Role of immunohistochemistry in the diagnosis and staging of cutaneous squamous-cell carcinomas (Review).

Non-melanoma skin cancer (NMSC) is the most common type of neoplasm affecting Caucasian individuals, with squamous-cell carcinoma (cSCC) being the second most common type of NMSC after basal-cell carcinoma. The immunohistochemical study of cSCC is of particular importance, especially for the diagnosis of its rare forms, for which accurate and early diagnosis is crucial for survival. In the present review of the literature, the potentially significant value of immunohistochemical markers were highlighted to more accurately assess the biological behaviour, the prognosis of cSCC and to optimize case management. The immunohistochemical markers were classified from a pathophysiological point of view in order to present the mechanism by which carcinogenesis occurs with its subsequent evolution and therefore, to develop a more accurate novel risk staging criteria for this type of neoplasm.

MLH1, BRAF and p53 - searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions.

BACKGROUND AND AIM: Colonic serrated lesions are premalignant lesions, using an alternative malignization pathway, including multiple genetic and epigenetic alterations, as: mismatch repair deficiency due to MutL homolog 1 (MLH1) promoter methylation, tumor protein p53 (TP53) mutations, activating mutations of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Our study aims to evaluate MLH1, BRAF and p53 immunohistochemical (IHC) status in sessile serrated lesions (SSLs), with and without dysplasia. MATERIALS AND METHODS: This is a retrospective case-control study including 20 SSLs with dysplasia and 20 SSLs without dysplasia (matching sex and age). IHC expression of MLH1, BRAF and p53 was evaluated as the percent of nuclear loss of MLH1, cytoplasmic positivity of BRAF and nuclear positivity of p53. Data concerning age, sex, localization of the lesion, dysplasia and IHC results were statistically processed using Microsoft Excel. RESULTS: We had very polymorphous patterns of IHC expression for BRAF, MLH1 and p53, especially in the dysplastic group. Thus, two patients were BRAF+∕MLH1-∕p53+, three were BRAF+∕MLH1-∕p53-, one was BRAF+∕MLH1+∕p53- and six were BRAF+∕MLH1+∕p53+. Dysplastic lesions without BRAF mutation exhibited the following phenotype: one case BRAF-∕MLH1-∕p53+, four BRAF-∕MLH1-∕p53- and three BRAF-∕MLH1+∕p53+. In the control group (SSLs without dysplasia), there was a more homogenous distribution of cases: eight cases BRAF+∕MLH1+∕p53-, seven BRAF-∕MLH1+∕p53-, one BRAF-∕MLH1-∕p53+, two BRAF-∕MLH1-∕p53- and two BRAF-∕MLH1+∕p53+. CONCLUSIONS: There are more routes on the serrated pathway, with different mutations and time of acquisition of each genetic or epigenetic lesion with the same morphological result. These lesions should be stratified according to their risk to poor outcome and their need to further surveillance.

Tumor Microenvironment in Diffuse Large B-Cell Lymphoma: Role and Prognosis.

Diffuse large B-cell lymphoma (DLBCL) represents 30-40% of all non-Hodgkin lymphomas (NHL) and is a disease with an aggressive behavior. Because about one-third of DLBCL patients will be refractory or resistant to standard therapy, several studies focused on identification of new individual prognostic and risk stratification biomarkers and new potential therapeutic targets. In contrast to other types of cancers like carcinomas, where tumor microenvironment was widely investigated, its role in DLBCL pathogenesis and patient survival is still poorly understood, although few studies had promising results. The composition of TME and its interaction with neoplastic cells may explain the role of several genes (beta2-microglobulin gene, CD58 gene), receptor-like programmed cell death-1 (PD-1) and its ligand (PD-L1), or other cell components (Treg) in tumor evasion of immune surveillance, resulting in tumor progression. Also, it was found that "gene expression profile" of the microenvironmental cells, the phenotype of tumor-associated macrophages (TAM), the expression of matricellular proteins like SPARC and fibronectin, the overexpression of several types of matrix metalloproteinases (MMPs) like MMP-2 and MMP-9, or the tissue inhibitors of matrix metalloproteinases (TIMPs) may lead to a favorable or adverse outcome. With this review, we try to highlight the influence of microenvironment components over lymphoid clone progression and their prognostic impact in DLBCL patients.

