Čimbenici rizika za razvoj zloćudnih nemelanomskih tumora kože nakon transplantacije bubrega [Risk factors for development of non-melanoma skin cancer after renal transplantation]

Borlinić, Tajana (2019) Čimbenici rizika za razvoj zloćudnih nemelanomskih tumora kože nakon transplantacije bubrega [Risk factors for development of non-melanoma skin cancer after renal transplantation]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Patients on immunosuppressive therapy are more prone to cancer development, with nonmelanoma skin cancers (NMSCs) being the most frequent ones. The aim of the study was to examine the incidence of NMSCs the group of renal transplant recipients (RTR). Risk factors for NMSC development were recorded, such as patients’ sex, age at transplantation, geographic background, duration of dialysis, type, intensity and duration of immunosuppression. In order to examine the role of Wnt4, the expression pattern was investigated in NMSCs of RTR and in a control group, a nontransplant group which is not under immunosuppressive therapy (77 paraffin embedded basal cell carcinomas (BCC) and 76 paraffin embedded squamous cell carcinomas (SCC)). Statistical significance was appointed to p<0,05. The incidence of NMSC among RTRs was 6,81%., with basal cell carcinoma being the most prevalent one (BCC:SCC ratio 1,76:1). Males were more affected than females (P=0,007), with shorter mean interval between the time of transplantation and first cancer development (P=0,0001). Mean dialysis time before transplantation was 3 years (2–6 years), and mean time to first NMSC development was 5 years respectively. There was difference between age at transplantation; mean age at transplantation for patients transplanted before the year 2010 was 44 (32–53) and mean age at transplantation after 2010 was 53 (43–61) (P<0,0001). Time to first NMSC development is decreasing in later group. NMSC was observed in 5,3% of RTR who live along the Adriatic coast and in 7,3% of RTR who live in the continental part of Croatia; the difference is not statistically significant (P =0,241), nor is the time to first NMSC development between those two groups of patients (P=0,564). Patients receiving more intense therapy (which includes 3 immunosuppressive agents) did not develop more NMSC then patients receiving only 2 immunosuppressive agents (6,64% compared to 8,42 %) (P=0,556). There was significant difference in the incidence of NMSC between the groups of patients treated with different immunosuppressive agents; 3,1% of patients receiving tacrolimus developed NMSC which is significantly lower than 14,3% of NMSC among patients receiving cyclosporinA (P<0,0001). In addition, 5,9% of patients receiving mycophenolat mofetil and 15,8% of patients receiving azathioprine developed NMSC (P=0,001). Immunohistochemical staining to Wnt4 antibody revealed cytoplasmic staining in NMSC cells and in the healthy tissue. Wnt4 staining was weaker in BCC and SCC when compared to the healthy skin (p<0,0001), pointing to influence of Wnt signaling in initial NMSC carcinogenesis. The difference between Wnt4 staining in RTR compared to control group indicates possible activation of different Wnt signaling pathways in carcinogenesis or coactivation of another Wnt ligands in the NMSC progression. However, the role of immunosuppression in Wnt4 expression and activation was not completely made clear. Our results indicate RTRs as a high-risk group for NMSC development. Therefore, patients should undergo a dermatological skin examination prior to transplantation as well as regular dermatological follow up after transplantation considering the guidelines and risk factors for each individual patient.

