The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1α expression and HIF-dependent attendant pathways.

To study the effect of melanogenesis on HIF-1α expression and attendant pathways, we used stable human and hamster melanoma cell lines in which the amelanotic vs. melanotic phenotypes are dependent upon the concentration of melanogenesis precursors in the culture media. The induction of melanin pigmentation led to significant up-regulation of HIF-1α, but not HIF-2α, protein in melanized cells for both lines. Similar upregulation of nuclear HIF-1α was observed in excisions of advanced melanotic vs. amelanotic melanomas. In cultured cells, melanogenesis also significantly stimulated expression of classical HIF-1-dependent target genes involved in angiogenesis and cellular metabolism, including glucose metabolism and stimulation of activity of key enzymes in the glycolytic pathway. Several other stress related genes containing putative HRE consensus sites were also upregulated by melanogenesis, concurrently with modulation of expression of HIF-1-independent genes encoding for steroidogenic enzymes, cytokines and growth factors. Immunohistochemical studies using a large panel of pigmented lesions revealed that higher levels of HIF-1α and GLUT-1 were detected in advanced melanomas in comparison to melanocytic nevi or thin melanomas localized to the skin. However, the effects on overall or disease free survival in melanoma patients were modest or absent for GLUT-1 or for HIF-1α, respectively. In conclusion, induction of the melanogenic pathway leads to robust upregulation of HIF-1-dependent and independent pathways in cultured melanoma cells, suggesting a key role for melanogenesis in regulation of cellular metabolism.

[Melanoma while using levodopa due to Parkinson's disease--causal association unlikely]. / Melanoom tijdens levodopagebruik wegens de ziekte van Parkinson--causaal verband onwaarschijnlijk.

A 75-year-old woman with Parkinson's disease presented with an amelanotic melanoma on her right lower leg with an inguinal lymph node metastasis. For the previous six years she had been treated with levodopa-carbidopa. The disease disappeared after inguinal lymph node dissection and hyperthermic isolated regional perfusion. It is sometimes thought that levodopa may have an activating effect on melanoma, due to its possible role in the biosynthetic pathway of melanin. However, on the basis of the literature available, such a causal association is unlikely.

Amelanotic corneal melanoma after a blast injury.

PURPOSE: To report a case of a corneal melanoma after trauma. METHODS: Case report. RESULTS: A 68-year-old man sustained an ocular injury from a blast furnace explosion in 1958. In 1998, he underwent a penetrating keratoplasty for a corneal scar. Histologic examination and cell markers of the host button revealed intrastromal and subepithelial melanoma. No clinical or microscopic evidence of adjacent conjunctival or uveal melanoma was found. CONCLUSION: Melanoma of the cornea can present as a stromal opacity after trauma.

Amelanotic malignant melanoma following cryosurgery for atypical lentigo maligna.

Cryosurgery is an alternative treatment option to surgical excision for lentigo maligna. Clinical evidence of recurrence is usually characterized by repigmentation at the treated site. We report two patients who developed amelanotic malignant melanoma following cryosurgery for a pigmented lentigo maligna. These cases illustrate the potential risk of treating lentigo maligna with cryosurgery.

c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype.

The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma, a complex and aggressive disease with a high propensity for metastasis, are poorly understood due in large part to the dearth of relevant experimental animal models. Here we used transgenic mice ectopically expressing hepatocyte growth factor/scatter factor (HGF/SF) to show that the Met signaling pathway is an important in vivo regulator of melanocyte function, whose subversion induces malignant melanoma. Tumorigenesis occurred in stages, beginning with the abnormal accumulation of melanocytes in the epidermis and dermis and culminating in the development of metastatic melanoma. Oncogenesis in this model was driven by creation of HGF/SF-Met autocrine loops through forced expression of the transgenic ligand and apparent selection of melanocytes overexpressing endogenous receptor, rather than paracrine stimulation or mutational activation of c-met. Preference for liver as a metastatic target correlated with high HGF/SF-Met autocrine activity, consistent with the notion that such activity may influence colonization. Although basic fibroblast growth factor and its receptor were both weakly expressed in the majority of melanomas examined, high levels were found only in those rare neoplasms with low or undetectable HGF/SF and Met expression, suggesting that these two tyrosine kinase receptor autocrine loops serve a critical overlapping function in melanocytic tumorigenesis. Our data support a causal role for HGF/SF-Met signaling in the development of melanoma and acquisition of the metastatic phenotype. Moreover, this transgenic mouse should serve as a highly useful model, facilitating our understanding of mechanisms by which human melanoma progresses to malignancy and expediting the development of efficacious therapeutic modalities designed to constrain metastasis.

Amelanotic malignant melanoma.

Amelanotic malignant melanoma (AMM) often defies clinical diagnosis because of its wide range of clinical appearances and lack of pigmentation. Biopsy of AMM typically yields the correct diagnosis, although the histological findings, especially in metastatic lesions, occasionally may be confused with other malignancies. In cases histologically challenging, immunohistochemical techniques frequently provide diagnostic information. Multiple mechanisms to explain amelanosis have been suggested, all resulting in a single, common amelanotic phenotype. Appropriate studies to compare outcomes of amelanotic versus pigmented melanomas have not been performed. Treatment recommendations for AMM are identical to those for pigmented melanomas, although accurately defining clinical margins of the neoplasm often is challenging. Overall, a high index of suspicion and a low threshold to biopsy unusual clinical lesions ultimately may allow for earlier diagnosis and treatment of these frequently lethal malignancies.

Mucosal melanoma following autologous stem cell transplantation for non-Hodgkin's lymphoma (NHL).

The incidence of secondary malignancy following autologous stem cell transplantation (ASCT) is increasing. We describe a patient with stage IVB Hodgkin's disease who developed primary amelanotic malignant melanoma of the tongue 18 months following autologous stem cell transplantation. She was treated by partial glossectomy and supra-omohyoid neck dissection followed by cytokine-mediated immunotherapy. Malignant melanoma of the skin is a frequent secondary solid tumor seen in patients undergoing stem cell transplantation. However, mucosal melanoma which is rare by itself (0.2-8%) has never been reported in NHL patients following ASCT. Early diagnosis and initiation of combined local and systemic treatments including immuno-therapy may improve the outcome of this rare but lethal complication.