoma (CTCL) lesions, both reactive T cells and malignant T cells intermingle. The disease progression is mostly slow. Recent evidence suggests that even if clinical remission is reached, malignant cells persist and a relapse follows sooner or later. To what extent tumour cell apoptosis occurs in the skin lesions either due to the reactive T cells or to therapeutic efforts is not known.

A retrospective study of the probability of the evolution of parapsoriasis en plaques into mycosis fungoides.

Parapsoriasis en plaque has been suggested to be an early manifestation of mycosis fungoides (cutaneous T-cell lymphoma). We explored the disease course of patients with small plaque or large plaque parapsoriasis in a 26-year retrospective cohort analysis of 105 parapsoriasis patients, who were clinically and histopathologically followed up in Helsinki and Tampere University Hospitals. Eventual later cancers of these patients were verified from the Finnish Cancer Registry. In the small plaque parapsoriasis group, 7 patients (10%) and in the large plaque parapsoriasis group 12 patients (35%), developed histologically confirmed mycosis fungoides during a median of 10 and 6 years, respectively. No significant differences were found regarding the risk of developing mycosis fungoides or the tendency to remission in patients treated with or without phototherapy. Our results show that not only large plaque parapsoriasis, but also small plaque parapsoriasis, as currently defined in textbooks, can progress to mycosis fungoides. The benefits of phototherapy are equivocal in parapsoriasis treatment as far as progression to cancer is concerned.

Ten-year Experience of Bexarotene Therapy for Cutaneous T-cell Lymphoma in Finland

Bexarotene is an oral retinoid shown to be active against the cutaneous manifestations of cutaneous T-cell lym-phoma (CTCL). Literature on the efficacy, dosing and side-effects of bexarotene is sparse. We present here data on 37 Finnish patients with CTCL treated with bexarotene during the last 10 years. Bexarotene was equally effective as monotherapy or when combined with other treatment modalities, resulting in overall responses of approximately 75%. Early-stage CTCL responded better than advanced-stage CTCL (83% vs. 33%). The mean time to observable response was 3 months and the mean duration of the response was 21 months. The dose of bexarotene was generally lower than recommended due to side-effects. Abrupt elevation of liver transaminases, resulting in cessation of treatment, was observed in 4 (11%) patients. We conclude that the dose of bexarotene should be titrated individually to achieve optimal results. Maintenance therapy with low-dose bexarotene is a feasible alternative.

Long-term Follow-up of Cancer Risk in Patients Treated with Short-term Cyclosporine

Cyclosporine increases the risk of skin and lymphoid tissue malignancies in organ transplant patients. A similar increase has been shown among psoriasis patients, but no data exist on the carcinogenic risk of cyclosporine monotherapy in skin diseases. We conducted a retrospective cohort study of 272 patients, all of whom had received at least one month of cyclosporine treatment. The cancer information on these patients was obtained from the Finnish Cancer Registry. The median follow-up time was 10.9 years and the median treatment time with cyclosporine was 8 months. We did not detect any increase in the risk of skin malignancies or lymphoma. The overall risk of cancer was almost identical to that expected in the general population (standardized incidence ratios (SIR) = 1.31, 95% confidence interval (CI) = 0.70-2.23). This study shows that short-term cyclosporine treatment is probably not related to subsequent malignancy. Since the CI of the SIR estimate was rather wide, larger studies are needed in the future.

Multinucleate cell angiohistiocytoma: a report of four cases in Finland.

Sir, Multinucleate cell angiohistiocytoma (MCAH) was first described in 1985 by Smith & Wilson-Jones (1). This condition is an unusual skin disorder most commonly affecting middle-aged women. Clinically, the lesions appear as painless multiple small erythematous papules usually located on the limbs, mainly on the dorsum of the hands, but also on the face, legs and chest. Typically, the slowly progressing MCAH papules reach the size of 2 – 15 mm and may become dome-shaped or flat (2 – 4). No constant associations with other cutaneous or systemic diseases have been reported. The differential diagnosis includes cutaneous vascular proliferations such as angiofibromas or Kaposi’s sarcomas as well as sarcoidosis, lupus erythematosus, insect bite, lichen planus, lymphocytoma and granuloma annulare (5, 6). We present four cases of MCAH diagnosed at the Helsinki University Central Hospital.

Cutaneous T-cell lymphoma-associated lung cancers show chromosomal aberrations differing from primary lung cancer.

