Malignant Melanoma [C43]
Dipl.-Ing. (FH) Tanja Hinrichsen,
Prof. Dr. med. Barbara Dockhorn-Dworniczak
A malignant skin melanoma is the skin tumor with the highest rate of metastasis and is responsible for more than 90% of deaths from skin tumors. The Robert Koch institute estimates approximately 2,500 deaths per year. It is estimated that about 17,500 cases of melanoma are newly diagnosed each year. Thus malignant melanomas are resposible for 1.5-2% of all malignant tumors in Germany. More than 90% are melanomas of the skin (cutaneous melanoma) and 5% are melanomas of the eye, particularly in the region of the retina (ocular melanoma), occasionally malignant melanomas can be found in areas of mucous membrane, e.g. in the colon. According to the WHO classification melanomas are classified clinically and histologically into four groups: lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), nodular melanoma (NM) and acral lentiginous melanoma (ALM). In addition, there are rare histological variants such as spitzoid melanoma, nevoid melanoma as well as desmoplastic, or neurotropic melanoma. Besides this classification, molecular microarray analyses showed a subdivision into four groups, in which characteristic gene expression patterns correlated with the localization of the tumor, the frequency of distinctive somatic mutations and with UV damage of the dermis.
If the melanoma is diagnosed at an early stage, it can usually be cured. However, early metastasis is problematic. The stages of loco-regional metastasis (AJCC 2009 Stadium IIIA, IIIB und IIIC) comprise clinically and prognostically heterogeneous patient groups. The 5-year survival rate is between 23% and 87%. The median survival of patients with stage IV metastatic melanomas is considered to be 8-12 months, whereby there is much inter-individual variation. For stage IV and unresectable stage III tumors, the combination of therapy with specific signal transduction inhibitors alongside established radio-chemotherapies and immunotherapies treatment is envisaged. BRAF mutations are detected in 40-60% of melanomas. 90% of these mutations result in an amino acid substitution of valine (V) by glutamic acid (E) and the amino acid change BRAF V600E. Other BRAF inhibitor sensitive changes such as BRAF V600K are less frequent. These changes are accompanied by constitutive activation of the RAF-MEK-ERK signal transduction pathway which is relevant for tumor development and progression of the melanoma.
In Phase III trials, patients with a BRAF V600 mutation have shown a better response to chemotherapy with the BRAF tyrosine kinase inhibitors vemurafenib and Dabrafenib, as well as the MEK1 / 2 inhibitor trametinib. Nevertheless, progression within 5 to 7 months is seen when a BRAF or MEK inhibitor is administered alone.
Activating mutations in NRAS are found in 20-30% of melanomas and typically exclude a mutation in BRAF. However, mutations in NRAS under therapy for a BRAF mutant melanoma are described as possibly resistance causing mutations. Despite promising early clinical data, only a small number of patients with a NRAS mutant melanoma benefit from therapy with a MEK inhibitor. However, preliminary data show a regression of the tumor as well as a response or stable disease with a combination of the MEK inhibitor binimetinib and the CDK4/6 inhibitor LEE011 in patients with metastatic NRAS mutant melanoma.
In 20-30% of gastric mucosa melanomas mutations or amplifications are found in KIT, which is rarely affected in cutaneous melanoma. However, 30% of patients with a KIT mutation show a response to imatinib.