Uudet kohdegeenit ihon T-solulymfoomien eri alaryhmissä

Ihon T-solulymfoomat (cutaneous T-cell lymphoma, CTCL) ovat ryhmä imukudossyöpiä, joiden esiintyvyys on nousussa erityisesti länsimaissa. Taudin syntymekanismit ovat suurelta osin tuntemattomat, diagnostiikka on vaikeaa ja siksi usein viivästynyttä eikä parantavaa hoitoa ole. CTCL ilmenee iho-oirein, vaikka syöpäsolut eivät ole iholla normaalisti esiintyviä soluja, vaan elimistön puolustusjärjestelmän soluja, jotka ovat tuntemattomasta syystä vaeltaneet iholle. Syöpäsolut ovat kypsiä T-auttajasoluja (Th-soluja) ja ilmentävät tyypin 2 immuunivasteelle ominaisia sytokiineja. Kromosomaalinen epästabiilius on tautiryhmän keskeinen piirre. CTCL-potilailla on lisääntynyt riski sairastua myös muihin syöpiin, erityisesti keuhkosyöpään ja non-Hodgkin –lymfoomiin. Väitöskirjatutkimuksen tavoitteena oli havaita CTCL:n syntymekanismeja selvittäviä kromosomi- ja geenimuutoksia. Erityisesti tavoitteena oli identifioida molekyylejä, jotka soveltuisivat diagnostisiksi merkkiaineiksi tai täsmähoidon kohteeksi. Työssä on tutkittu kahta tautiryhmän yleisintä muotoa, mycosis fungoidesta (MF) ja Sezaryn syndroomaa (SS) sekä harvinaisempaa vaikeasti diagnosoitavaa subkutaanista pannikuliitin kaltaista T-solulymfoomaa (SPTL). Lisäksi on tutkittu CTCL:ään liittyvää keuhkosyöpää ja verrattu sitä tavalliseen (primaariin) keuhkosyöpään. Tutkimusmenetelminä on käytetty esimerkiksi molekyylisytogeneettisiä metodeja ja mikrosiruja. Väitöskirjatyössä havaittiin ensimmäinen CTCL:lle ominainen toistuva geenitason muutos: puutos- tai katkoskohta NAV3-geenissä. Tämän geenipoikkeavuuden havaittiin esiintyvän useissa taudin alaryhmissä (MF, SS, SPTL). NAV3-geenipuutoksen osoittaminen FISH-tekniikalla on sovellettavissa kliiniseen diagnostiikkaan. Tutkimukset geenipuutoksen aiheuttamista toiminnallisista seurauksista ovat käynnissä. Työssä saatiin myös uutta tietoa taudin syntymekanismeista havaitsemalla useiden Th1-tyypin immuunivasteelle ominaisten geenien alentunut ilmeneminen CTCL-potilailla. Tämän lisäksi potilasnäytteissä havaittiin eräiden solun pinta-antigeenien lisääntynyt ilmeneminen, mikä luo pohjan uusien vasta-ainepohjaisten täsmähoitojen kehittämiselle. Väitöskirjatutkimuksessa todettiin myös CTCL:ään liittyvän keuhkosyövän eroavan kromosomi- ja geenimuutosten suhteen verrokkikeuhkosyövästä, mikä jatkossa antaa aiheen tutkia syöpäkantasolujen merkitystä CTCL:n ja sen liitännäiskasvainten kehittymisen taustalla.Cutaneous T-cell lymphomas (CTCL) represent a group of non-Hodgkin lymphomas showing a growing incidence especially in the Western world. The mechanisms leading to the disease are largely unknown, diagnosis is difficult and therefore often delayed, and no curative therapy exists. CTCL presents with skin symptoms although the malignant cells are not derived of human skin but of human immune system instead. The malignant cells are mature T helper memory cells, and preferentially express cytokines characteristic to T-helper 2 (Th2) type immune response. Chromosomal instability is a typical feature of CTCL. Some secondary cancers occur in CTCL patients more often than in general population, the most common of which are lung cancers and non-Hodgkin lymphomas. The aim of the study was to identify genes relevant to CTCL pathogenesis to clarify the poorly understood pathomechanisms behind the disease group. The two most common subgroups of CTCL, mycosis fungoides (MF) and Sezary syndrome (SS), as well as the difficult to diagnose subcutaneous panniculitis like T-cell lymphoma (SPTL), were studied. To reveal the molecular pathogenesis underlying CTCL-associated lung cancer, CTCL-associated lung cancer samples were analysed and compared to primary / reference lung cancer samples. Identification of potential novel diagnostic markers as well as target molecules for therapy was a special focus of the study. To achieve this, patient derived material was studied with molecular cytogenetic techniques, microarrays and gene expression analyses. This study identified the first specific, recurrent gene-level aberration in CTCL, namely the deletion / translocation of neuron navigator 3 (NAV3) gene, characteristic to many different CTCL subgroups, namely MF, SS, and SPTL. NAV3 is a putative haploinsufficient tumor suppressor influencing the differentiation of T-helper cells. The pathways affected by its aberrant function, are currently being studied. Novel insights to CTCL pathogenesis were achieved through the observation that several genes specific for Th1 type immune response (e.g. T-bet, RANTES, and NKG7) were downregulated in CTCL. For the first time, CTCL-associated lung cancers were observed to show chromosomal aberrations differing from primary lung cancers. This finding warrants further prospective studies to identify the common underlying factors between CTCL and CTCL-associated lung cancer. Demonstration of NAV3 deletion by FISH provides a novel diagnostic tool, and overexpression of certain membrane antigens (e.g. MS4A4A, LIR9 and CD52) will provide the basis for developing novel antibody-based therapeutic means

