| Abstract | Cilj rada: Pojavnost melanoma je u stalnom porastu. Mnogo je nepoznanica u procjeni prediktivnih čimbenika; prognoza i tijek bolesti vrlo često ne ovisi o stadiju u kojem je bolest otkrivena. U trećine bolesnika do smrtnog ishoda dolazi unutar pet godina. Cilj rada je pokušati analizom vlastitih podataka razjasniti obrazac tijeka bolesti, demografske karakteristike, moguće prediktivne čimbenike agresivnijih oblika bolesti i utjecaj na poslijeoperacijsko liječenje i ishod bolesti. U podskupini bolesnika s intermedijantnim melanomom Clark III grupe istražiti uz utjecaj kliničkih i patohistoloških pokazatelja i angiogenezu, analizom nastanka tumorskog žilja i izražaja čimbenika rasta žiljnog endotela VEGF A i C te HIF1. Za kliničku praksu bilo bi važno, dopuniti činjenice o pokazateljima koji bi pripomogli odrediti prognostički rizične oblike bolesti i nužnost adjuvantne poslijeoperacijske terapije. Materijal i postupci: U skupini od 157 radikalno operiranih bolesnika s malignim melanomom stadija bolesti T1b do T4a N0 M0 prema TNM klasifikaciji, analizirani su klinički podaci i uspoređeni su sa podacima iz patohistoloških uzoraka. Bolesnici su potom svrstani i u grupe prema primijenjenom modalitetu adjuvantnog liječenja - kemoterapija dakarbazinom, imunoterapija interferonom alfa-2b ili opservacijski protokol (bez medikamentozne terapije). Analizirao se tijek bolesti u ovisnosti o čimbenicima - vrijeme do progresije bolesti u intervalima od 2, 5 i 10 godina te preživjelost. Posebno se potom izdvojila skupina sa Clark III stadijem bolesti, unutar koje su uz već navedene karakteristike, posebno određivani ekspresija VEGF A i VEGF C u tumoru, te učinjena procjena vaskularizacije (MVD-median vascular density) i istražio njihov utjecaj na odabrano liječenje kroz tijek i ishod bolesti. Uzorci analize HIF1 nisu bili primjereni za daljnju interpretaciju i statističku analizu. VRezultati i rasprava: unutar promatranog perioda u cijeloj je skupini 38% bolesnika imalo progresiju bolesti, a u Clark III skupini njih 37%. Najviše malih tumora T1 stadija imale su žene, a najveći broj T4 tumora muškarci (p=0,013). Postoje razlike u anatomskoj distribuciji primarnog sijela melanoma (p=0,043). Najčešće sijelo prve progresije bile su limfne regije u 47% ispitanika. Pri analizi cijele skupine, modalitet adjuvantnog liječenja nije značajno utjecao niti na nastanak metastaza, niti na lokalizaciju prvog sijela metastaziranja, ni na duljinu preživljenja bolesnika. Spol i dob također ne utječu na vremenski razmak u kojem nastaje progresija bolesti, kao niti na preživjelost. U skupini bolesnika liječenoj imunoterapijom značajniji je broj mlađih osoba (p<0,001) i značajno je veća smrtnost nego u ostalim skupinama (p=0,048). Starosna dob bolesnika kod postavljanja dijagnoze je analizama potvrđena kao važna, Prema rezultatima, bolesnici dobi starije od 60 godina imaju 1,069 puta veće izglede preživljenja nego mlađi (relativni rizik smrti 1,069). Što se progresija kasnije javlja, to je manji rizik smrti (1/0,452=2,21). U skupini Clark III melanoma, istovremeno je utvrđen statistički značajan izraziti rizik od progresije i smrti u osoba mlađih od 41. godine (p=0,003). Usporedba krivulja preživljenja prema dobnim skupinama ukazuje na statistički značajnu razliku (p =0,008), a usporedba krivulja prema spolu pokazuje marginalno značajnu razliku (p =0,083). Progresija ne ovisi o lokalizaciji primarnog melanoma, T stadiju, niti o odabranom modalitetu liječenja. Dob i spol ne utječu na sijelo metastaza. Značajno je veća smrtnost kod tumora na ramenu (p<0,005), značajno najmanja kod tumora na nogama (p=0,018). Preživljenje ne ovisi o stadiju po Breslowu i veličini T lezije. Angiogeneza je potvrđena umjerenim do jakim izražajem VEGF A i C u uzorcima gotovo svih testiranih bolesnika, i korelira u izražaju sa stadijem po Breslowu i TNM klasifikacijom, kao i potvrđena gustoća žilja (MVD). Nije dokazan utjecaj izražaja VEGF niti gustoće MVD na prvo metastatsko sijelo niti na ishod bolesti. VIZaključak: dob je relevantan čimbenik pri procjeni rizika progresije bolesti. Posebnu pažnju treba obratiti prevenciji melanoma u muškaraca, u kojih se uglavnom bolest javlja u lokalizirano uznapredovalijoj fazi, te mlađim osobama. Niti u jednoj analizi nije potvrđena superiornost niti jednog od oblika do sada korištenih adjuvantnog liječenja, stoga trenutno opcija bez terapije ostaje kao najmanje škodljiva za bolesnika. Postoji naznaka korelacije gustoće žilja i izražaja VEGF C koju je potrebno dodatno istražiti. |
