Skin melanoma heterogeneity and its molecular aspects

U Hrvatskoj je zabilježen 2,7 postotni godišnji porast mortaliteta od melanoma kože. U više studija otkriveno je da osobe koje razviju melanom na abdomenu imaju znatno veći broj madeža od osoba koje razviju melanom na glavi ili vratu. Suprotno tome, melanomi na glavi i vratu povezani su sa solarnom keratozom, ali vrlo slabo s brojem madeža. Otkrivena je povezanost podtipa lentigo maligna melanoma sa značajnim izlaganjem suncu, ali nikakve konstantne korelacije nisu pronađene kod drugih histoloških podtipova. Nova molekularno genetska istraživanja snažno podržavaju koncept da su melanomi nastali na centralnim dijelovima tijela kod mlađih osoba s velikim brojem melanocitnih madeža biološki različiti od melanoma nastalih kumulativnim djelovanjem na suncem oštećenoj koži starijih ljudi i da su madeži i melanomi istog puta nastanka vođeni istim genetskim promjenama. Epidemiološke stručne analize brzo su utvrdile da visok stupanj izloženosti suncu znači veći broj madeža u ranom djetinjstvu. Višestruka istraživanja pokazala su da BRAF-mutirajući melanomi najčešće spadaju u superficijalno-šireći podtip i pojavljuju se na koži koja je povremeno bila izložena suncu kao i da češće metastasiziraju u regionalne limfne čvorove nego melanomi bez BRAF mutacija. KIT-mutiranimelanomi se pojavljuju u koži, na noktima, na mukozi ili na koži koja je oštećena suncem te najčešće isključuju BRAF mutaciju. Melanomi s ovom mutacijom vrlo često imaju in situ komponente koje su slabo ograničene, što je rezultat pojačane lateralne mobilnosti neoplastičnih melanocita nakon aktivacije SCF KIT puta.Croatia has recorded a 2.7 percent annual increase in melanoma of the skin mortality. Several studies have found that people who develop melanoma on the abdomen carry a significantly higher number of nevi than people who develop melanoma on the head or neck. In contrast, melanoma on the head and neck is associated with solar keratosis, but not with the number of nevi. The correlation was found between lentigo maligna melanoma incidence and exposure to the sun. No similar correlation was found in other histological subtypes of melanoma. New molecular genetic studies support the concept that melanomas arising in the central parts of the body of young people carring multiple nevi are biologically different from melanoma caused by cumulative action of the sun-damaged skin in older patients. Epidemiological expert analysis quickly determined that a high degree of exposure to the sun means a larger number of moles in early childhood. Multiple studies have shown that BRAF-mutant melanoma most often fall into the superficial-spreading subtype and appear on skin that has occasionally been exposed to the sun and that they more often methasize to regional lymph nodes than melanomas without the BRAF mutation. KITmutated melanoma appear in the skin, the nails, the mucosa or the skin, which is damaged by the sun and usually exclude BRAF mutations. Melanomas with this mutation often carry na poorly delimited in situ components as a result of enhanced lateral mobility of neoplastic melanocytes after the SCF KIT pathway activation

Atypical Spitz Tumor of Uncertain Biologic Potential with Inopportune Localization in 7- year-old Boy

Letter to the editor No abstract available</p

Malignant Skin Melanoma in Croatia

Global heating and increased solar ultraviolet irradiance have caused an increase in number of many diseases, particularly skin malignant diseases. Aim of this study was to investigate the influence of climate changes on the health of the population of the Primorsko-goranska and Istria Counties. We gathered and analyzed data about the frequency of skin malignant melanoma in the period of eight years (1998–2005). The data were collected from the Croatian cancer registry. The incidence of malignant skin cancer was estimated overall, by age group and gender. We found that the incidence of the skin melanoma was approximately the same in both counties during the period 1998–2005. However, significant increase has been noted when compared to the situation in the period 1977–1996 (p=4.95 E–13) The incidence of malignant skin melanoma has risen during the last ten years. It is differently distributed between gender and age groups in Primorsko-goranska and Istria County. It can be related to climate changes, but also to different ways way of life between these two counties