Mycosis fungoides and Sezary syndrome : a population-wide study on prevalence and health care use in Finland in 1998-2016

Background Information about health care use and costs of cutaneous T-cell lymphoma (CTCL) patients is limited, particularly in a European setting. Methods In this population-wide study we set out to investigate prevalence, and trends in health care use in two CTCL subtypes, mycosis fungoides (MF) and Sezary syndrome (SS) over a time period of 19 years in 1998-2016 by using a nation-wide patient register containing data on all diagnosed MF and SS cases in Finland. Results The prevalence of diagnosed MF and SS rose from 2.04 to 5.38/100000, and from 0.16 to 0.36/100000 for MF and SS respectively during 1998-2016. We found a substantial decrease in inpatient treatment of MF/SS in the past two decades with a mean of 2 inpatient days/patient/year due to MF/SS in 2016, while the mean numbers of MF/SS related outpatient visits remained stable at 8 visits/year/patient. Most MF/SS-related outpatient visits occurred in the medical specialty of dermatology. In a ten-year follow-up after MF/SS diagnosis, the main causes for outpatient visits and inpatient stays were MF/SS itself, other cancers, and other skin conditions. Also cardiovascular disease and infections contributed to the number of inpatient days. Mean total hospital costs decreased from 11,600 eur/patient/year to 3600 eur/patient/year by year 4 of the follow-up, and remained at that level for the remainder of the 10-year follow-up. MF/SS accounted for approximately half of the hospital costs of these patients throughout the follow-up. Conclusions The nearly 3-fold increase in prevalence of diagnosed MF/SS during 1998-2016 puts pressure on the health care system, as this is a high-cost patient group with a heavy burden of comorbidities. The challenge can be in part answered by shifting the treatment of MF/SS to a more outpatient-based practice, and by adapting new pharmacotherapy, as has been done in Finland.Peer reviewe

Mycosis fungoides and Sezary syndrome : a population-wide study on prevalence and health care use in Finland in 1998-2016

Background Information about health care use and costs of cutaneous T-cell lymphoma (CTCL) patients is limited, particularly in a European setting. Methods In this population-wide study we set out to investigate prevalence, and trends in health care use in two CTCL subtypes, mycosis fungoides (MF) and Sezary syndrome (SS) over a time period of 19 years in 1998-2016 by using a nation-wide patient register containing data on all diagnosed MF and SS cases in Finland. Results The prevalence of diagnosed MF and SS rose from 2.04 to 5.38/100000, and from 0.16 to 0.36/100000 for MF and SS respectively during 1998-2016. We found a substantial decrease in inpatient treatment of MF/SS in the past two decades with a mean of 2 inpatient days/patient/year due to MF/SS in 2016, while the mean numbers of MF/SS related outpatient visits remained stable at 8 visits/year/patient. Most MF/SS-related outpatient visits occurred in the medical specialty of dermatology. In a ten-year follow-up after MF/SS diagnosis, the main causes for outpatient visits and inpatient stays were MF/SS itself, other cancers, and other skin conditions. Also cardiovascular disease and infections contributed to the number of inpatient days. Mean total hospital costs decreased from 11,600 eur/patient/year to 3600 eur/patient/year by year 4 of the follow-up, and remained at that level for the remainder of the 10-year follow-up. MF/SS accounted for approximately half of the hospital costs of these patients throughout the follow-up. Conclusions The nearly 3-fold increase in prevalence of diagnosed MF/SS during 1998-2016 puts pressure on the health care system, as this is a high-cost patient group with a heavy burden of comorbidities. The challenge can be in part answered by shifting the treatment of MF/SS to a more outpatient-based practice, and by adapting new pharmacotherapy, as has been done in Finland.Peer reviewe

