Multivariate Regression Analysis Of Several Bio-markers And Clinical Characteristics In The Prognosis Of Malignant Melanoma

Background:Malignant melanoma (malignant melanoma MM) is a kind of skin tumor caused by excessive proliferation of abnormal black element cell. Its incidence differs from different ethnic,、regional、race. The incidence of whites is far higher than blacks. The whites live in Queensland, Australia, whose incidence is as much as17/10. Although malignant melanoma skin accounts for only5%of all skin malignant tumor, but the skin cancer deaths in patients with malignant melanoma of more than75%. Malignant melanoma is a kind of highly fatal cancer.MM happen primarily mostly since But malignant transformation of long-term pigment skin lesions is not rare in the clinical. Progression caused by trauma, rubbing, laser, frozen, chemical mordants always happen. Primary MM performance skin nodular or radioactive growth lesions. Can be tan, brown, blue, pink or black, normal skin texture disappear, the edge can be indented, lesions can show local uplift, occur secondary ulcer、bleeding or pain, satellite nodules can appear terminally. The following circumstances indicate early malignant alteration of pigment skin lesions: color change; uneven margins; lesions uplift; short-term rapid increases; surface not smooth, take off bits, drainage, hemorrhage; Local pain.In recent decades, the incidence of MM continuously increases. According to statistics, the new MM cases in United States in2008is64280. including8420cases of death. However, the number is too conservative, because a lot of shallows and carcinoma in situ are not counted. MM grows the most fastly in men’s malignant disease, secondly only to lung cancer in women. Peoples born in2000likely happen MM1/58in men while1/82in women. MM happens in men and women respectively the fifth and sixth of all the malignant diseases, secondly only to adult leukemia according to the risk of death. The median age of onset is45to55years old. high risk factors relate to MM including clear family history、melanoma history、multiple atypical or dysplastic mole、congenital genetic mutations.besides internal causes, the sun may also push it happening which more easily in whites.however,MM happens under every condition.The reasons of increasing incidence of MM in our country include (1) estrogen drugs abuse;(2) immunodeficiency;(3) Atmospheric pollution;(4) Chemical skin pollution;(5) Lack of knowledge, insufficient attention. The mortality of advanced MM is large, unfortunately most patients diagnosed too late in our country.So that is a urgent problem:how to diagnose correctly in time and set a individual treatment?Diagnosis is not difficult for pigment MM which is different from other tumor in color. On the contrary, lack of typical clinical and pathological features, early diagnosis is relatively difficult for nonpigment MM. Immunohistochemical tests may help.Commonly used immunohistochemical biomarkers for diagnosis are HMB45、 S-100and Vimentin. HMB45is a monoclonal antibody related to antigen of MM which have highly specificity(>90%) and certainly sensitivity. S-100protein is also a good diagnosis biomarker with sensitivity, but specificity is poor. Vimentin is highly express in MM rate, but lack of specificity.The numbers of MM cases worldwide are increasing faster than any other cancers. The incidence of MM was occurring at a faster rate than for most neoplasm worldwide, and melanoma metastasis is still the most formidable problem. So it is necessarily to find some biomarkers associated with melanoma metastasis and prognosis. MM is characterized by its intensive metastasis, therapy-resistant and high mortality. One person dies per hour from metastatic melanoma. Hence tremendous research efforts have been thrown into seeking some biomarkers of metastasis and prognosis forecasting for melanoma. Some studies have revealed several putative genes and molecular markers associated with melanoma metastasis.Many clinical pathological factors and molecular biomarkers relate to the prognosis of MM. Tumor thickness, ulceration, tumor location, pathology classification and the sentinel lymph node (sentinel lymph node biopsy SLNB) are considered as the independently prognostic factors. Besides, Age, Clark classification, margins, AJCC stages, numbers of lymph node metastasis, LDH value, S-100protein level also be regarded as the prognostic factors.S-100protein, a pronounced diagnosis index, was reported that associated with nodal tumor load, and when elevated, predicts a shorter DFS.It is reported that S100B is a prognostic factor for melanoma as elevated levels correlate with disease progression and poor outcome. Also S100A13may represent a new angiogenic and prognostic marker in melanomaVimentin, a major constituent of the intermediate filament family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Vimentin is over-expressed in various epithelial cancers. The aberrant immunohistochemical expression of vimentin in primary melanoma tissues may help to call attention for patients with high risk of hematogenous metastasis. That might be as a novel metastatic indicator for melanoma. In a word, vimentin is not only the diagnostic marker but also the hematogenous metastasis predictor for melanomas clinically.By virtue of its over-expression in cancer and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy; however, more research would be crucial to evaluate its specific role in cancer.Melanoma metastasis is the most insidious and life-threatening. To identify the metastasis-associated biomarkers may help to provide risk assessments and personal therapeutic strategies for melanoma patients. The earlier detection such accurate biomarkers in the primary tumors, the better prognosis and interventional treatments would patients have. Till now, there have been a number of researches focusing on detecting the metastatic biomarkers for melanoma by using the proteomics methodologies. So far, the research of clinical pathological factors and molecular markers relevant to the prognosis of MM has not yet get a clear consensus.Objective:After decades of research, the prognosis of MM have a large degree of progress but still poor,especially for the advanced cases(OS<1year).Prior research considered that tumor thickness; Lymph node metastasis; Age and gender; primary