Real-Time Expression of hTERT in Primary Melanoma Biopsies

Skin melanoma is by far the most lethal skin cancer, it is unpredictable by nature and presents a severe diagnostic problem. One of the major issues in melanoma diagnostics is to differentiate it with confidence from a dysplastic nevus. Thus, the aim of this study was to evaluate hTERT expression on a spectrum of dermal lesions (from normal skin to primary melanoma) in order to examine its possible role as a diagnostic marker in melanoma diagnostics. In this study we analyzed the expression of hTERT by real-time PCR on 58 freshly obtained biopsy samples (4 samples of normal skin, 12 dermal nevi, 23 dysplastic nevi, 19 primary melanomas). Our results showed slightly greater hTERT expression in dysplastic nevi than melanomas with major data overlap. Considering the given results, hTERT does not seem to be a reliable diagnostic marker for melanoma

The patterns of melanoma presentation

There is a global rising incidence of melanoma. For different reasons patterns of incidence, appearance, gender, anatomical distribution and outcome vary in different geographic area. Screening programs leaded to better early detection of melanoma in Australia and some world areas. National Cancer registry and practice data show incidence in Croatia is constantly rising. Despite public education programs about early discovery, in clinics we still see many new advanced stage melanoma.We analyzed data from 157 patients, cured and followed for 10 years for T1b-T4aN0 skin melanoma. There was a difference in anatomical distribution of melanoma lesions in correlation with patients age (ANOVA test, F=3.51, p=0,009). A higher prevalence of shoulder melanoma in young people was found, and head/neck in old (post-hoc Sheffe test, p=0.038).The T4 lesions were more found in men, and T1 mainly in women (Pearson c2 test, c2 =12.08, p=0.016). There was no difference in Clark level, but significantly higher Breslow stage was found in men (t=-2.52, p=0.013). Men were much prone to have head and neck, body, and shoulder melanoma; women had more melanoma on their legs and arms. Clark and Breslow level were strongly correlated in leg melanoma; head localization had no correlation at all. As conclusion, more attention should be devoted to improve results in melanoma detection in men, especially with the prevalence of body (back), head/neck localization, sometimes not prone to visual detection. Pattern of distribution show also the need for more attention to shoulder melanoma in younger people.</p

Proteinska ekspresija i genska amplifikacija EGFR-a i ciklina D1 u nodularnom melanomu