| Abstract (english) | Aim: The incidence of malignant melanoma is constantly rising, accompanied with many uncertainties about prognostic factors and patterns of spread. Disease progression very often does not depend on the initial stage of the melanoma. By analyzing the data from our patients, we attempt to clarify the course of disease, demographic characteristics and possible demographic and histopathological factors in order to predict the aggressive forms of the disease and the influence on postoperative treatment and survival. In patients with intermediate thickness melanoma Clark III stage, besides clinical and histopathological, to investigate the influence of angiogenesis (median vascular density MVD, VEGF A and C,H IF 1) on time to progression and survival. Patients and Methods:In a group of 157 radically treated patients with malignant melanoma stage T1b and T4a N0 M0, clinical data were analyzed and compared with data from the histological specimens. Patients were then divided into groups according to the applied adjuvant treatment modality - dacarbazine chemotherapy, immunotherapy with interferon alfa-2b or observation protocol (without drug therapy). We analyzed the course of the disease, in correlation with factors - time to disease progression at intervals of 2, 5 and 10 years and survival. In a subgroup with Clark stage III disease, in which besides the already mentioned features, especially we determined expression of VEGF A and VEGF C in the tumor and the assessment of vascularization (MVD - median vascular density) and their impact on the chosen course of treatment through disease outcome was investigated. The HIF1 samples were not suitable for further interpretation and statistical analysis. Results and discussion: within the observed period in the whole group 38% patients had VIIIdisease progression, and in the Clark III group, 37%. Women had mostly small stage T1 tumors and the largest number of T4 tumors was in males (p=0, 013). There are differences in the anatomic distribution of melanoma primary sites (p = 0.043). The first sites of progression were lymph regions in 47% of patients. When analyzing the entire group, the modality of adjuvant treatment did not significantly affect neither the formation of metastases, the localization of the first sites for metastasis, nor the length of survival of patients. Gender and age also did not affect the time period in which disease progression occurs, nor survival. In the group of patients treated with immunotherapy there is a significant proportion of younger people (p <0.001) and significantly higher mortality than in other groups (p = 0.048). The age of patients at diagnosis was confirmed by analysis as important; according to the results, patients aged older than 60 years have 1.069 times higher chance of survival than younger (relative risk of death 1.069). The later progression occurs; the lower is risk of death (1/0, 452 = 2.21). The group Clark III melanomas, the statistically significant risk of progression and death is seen in people younger than 41st years (p = 0.003). Comparison of survival curves by age groups indicates a statistically significant difference (p = 0.008), and comparison of survival curves by gender shows a marginally significant difference (p = 0.083). Progression does not depend on the localization of the primary melanoma, primary T stage, or on the selected treatment modality. Age and gender do not affect the seat of metastases. Significantly higher mortality is seen in the tumor on the shoulder (p <0.005), significantly the lowest at the feet of the tumor (p = 0.018). Survival does not depend on the stage by Breslow and T lesion size. Angiogenesis is confirmed as moderate to strong according to expression of VEGF A and C in samples of almost all tested patients, which correlates with the stage by Breslow and TNM classification, and confirmed vascular density (MVD). We did not statistically confirm the impact of VEGF expression or MVD density on the localization of the first seat of metastatic disease or the outcome. IXConclusion: Age is a relevant factor in assessing the risk of disease progression. Particular attention should be paid to the prevention of melanoma in men, in whom the disease usually occurs in a much progressive form of localized disease, and younger people. No analysis confirmed the superiority of any of the forms of so far used adjuvant treatment, thus “no treatment” option currently remains as the least harmful to patients. There are indications of the correlation of vascular density and VEGF C expression that needs further investigation. |
