Hirnmetastasen des malignen Melanoms

The majority of patients with metastatic melanoma will develop brain metastases, which are the most common cause of death. Until recently, local therapies (e.?g., neurosurgery, radiotherapy) were the only options for brain metastases; however, effective systemic treatment options are now available. Upon suspicion of brain metastases, diagnostic staging with brain MRI and a neurological investigation are indicated. Prognostic factors such as number of cerebral metastases and symptoms, serum lactate dehydrogenase and S?100 levels, extracerebral metastases, and ECOG status are considered during therapeutic planning. Treatment planning and therapeutic interventions should be based on an interdisciplinary and multimodal approach. Established treatments for singular brain metastases are neurosurgical resection and stereotactic radiotherapy, which can prolong survival. In patients with asymptomatic BRAF V600E-mutant brain metastases, the BRAF inhibitors dabrafenib, vemurafenib, and immunotherapy with ipilimumab are used. In the case of multiple symptomatic brain metastases, palliative whole-brain radiotherapy is used for treatment, although it has failed to show an overall survival benefit. Increased intracranial pressure and epileptic seizures are addressed with corticosteroids and anticonvulsants. Current clinical studies for melanoma patients with brain metastases are investigating new treatment options such as PD-1 antibodies, combined ipilimumab and nivolumab, combined BRAF inhibitors and MEK inhibitors, and stereotactic radiation in combination with immunotherapy or targeted therapy.     

Melanoma localmente avanzado. Estudio y tratamiento

Locally advanced melanoma is characterized clinically by the appearance of in-transit or satellite metastases, and is considered stage IIIB or IIIC according to the 2002 classification of the American Joint Committee on Cancer. Despite the absence of distant metastases, the management of locally advanced melanoma is complicated and the disease is associated with a reduction in overall survival.The initial step in the approach to the patient with locally advanced melanoma involves the restaging in order to exclude the presence of distant metastases. Positron emission tomography-computed tomography is currently accepted as the most accurate restaging technique. Surgical excision of the metastases continues to be the treatment of choice for locally advanced melanoma.In the case of unresectable metastases, hyperthermic isolated limb perfusion with melphalan with or without tumor necrosis factor has achieved complete responses in up to 60 % of patients treated, with very rare severe locoregional and systemic toxic effects. Radiation therapy, chemotherapy, and biochemotherapy are options that, even though they have not been tested in patients with only in-transit metastases, may have a role in unresectable, locally advanced melanoma without distant metastases.In any case, therapeutic options for locally advanced melanoma should be individualized, and should take into consideration the availability of each of these techniques as well as the experience of the health care team.     

Experiencia en el tratamiento de satelitosis y metástasis cutáneas en tránsito de melanoma con interleucina 2 intralesional

IntroductionAlthough metastatic melanoma has a poor prognosis, cutaneous metastases represent a special case given their ready accessibility, making it possible for dermatologists to apply local treatment. We report our experience with intralesional treatment with interleukin (IL) 2 in 7 patients with cutaneous metastases from malignant melanoma.Material and methodsA total of 244 lesions in 7 patients with satellitosis and/or cutaneous metastases from malignant melanoma were treated with intralesional IL-2 twice a week. The maximum dose in each patient ranged from 3 to 18 million units per session, according to the number and size of lesions.ResultsComplete or partial remission was achieved in almost all lesions (95.9 % and 3.7 %, respectively). Only 1 lesion (0.4 %)—the largest and located subcutaneously—did not respond to intralesional treatment and required alcoholization and subsequent surgical removal to achieve cure. All partial responses occurred in subcutaneous lesions larger than 2 cm. Treatment was well tolerated with only a few mild side effects (grade 1-2).ConclusionsIL-2 may be an effective and well-tolerated treatment option in patients with satellitosis and cutaneous metastases from melanoma. Lesions smaller than 2 cm and located in the epidermis or superficial dermis respond better than those larger than 2 cm or located in the subcutaneous cellular tissue. More studies are necessary to establish appropriate doses and regimens.     

Ichthyosiform scaling secondary to megavoltage radiotherapy.