Abstract in Croatian

Bolesnici liječeni imunosupresivnom terapijom pokazuju povećanu sklonost razvoju tumora, od kojih su najčešći zloćudni nemelanomski tumori kože (NMSC). Istražili smo pojavnost NMSC u populaciji bolesnika s transplantiranim bubregom (BTB). Zabilježili smo rizične čimbenike za razvoj NMSC uključujući: spol bolesnika, dob pri transplantaciji, geografsku regiju u kojoj žive, trajanje nadomještanja bubrežne funkcije dijalizom te vrstu, intenzitet i trajanje imunosupresivne terapije. Izraženost imunohistokemijskog biljega Wnt4 ispitali smo u NMSC BTB i u NMSC bolesnika kontrolne skupine koji nisu pod imunosupresivnom terapijom (77 bazocelularnih i 76 planocelularnih u potpunosti uklonjenih tumora). Razina statističke značajnosti određena je na P<0,05. Pojavnost NMSC u BTB bila je 6,81% s omjerom pojavnosti bazocelularnog i planocelularnog karcinoma 1,76:1. Muškarci s transplantiranim bubregom češće obolijevaju od zloćudnih nemelanomskih tumora od žena s transplantiranim bubregom, i imaju 50% veću vjerojatnost obolijevanja (P=0,007, OR 1,98 (1.20–3,27)). Nismo uočili značajnu razliku u starosti muškaraca i žena s transplantiranim bubregom pri razvoju tumora, no razdoblje od transplantacije do pojave prvog tumora kraće je u muškaraca (P=0,002). Ukupno, BTB u značajno mlađoj životnoj dobi razvijaju NMSC u usporedbi s bolesnicima kontrolne skupine (P<0,0001). Medijan trajanja dijalize prije transplantacije bio je 3 godine (2–6 godina), a medijan razvoja prvog zloćudnog nemelanomskog tumora u BTB je 5 godina. Medijan starosti bolesnika pri transplantaciji transplantiranih prije 2010.g. je 44 godine (32–53), dok je medijan starosti bolesnika pri transplantaciji transplantiranih nakon te godine 53 godine (43–61), što predstavlja značajnu statističku razliku (P<0,0001), dok se istovremeno u bolesnika starijih pri transplantaciji smanjuje vrijeme do pojave prvog karcinoma. NMSC su utvrđeni u 7,3% BTB koji žive u kontinentalnom dijelu Republike Hrvatske (RH) te u 5,3% BTB koji žive u primorskom dijelu RH, što nije statistički značajno (P=0,241, OR 1,397 (0,797–2,448)). Vrijeme od transplantacije do pojave NMSC podjednako je za bolesnike koji žive u kontinentalnom i bolesnike koji žive u primorskom dijelu Republike Hrvatske (P=0,564). Tumori su se razvili u 6,64% bolesnika na trojnoj imunosupresivnoj terapiji, dok je 8,42% bolesnika na dvojnoj imunosupresivnoj terapiji razvilo zloćudni nemelanomski tumor kože (P=0,556). Značajna je razlika u vrsti imunosupresivne terapije, 3,1 % bolesnika imunosuprimiranih takrolimusom razvilo je zloćudni nemelanomski tumor kože, što je značajno manje u odnosu na 14,3% bolesnika koji su imunosuprimirani ciklosporinomA (P<0,0001). Nadalje, 5,9% bolesnika imunosuprimiranih mikofenolat mofetilom i 15,8% bolesnika imunosuprimiranih azatioprinom razvilo je NMSC (P=0,001). Imunohistokemijskim bojanjem na Wnt4 protutijelo pronašli smo pozitivitet unutar stanične citoplazme zdrave kože i tumorskih stanica. Izraženost Wnt4 manja je u bazocelularnim i planocelularnim karcinomima kože u odnosu na zdravu kožu (p<0,0001) ukazujući na utjecaj Wnt signala u inicijalnoj karcinogenezi NMSC. Razlika u izraženosti Wnt4 pozitiviteta u BTB u odnosu na kontrolnu skupinu ukazuje na moguću aktivaciju različitih Wnt signalnih putova ili koaktivacijom drugih Wnt liganada u progresiji NMSC no ne i na ulogu imunosupresije u izraženosti Wnt4 signala. Naši rezultati pokazuju kako su bolesnici s transplantiranim bubregom visoko rizična skupina za razvoj zloćudnih NMSC. Svaki bolesnik bi prije transplantacije trebao obaviti dermatološki pregled te bi isti bilo uputno ponavljati nakon transplantacije bubrega sukladno smjernicama i rizičnim čimbenicima svakog pojedinog bolesnika.

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