Invasion In Cutaneous Melanoma Research Articles

The Dark Side of Melanin Secretion in Cutaneous Melanoma Aggressiveness.

Skin cancers are among the most common cancers worldwide and are increasingly prevalent. Cutaneous melanoma (CM) is characterized by the malignant transformation of melanocytes in the epidermis. Although CM shows lower incidence than other skin cancers, it is the most aggressive and responsible for the vast majority of skin cancer-related deaths. Indeed, 75% of patients present with invasive or metastatic tumors, even after surgical excision. In CM, the photoprotective pigment melanin, which is produced by melanocytes, plays a central role in the pathology of the disease. Melanin absorbs ultraviolet radiation and scavenges reactive oxygen/nitrogen species (ROS/RNS) resulting from the radiation exposure. However, the scavenged ROS/RNS modify melanin and lead to the induction of signature DNA damage in CM cells, namely cyclobutane pyrimidine dimers, which are known to promote CM immortalization and carcinogenesis. Despite triggering the malignant transformation of melanocytes and promoting initial tumor growth, the presence of melanin inside CM cells is described to negatively regulate their invasiveness by increasing cell stiffness and reducing elasticity. Emerging evidence also indicates that melanin secreted from CM cells is required for the immunomodulation of tumor microenvironment. Indeed, melanin transforms dermal fibroblasts in cancer-associated fibroblasts, suppresses the immune system and promotes tumor angiogenesis, thus sustaining CM progression and metastasis. Here, we review the current knowledge on the role of melanin secretion in CM aggressiveness and the molecular machinery involved, as well as the impact in tumor microenvironment and immune responses. A better understanding of this role and the molecular players involved could enable the modulation of melanin secretion to become a therapeutic strategy to impair CM invasion and metastasis and, hence, reduce the burden of CM-associated deaths.

Hematoxylin and eosin or double stain for CD34/SOX10: Which is better for the detection of lymphovascular invasion in cutaneous melanoma?

BackgroundLymphovascular invasion (LVI) is considered an unfavorable prognostic factor in cutaneous melanoma (CM). However, its detection by hematoxylin and eosin (H&E) is challenging, with discordant data about its association with clinical-pathological features and no previous studies investigating the inter- (IrOA) and intra-observer (IaOA) agreement. Herein, we tested H&E and double staining (DS) for CD34/SOX10 to detect the LVI in a cohort of 92 CMs, evaluating the IrOA, the IaOA, and the association with the other clinical-pathological features. MethodsFive authors independently evaluated 92 consecutive and retrospectively enrolled cases of CMs. We assessed the IrOA (Fleiss’s Kappa/FK and intraclass correlation coefficient/ICC) and the IaOA (Cohen’s Kappa/CK) with both H&E and CD34/SOX10. Furthermore, we compared the LVI assessment with the two stains and analyzed the association with other clinical-pathological features [χ2 tests for dichotomous and categorical data; Student t-test (normal distribution) and Mann-Whitney U-test (non-normal distribution) for continuous data]. ResultsThe IrOA was almost identical with H&E (FK=0.446; ICC=0.805) and CD34/SOX10 (FK=0.454; ICC=0.810); by contrast, the IaOA was higher with H&E for one pathologist (CK: 0.809) and with CD34/SOX10 for the other one (CK: 0.563). Applying previously defined criteria, LVI was detected in 10 (9.2%) and 11 (10.1%) cases with H&E and CD34/SOX10, respectively (p = 1.000). Both H&E and CD34/SOX10 were significantly associated with vertical growth phase (H&E, p: 0.014; CD34/SOX10, p: 0.010), mitosis ≥ 1/mm2 (H&E, p: 0.000; CD34/SOX10, p: 0.004), pT (H&E, p: 0.000; CD34/SOX10, p: 0.001), Breslow thickness (H&E, p: 0.000; CD34/SOX10, p: 0.001), and lymph node and/or distant metastasis (H&E, p: 0.005; CD34/SOX10, p: 0.000); only H&E was associated with ulceration (p: 0.002) and distant metastasis (p: 0.000), conversely, only CD34/SOX10 was associated with lymph node metastasis (p: 0.003). ConclusionsCD34/SOX10 does not improve the IrOA and the IaOA of the LVI assessment in CM; furthermore, H&E and CD34/SOX10 show a similar profile of association with the other unfavorable clinical-pathological features of CM. As result, CD34/SOX10 could be a redundant diagnostic tool if applied for the prognostic characterization of not-selected CM in a routine diagnostic scenario.