Acquired ichthyosis is a rare dermatosis associated with a number of malignancies. Side effects seen on the skin secondary to megavoltage radiotherapy are uncommon but may include fine dry desquamation and tanning. We present a case of ichthyosiform scaling limited to the radiation fields in a patient treated for brain metastases of a primary small cell lung carcinoma. The reader is reminded that side effects of megavoltage treatment do occur on the skin. A brief review of these effects is included.     

Electrochemotherapy of skin tumors

Electrochemotherapy represents a new innovative technology using a combination of electroporation and application of very low dose cytotoxic drugs for the treatment of cutaneous and subcutaneous skin tumors and metastases. Based on a high number of preclinical and clinical studies this procedure has been established as a simple, safe and very effective tumor treatment whose costs are acceptable. The procedure can be performed as a single treatment of localized disease as well as a repeated palliative treatment of cutaneous metastases regardless of the tumor type. Because of the lack of significant side effects and of short duration the procedure can be performed on an out-patient basis. Several studies led to the validation of standard operating procedures for its use in daily clinical practice. This treatment has become established in many different European countries.     

Elektrochemotherapie von Hauttumoren

Electrochemotherapy represents a new innovative technology using a combination of electroporation and application of very low dose cytotoxic drugs for the treatment of cutaneous and subcutaneous skin tumors and metastases. Based on a high number of preclinical and clinical studies this procedure has been established as a simple, safe and very effective tumor treatment whose costs are acceptable. The procedure can be performed as a single treatment of localized disease as well as a repeated palliative treatment of cutaneous metastases regardless of the tumor type. Because of the lack of significant side effects and of short duration the procedure can be performed on an out-patient basis. Several studies led to the validation of standard operating procedures for its use in daily clinical practice. This treatment has become established in many different European countries.     

Intralesional therapy of melanoma metastases with recombinant interferon-beta]

In ten patients with metastasizing melanomas, discontinuous intratumoral treatment with recombinant interferon beta (rIFN-beta) was administered into 19 cutaneous or palpable subcutaneous metastases. Among the 16 metastases treated with 5 x 10(6) IU per injection, 8 showed partial or complete remission. No recurrence was observed during the 4-9-month follow-up period. There was no regression in 3 metastases treated with 3 x 10(6) IU rINF-beta per injection. No systemic antineoplastic effects were observed in any of the cases. The IFN-beta serum levels were measurably increased following intratumoral application. Local treatment led to a significant increase in (2'-5')oligoadenylate synthetase in the mononuclear blood cells and in the serum. Side-effects of the treatment were moderate; there was a temporary increase in transaminases, a decrease in thrombocytes and influenza-like symptoms. The results show that IFN-beta has a dose-dependent antitumour effect on malignant melanomas.     

Head and neck squamous cell carcinoma skin metastases below of the diaphragm

Cutaneous metastases from carcinoma are relatively uncommon in clinical practice. Metastasis to skin sites from squamous cell carcinoma of the mucosa of the head and neck are also very rare. However, skin metastases may be the first clinical evidence of the malignant disease or its loco-regional recurrence. Early recognition of skin metastasis can lead to an accurate and prompt diagnosis and timely treatment. Patients with skin metastases have very poor prognosis. We report on four such patients, one of them with multiple skin metastases from the squamous cell carcinoma in the cervical part of the esophagus above and below the level of the diaphragm. In reviewing the literature, only two cases of solitary skin metastases below the diaphragm from laryngeal squamous cell carcinomas have been reported     

