The Risk of Cancer Associated with Immunosuppressive Therapy for Skin Diseases

The possible carcinogenic risk of immunosuppressive therapies is an important issue in everyday clinical practise. Carcinogenesis is a slow multi step procedure, thus a long latency period is needed before cancer develops. PUVA therapy is used for many skin diseases including psoriasis, early stage cutaneous T cell lymphoma, atopic dermatitis, palmoplantar pustulosis and chronic eczema. There has been concern about the increased melanoma risk associated to PUVA therapy, which has previously been associated with an increased risk on non-melanoma skin cancer, especially squamous cell carcinoma. The increased risk of basal cell carcinoma (BCC) is also documented but it is modest compared to squamous cell carcinoma (SCC). This thesis evaluated melanoma and noncutaneous cancer risk associated to PUVA, and the persistence of nonmelanoma cancer risk after the cessation of PUVA treatment. Also, the influence of photochemotherapy to the development of secondary cancers in cutaneous T cell lymphoma and the role of short term cyclosporine in later cancer development in inflammatory skin diseases were evaluated. The first three studies were performed on psoriasis patients. The risk of melanoma started to increase 15 years after the first treatment with PUVA. The risk was highest among persons who had received over 250 treatments compared to those under 250 treatments. In noncutaneous cancer, the overall risk was not increased (RR=1.08,95% CI=0.93-1.24), but significant increases in risk were found in thyroid cancer, breast cancer and in central nervous system neoplasms. These cancers were not associated to PUVA. The increased risk of SCC was associated to high cumulative UVA exposure in the PUVA regimen. The patients with high risk had no substantial exposure to other carcinogens. In BCC there was a similar but more modest tendency. In the two other studies, the risk of all secondary cancers (SIR) in CTCL patients was 1.4 (95% CI=1.0-1.9). In separate sites, the risk of lung cancer, Hodgkin and non-Hodgkin lymphomas were increased. PUVA seemed not to contribute to any extent to the appearance of these cancers. The carcinogenity of short-term cyclosporine was evaluated in inflammatory skin diseases. No increased risk for any type of cancer including the skin cancers was detected. To conclude, our studies confirm the increased skin cancer risk related to PUVA treatment in psoriasis patients. In clinical practice, this has led to a close and permanent follow-up of patients treated with PUVA. In CTCL patients, PUVA treatment did not contribute to the development of secondary cancers. We could not detect any increase in the risk of cancer in patients treated with short term cyclosporine, unlike in organ transplant patients under such long-term therapy.Vaikeiden tulehduksellisten ihosairauksien hoidossa joudutaan käyttämään elimistön puolustusjärjestelmään vaikuttavia hoitoja ja lääkkeitä. Näitä hoitomuotoja ovat mm. PUVA-hoito sekä siklosporiinilääkitys. Edellämainitut hoidot ovat tehokkaita, mutta puolustusjärjestelmään vaikuttavina hoitoina niihin voi pitkällä aikavälillä liittyä lisääntynyt syöpäriski. Syövän kehittyminen on monimutkainen, useita vuosia kestävä tapahtumasarja. Hoitojen mahdolliset pitkäaikaissivuvaikutukset eivät ole olleet tiedossa niitä aloitettaessa, ja epidemiologiset pitkäaikaistutkimukset ovat ainoa tapa saada uutta tietoa eri hoitomuotojen mahdollisesta syöpäriskistä. PUVA-hoito toteutetaan herkistämällä iho ensin psoraleenilla ja sen jälkeen valottamalla UVA-säteillä. Yleisiä PUVA:lla hoidettavia ihosairauksia ovat mm. psoriaasi, lichen planus, palmoplantaarinen pustuloosi, prurigo nodularis, ihon T-solulymfooma ja erilaiset ekseemat. Immuunivastetta hillitsevällä siklo-sporiinilla hoidetaan nykyisin esim. atooppista ekseemaa, psoriaasia, palmoplantaarista pustuloosia ja hankalaa käsiekseemaa. Molempiin edellä mainittuihin hoitoihin tiedetään liittyvän lisääntynyt syöpäriski. PUVA-hoito lisää erityisesti ihon okasolusyöpien riskiä, ja myös siklosporiinia saavilla elinsiirtopotilailla näiden syöpien riski on lisääntynyt. Väitöskirjatyössä tutkittiin sisäisen PUVA-hoidon yhteyttä melanooman ja sisäelinsyöpien kehittymiseen sekä sisäisen PUVA-hoidon yhteyttä ihosyöpien ilmaantumiseen PUVA-hoidon päättymisen jälkeen. Lisäksi tutkittiin ihon T-solulymfoomaa sairastavien potilaiden muiden syöpien riskiä ja niiden mahdollista yhteyttä PUVA-hoitoon. Tutkimme myös lyhytaikaisen, ihotauteihin käytetyn siklosporiinihoidon vaikutusta myöhemmin ilmaantuviin syöpiin. Tuloksissa pitkäaikaiseen sisäiseen PUVA-hoitoon liittyi lisääntynyt melanoomariski, joka oli suurimmillaan yli 250 PUVA-hoitokertaa saaneilla ja/tai yli 15 vuoden kuluttua hoidon aloittamisesta. Sisäelinsyöpien kokonaisriski ei ollut kohonnut, mutta kilpirauhas-, rinta- ja keskushermostosyöpien osuus oli lisääntynyt. Nämä potilaat eivät kuitenkaan olleet saaneet suuria PUVA-hoitoannoksia (yli 300 kertaa). PUVA-hoidon ihosyöpiä (oka- ja tyvisolusyöpiä) lisäävä vaikutus on pysyvä, vaikka hoito lopetetaan. Ihon T-solulymfoomaa sairastavilla potilailla keuhkosyöpä- ja lymfoomariski olivat kohonneet, mutta PUVA-hoidolla ei ollut vaikutusta tähän. Potilailla, jotka olivat saaneet lyhytaikaisesti siklosporiinihoitoa, ei voitu todeta lisääntynyttä syöpäriskiä eikä ihosyöpien määrä ollut merkittävästi lisääntynyt. Yhteenvetona väitöskirjatyö osoitti, että PUVA-hoidon syöpää aiheuttava vaikutus rajoittuu pelkästään iholle. Pitkäaikainen PUVA-hoito lisää melanoomariskiä ja myös muiden ihosyöpien riskiä, vaikka hoito olisi jo lopetettu. Iholymfoomapotilailla todetut syövät eivät olleet yhteydessä PUVA-hoitoihin, ja lyhyt-aikaisen siklosporiinihoidon ei voitu osoittaa aiheuttavan syöpiä. PUVA-hoidon osalta löydös on merkittävä ja on johtanut runsaasti PUVA-hoitoja saaneiden potilaiden tarkkaan seurantaan

