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Background: The incidence and mortality of malignant melanoma have been rising during the past decades, the latter being due to the high invasion capacity and the metastatic potential of melanoma cells to distant organs. Objective: We investigated the distribution pattern of melanoma metastases taking into account different clinicopathological subtypes of melanoma. Methods: We studied 310 stage IV (AJCC 2009) melanoma patients retrospectively with regard to potential correlations between frequency and occurrence of metastasis and the genetic background and pathological/clinical melanoma subtypes. For all patients, the time to distant metastasis (TTDM) and the distribution patterns of metastases were analyzed and correlated to the median survival time. Results: Superficially Spreading (SSM) and Nodular melanomas (NMM) spread to the brain more frequently than Acrolentiginous (ALM) and Mucosal (MM) melanomas (p = 0.0012). The preference to affect the skeleton was significantly higher for ALM and MM in comparison to SSM and NMM (p = 0.0049). Lentigo maligna (LMM) tumors showed a significantly lower metastatic spread to distant lymph nodes (p = 0.0159). BRAF mutant versus wildtype tumors showed no significant differences concerning localization of metastasis but patients with BRAF mutant tumors were significantly younger at primary diagnosis and had a significantly shorter stage IV survival (p = 0.0106). Conclusion: This study shows a clear distinction of melanoma subtypes with regard to metastasizing preferences. Further knowledge about melanoma subtype specific characteristics, including molecular markers predictive of homing preferences, may help to understand and manage this heterogeneous disease in terms of prognosis and follow-up procedures.

Institute 1 Haut und Allergie, Zentrum Brunnehof, Uster/Schweiz 2 kempf und pfaltz. histologische diagnostik, Zürich/Schweiz Bibliografie DOI http://dx.

8563 Background: Melanoma is subdivided into molecular defined groups. One major subtype is characterized by a mutation in the BRAF gene. BRAF is less commonly mutated in acrolentiginous (ALM) and mucosal (MM) melanomas, instead these subtypes predominantly show aberrations in the KIT/CD117 gene. KIT aberrations predict the outcome of targeted therapies in ALM and MM patients, however the particular role of KIT expression in these melanoma subtypes remains controversial. To explore the relationship between KIT expression, mutation, and tumor stages, we investigated immunohistochemical KIT expression and mutation status in primary ALM/MM lesions and their metastases. We also compared the frequency of KIT mutations of MM in different anatomic locations. Methods: KIT immunoreactivity and mutation status was assessed in 41 ALM and 25 MM patients, using polyclonal rabbit anti-human KIT/CD117 antibody, and PCR was performed for KIT gene exons 9,11,13,17 and 18. Of these, 19 ALM and 15 MM patients had matched primary and metastatic lesions. Phosphorylated extracellular regulated kinase (P-ERK) was investigated in a subset of 8 ALM and 8 MM matched primary/metastatic pairs by immunohistochemistry. Results: Heterogeneous KIT immunoreactivity was observed in both primary and metastatic lesions. Mutations were present in four of 41 ALM (10%) and five of 25 MM (20%) patients. Only vulvar mucosal samples carried KIT mutations in contrast to sinonasal lesions (p= 0.0109). In KIT-mutated tumors, the mutations were present in KIT expressing as well as KIT negative cells, as shown by Laser Capture Microdissection (LCM). P-ERK expression was preferentially found in metastases. Conclusions: KIT expression is heterogeneous and shows no relationship with disease progression and mutation status, therefore KIT immunoreactivity is not a valuable marker for treatment decisions. In mucosal melanoma patients, KIT mutation frequency is significantly associated with anatomic location. Vulvar melanoma patients are prone to carry activating KIT mutations and thus may be more likely to benefit from KIT-targeted therapies than other subtypes. Therefore, especially vulvar melanoma patients should be screened for activating KIT mutations.

Acrolentiginous melanoma (ALM) accounts for 5% of all melanoma types. Even though it occurs in all ethnic groups, a preference in dark skin has been observed over the time. A lack of typical alarming signs still results in late diagnosis. Recently, distinct molecular characteristics have been defined for melanoma by Bastian et al. ALM and mucosal melanoma are suggested to show aberrations in the cKIT gene. It is involved in tumorigenic growth signaling. cKIT tyrosine kinase receptor has been yet proven as a successful target in chronic myeloid leukemia and in gastrointestinal stromal tumors. Histologically, mucosal melanomas show ALM characteristics. Specific staining with proliferating cell nuclear antigen for cutaneous melanoma in general and cKIT protein expression for ALM and mucosal melanomas in particular, can help to identify this tumor in comparison with benign melanocytic lesions. Genetic aberrations do not necessarily correlate with the KIT protein expression. Several studies applying small molecule inhibitors such as Imatinib have been performed in patients with melanoma. Single-patient cases with known cKIT mutations revealed impressive clinical response.