Synergistic effects of interferon‐beta and nivolumab in oral mucosal melanoma

Mucosal melanoma is a rare aggressive cancer with a very poor prognosis. Clinical and pathological characteristics of mucosal melanoma differ from those of cutaneous melanoma and there are no established management guidelines for mucosal melanoma. Complete surgical excision is one of the most effective treatments for localized lesions, while targeted therapies and immunotherapies, such as monoclonal antibodies that target cytotoxic T‐lymphocyte‐associated molecule‐4, and the programmed death (PD)‐1/PD‐ligand 1 pathway inhibitors, are treatment options for unresectable or metastatic lesions. Here, we describe the case of a patient with oral mucosal melanoma with multiple metastases. In our case, local injection of interferon (IFN)‐β with dacarbazine–nimustine–vincristine therapy provided antitumor effects on an invasive tumor on the upper gingiva. Nivolumab therapy produced complete remission of lymph node and bone metastases. In contrast, the remaining in situ portion of oral mucosal melanoma on the hard palate was refractory to IFN‐β monotherapy and nivolumab therapy. However, after administration of nivolumab, peritumoral injection of IFN‐β showed rapid therapeutic effects. Our case suggested that nivolumab upregulated the antitumor effects of IFN‐β, which induced the recruitment of CD8⁺ T cells into the tumor microenvironment contributing to the deletion of tumor cells. Combination therapy of IFN‐β and nivolumab may be a potential treatment option for patients with oral mucosal melanoma.     

Intralesional therapy of metastatic spreading melanoma with beta‐interferon

A 74‐year‐old female patient developed multiple local metastases after excision of a nodular melanoma of the left cheek. There was no regression after treatment with dacarbazine (DTIC^®) and radiotherapy. After treatment with intralesional interferon‐β, the metastases regressed completely. The dosage was 5 million IU interferon‐β (Fiblaferon^®) three times weekly with courses of two and four weeks, separated by a month. Except for local swelling and inflammation, no side effects occurred. Five years after completing therapy, the patient is still tumor‐free.     

Metastatic basal cell carcinoma with squamous differentiation: report of a case with response of cutaneous metastases to electrochemotherapy

BACKGROUND: Metastatic basal cell carcinoma is a rare disease with poor prognosis. Palliative therapeutic approaches include surgery, radiotherapy, and/or chemotherapy. These treatment modalities are invasive and risky and associated with relevant adverse effects. Electrochemotherapy is a recently described therapy that relies on the permeation of cancer cell membranes by electrical pulses to enhance cytotoxic drug penetration. It has been successfully used in the treatment of primary and metastatic skin cancers. We report a case of metastatic basal cell carcinoma in which electrochemotherapy was effective in inducing local regression of skin metastases. OBSERVATIONS: A 75-year-old man presented with a pigmented, deeply infiltrating nodule in the right axilla manifesting as basal cell carcinoma with squamous differentiation at histopathologic examination. Despite 2 wide surgical resections involving lymphadenectomy with axillary vein substitution and systemic chemotherapy, a progressive metastatic spreading, both cutaneous and visceral, occurred in the following 2 years. Three successive sessions of electrochemotherapy with bleomycin sulfate were then performed on isolated skin metastases. The treatment was well tolerated and led to a rapid clinical and histologic regression of the treated lesions. Conclusion Electrochemotherapy is an effective and well-tolerated adjunct to the therapeutic options in metastatic basal cell carcinoma, characterized by an advantageous risk-benefit ratio and minimal downtime.     

Effectiveness of imiquimod limited to dermal melanoma metastases, with simultaneous resistance of subcutaneous metastasis

Successful management of epithelial skin cancers with imiquimod 5% cream (Aldara^®), an immunomodulatory agent, led to speculation that it may promote an immune response against melanoma. Studies, mostly case reports, have assessed the value of imiquimod as a topical treatment for dermal melanoma metastases that prove difficult to manage surgically. The precise value of imiquimod, however, in treatment of dermal and subcutaneous metastases remains unclear. A case at our institution elucidates histopathologically that subcutaneous metastases may progress despite excellent treatment of superficial dermis in the same location. In preparation for a clinical trial using imiquimod to treat patients with dermal melanoma metastases, we have treated several patients off protocol. We present a case report in which the observed changes are documented photographically and histologically. The patient experienced dramatic improvement in the locally treated dermis with concurrent regional treatment failure in the subcutaneous space. Our experience supports growing evidence that imiquimod for some provides an effective option for dermal disease. The unique histological documentation we provide regarding the differential effectiveness of imiquimod in treating various tissue components may help guide future investigations regarding optimal clinical application of imiquimod therapy for melanoma metastases.     