CILJ ISTRAŽIVANJA: Budući da nodularni melanom(NM) inicijalno raste vertikalno te stoga naraste brzo i ima visoki metastatski potencijal potrebno je otkrivati i razvijati nove biomarkere koji bi se koristili u prognozi preživljenja pacijenata i diferencijalnoj dijagnostici navedenog tumora. Cilj ove studije je ispitati ulogu i značaj nuklearne EGFR (nEGFR), membranske EGFR (mEGFR) i ciklin D1 proteinske ekspresije, te EGFR i CCDN1 genske amplifikacije kao dijagnostičkih i prognostičkih biomarkera u nodularnom melanomu kože. MATERIJAL I METODE: Materijal su bioptički uzorci iz arhive Zavoda za patologiju i patološku anatomiju Medicinskog fakulteta u Rijeci. Istraživanu skupinu čini 110 uzoraka tkiva nodularnog melanoma dok kontrolnu skupinu čini 30 uzoraka tkiva složenih nevusa i 38 uzoraka tkiva displastičnih nevusa. Navedeni materijal je objedinjen u tkivne mikroareje koji su analizirani imunohistokemijskim bojenjema specifičnim na mEGFR, nEGFR te ciklin D1 kao i flourescentnom in situ hibridizacijom specifičnom za EFGR i CCDN1 gene. REZULTATI: Proteinska ekspresija nEGFR-a u NM uzorcima je statistički značajno manja od ekspresije u kontrolnoj skupini p=0,0337. NM uzorci su pokazali značajno veći udio polisomije kromosoma 7 te polisomije kromosoma 11 u usporedbi s kontrolnom skupinom p=0,0049. Utvrđen je veći udio snažne proteinske ekspresije mEGFR-a u NM uzorcima s manjom Breslow debljinom p=0,0426 te korelacija s pojavnošću ulceracije p= 0,0226. Kaplan-Meier metodom analize desetogodišnjeg preživljenja pacijenta utvrdili smo 2,76 puta veći rizik od kraćeg preživljenja za pacijente s prekomjernom mEGFR ekspresijom i 3,06 puta veći rizik od kraćeg preživljenja za pacijente s prekomjernom nEGFR ekspresijom. Međutim navedeni biomarkeri nisu potvrđeni kao samostalni prognostički čimbenici u multivarijatnoj analizi. ZAKLJUČAK: Naši rezultati ukazuju na važnu ulogu nEGFR-a u aktivaciji proliferacije u benignim melanocitnim lezijama, no čini se kako nEGFR ne sudjeluje u malignoj transformaciji melanocita. Proteinska ekspresija membranskog EGFR-a je povezana s pojavnošću ulceracije i kraćim preživljenjem pacijenata. Proteinska ekspresija nuklearnog EGFR-a također korelira s kraćim preživljanjem pacijenata. Iako ovi markeri nisu potvrđeni kao nezavisni prognostički čimbenici važno je dalje istražiti njihov utjecaj na biološko ponašanje nodularnog melanoma.AIM:Considering that nodular melanoma (NM) has a potential to show an early distant metastasis there is an urgent need for the discovery and evaluation of new diagnostic and prognostic biomarkers. We aimed to investigate protein expression of membrane and nuclear EGFR (mEGFR and nEGFR), cyclin D1 and the corresponding gene status in NM samples and correlate the obtained results with clinicopathological parameters and overall survival of patients. MATERIAL AND METHODS: 110 NM samples, 30 compound nevi and 38 dysplastic nevi were collected from the Department of Pathology, School of Medicine Rijeka. Collected biopsy material was integrated into tisssue microarrays and immunohistochemicaly stained for nEGFR, mEGFR and cyclin D1. Flourescence in situ hybridization specific analysis for EGFR and CCDN1 genes was also performed. RESULTS: nEGFR expression was significantly lower in the NM samples compared to the control group, p=0,0337. NM samples showed a significantly higher number of chromosome 7 and chromosome 11 polisomy than the control group p=0,0049. It was also observed that membrane EGFR 3+ NM samples presented ulceration significantly more often than membrane EGFR negative (0) NM samples. In univariate analysis, performed on 44 patients with follow-up data, both nuclear and membrane EGFR overexpression showed a correlation with a shorter overall survival. Nuclear EGFR (++,+++) showed 3,06 and membrane EGFR (2+,3+) showed 2,76 greater mortality risk compared to patients with low and negative nuclear and membrane EGFR expression (p< 0,05).However, neither of those markers was confirmed to be an independant prognostic marker in the multivariate analysis. CONCLUSION: Our results suggest an important role of nEGFR protein expressiom in benign melanocytic proliferation activation, but it seems that nEGFR is not involved in melanocyte malignant transformation. Membrane EGFR protein expression is associated with ulceration presentation and shorter overall survival. Nuclear EGFR protein expression is also associated with NM patients shorter overall survival . Although these markers were not confirmed as independant prognostic markers in multivariate analysis it is important to further evaluate their influence on nodular melanoma biological behaviour

Proteinska ekspresija i genska amplifikacija EGFR-a i ciklina D1 u nodularnom melanomu