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

Peer reviewe

Pulsed Dye Laser-mediated Photodynamic Therapy is Less Effective than Conventional Photodynamic Therapy for Actinic Field Cancerization : A Randomized Half-side Comparative Study

Previous research presents pulsed dye laser-mediated photodynamic therapy as a promising alternative to conventional red-light photodynamic therapy. In this study, 60 patients with 2 or more actinic keratoses randomly received either of these treatments on each side of the head. A physician blinded to the treatment evaluated treatment response at 6 months for each lesion, as completely, partially or not healed. Significantly lower complete clearance rates (10.3% vs 44.9%) and lesion-specific complete clearance rates were found for pulsed dye laser-mediated photodynamic therapy (47.9%) vs conventional red-light photodynamic therapy (73.4%). Significantly lower pain scores were found for pulsed dye laser-mediated photodynamic therapy, with a mean numerical rating of 2.3, compared with 4.1 for conventional red-light photodynamic therapy. The study population had a mean of 7.9 lesions, and 78% of patients had been treated previously for actinic keratoses on the treatment area. To conclude, in a population with severe sun damage, pulsed dye laser-mediated photodynamic therapy seems less effective than conventional red-light photodynamic therapy. Pulsed dye laser-mediated photodynamic therapy may still be a treatment option for patients who are not compliant with conventional red-light photodynamic therapy.Peer reviewe

Molecular characterization of subcutaneous panniculitis-like T-cell lymphoma reveals upregulation of immunosuppression- and autoimmunity-associated genes

Peer reviewe

Expression of Human Endogenous Retrovirus-W Including Syncytin-1 in Cutaneous T-Cell Lymphoma

Peer reviewe

Cutaneous granulomas caused by subcutaneous injections of leuprorelin acetate

Non peer reviewe

Ablative Fractional Laser Enhances Artificial or Natural Daylight Photodynamic Therapy of Actinic Field Cancerization: A Randomized and Investigator-initiated Half-side Comparative Study

Artificial daylight photodynamic therapy is a near-painless treatment for actinic keratoses, which can be performed indoors using a controlled light dose. Daylight photodynamic therapy is approved only for treatment of grade I–II actinic keratoses. The aim of this study was to evaluate whether fractional laser pre-treatment improves the outcomes of daylight photodynamic therapy for actinic keratoses of all grades. In addition, the study compared the outcomes of artificial and natural daylight photodynamic therapy. This randomized single-blinded split-side comparative study included 60 patients with  ≥ 2 actinic keratoses of the head. Fractional laser pre-treatment was assigned randomly for actinic keratoses on 1 side of the head and, subsequently, the entire treatment area was treated with artificial or natural daylight photodynamic therapy. Fractional laser-mediated daylight photodynamic therapy achieved significantly higher complete clearance (50.0% vs 30.3%, p = 0.04), partial clearance (78.6% vs 50.0%, p < 0.01) and lesion-specific clearance (86.2% vs 70.2%, p < 0.01) than daylight photodynamic therapy alone at the 6-month follow-up. No significant differences were found in the outcomes of artificial vs natural daylight photodynamic therapy or grade I lesions vs grade II–III lesions. Thus, fractional laser pre-treatment appears to significantly increase the efficacy of artificial and natural daylight photodynamic therapy, and to be suitable for treatment of actinic keratoses of all grades

Clinicopathological Characterization and Genomic Aberrations in Subcutaneous Panniculitis-Like T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphomas (SPTLs) represent a rare, difficult-to-diagnose, and poorly characterized subtype of cutaneous T-cell lymphomas (CTCLs) affecting younger people more than the other CTCL forms. We performed a thorough clinical, immunohistological, and molecular analysis of nine Finnish SPTL patients. Specifically, we performed single-cell comparative genomic hybridization (CGH) from laser microdissected, morphologically malignant SPTL cells, as well as loss of heterozygosity (LOH) and fluorescence in situ hybridization (FISH) analysis for the NAV3 (neuron navigator 3) gene. CGH revealed large numbers of DNA copy number changes, the most common of which were losses of chromosomes 1pter, 2pter, 10qter, 11qter, 12qter, 16, 19, 20, and 22 and gains of chromosomes 2q and 4q. Some of the DNA copy number aberrations in SPTL, such as loss of 10q, 17p, and chromosome 19, overlap with those characteristic of common forms of CTCL (mycosis fungoides (MF) and Sezary syndrome (SS)), whereas 5q and 13q gains characterize SPTL. Allelic NAV3 aberrations (LOH or deletion by FISH), previously found in MF and SS, were identified in 44% of the SPTL samples. This study demonstrates that SPTL is also moleculocytogenetically a uniform entity of CTCL and supports the current World Health Organization–European Organization for Research and Treatment of Cancer (WHO–EORTC) classification defining SPTL as a subgroup of its own