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

3C Seismic Interferometry at the Polymetallic Kylylahti Deposit, Outokumpu District, Finland

Non peer reviewe

Cutavirus DNA in Malignant and Nonmalignant Skin of Cutaneous T-Cell Lymphoma and Organ Transplant Patients but Not of Healthy Adults

Peer reviewe

The Transcription Factor Twist1 Has a Significant Role in Mycosis Fungoides (MF) Cell Biology: An RNA Sequencing Study of 40 MF Cases

The purpose of this RNA sequencing study was to investigate the biological mechanism underlying how the transcription factors (TFs) Twist1 and Zeb1 influence the prognosis of mycosis fungoides (MF). We used laser-captured microdissection to dissect malignant T-cells obtained from 40 skin biopsies from 40 MF patients with stage I–IV disease. Immunohistochemistry (IHC) was used to determinate the protein expression levels of Twist1 and Zeb1. Based on RNA sequencing, principal component analysis (PCA), differential expression (DE) analysis, ingenuity pathway analysis (IPA), and hub gene analysis were performed between the high and low Twist1 IHC expression cases. The DNA from 28 samples was used to analyze the TWIST1 promoter methylation level. In the PCA, Twist1 IHC expression seemed to classify cases into different groups. The DE analysis yielded 321 significant genes. In the IPA, 228 significant upstream regulators and 177 significant master regulators/causal networks were identified. In the hub gene analysis, 28 hub genes were found. The methylation level of TWIST1 promoter regions did not correlate with Twist1 protein expression. Zeb1 protein expression did not show any major correlation with global RNA expression in the PCA. Many of the observed genes and pathways associated with high Twist1 expression are known to be involved in immunoregulation, lymphocyte differentiation, and aggressive tumor biology. In conclusion, Twist1 might be an important regulator in the disease progression of MF

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

Peer reviewe

Skin Microbiome in Cutaneous T-Cell Lymphoma by 16S and Whole-Genome Shotgun Sequencing

Non peer reviewe