CILJ ISTRAŽIVANJA: Budući da nodularni melanom(NM) inicijalno raste vertikalno te stoga naraste brzo i ima visoki metastatski potencijal potrebno je otkrivati i razvijati nove biomarkere koji bi se koristili u prognozi preživljenja pacijenata i diferencijalnoj dijagnostici navedenog tumora. Cilj ove studije je ispitati ulogu i značaj nuklearne EGFR (nEGFR), membranske EGFR (mEGFR) i ciklin D1 proteinske ekspresije, te EGFR i CCDN1 genske amplifikacije kao dijagnostičkih i prognostičkih biomarkera u nodularnom melanomu kože. MATERIJAL I METODE: Materijal su bioptički uzorci iz arhive Zavoda za patologiju i patološku anatomiju Medicinskog fakulteta u Rijeci. Istraživanu skupinu čini 110 uzoraka tkiva nodularnog melanoma dok kontrolnu skupinu čini 30 uzoraka tkiva složenih nevusa i 38 uzoraka tkiva displastičnih nevusa. Navedeni materijal je objedinjen u tkivne mikroareje koji su analizirani imunohistokemijskim bojenjema specifičnim na mEGFR, nEGFR te ciklin D1 kao i flourescentnom in situ hibridizacijom specifičnom za EFGR i CCDN1 gene. REZULTATI: Proteinska ekspresija nEGFR-a u NM uzorcima je statistički značajno manja od ekspresije u kontrolnoj skupini p=0,0337. NM uzorci su pokazali značajno veći udio polisomije kromosoma 7 te polisomije kromosoma 11 u usporedbi s kontrolnom skupinom p=0,0049. Utvrđen je veći udio snažne proteinske ekspresije mEGFR-a u NM uzorcima s manjom Breslow debljinom p=0,0426 te korelacija s pojavnošću ulceracije p= 0,0226. Kaplan-Meier metodom analize desetogodišnjeg preživljenja pacijenta utvrdili smo 2,76 puta veći rizik od kraćeg preživljenja za pacijente s prekomjernom mEGFR ekspresijom i 3,06 puta veći rizik od kraćeg preživljenja za pacijente s prekomjernom nEGFR ekspresijom. Međutim navedeni biomarkeri nisu potvrđeni kao samostalni prognostički čimbenici u multivarijatnoj analizi. ZAKLJUČAK: Naši rezultati ukazuju na važnu ulogu nEGFR-a u aktivaciji proliferacije u benignim melanocitnim lezijama, no čini se kako nEGFR ne sudjeluje u malignoj transformaciji melanocita. Proteinska ekspresija membranskog EGFR-a je povezana s pojavnošću ulceracije i kraćim preživljenjem pacijenata. Proteinska ekspresija nuklearnog EGFR-a također korelira s kraćim preživljanjem pacijenata. Iako ovi markeri nisu potvrđeni kao nezavisni prognostički čimbenici važno je dalje istražiti njihov utjecaj na biološko ponašanje nodularnog melanoma.AIM:Considering that nodular melanoma (NM) has a potential to show an early distant metastasis there is an urgent need for the discovery and evaluation of new diagnostic and prognostic biomarkers. We aimed to investigate protein expression of membrane and nuclear EGFR (mEGFR and nEGFR), cyclin D1 and the corresponding gene status in NM samples and correlate the obtained results with clinicopathological parameters and overall survival of patients. MATERIAL AND METHODS: 110 NM samples, 30 compound nevi and 38 dysplastic nevi were collected from the Department of Pathology, School of Medicine Rijeka. Collected biopsy material was integrated into tisssue microarrays and immunohistochemicaly stained for nEGFR, mEGFR and cyclin D1. Flourescence in situ hybridization specific analysis for EGFR and CCDN1 genes was also performed. RESULTS: nEGFR expression was significantly lower in the NM samples compared to the control group, p=0,0337. NM samples showed a significantly higher number of chromosome 7 and chromosome 11 polisomy than the control group p=0,0049. It was also observed that membrane EGFR 3+ NM samples presented ulceration significantly more often than membrane EGFR negative (0) NM samples. In univariate analysis, performed on 44 patients with follow-up data, both nuclear and membrane EGFR overexpression showed a correlation with a shorter overall survival. Nuclear EGFR (++,+++) showed 3,06 and membrane EGFR (2+,3+) showed 2,76 greater mortality risk compared to patients with low and negative nuclear and membrane EGFR expression (p< 0,05).However, neither of those markers was confirmed to be an independant prognostic marker in the multivariate analysis. CONCLUSION: Our results suggest an important role of nEGFR protein expressiom in benign melanocytic proliferation activation, but it seems that nEGFR is not involved in melanocyte malignant transformation. Membrane EGFR protein expression is associated with ulceration presentation and shorter overall survival. Nuclear EGFR protein expression is also associated with NM patients shorter overall survival . Although these markers were not confirmed as independant prognostic markers in multivariate analysis it is important to further evaluate their influence on nodular melanoma biological behaviour

Proteinska ekspresija i genska amplifikacija EGFR-a i ciklina D1 u nodularnom melanomu