Multiple combinations of melanocytic and vascular endothelial markers enhance the detection rate of lymphovascular invasion in cutaneous melanoma.

Lymphovascular invasion (LVI) is believed to be the mechanism by which melanoma cells can disseminate to regional lymph nodes and distant sites and may be predictive of adverse outcome. Lymphovascular invasion often difficult to detect on hematoxylin-eosin (HE) stained sections, are readily identified with dual immunohistochemistry (IHC) for melanocytic and vascular markers. A total of 100 primary cutaneous malignant melanoma cases that had a Breslow thickness of 1-4 mm and lacked LVI by conventional HE assessment were included. We compared the LVI detection rates of double staining for CD31/S100 and CD34/S100, and D2-40/S100, and examined the association of LVI with clinical outcomes. The dual immunohistochemical positivity for CD31/S100, CD34/S100, and D2-40/S100 were 40(40%), 17(17%) and 35(35%), respectively. On multivariate analysis, LVI was an independent predictor of SLN status. Multivariate analysis revealed that LVI and male gender were independent risk factors for overall survival. The recognition of LVI is improved by dual IHC and predicts SLN metastasis. The detection of LVI using dual IHC, especially by a combination of CD31/S100 and D2-40/S100 is a useful step that inclusion should be recommended in basic evaluation parameters for cutaneous melanoma.

FOXD2-AS1 correlates with the malignant status and regulates cell proliferation, migration, and invasion in cutaneous melanoma.

Long noncoding RNA (lncRNA) FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) has been shown to be dysregulated in several types of human cancer. However, the role of FOXD2-AS1 in cutaneous melanoma was still unclear. In our study, FOXD2-AS1 expression has been found to be upregulated in cutaneous melanoma tissue specimens and cell lines compared with that in normal tissue specimens and normal human epidermal melanocyte, respectively. Furthermore, high expression of FOXD2-AS1 was obviously correlated with deep Breslow thickness, present ulceration, high Clark level and distant metastasis in cutaneous melanoma patients. However, there were no statistical associations between FOXD2-AS1 expression and cutaneous melanoma patients' disease-free survival and overall survival. The results of loss-of-function study showed that inhibition of FOXD2-AS1 suppresses cutaneous melanoma cell proliferation, migration and invasion through regulating phospho-Akt expression. In conclusion, FOXD2-AS1 is associated with clinical progression in cutaneous melanoma patients, and functions as oncogenic lncRNA in cutaneous melanoma cells.

Association between Patient’s Basic Characteristic and Clark Level in Cutaneous Malignant Melanoma

Background : Malignant melanoma is a cancer that begins in the melanocytes. Melanoma is commonly happened on older people, male and located on sun exposure body area, such as face, neck and lower limb. Melanoma cases occur less than 5% of skin cancer but cause a majority of skin cancer deaths because melanoma has an aggressive behavior. Age, sex, location of lesion, and type of melanoma influences the melanoma invasion. The cutaneous melanoma invasion could be assessed with the Clark level. This study is aimed to determine the association between patient’s basic characteristic and Clark level in cutaneous malignant melanoma. Methods : This study used cross sectional analytic design. The medical records and histopathology slide from the Department of Anatomic Pathology Dr. Hasan Sadikin General Hospital from 2008−2012 took as a sample. Forty one data were meet the inclusion criteria. Furthermore, those data were analyzed using chi-square test. Result : Overall, patient’s characteristic in this study, commonly occurred on female (66%), 50−59 years group age (35%), non-cephalic/acral location (71%), and the level V in Clark level (73%). Location of lesion showed an association with Clark level (p=0.023), whereas, age and sex was not significant (p=0.679 and p=0.389). Conclusions : There is an association between location of lesion and Clark level [AMJ.2017;4(1):25–9] DOI: 10.15850/amj.v4n1.1015

Prognostic significance of nestin in primary malignant melanoma of the oral cavity.