Merkel cell carcinoma metastatic to the transverse colon: Disease free after six years – cure or just prolonged remission?

Merkel cell carcinoma is an uncommon but highly immunogenic skin malignancy that has the potential to metastasize to any site in the body. Despite treatment many patients experience relapse, often to distant sites beyond the site of initial treatment. The development of distant soft tissue or visceral metastases is considered incurable, despite treatment with prognosis usually being measured in months. We report the case of an elderly man who developed colonic metastases from a head and neck primary and with treatment has survived disease free for over 6 years. Such reports are infrequently documented and highlight the unpredictable nature of this disease.     

Palliative treatment of skin metastases in dermato‐oncology

Patients with metastatic melanoma, but also other solid tumors (e.g., lung or breast cancer), may develop cutaneous metastases in advanced stages. The goal of treatment is to alleviate symptoms such as pain, fetor, secretions, or bleeding. Current treatment modalities are based on a multimodal treatment approach. Beside surgery, treatment options such as electrochemotherapy, isolated limb perfusion, radiotherapy, and local administration of cytokines or chemotherapy agents are available. In case of concomitant visceral metastases, this local treatment approach may not affect overall survival, but the palliation of these tumor‐associated symptoms very often improves the quality of life for the patient.     

Topical imiquimod and intralesional interleukin-2 increase activated lymphocytes and restore the Th1/Th2 balance in patients with metastatic melanoma

Background  Patients with metastatic skin disease in malignant melanoma are difficult to treat, with unresectable lesions proving the biggest challenge. We have recently published data showing a significant clinical response in patients with multiple in-transit melanoma metastases treated with a combination of topical imiquimod and intralesional interleukin (IL)-2. Here we report the results of immunological analysis with the aim of highlighting correlations with our clinical findings.
Objectives  To investigate the systemic effects of our localized combination treatment in patients with accessible metastases of melanoma, and to correlate this with their clinical responses.
Methods  The peripheral blood mononuclear cells of patients were collected at various time points throughout the treatment. Using antibodies to T-cell subsets we measured the changes in cell populations, and along with polyclonal stimulation, changes in cytokine production from these cells over a treatment course.
Results  We report an increase in the mean CD4/CD8 ratio from 2·78 to 3·54 with treatment ( P  < 0·01), and a rise in the percentage of CD25+ cells in the CD4+ population from 14·52% to 38·56%. Furthermore, staining with activation and T-regulatory markers showed that the majority of this population is activated T cells. Cytokine analysis on polyclonally stimulated peripheral blood mononuclear cells showed an increase in the ability of cells to produce interferon (IFN)-γ over the treatment course, with an initial rise in the IFN-γ/IL-5 ratio in five of six patients.
Conclusions  The results of this study provide evidence that, in the majority of patients with in-transit metastases of melanoma, therapy with a combination of topical imiquimod and intralesional IL-2 induces a systemic immunological effect by reversing some of changes noted in patients with malignant disease.     

Topical treatment of melanoma skin metastases with imiquimod

The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5 % imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes.     

Imiquimod,a topical immune response modifier,in the treatment of cutaneous metastases of malignant melanoma

BACKGROUND: Imiquimod 5% cream (Aldara, a novel topical immune response modifier, has been approved for the topical treatment of anogenital HPV-induced warts. In addition, several studies have demonstrated antitumoral activity in solar keratoses, superficial basal cell carcinomas and Bowen's disease. AIM: Given the convincing therapeutic results of imiquimod when used for treating selected types of epithelial skin cancer, we became interested to study imiquimod as an adjuvant for treating cutaneous metastases of malignant melanoma. METHODS: Three patients with multiple, i.e. more than 15, cutaneous in-transit metastases of malignant melanoma in unilateral localization on the leg were treated topically with imiquimod 5% cream. RESULTS: Twice daily application under occlusive conditions for a period of 21-28 weeks resulted in >90% regression of cutaneous metastases in 2 patients. The third patient showed marked response only when topical imiquimod was intermittently supplemented by intralesional interleukin (IL)-2 for 2 weeks. Unwanted side effects were mild in all patients. CONCLUSION: Overall, imiquimod as a single agent or in combination with intralesional IL-2 may be a promising immunomodulatory compound for the adjuvant topical treatment of patients with multiple cutaneous metastases of malignant melanoma.     

