The frequency of MM among all skin cancers is 3-5%. It is responsible for 75% of deaths due to skin cancers and 1-2% of deaths due to all cancers 1-3, 20. It is stated that the incidence of whites in industrial countries has increased significantly in the last two decades, and nowadays its incidence has stabilized and even decreased. The incidence of melanomas is highest in Northern Australia. There are 42.89 new cases per 100,000 in women and 55.8 new cases in men every year. This rate is 8 in England, 24.4 in South Africa and 4.9 in Scotland. While the lifetime risk of melanoma development was 1 in 120 in the USA in 1987, this rate was reported as 1 in 75 in 2000 21.
In a study conducted in Germany, the number of cases documented annually increased by 53.2% between 2002 (N = 4779) and 2011 (N = 7320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011 compared with a negative trend for stage UICC II. No trends were found for UICC III and IV stages, respectively 22.
Survival rates increase in patients with melanoma, as patients present earlier and with thinner melanoma. Five-year survival rates have been reported at 85% or more in women and 75% in men. Again, in another cohort analysis of 4791 patients diagnosed with primary CMM between 1976 and 2001 in southern Germany, primary CMM diagnosis during 1990-2001 was associated with a more favorable 10-year survival (88.6% versus 80.0%, P <.0001) compared with 1976-1989. Median tumor thickness at primary diagnosis was significantly lower in the second period (0.75 mm vs 1.07 mm, P <.0001). That is, tumor thickness has been found to be a dominant prognosis determinant 23.
In the study, the number of patients with ulcers (66%) and the number of cases with Breslow thickness ˃4 mm (53%) were higher in MMMs compared to CMMs. This situation may be associated with the worse prognosis in MMMs compared to skin melanomas.
In MMMs, there are many prognostic factors other than tumor thickness that have different importance. These are histological type, ulceration, mitotic index, presence of satellites, angiolymphatic invasion, advanced stage, occult metastases, local recurrence, Clark invasion depth, location, accompanying nevus, lymphocytic infiltration, regression, nuclear volume, sex, vitiligo, age and can be counted as pregnancy 1-3, 24.
Also, risk factors for MM development include hair and skin color, the presence of multiple freckles, PUVA therapy, the presence of multiple large atypical nevi, genetic factors (CDK2A and CDK4 mutations), xeroderma pigmentosum, immunosuppression, chemicals, oil, and exposure to printer products. involves trauma (for subungual melanoma) and burns counted 1-3.
According to AJCC staging, three important histopathological criteria are Breslow thickness, ulcer and mitotic index (25). Age, gender, and anatomic location of the primary tumor that are not included in the AJCC system also affect the survival of primary MM cases (26,27). When these factors are combined with histopathological features, they show a better prognosis than AJCC system 24.
Since the late 1980s, immunohistochemistry markers such as Ki-67, c-Kit, MMPs, metallothionein, bcl-2, which contributed to the determination of treatment protocols, were added to these criteria (4-18). In this study, the number of cases with a high Ki-67 index (66%) was found to be higher in MMM cases compared to the CMM group. This situation may be associated with a worse prognosis in MMMs compared to skin melanomas.
c-Kit (CD117) is a tyrosine-kinase receptor typically found in GISTs and is also associated with the function and proliferation of melanocytes 28.
Gonzalez et al. showed that melanoma expresses c-kit, a gastrointestinal stromal tumor marker, but has not been extensively evaluated for protein kinase Cθ (PKCθ) or DOG1, and these stains have not been associated with prognostic factors. They immunostained 62 primary cutaneous and 15 metastatic melanomas for polyclonal c-kit (pc-kit), monoclonal c-kit (mc-kit), PKCθ, and DOG1, and correlated the results with prognostic parameters and survival. 34 (55%) of cutaneous melanomas were stained for pc-kit, 30 (48%) for mc-kit, 11 (18%) for PKCθ, and 2 (3%) for DOG1 29.
Went et al. investigated C-KIT (CD117) expression in various tumors. For this purpose, the positivity of KIT in 28 of 28 GIST cases, 42 of 50 seminomas, 34 of 52 adenoid cystic carcinomas, 14 of 39 MM, 8 of 47 large cell carcinomas of the lung, as well as 47 other tumors. In addition, they investigated the KIT gene mutation in the same patient group. Among these cases, KIT gene mutation was found in 6 of 12 GIST cases analyzed and only 1 of 24 other tumors. Thus, it is important that they have shown that KIT gene mutation is rare in cases with c-Kit positivity due to IHC 30. Ni et al. also reported that 7 out of 40 anorectal melanoma cases had a c-kit mutation, whereas 16 of 40 cases had CD117 expression, and 3 of these 16 cases also found c-kit mutations 31. In the study of Alessandirini et al., C-KIT stains were documented in 48% of melanomas, 50% of PAMs and 24% of nevi. The mean score of KIT staining in the melanomas/PAMs group was significantly different from nevi (p=0.0076). No statistically significant differences were detected between either c-kit immunostaining score or pattern and each of the other clinico-pathologic parameters considered. No KIT gene mutations were detected in melanomas and nevi. A silent mutation/polymorphism in KIT exon 13 was found in one PAM 32.