Several studies have examined the correlation between nestin expression and the degree of tumor invasion in cutaneous melanoma. However, no information has been reported on nestin in primary mucosal melanoma of the head and neck. The present study examined the expression and prognostic significance of nestin in patients with primary mucosal melanoma of the oral cavity. Nestin expression was examined immunohistochemically in 39 patients (six oral melanoma in-situ cases and 33 invasive oral melanoma cases) and analyzed for association with disease progression. Age, sex, anatomic site, stage, level of invasion, regional lymph node metastasis, surgical margin involvement, and treatment modality were also analyzed. In the 33 invasive melanoma cases, invasion depth correlated significantly with prognosis in univariate and multivariate analyses. High-intensity nestin staining was observed in 14 of the 33 cases and a high proportion of nestin-positive cells was observed in 16 cases. In stage III oral melanoma cases, nestin expression was not significantly associated with disease progression. However, in stage IV cases, both the intensity and the proportion of nestin expression were significantly associated with disease progression (P=0.022 and 0.005, respectively). In all 33 invasive cases, multivariate analyses showed that both the intensity and the proportion of nestin were significantly associated with a poor prognosis (P=0.014 and 0.009; hazard ratio, 3.59 and 4.05; 95% confidence interval, 1.29-9.98 and 1.42-11.56, respectively). In conclusion, nestin can be a valuable prognostic indicator in the advanced-stage (stage IV) cases of oral mucosal melanoma.

Elastic staining does not assist detection of venous invasion in cutaneous melanoma

The aim of the present study was to determine the benefit of orcein elastic staining of primary cutaneous melanoma specimens in detecting venous invasion. Primary cutaneous melanomas in vertical growth phase were assessed for vascular invasion. All tumour blocks were stained with haematoxylin and eosin (H&E) and orcein. The cases were reviewed by two pathologists. Vascular invasion was not identified more frequently on orcein stained slides than on H&E stained ones. Elastosis and periappendiceal elastic fibres interfered with vascular invasion detection with elastic staining. Based on our study, we conclude that elastic stains such as orcein do not improve the detection rate of venous invasion in primary cutaneous melanomas.

Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis

Sentinel lymph node (SLN) metastasis is a major determinant for staging, prognostication and clinical management of patients with cutaneous melanoma. However, the role of lymphatic vs. vascular invasion (VI) for SLN spread remains unclear. We compared the frequency of lymphatic invasion (LI) vs. VI in melanoma sections from 94 patients with a mean three-year clinical follow up using immunostains for the lymphatic endothelial markers D2-40 (podoplanin) and LYVE-1 and the panvascular marker CD31. LI occurred more frequently than VI (16 vs. 3%, respectively, p = 0.001) and correlated with higher American Joint Committee on Cancer stage at diagnosis (p = 0.0004). In a univariate analysis, LI was strongly associated with SLN metastasis (p = 0.008), independent of tumor thickness. In a multivariate analysis, LI was not a significant risk factor for SLN metastasis. The presence of intratumoral lymphatics (ITLs) was associated with distant metastasis, whereas VI was rare and did not correlate with SLN or distant metastasis. A combination of LI and ITL had higher positive and negative predictive values for the risk of developing SLN metastasis compared with routine histology and VI. Detection of LI in the primary tumor may aid in identifying melanoma patients with the propensity to develop SLN metastasis.

Penetration of human metastatic melanoma cells through an authentic dermal-epidermal junction is associated with dissolution of native collagen types IV and VII.

The events occurring during the penetration of melanoma cells through the dermal-epidermal junction, which is the first crucial step in the process of metastasis, are poorly understood, partly because no suitable tissue models exist. In the in vitro model reported here, two melanoma clones (T1C3, which generates lung metastases in experimental animals, and IC8, which does not) derived from a single parental cell line were co-seeded with normal allogenic keratinocytes onto acellular human de-epidermized dermis with preserved intact basement membrane and cultured for up to 1 month at an air-liquid interface. Histological, immunohistochemical and ultrastructural studies showed that melanoma cells from the metastatic clone (T1C3), but not from the non-metastatic clone (IC8), penetrated the dermal-epidermal junction to invade the dermis after 3 weeks of culture. Local invasion was associated with the dissolution of the native epidermal basement membrane collagens type IV and VII. Confocal laser scanning microscopy analysis demonstrated that numerous T1C3 cells were able to colonize the interstitial dermis and to rapidly penetrate empty dermal cavities. Our model represents a significant technical advance over others currently available since: (i) the organized three-dimensional architecture of the native dermal-epidermal junction is preserved; (ii) the active invasion process coincides with the dissolution of native components of the epidermal basement membrane, i.e. collagen types IV and VII; and (iii) the ability of melanoma cells to cross the dermal-epidermal junction correlates with their metastatic potential. This model provides a valuable tool for the study of the time-course of the cellular and molecular events that occur during the earliest steps of invasion in cutaneous melanoma. It also offers new opportunities to study the possible role of the keratinocyte environment in melanoma invasion.

Problems in the measurement of tumor thickness and level of invasion in cutaneous melanoma

Problems in the measurement of tumor thickness and level of invasion in cutaneous melanoma