Učestalost, vrsta i lokalizacija premalignih i malignih lezija kože kod bolesnika nakon transplantacije bubrega

Abstract

Osobe kojima su transplantirani organi imaju povećan rizik pojave malignih oboljenja, među kojima dominiraju maligni tumori kože. Smatra se da je osnovni razlog primena imunosupresivne terapije, ali još nije sasvim jasan mehanizam i nivo dejstva različitih imunosupresiva. Važan uticaj na nastanak većine malignih tumora kože ima ultraljubičasto (UV) zračenje koje izaziva pojačano starenje kože u vidu histološki prepoznatljivog fotooštećenja, sa odlikama razvoja elastoze i limfocitne infiltracije. U našoj zemlji do sada nisu sprovođena istraživanja rizika pojave maligniteta kože kod transplantiranih pacijenata, ne postoje podaci o njihovoj incidenci, uticaju imunosupresivne terapije i drugim potencijalnim faktorima rizika. U dostupnoj literaturi nema objavljenih radova iz oblasti analize histološkog fotooštećenja kože kod osoba na imunosupresivnoj terapiji. Ciljevi ove studije preseka bili su utvrđivanje učestalosti, vrste i lokalizacije premalignih i malignih lezija kože kod pacijenata nakon transplantacije bubrega, povezanosti njihove pojave sa dužinom, vrstom i režimom primene imunosupresivne terapije i sa histološki verifikovanim fotooštećenjem perilezionalne kože. U studiju je uključeno 66 pacijenata kojima je transplantiran bubreg (primaoci organskog transplantata – POT). Relevantni podaci su prikupljeni putem upitnika i iz medicinske dokumentacije, kliničko-dermoskopskim pregledom kože uočene suspektne lezije su bioptirane u cilju postavljanja dijagnoze i utvrđivanja histoloških parametara fotooštećenja, a u studiju su uključeni i maligni tumori kože POT ispitanika uklonjeni u periodu od prethodnih 5 godina ali nakon transplantacije. Radi komparacije prisutnih faktora rizika i stepena fotooštećenja kože sa opštom populacijom formirana je kontrolna grupa (KG) ispitanika kojima je prethodno bioptirana koža, bez oboljenja bubrega i bez imunosupresije, slična po polu i životnoj dobi sa onim POT ispitanicima kojima je urađena biopsija. Za svaku leziju iz POT grupe obezbeđene su po 2 lezije iz KG, tako da je pojedinim ispitanicima POT grupe analizirano više lezija, dok je u KG 1 ispitanik – 1 lezija. Osnovno oboljenje bubrega do započinjanja dijalize kod ispitanika POT grupe prosečno je trajalo 7,67 godina, u strukturi oboljenja bubrega dominirao je hronični glomerulonefritis sa 31,8%, a ispitanici su na dijalizi bili prosečno 4,54 godine. Prosečna životna dob ispitanika u momentu transplantacije iznosila je 42,5 godina, 60,6% imalo je isključivo kadaveričnu transplantaciju, a prosečno trajanje jatrogene imunosupresije iznosilo je 4,89 god. U POT grupi bioptirane su 33 lezije, među kojima su od značaja za studiju bile 2 (6,1%) aktinične keratoze (AK), 3 (9,1%) displastična nevusa (DN), 1 (3,0%) melanom (MM), 3 (9,1%) skvamocelularna karcinoma (SCK) i 6 (18,2%) bazocelularnih karcinoma (BCK). U POT grupi učestalost MM bila je 1,5%, učestalost SCK 4,5%, učestalost BCK 9,1%, dok je utvrđeni relativan rizik pojave MM u POT populaciji 227 puta veći, BCK 316 puta veći, a SCK 805 puta veći nego u opštoj populaciji. Relativan rizik nastanka AK i DN nije određen zbog izostanka zvanične registracije u opštoj populaciji. POT grupa i KG nisu se statistički značajno razlikovale po Ficpatrikovom fototipu kože, profesionalnoj izloženosti UV zračenju, upotrebi solarijuma, broju solarnih opekotina, ličnoj anamnezi malignih tumora kože i konzumiranju cigareta. Pripadnici KG su se značajno više rekreativno izlagali UV zračenju, češće koristili sredstva za zaštitu od sunčevog zračenja, češće imali bliske srodnike sa malignim tumorima kože, češće konzumirali alkohol, značajno veći broj ispitanika KG imao je pregled kompletne kože i informaciju o merama prevencije od strane lekara, dok 50% ispitanika POT grupe nije znalo da su pod povećanim rizikom pojave maligniteta kože. U stepenu elastoze među grupama nije postojala statistički značajna razlika, dok je limfocitna infiltracija bila marginalno izrazitija u POT grupi bez obzira na vrstu lezije. U POT grupi utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom perilezionalne limfocitne infiltracije i elastoze. U KG utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom limfocitne infiltracije, dok nije bilo statistički značajne razlike u stepenu perilezionalne elastoze. U studiji je utvrđeno da osobe nakon transplantacije bubrega imaju statistički značajno veći rizik nastanka BCK, SCK i MM kože u odnosu na opštu populaciju, sa najčešćom lokalizacijom ovih tumora u predelu glave. Dužina primene imunosupresivne terapije uopšteno nije statistički značajno uticala na pojavu premalignih i malignih tumora kože, ali je kumulativna doza pojedinih imunosupresiva poput ciklosporina i azatioprina imala statistički značajan uticaj na pojavu premalignih i malignih lezija kože. Dužina imunosupresije je statistički značajno uticala na stepen elastoze, ali je imala marginalan uticaj na stepen perilezionalne limfocitne infiltracije.