Matrix metalloproteinases expression in lentigo maligna∕lentigo maligna melanoma - a review of the literature and personal experience.

Cutaneous melanoma is the most aggressive type of skin cancer, with high invasive potential. Lentigo maligna melanoma (LMM) is a relatively rare type, accounting for about 10% of all melanomas, while the most common subtype of melanoma on the face, typically on chronically sun-exposed skin of elderly people. Its in situ stage is lentigo maligna (LM). During the process of transformation from LM to LMM, tumor cells secrete or induce the release from neighboring cells of large amounts of matrix metalloproteinases (MMPs) that degrade the extracellular matrix. Some MMPs, as MMP3 and MMP9 expressed melanoma cells is associated with statistical significance in both in vitro and in vivo studies, with an invasive phenotype. Unfortunately, there is scarce data published about MMPs expression in LM∕LMM, as majority of research on melanoma refer to superficial spreading and nodular melanoma. Our personal, unpublished yet fully data is an attempt to complete a specific panel of immunohistochemical markers that could explain the slow growing rate of LMM.

CEACAM1: Expression and Role in Melanocyte Transformation.

Metastases represent the main cause of death in melanoma patients. Despite the current optimized targeted therapy or immune checkpoint inhibitors the treatment of metastatic melanoma is unsatisfactory. Because of the poor prognosis of advanced melanoma there is an urgent need to identify new biomarkers to differentiate melanoma cells from normal melanocytes, to stratify patients according to their risk, and to identify subgroups of patients that require close follow-up or more aggressive therapy. Furthermore, melanoma progression has been associated with the dysregulation of cell adhesion molecules. We have reviewed the literature and have discussed the important role of the expression of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in the development of melanoma. Thus, novel insights into CEACAM1 may lead to promising strategies in melanoma treatment, in monitoring melanoma patients, in assessing the response to immunotherapy, and in completing the standard immunohistochemical panel used in melanoma examination.

Dendritic cells in melanoma - immunohistochemical study and research trends.

Cutaneous dendritic cells play multiple physiological roles and are involved in various pathophysiological processes. Research studies of dendritic cells abound in the medical literature. Nevertheless, the role of dendritic cells in melanoma regression phenomenon is not completely understood. We conducted a scientometric analysis in order to highlight the current state on research regarding dendritic cells and melanoma. We also performed an immunohistochemical study, using specific markers for dendritic cells (CD1a, langerin). We evaluated the frequency and distribution of dendritic cells in areas of tumor regression compared to the areas of inflammatory infiltrate of melanoma without regression. The immunohistochemical study we performed revealed that dendritic cells are more frequent in the regressed areas, comparing with non-regressed ones. In regressed areas, dendritic cells have a predominant nodular pattern (19 cases), followed by diffuse isolate pattern (eight cases) and mixed pattern (diffuse and nodular) (three cases). In melanoma without regression, most cases presented a diffuse pattern (27 cases) of dendritic cells distribution. In conclusion, our immunohistochemical study stressed differences between frequency and distribution of dendritic cells located in the melanoma with regression and melanoma without regression. These data suggest that dendritic cells are involved in the regression phenomenon. Following the literature analysis we obtained, we observed that dendritic cells profile in melanoma with regression was poorly studied. Insights into antitumor immune response and dendritic cells may be essential for the understanding of the potential prognostic role of dendritic cells in melanoma and for the development of new promising therapeutic strategies for melanoma.

Morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results.

Halo (Sutton's) phenomenon has been described as a depigmented halo that is associated most commonly with acquired melanocytic nevi; but it may be associated with various types of melanocytic skin tumors, melanoma being the most concerning. Different authors have been preoccupied with elucidating morphological features of melanocytic tumors associated with a depigmented halo. We reviewed the literature and discussed the main features of melanocytic halo tumors regarding histopathological, immune microenvironment profile and dermatoscopic appearance. We highlighted similarities and differences between Sutton's nevus and halo melanoma, also presenting relevant aspects of our results. Depigmented halo must be regarded as a phenomenon that may be associated with different types of melanocytic tumors and with a broad spectrum of histopathological atypia degree. Certain correlations between the shape, diameter, symmetry observed in clinical examination, histopathological appearance, dermatoscopic aspect of peritumoral halo and central tumor type could not be established due to insufficient data and contrasting results. Further studies are expected to add valuable information regarding the depigmented halo tumors features.