Liu et al. investigated c-Kit and Sox10 expressions in 28 patients with sinonasal mucosal melanoma, and determined c-Kit expression in 24 patients, therefore they emphasized that c-Kit expression may be useful in the regulation of treatment. However, they also stated that Sox10 is a sensitive determinant in SSMs 33. In the study, c-Kit expression was detected in all conjunctival MM's. In addition, C-KIT expression was found in all but 3 of 11 nonconjunctival cases in the MMM group.
Weinlich et al. investigated the relationship between MT overexpression and prognostic factors in their second study, which included 1270 cases in 2006. While MT overexpression was determined in 310 cases (24.4%), MT was found negative in 960 cases (75.6%). The female / male ratio (51% / 49%) of the patients were close to each other, and the mean age at which lesions were excised was 54 years (7-95). During their follow-up, it was found that the disease progressed in 167 cases and death due to metastatic disease occurred in 110 cases. MT overexpression was detected in 117 of 167 cases and 80 of 110 cases in these groups. The proportion of MT positive melanomas increases with greater Clark invasion depth and Breslow thickness17. Accordingly, they also investigated whether MT overexpression was an independent prognostic factor or only a parameter correlated with increasing degree of invasion or tumor thickness. For this purpose, they found that MT overexpression was significant in a statistical model for disease progression (p <0.001). In conclusion, MT overexpression is a strong, highly significant factor independent of tumor thickness, and determines and measures the risk of disease progression.
Weinlich et al. recently investigated the role of MT overexpression in sentinel lymph node biopsies in melanoma progression in 158 cases in 2007, and determined that metastases developed in 28 patients (17.7%), and 17 (10.7%) died from disseminated disease; demonstrated that the results support the validity of MT overexpression as a useful prognostic marker in patients with primary melanoma18. In the study, the number of cases with MT expression <10% was found to be higher in the skin and extradermal group than the cases with MT overexpression. However, most of the MT negative cases were histologically of NM type and Breslow thickness was higher. In addition, in the MMM group, in patients with low MT expression, ulcers were observed at a higher rate. These findings oft he study can be interpreted as indirectly, that the loss of MT expression indicates a serious prognosis, albeit a little.
Espindola and Corleta detected 74.3%, 85.7%, and 82.4% bcl-2 expression in lymph node, subcutaneous and visceral metastases, respectively, but after univariate and multivariate analyzes, positive bcl-2 expression and overall survival for the types of metastases evaluated were no correlation was found (13). In our series, bcl-2 expression among CMMs, 10 cases (33.3%) with <5% staining, 6 cases (20.0%) with 5-50% staining and 14 cases (46.7%) with ˃50% expression was found. Also, among MMMs, 6 cases (40.0%) with <5% staining and 9 cases (60.0%) with 50% staining were determined. There were no cases showing 5-50% expression in MMMs. When CMM and MMMs were compared in terms of bcl-2 expression, the difference was found to be statistically insignificant (p˃0.05).
Väisänen et al. in their CMM series of 157 cases, investigated the effect of MMP-2 expressions on Ki67 and p53 expression as well as survival, overexpression of the MMP-2 protein and high metastatic potential melanomas characterized by Ki67 and low MMP-2. They founded overexpression of the matrix metalloproteinase 2 protein in conjunction with overexpression of Ki67 characterized melanomas with high metastatic potential and was associated with declined survival with a 10-year disease-specific survival of 33% compared with 85% in the cases with low matrix metalloproteinase-2 and low Ki-67 levels (p = .002). Similarly, in cases with overexpression of matrix metalloproteinase-2 and a positive immunoreaction for p53, the 10-year disease-specific survival was only 42% compared with 80% in patients with matrix metalloproteinase-2 less than 20% and a negative immunostaining for p53 (p < .001). The presence of all 3 adverse prognostic factors was prognostically more significant than any marker alone with a 10-year survival of only 28%. This combination of determining matrix metalloproteinase 2, Ki67, and p53 immunoreactive proteins could be beneficial in the selection of high-risk melanoma patients for future adjuvant trials (9). In our series, 7 cases (24.1%) with <5% MMP-2 expression in their CMMs, 6 cases (20.7%) with 5-20%, 4 cases (13.8%) with 21-50% and 12 cases with 50% (% 41.4) was determined. There were no cases with MMP-2 expression rate <5% and 5-20% in MMMs. 7 cases (46.7%) with 21-50% staining and 8 cases (53.3%) with 50% staining were identified. When compared in terms of MMP-2 expression, the difference between two groups was found to be statistically significant (p <0.05).
As a result, when the CMM and MMM groups were compared, the difference between them was statistically significant in staining with Ki-67 and MMP-2, while staining with c-Kit, MT and bcl-2 was statistically insignificant. It was thought that high MMP-2, c-Kit, bcl-2 expressions and high Ki-67 index as well as MT expression loss were thought to be associated with poor prognosis when evaluated with associated histological prognostic factors. However, in order to precisely determine the prognosis of MMs and to determine more effective treatments, larger case series should be followed with molecular pathology studies.