Clinicopathological and molecular aspects of cutaneous Melanoma

Clinicopathological and molecular aspects of cutaneous melanoma. Melanoma arises form the transformation of neural crest-derived melanocytes, the pigment cells of the skin, which reside in the basal layer of the epidermis. Melanoma is the deadliest form of skin cancer and one of the most aggressive of all neoplasms. The incidence of cutaneous melanoma has increased rapidly during the past several decades, and continues to do so at an alarming rate. Although localized melanoma is frequently curable by surgical excision, metastatic melanoma is inherently resistant to most systemic treatments, and survival of patients with advanced disease has not improved in more than 30 years. Hence the survival of patients is based on screening, early detection, and wide resection of the primary lesion. As treatment of metastatic melanoma moves rapidly into the era of targeted therapy, there is an ever growing need to untangle the underlying genetic complexity and cellular signalling heterogeneity of this highly malignant tumor. It is widely hoped that an understanding of how genetic and signalling profiles dictate pharmacologic response will allow for the selection of optimal patient sub-populations for clinical trials. Although we have an increasingly good understanding of the genetics and biochemistry of melanoma, the mechanisms underlying their combinatorial interactions are still poorly defined and need to be fathomed to ultimately lead to more successful therapeutic strategies and evidence-based management of patients with melanoma. The goal of this thesis, therefore, is to highlight some of the issues that have arisen over the past decade. This thesis is divided into three parts. The first part describes molecular and cellular aspects of melanoma. The second part describes clinicopathological aspects of melanoma, especially studies concerning the sentinel lymph node. Part three is a discussion of the current knowledge of melanoma and future perspectives in molecular and clinical melanoma research. The overall conclusions we can draw from the research described in this thesis are: 1) Melanoma is a complex tissue resulting from disrupted skin homeostasis, rather than putting the focus on the melanoma cell, and the genes within it, alone. 2) During transformation and progression of melanocytes to melanoma cells, there are reciprocal and conspirational interactions between the neoplastic cells and the adjacent stromal cells. Skin cells within the cancerous tissue are not idle bystanders, but rather active participants that shape the aggressive features of this neoplasm. 3) Careful clinical observations and what they teach us about the biology of melanoma still have a place in modern medicine, even in the molecular age. 4) Patients with positive sentinel lymph nodes are a heterogeneous group; not all sentinel node-positive patients have necessarily a poor prognosis. 5) Sentinel lymph node tumor load, i.e. depth of invasive penetration, or metastatic size, can be used to predict the absence of additional metastatic lymph nodes in melanoma patients. 6) Based on low sentinel tumor load and limited Breslow thickness of the primary tumor, a subgroup of melanoma patients with a positive sentinel node can be identified who will not significantly benefit from completion lymph node dissection. 7) Selective sentinel node guided lymph node dissection is potentially curative for a subset of patients. 8) Even if selective sentinel lymph node guided lymph node dissection in and by itself should not improve survival, it is of great prognostic value and should be continued until another, less invasive staging procedure with similar predictive value is available.