Metastases in dermatological patients with squamous cell carcinoma.

Two hundred eleven patients in whom squamous cell carcinoma (SCC) of the skin had been diagnosed between 1950 and 1959 were followed up from Jan 1, 1976, to establish the incidence of metastases. A systemic study was carried out through follow-up examinations and tracing through population registers. We found 3.3% metastases in 153 patients with skin SCC and 11% metastases in 55 patients with labial SCC. Three patients with genital SCC were free of metastases. These results and the available literature on patients with SCC of osteomyelitic foci and scars from burns or x-ray treatment indicate that sharp distinctions must be made among three groups of SCC; mucocutaneous, primary cutaneous, and cutaneous SCC secondary to inflammatory and degenerative processes. The incidence of metastases in the three groups is approximately 11%, 3%, and 10% to 30%, respectively. Percentages found are important to dermatology clinics because skin SCC should be considered a malignant tumor with a higher incidence of metastases than previously assumed.     

Surgical therapy of regional lymph nodes in cancers of the lower lip

Based on a retrospective follow-up study of patients with lower-lip carcinoma from 1968 to 1980, the incidence of metastases of such lesions was broken down according to tumor classification, and the survival rates for these patients were computed. In the total group of 89 patients with primary surgical treatment of the tumor and lymph nodes, 17 (19.1%) were found to have metastases. Among these tumors, 5 were classified as T1, 10 as T2, and 2 as T3. Analysis of the survival rate yielded the following results. To date, there has been no recurrence in any of the patients who underwent suprahyoid lymph-node removal with no histological evidence of lymph-node metastases. Of the 17 patients in whom histological lymph-node metastases were identified in the submandibular region following primary suprahyoid neck dissection, 64.7% showed no evidence of disease for 5 years on average, and all are still alive. In contrast, 90% of the patients died in whom the primary tumor was just treated locally and who did not undergo radical removal of the suprahyoid lymph-node until secondary metastases had occurred. In the light of our experience, suprahyoid lymph-node removal appears to be indicated as part of the primary treatment of lower-lip carcinoma, independent of the prevailing tumor stage. This may not apply to tumors that are clearly less than 1 cm in size.     

Cutaneous metastases from internal malignancies: a clinicopathologic and immunohistochemical review

Skin metastases occur in 0.6%-10.4% of all patients with cancer and represent 2% of all skin tumors. Skin metastases from visceral malignancies are important for dermatologists and dermatopathologists because of their variable clinical appearance and presentation, frequent delay and failure in their diagnosis, relative proportion of different internal malignancies metastasizing to the skin, and impact on morbidity, prognosis, and treatment. Another factor to take into account is that cutaneous metastasis may be the first sign of clinically silent visceral cancer. The relative frequencies of metastatic skin disease tend to correlate with the frequency of the different types of primary cancer in each sex. Thus, women with skin metastases have the following distribution in decreasing order of frequency of primary malignancies: breast, ovary, oral cavity, lung, and large intestine. In men, the distribution is as follows: lung, large intestine, oral cavity, kidney, breast, esophagus, pancreas, stomach, and liver. A wide morphologic spectrum of clinical appearances has been described in cutaneous metastases. This variable clinical morphology included nodules, papules, plaques, tumors, and ulcers. From a histopathologic point of view, there are 4 main morphologic patterns of cutaneous metastases involving the dermis, namely, nodular, infiltrative, diffuse, and intravascular. Generally, cutaneous metastases herald a poor prognosis. The average survival time of patients with skin metastases is a few months. In this article, we review the clinicopathologic and immunohistochemical characteristics of cutaneous metastases from internal malignancies, classify the most common cutaneous metastases, and identify studies that may assist in diagnosing the origin of a cutaneous metastasis.