Melanoma is increasing in incidence. However, survival outcomes can vary widely even within the same stage and the same histotype. Current American Joint Committee on Cancer¿s (AJCC) staging for cutaneous melanoma is based on primary tumor thickness and presence of ulceration, mitoses, nodal spread, and distant metastases as determinants of prognosis. Given the clinical and biological heterogeneity of primary melanoma, new prognostic tools are needed to more precisely identify the patients most likely to develop advanced disease.
Inflammation plays a central role in melanoma microenvironment changes. In addition, miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. miRNAs also strongly act on some components of the immune system, regulating the activity of key elements such as antigen presenting cells, and can facilitate an immune evasive/suppressive phenotype. Understanding the reciprocal coevolution of melanoma and immune cell phenotypes during disease progression and in response to therapy is a prerequisite to improve current treatment strategies. Such tools would affect clinical surveillance strategies and aid in patient selection for adjuvant therapy.
Here, we propose to study the inflammatory microenvironment and expression of specific microRNAs in primary melanoma and sentinel limph node as prognostic factors to differentiate lesions with high and low malignant potential. To accomplish this task, we sought to analize a group of about 100 primary melanomas and 50 sentinel lymph nodes to correlate specific alterations in inflammatory cytokine/chemokines and miRNAs expression with tumor progression. We will use a combined approach of real time PCR assays to detect both mRNAs and miRNAs as well as in situ immunohistochemistry techniques on paraffin-embedded sections to detect inflammatory cyto-/chemokines.
By organizing the project in such a way, we hope to provide researcher with a clearer top-down view, enabling the identification of missing knowledge to guide future analysis of inflammation signature and miRNA detection possibly useful as additional biomarkers in the melanoma clinical management.
The incidence of malignant melanoma (MM) has drastically increased in the past decades. Approximately 70 % of new cases of MM are thin melanomas (TM), which are lesions of 0,8 mm in Breslow thickness. In the absence of other risk factors (such as ulceration and/or mitotic rate C1/mm2 ), TM present a 10-year survival rate of 96 %; however, it is known that a portion of this group could develop recurrences and die. In this regard, some authors propose the use of sentinel lymph node biopsy (SLNB) for primary lesions of 0,8 mm (sometimes 1 mm if ulceration, regression or mitosis are present), but the universal application of SLNB would expose a large number of low-risk patients to the morbidity related to the procedure. Some centers have tried to select patients with TM at risk to disease progression according to several parameters, but these factors varied from series to series. Therefore, we have analyzed our casistic of patients with TM to record the percentage of disease progression and put in evidence any significant predictive factor, if present.
Several studies showed numerous parameters indicative of unfavorable prognosis for TM patients including male sex, advanced age, trunk and head/neck anatomic sites, III and IV Clark levels, presence of marked regression, absence of inflammatory infiltrate, presence of ulceration areas and high mitotic rate . However, existing prognostic factors cannot reliably differentiate high- and low-risk TM patients. To the best of our knowledge, only a few studies have analyzed the molecular profile of TM and to date there is no molecular predictor of disease progression. In recent years, significant advances in the genetic field have led to the identification of specific driver mutations in melanocytic tumors. BRAF, NRAS and TP53 mutations are the most prevalent pathogenic alterations in melanoma, but other genetic changes revealed a complex pattern that could be evaluated to predict the risk of developing metastases.
MSLT-I demonstrated that in patients with cutaneous melanoma wide excision and sentinel lymph node biopsy (SLNB) followed by immediate completion lymph node dissection (ICLND) for patients with positive sentinel nodes did not provide overall or melanoma-specific survival advantage over wide excision and observation. MSLT-II demonstrated that ICLND did not increase overall or melanoma-specific survival compared with close clinical observation and delayed CLND, even among patients with melanoma and positive SLNs. These results indicate that SLN biopsy (SLNB) followed by ICLND has no survival value, and SLNB should now be regarded solely as a staging procedure. Its role as a staging procedure in the management of patients with melanoma deserves reappraisal.
Sentinel node status is highly correlated to Breslow thickness. Because ICLND should no longer be recommended, the important question is what additional prognostic information is provided by SLNB above and beyond the clinical and pathologic features of the tumor, and do they outweigh the cost and morbidity of the procedure (6% incidence of lymphedema).
Given the high rate of significant morbidity and 1% mortality of some regimens of treatment, it is imperative to choose patients with a high risk of recurrence and death for adjuvant trials. The predictive value of SLN status is limited. For example, 15% and 35% of patients with intermediate and thick melanomas, respectively, who have a negative sentinel node will die of melanoma within 10 years.
A prognostic assay based on the described miRNA expression and inflammation signature combined with the currently used staging criteria may improve accuracy of primary melanoma patient prognoses and aid clinical management of patients, including selection for adjuvant treatment or clinical trials of adjuvant therapies
Metastasis to the lymph node is preceeded by changes in the lymph node microenvironment. A more comprehensive understanding of the molecular signals in the premetastatic lymph node niche that facilitate tumor metastasis could provide therapeutic targets to control lymph node metastasis.
Although several advances have been made in the field of lymphatic metastasis, unanswered questions regarding the effects of the lymph node microenvironment on the metastatic potential of tumor cells in the lymph node or on anti-tumor immune response still remain. The ability of metastatic tumor cells in the lymph node to progress to distant sites remains controversial and we lack biomarkers to identify patients at risk of systemic spread from lymph node metastases.