site; therapy methods, serum LDH value are relevant to prognosis. With the development of the modern molecular biology, researchers have realized that several molecular biomarkers playing important roles in tumor growth and metastasis. Whether S100, HMB45and Vimentin influence the tumor prognosis is still obscure. The relationship between prognosis of MM and several clinical pathological and molecular factors would be investigated in this study. Methods:1. Collecting materials, following-up the prognosis, calculating survival time (from surgery day to the date of death or late November2011).2. Settling the data, classifying the date by age, gender, primary situ, ulceration, margins, Clark classification, AJCC stages, SLNB and transfer numbers, therapy methods and effects.3. Immunohistochemical staining was performed using the avidin-biotin peroxidase complex (ABC) method, according to the manufacturer’s instructions.4. Statistical methods:127cases’ clinical pathological features and molecular bio-makers were analysed by univariate and multivariate regression. All data were treated with SPSS13.0, P<0.05was represented statistically significant.Results:1. Overall survival time:a complete follow-up was done to all the cases, follow-up time is1-138months, the median OS is36.00months, including72death cases (56.7%). The OS of127cases is36.00months. The survival rates for one, three and five years are respectively79%,50%and40%.2. Univariate regression of127cases’ clinical pathological features and molecular bio-makers results:age,、ulceration,、Clark classification,、margins,、AJCC stages、therapy and curative effect、S-100protein level are relevant to prognosis(P<0.05); gender、primary site、SLN and lymph node metastasis number、vimentin、 HMB45have no correlation with the prognosis of MM (P>0.05).3. Multivariate regression of127cases’ clinical pathological features and molecular bio-makers results:age、Clark classification、margins,、effect and S-100protein are independent prognosis factors of MM.4. Immunohistochemical results:in127cases’ tumor tissue,10cases express negative(-) for S-100protein, while57cases of weak positive (+),35cases of medium positive (++),25cases of strong positive (+++); related to Vimentin protein28cases express negative (-),80cases of weak positive (+),11cases of medium positive (++),8cases of strong positive (+++);13cases express negative (-) for HMB45protein,82cases of weak positive (+),22cases of medium positive (++),10cases of strong positive (+++). The positive expression rates of S-100, Vimentin and HMB45are respectively92.1%,78.0%and89.8%.Conclusions:1. The median OS of127cases is36.00months, the survival rates for one, three and five years are respectively79%,50%and40%which indicate the poor prognosis of MM.2. In this study, age, ulceration, Clark classification, margins, AJCC stages, therapy and curative effect are relevant to the prognosis of MM.Age,Clark classification,Curative effect and margins are independent prognostic factors for MM which is consistent with many present research results. The result that ender, primary situ, SLN, lymph node metastasis number having no correlation with the prognosis of MM may due to the small sample size. More research need to be done about the relationship to the MM’s prognosis.3. Immunohistochemical experiment results that the positive expression rates of S-100, Vimentin and HMB45are respectively92.1%,78.0%and89.8%which indicate the importance to the diagnosis of MM. Accordance to the present research our statistical analysis results that S-100protein is the independent prognosis factor. Vimentin has no correlation to the prognosis in our study may due to non-classifying the ways of tumor metastasis.Several research have showed that over-expression of vimentin was frequently observed in primary melanoma patients with hematogenous metastasis, not associated with lymph node metastasis.By virtue of its over-expression in cancer and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy; however, more research would be crucial to evaluate its specific role in cancer.4. In the present,only the serum LDH levels affect AJCC stage.It has indicated that S100-B could be used as a prognostic marker in the stratification of new adjuvant trials to select stage Ⅲ patients for adjuvant systematic treatment.For stage ⅡB/Ⅲ whether serum S100B were useful in predicting the prognosis is come up. The search for melanoma biomarkers is crucial, as the incidence of melanoma continues to rise. New serum biomarkers of melanoma progression and metastatic disease are still awaited in order to provide efficient rationale for followup and treatment choices. Our study shows that S100protein is a independent prognostic factor for MM,and micro-array technology and proteomic research will surely provide new candidates such as S-100in the near future allowing more accurate definition of the individual prognosis and prediction of the therapeutic outcome and select patients for early adjuvant strategies.5. Melanoma treatment represents a challenge to oncologists due to its aggressive course and early and multiple metastases. Surgical excision of lesions is a highly effective intervention, but only in early stages. In contrast, median survival of patients with metastatic melanoma is still below one year. With the rapid development of tumor immunology, and molecular biology technology, adoptive immunotherapy, biochemistry therapy, cancer vaccine have shown sound application prospect. Immunogenicity of tumour cells, immuno-modulation and direct targeting of signal pathways are promising avenues and matter of dated and innovative research in melanoma.High-dose interleukin-2for1year allowed to do in Ⅱ b (including Ⅱ b) patients. Recent advances in molecular pathogenesis and the availability of targeted therapies have produced several positive results. In2011the FDA and EMA have approved new drugs, ipilimumab and vemurafenib, that might be a major breakthrough in treating patients with advanced melanoma.Administration of multi-agent regimens and high-dose interleukin-2is complex and associated with significant toxicities.Therapy should be restricted to an institution with medical staff experienced in the administration and management of regimens.Trials investigating combinations of these novel agents with existing immunomodulators are at present underway.