CILJ ISTRAŽIVANJA: Budući da nodularni melanom(NM) inicijalno raste vertikalno te stoga naraste brzo i ima visoki metastatski potencijal potrebno je otkrivati i razvijati nove biomarkere koji bi se koristili u prognozi preživljenja pacijenata i diferencijalnoj dijagnostici navedenog tumora. Cilj ove studije je ispitati ulogu i značaj nuklearne EGFR (nEGFR), membranske EGFR (mEGFR) i ciklin D1 proteinske ekspresije, te EGFR i CCDN1 genske amplifikacije kao dijagnostičkih i prognostičkih biomarkera u nodularnom melanomu kože. MATERIJAL I METODE: Materijal su bioptički uzorci iz arhive Zavoda za patologiju i patološku anatomiju Medicinskog fakulteta u Rijeci. Istraživanu skupinu čini 110 uzoraka tkiva nodularnog melanoma dok kontrolnu skupinu čini 30 uzoraka tkiva složenih nevusa i 38 uzoraka tkiva displastičnih nevusa. Navedeni materijal je objedinjen u tkivne mikroareje koji su analizirani imunohistokemijskim bojenjema specifičnim na mEGFR, nEGFR te ciklin D1 kao i flourescentnom in situ hibridizacijom specifičnom za EFGR i CCDN1 gene. REZULTATI: Proteinska ekspresija nEGFR-a u NM uzorcima je statistički značajno manja od ekspresije u kontrolnoj skupini p=0,0337. NM uzorci su pokazali značajno veći udio polisomije kromosoma 7 te polisomije kromosoma 11 u usporedbi s kontrolnom skupinom p=0,0049. Utvrđen je veći udio snažne proteinske ekspresije mEGFR-a u NM uzorcima s manjom Breslow debljinom p=0,0426 te korelacija s pojavnošću ulceracije p= 0,0226. Kaplan-Meier metodom analize desetogodišnjeg preživljenja pacijenta utvrdili smo 2,76 puta veći rizik od kraćeg preživljenja za pacijente s prekomjernom mEGFR ekspresijom i 3,06 puta veći rizik od kraćeg preživljenja za pacijente s prekomjernom nEGFR ekspresijom. Međutim navedeni biomarkeri nisu potvrđeni kao samostalni prognostički čimbenici u multivarijatnoj analizi. ZAKLJUČAK: Naši rezultati ukazuju na važnu ulogu nEGFR-a u aktivaciji proliferacije u benignim melanocitnim lezijama, no čini se kako nEGFR ne sudjeluje u malignoj transformaciji melanocita. Proteinska ekspresija membranskog EGFR-a je povezana s pojavnošću ulceracije i kraćim preživljenjem pacijenata. Proteinska ekspresija nuklearnog EGFR-a također korelira s kraćim preživljanjem pacijenata. Iako ovi markeri nisu potvrđeni kao nezavisni prognostički čimbenici važno je dalje istražiti njihov utjecaj na biološko ponašanje nodularnog melanoma.AIM:Considering that nodular melanoma (NM) has a potential to show an early distant metastasis there is an urgent need for the discovery and evaluation of new diagnostic and prognostic biomarkers. We aimed to investigate protein expression of membrane and nuclear EGFR (mEGFR and nEGFR), cyclin D1 and the corresponding gene status in NM samples and correlate the obtained results with clinicopathological parameters and overall survival of patients. MATERIAL AND METHODS: 110 NM samples, 30 compound nevi and 38 dysplastic nevi were collected from the Department of Pathology, School of Medicine Rijeka. Collected biopsy material was integrated into tisssue microarrays and immunohistochemicaly stained for nEGFR, mEGFR and cyclin D1. Flourescence in situ hybridization specific analysis for EGFR and CCDN1 genes was also performed. RESULTS: nEGFR expression was significantly lower in the NM samples compared to the control group, p=0,0337. NM samples showed a significantly higher number of chromosome 7 and chromosome 11 polisomy than the control group p=0,0049. It was also observed that membrane EGFR 3+ NM samples presented ulceration significantly more often than membrane EGFR negative (0) NM samples. In univariate analysis, performed on 44 patients with follow-up data, both nuclear and membrane EGFR overexpression showed a correlation with a shorter overall survival. Nuclear EGFR (++,+++) showed 3,06 and membrane EGFR (2+,3+) showed 2,76 greater mortality risk compared to patients with low and negative nuclear and membrane EGFR expression (p< 0,05).However, neither of those markers was confirmed to be an independant prognostic marker in the multivariate analysis. CONCLUSION: Our results suggest an important role of nEGFR protein expressiom in benign melanocytic proliferation activation, but it seems that nEGFR is not involved in melanocyte malignant transformation. Membrane EGFR protein expression is associated with ulceration presentation and shorter overall survival. Nuclear EGFR protein expression is also associated with NM patients shorter overall survival . Although these markers were not confirmed as independant prognostic markers in multivariate analysis it is important to further evaluate their influence on nodular melanoma biological behaviour