Cutaneous T‐cell lymphoma (CTCL) patients have an increased risk of certain secondary cancers, the most common of which are lung cancers, especially small cell lung cancer. To reveal the molecular pathogenesis underlying CTCL‐associated lung cancer, we analyzed genomic aberrations in CTCL‐associated and reference lung cancer samples. DNA derived from microdissected lung cancer cells of five CTCL‐associated lung cancers and five reference lung cancers without CTCL association was analyzed by comparative genomic hybridization (CGH). Fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and loss of heterozygosity (LOH) analysis were performed for selected genes. In CTCL‐associated lung cancer, CGH revealed chromosomal aberrations characterizing both lung cancer and CTCL, but also losses of 1p, and 19, and gains of 4q and 7, hallmarks of CTCL. LOH for the CTCL‐associated NAV3 gene was detected in two of the four informative primary lung cancers. FISH revealed increased copy number of the KIT gene in 3/4 of CTCL‐associated lung cancers and 1/5 of primary lung cancers. PDGFRA and VEGFR2 copy numbers were also increased. IHC showed moderate KIT expression when the gene copy number was increased. CTCL‐associated lung cancer shows chromosomal aberrations different from primary lung cancer, especially amplifications of 4q, a chromosome arm frequently deleted in the latter tumor type. Copy numbers and expression of selected genes in chromosome 4 differed between CTCL‐associated and reference lung cancers. These preliminary observations warrant further prospective studies to identify the common underlying factors between CTCL and CTCL‐associated lung cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat.

Novel TBL1XR1, EPHA7 and SLFN12 mutations in a Sezary syndrome patient discovered by whole exome sequencing

Sezary syndrome (SS) is an aggressive leukaemic variant of cutaneous T‐cell lymphoma. Recurrent chromosomal aberrations have been found in SS, but the whole genetic mutation spectrum is unknown. To better understand the molecular pathogenesis of SS, we performed exome sequencing, copy number variation (CNV) and gene expression analysis of primary SS cells. In our index patient with typical SS, we found novel somatic missense mutations in TBL1XR1, EPHA7 and SLFN12 genes in addition to larger chromosomal changes. The mutations are located in biologically relevant genes affecting apoptosis and T‐cell maturation. They may play a role in the pathobiology of the disease, but no recurrent mutations were discovered in nine additional patients with SS studied. Thus, screening of larger patient cohorts is needed to confirm their prevalence and biological significance in SS.

Molecular markers associated with clinical response to bexarotene therapy in cutaneous T-cell lymphoma.

Bexarotene (Targretin(®)), was registered for the treatment of cutaneous T-cell lymphoma (CTCL) in 2002, and has been reported to induce a 45% overall response. Responses are mostly partial or generate a stable, skin-restricted disease. This study explored the usefulness of a novel cancer-associated gene, NAV3 and corresponding chromosome 12 copy numbers as possible biomarkers to monitor the therapeutic response to bexarotene in 21 Finnish patients with CTCL. Six patients (29%) reached complete remission (CR) and 3 of these remained in CR for more than 24 months, 12 (57%) reached a partial response (PR, with one stable disease) and 3 were non-responders. Low-level NAV3 deletions were detected using a fluorescence in-situ hybridization (FISH) assay in the lesions of 5 patients, 4 of whom were non-responders or progressed after short PR. This occurrence of NAV3 deletions was statistically significant compared with non-progressors (p = 0.011, Fishers exact test). Chromosome 12 tetraploidy was found in the lesions of two of the 3 patients with CR who remained in remission. While such tetraploidy is a feature of proliferating normal T cells, this observation may reflect a favourable anti-tumour immune response among the skin-infiltrating lymphocytes.

Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas

ABSTRACT Indoleamine 2,3-deoxygenase 1 (IDO1) induces immune tolerance in the tumor microenvironment (TME) and is recognized as a potential therapeutic target. We studied the expression of both IDO1 and the related tryptophan 2,3-dioxygenase (TDO) in several different subtypes of cutaneous T-cell lymphoma (CTCL), and evaluated the kynurenine (KYN) pathway in the local TME and in patient sera. Specimens from the total of 90 CTCL patients, including mycosis fungoides (MF, n = 37), lymphomatoid papulosis (LyP, n = 36), primary cutaneous anaplastic large cell lymphoma (pcALCL, n = 4), subcutaneous panniculitis-like T-cell lymphoma (SPTCL n = 13), and 10 patients with inflammatory lichen ruber planus (LRP), were analyzed by immunohistochemistry (IHC), immunofluorescence (IF), quantitative PCR, and/or liquid chromatography–tandem mass spectrometry (LC–MS/MS). Three CTCL cell lines also were studied. Expression of both IDO1 and TDO was upregulated in CTCL. In MF specimens and in the MF cell line MyLa2000, IDO1 expression exceeded that of TDO, whereas the opposite was true for LyP, ALCL, and corresponding Mac1/2A cell lines. The spectrum of IDO1-expressing cell types differed among CTCL subtypes and was reflected in the clinical behavior. In MF, SPTCL, and LyP, IDO1 was expressed by malignant cells and by CD33+ myeloid-derived suppressor cells, whereas in SPTCL CD163+ tumor-associated macrophages also expressed IDO1. Significantly elevated serum KYN/Trp ratios were found in patients with advanced stages of MF. Epacadostat, an IDO1 inhibitor, induced a clear decrease in KYN concentration in cell culture. These results show the importance of IDO1/TDO-induced immunosuppression in CTCL and emphasize its role as a new therapeutic target.