Current state of melanoma diagnosis and treatment

Abstract

Melanoma is the deadliest form of skin cancer. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop significantly. Therefore, early and correct diagnosis is key for ensuring patients have the best possible prognosis. Melanoma misdiagnosis accounts for more pathology and dermatology malpractice claims than any cancer other than breast cancer, as an early misdiagnosis can significantly reduce a patient's chances of survival. As far as treatment for metastatic melanoma goes, there have been several new drugs developed over the last 10 years that have greatly improved the prognosis of patients with metastatic melanoma, however, a majority of patients do not show a lasting response to these treatments. Thus, new biomarkers and drug targets are needed to improve the accuracy of melanoma diagnosis and treatment. This article will discuss the major advancements of melanoma diagnosis and treatment from antiquity to the present day.

Keywords: Melanoma; diagnosis; epigenetics; immunohistochemistry; immunotherapy; treatment.

Figure 1.

Oncogenic pathways commonly misregulated in melanoma. Mutations in NRAS, BRAF, GNAQ and c-KIT lead to constitutive MAPK signaling leading to unbridled proliferation and survival. The phosphatidylinositol 3ʹ kinase (PI3K) cascade is activated by oncogenic NRAS. Mutations of the CDKN2A gene leads to loss of P16^INK4A or P14^ARF or both depending on where the mutations occur. CDKN2A mutations are common in hereditary melanoma.

Figure 2.

Regulation of T-cell response by CTLA4 and PD1. (A) T-cell activation by dendritic cells requires signaling by both the MHC and CD28 complexes. Binding of the CTLA4 to B7-1/2 (CD80/86) suppresses T-cell activation and acts as a feedback mechanism to prevent ongoing immune response. Binding to the MHC class I complex on melanoma cells leads to T-cell activation. After persistent activation, T-cells upregulate PD-1 expression. When PD-1 binds to the PD-L1/2 expressed by tumor cells, this leads to deactivation of T-cells. (B) Antibodies against CTLA4, PD1 or PD-L1/2 prevent binding to associated ligands leading to activation of T-cells and stimulation of an immune response to tumor cells. Abbreviations: DC, dendritic cell; CTLA4, cytotoxic T lymphocyte antigen 4; PD1, programmed death 1; TCR, T-cell receptor; MHC, major histocompatibility complex; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2.