Organ transplant recipients are at an increased risk of developing malignancies, with the predominance of malignant skin tumors. The main cause is considered to be the administration of immunosuppressive therapy, but the mechanism and effect levels of different immunosuppressive agents are still not completely clear. Ultraviolet (UV) rays also influence the development of malignant skin tumors, causing increased skin aging with histologically recognisable photo damage, with its hallmark being development of elastosis and lymphocytic infiltration. No research on the topic of risks of malignant skin tumors in transplant patients has been done in our country, there is no data on their incidence, or on the effects of immunosuppressive agents and other potential risk factors. There are also no published studies in the field of hystological photo damage analysis in patients on immunosuppressive therapy. The aims of this study were to establish the rates of occurance, types and localisation of premalignant and malignant skin lesions in kidney transplant recipients (KTR) and to associate their advent with the length, type and regimen of immunosuppressive therapy. A total of 66 KTR patients were enrolled in the study. Relevant information was gathered through a specially constructed questionnaire and from the medical records, followed by combined clinical and dermoscopic skin examination to detect suspicious lesions which were biopsied in order to determine the histopathologic diagnosis of the lesion and perilesional degree of photo damage. The study also encompassed malignant skin tumors of KTR patients that have been removed in the last 5 years, but after the transplantation. For the sake of comparison of the risk factors and the levels of photo damage with the general population, an age and sex - matched control group (CG) of patients with previous skin biopsy but without kidney disease and immunosuppression was formed. For each lesion from KTR group, 2 lesions from CG were provided, meaning that some KTR patients had several lesions analysed, whereas in the CG only 1 lesion per patient was analyzed. The average duration of underlying kidney diseases in KTR was 7,67 years, the most frequent being chronic glomerulonephritis (31,8%), and an average duration of dialysis was 4,54 years. The mean age at transplantation was 42,5 years, with 60,6% of the KTR having exclusively cadaveric graft. The mean duration of the iatrogenic immunosuppression was 4,89 years. In the KTR group a total of 33 lesions were biopsied, 2 of which were actinic keratoses (AK) (6,1%), 3 were dysplastic nevi (DN) (9,1%), 1 melanoma (MM) (3,0%), 3 squamous cell carcinomas (SCC) (9,1%) and 6 basal cell carcinomas (BCC) (18,2%). The estimated frequency of MM was 1,5%, SCC 4,5%, BCC 9,1%, and the estimated relative risk of MM in KTR being 227, BCC 316, and SCC 805 times higher compared to the general population. The relative risk of AK and DN development could not have been estimated as there are no official records in the general population. The KTR and CG were not significantly different judging by the Fitzpatrick skin phototype, occupational UV exposure, sunbed usage, personal history of skin cancers, or smoking. The controls were recreationally more exposed to UV rays, used sun protective measures more frequently, had more relatives with skin cancers and consumed alcohol more frequently. A significantly greater number of controls had had complete skin examination and protective measures counceling by the doctor, while 50% of KTR patients did not even know that they were at an increased risk of malignant skin tumor development. There was no significant difference in elastosis levels among the groups, whereas the lymphocitic infiltration was only marginally greater in the KTR group. A significant association between the level of perilesional photodamage and developement of malignant tumors was estimated for the KTR group, whereas in the CG only the perilesional lymphocitic infiltration was strongly associated to malignant lesions. The study results suggest that KTR patients have a significantly higher risk of BCC, SCC and MM development in comparison with the general population, the most common localisation being in the head region. The duration of the immunosuppressive therapy had no significant effect on the premalignant and malignant tumors development, whereas the cummulative dose of certain immunosuppressives (such as cyclosporine and azathioprine) affected the development notably. The duration of immunosuppression statistically influenced the elastosis levels, but had only a marginal influence on the perilesional lymphocitic infiltration levels.