Endothelin-3 is produced by metastatic melanoma cells and promotes melanoma cell survival

BACKGROUND: Endothelin-3 (ET-3) is an essential paracrine factor for the proliferation, migration, and survival of embryonic melanocytes during fetal development. Its expression is tightly regulated, being completely turned off in adult skin. OBJECTIVE: In this study, results are presented that demonstrate abnormal expression of ET-3 by metastatic melanoma cells in both tissue biopsies and cell culture. Further, in vitro experiments showed that metastatic melanoma cells have the capacity to respond to ET-3 stimulation by increasing survival. CONCLUSION: Therefore, an abnormal autocrine stimulation pathway involving ET-3 is present in metastatic melanoma cells. Blocking this signal transduction pathway may prove useful for the treatment of metastatic melanoma.     

Inflammatory metastatic melanoma

An 87-year-old woman developed erythema, induration and tenderness of the skin overlying each breast. One year before, she had undergone an axillary lymph node dissection because of metastases from melanoma. The primary site was unknown. A skin biopsy showed pigmented tumor nests within the dermal lymphatic vessels, and immunohistochemistry confirmed the melanocytic origin. The diagnosis of inflammatory metastatic melanoma was made.     

Intravascular metastatic melanoma: A difficult diagnosis

Melanoma is a common cancer with the potential for widespread metastasis; however intravascular metastasis is extremely rare. We report an unusual case of a patient with metastatic melanoma in whom ¹⁸F‐fluorodeoxyglucose positron emission tomography‐computed tomography (FDG PET‐CT) demonstrated an intravascular melanoma metastasis in the superior vena cava (SVC), successfully treated with external beam radiotherapy. To our knowledge, this is the first reported case where FDG PET‐CT was used to make this diagnosis.     

Six cases of metastatic malignant melanoma with apparently occult primary lesions.

We report here six cases of malignant melanoma in which metastatic lesions were detected first. Of these, two cases showed some peculiar features: one exhibited widespread subcutaneous bleeding, probably due to venous rupture, and the other case had a rare primary lesion on the penis. In the Japanese literature, there have been 46 cases of malignant melanoma in which metastatic lesions were detected prior to the initial ones. The preferential site for metastasis was the lymph node (32 cases). The primary lesion was unknown in 35 patients. The outcomes were available for 36 of the 46 patients; 23 died, including 18 who died within two years.     

Cutaneous melanoma: available therapy for metastatic disease

Survival of melanoma varies widely by stage, from a potentially highly curable disease when detected in early stages, to a disease with dismal prognosis when it reaches advanced inoperable stages. Stage IV melanoma defines distant metastasis and continues to comprise an ominous prognosis, with a median survival of 6-9 months. Currently, there is no therapeutic agent known to prolong survival in patients with metastatic melanoma. Therapeutic approaches studied in metastatic melanoma include chemotherapy, biochemotherapy, nonspecific immune adjuvants, cancer-specific vaccines, cytokines, monoclonal antibodies, and specific immunostimulants. Chemotherapy with single-agent dacarbazine is the only United States Food and Drug Administration (US-FDA)-approved chemotherapy agent for metastatic melanoma. Immunological approaches have yielded the only newly US-FDA-approved agent for metastatic disease in 30 years, high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma, but with associated high toxicity rate and cost. A number of novel therapeutic agents are undergoing active clinical investigation.     

Diffuse melanosis after chemotherapy-induced tumor lysis syndrome in a patient with metastatic melanoma

Diffuse melanosis is a rare event associated with advanced metastatic malignant melanoma. A 35-year-old woman with stage IV melanoma is presented, who developed slate bluish-gray to brown discoloration of her skin after chemotherapy-induced tumor lysis syndrome. A number of studies were performed to re-evaluate possible mechanisms of melanosis. Skin tissue was examined on routine hematoxylin-and-eosin-stained sections, Fontana stains, immunohistochemical studies with antibodies for Melan-A, gp100, tyrosinase, FXIIIa, and CD68, and by electron microscopy. The main cell types found to contain melanin pigment were histiocytes and dendritic cells. In the dermis, they were distributed mainly around venules. In the subcutaneous fat, they were scattered throughout the fat lobule. Melanin pigment was not only seen within cells but also extracellularly. No melanoma cells were seen in the skin. No increase in melanin pigment or number of melanocytes was seen in the epidermis. A bone marrow biopsy contained melanophages but no melanoma cells. Ultrastructural examination of the patient's serum revealed the presence of melanosomes. Sequence analysis of the tumor's cDNA failed to identify any mutations in the tyrosinase gene, and no tyrosinase protein was detected in non-melanocytic cells, indicating that it was unlikely that a mutation had resulted in a secretory form of the protein. These findings document that diffuse melanosis may result from tumor lysis, with release of melanosomes into the bloodstream.     

Angiosarcomatous transdifferentiation of metastatic melanoma

Melanoma is known to show considerable variation in its histopathological presentation. In exceptional cases, heterologous or divergent differentiation (metaplastic melanoma) can be observed. We report a case of a 69-year-old man who was diagnosed with nodular melanoma on the right upper leg. One year later, the patient presented with an inguinal lymph node metastasis and a lymph node dissection was carried out. In two out of five positive lymph nodes, an angiosarcomatous component was found next to a conventional melanoma component. Shortly after, the patient developed two in-transit metastases in which again an angiosarcomatous component was seen. The vascular component stained positive for ERG and CD31 and negative for melanocytic markers (Mart-1, S100, SOX-10), while the conventional melanoma had an opposite staining pattern. Molecular analysis on both components showed an identical mutation in the NRAS gene, which in our opinion proves the divergent differentiation. To the best of our knowledge, this is the first case report describing angiosarcomatous transdifferentiation of melanoma.     

转移性黑素瘤的治疗选择

黑素瘤的发病率不断增加,尽管该病早期发现可治愈,但晚期黑素瘤患者有全身器官的广泛的转移,且中位生存期<10个月。随着对黑素瘤细胞基因和恶性转化驱动因素的分子水平的研究,大量的治疗靶点研究和开发,新的治疗模式--免疫治疗已用于晚期黑素瘤的治疗。     

Targeted therapies for metastatic melanoma

The next few years may show that when the novel therapeutics reviewed in this article are used in thoughtful combinations, a new standard of care for the treatment of advanced melanoma will emerge. As more understanding is gained on the different signaling pathways for tumor cell growth and mechanisms of action of the different classes of drugs, the ability to identify different subsets of patients with differentially dysregulated oncogenic signaling pathways may allow for more individualized treatments of advanced melanoma in the near future, which will ultimately translate into improved survival.     

转移性恶性黑素瘤一例

患者女,62岁,因右腹股沟包块4个月入院。患者于2018年1月2日因右足拇趾单侧疼痛流脓4个月,在江苏省苏北人民医院手足外科行右拇趾肉芽组织切除、嵌甲根治术,术后切口愈合良好……     

Systemic therapy of metastatic melanoma

For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70 %, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long‐term survival rates of approximately 20 %, the anti‐CTLA‐4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune‐mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti‐PD‐1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45 % and one‐year survival rates of > 70 %. The combination of ipilimumab and nivolumab has shown response rates of up to 58 % and a median progression‐free survival of > 11 months. While this combination is expected to result in a rapid and long‐lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long‐term survival a possibility, not only acute but also long‐term therapeutic side effects must be taken into account.