Femtosecond pulsed laser photodynamic therapy activates melanin and eradicates malignant melanoma.

Photodynamic therapy (PDT) relies on a series of photophysical and photochemical reactions leading to cell death. While effective for various cancers, PDT has been less successful in treating pigmented melanoma due to high light absorption by melanin. Here, this limitation is addressed by 2-photon excitation of the photosensitizer (2p-PDT) using ~100 fs pulses of near-infrared laser light. A critical role of melanin in enabling rather than hindering 2p-PDT is elucidated using pigmented and non-pigmented murine melanoma clonal cell lines in vitro. The photocytotoxicities were compared between a clinical photosensitizer (Visudyne) and a porphyrin dimer (Oxdime) with ~600-fold higher σ2p value. Unexpectedly, while the 1p-PDT responses are similar in both cell lines, 2p activation is much more effective in killing pigmented than non-pigmented cells, suggesting a dominant role of melanin 2p-PDT. The potential for clinical translational is demonstrated in a conjunctival melanoma model in vivo, where complete eradication of small tumors was achieved. This work elucidates the melanin contribution in multi-photon PDT enabling significant advancement of light-based treatments that have previously been considered unsuitable in pigmented tumors.

RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma.

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.

Unusual Presentation of Unilateral Choroidal Melanoma with Bilateral Vasculitis in Young Individual: A Case Report and Review of Literature.

Ocular melanoma stands as the predominant primary intraocular malignancy, albeit infrequently exhibiting ipsilateral inflammatory manifestations. In this article, we present an exceptional case involving a middle-aged male who presented with unilateral ocular choroidal melanoma alongside bilateral retinal vasculitis. The patient initially received temporary steroid treatment, followed by brachytherapy, which contributed to the resolution of vasculitis symptoms. The study aims to document the atypical occurrence of bilateral retinal vasculitis, which could potentially masquerade as melanoma, emphasizing the need for heightened vigilance and further investigations when encountering choroidal masses in its presence. Future research endeavors are warranted to better understand the incidence of such occurrences in this context.

Multiple neoplasms in patients with uveal melanoma: a systematic review.

PURPOSE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients. METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms. RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin's lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies. CONCLUSION: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.

Oncoviruses and melanomas: A retrospective study and literature review.

The role of human oncoviruses in melanoma has been poorly investigated. The aim of this study was to investigate the association between oncoviruses and melanomas searching for human papillomavirus (HPV), Epstein Barr virus (EBV), and human herpesvirus 8DNA in melanoma specimens. Formalin-fixed and paraffin-embedded tissue specimens of cutaneous, mucosal, and ocular melanomas (OM) were selected from the Pathology Departments of the Galliera Hospital (Genoa) and the University Hospitals of Turin and Cagliari. Cutaneous and mucosal nevi have been collected as controls. The oncoviruses search has been performed with different polymerase chain reaction reagent kits. Fifty-four melanomas (25 mucosal, 12 ocular, and 17 cutaneous) and 26 nevi (15 cutaneous and 11 mucosal) specimens were selected. The detection rate for one of the investigated oncoviruses was 17% in mucosal, 20% in ocular, and 0% in cutaneous melanomas (CMs). Despite the differences between groups seeming remarkable, there was no statistical significance (p > 0.5). Our data do not support a primary role of oncoviruses in melanoma carcinogenesis; however, the finding of HPV and EBV DNA in a considerable fraction of mucosal and OMs suggests that these viruses may act as cofactors in the development of extra-CMs.

Emerging roles of microRNAs and their implications in uveal melanoma.

Uveal melanoma (UM) is the most common intraocular malignant tumor in adults with an extremely high mortality rate. Genetic and epigenetic dysregulation contribute to the development of UM. Recent discoveries have revealed dysregulation of the expression levels of microRNAs (miRNAs) as one of the epigenetic mechanisms underlying UM tumorigenesis. Based on their roles, miRNAs are characterized as either oncogenic or tumor suppressive. This review focuses on the roles of miRNAs in UM tumorigenesis, diagnosis, and prognosis, as well as their therapeutic potentials. Particularly, the actions of collective miRNAs are summarized with respect to their involvement in major, aberrant signaling pathways that are implicated in the development and progression of UM. Elucidation of the underlying functional mechanisms and biological aspects of miRNA dysregulation in UM is invaluable in the development of miRNA-based therapeutics, which may be used in combination with conventional treatments to improve therapeutic outcomes. In addition, the expression levels of some miRNAs are correlated with UM initiation and progression and, therefore, may be used as biomarkers for diagnosis and prognosis.

Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.

Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma.

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.

Is it necessary to perform eye examination for patients with cutaneous atypical nevi?

Regular dermatological examination for patients with dysplastic nevi is indicated. However, the literature on whether those patients should also be examined by ophthalmologists or not regarding a relation between suspicious lesions for ocular melanoma and cutaneous dysplastic nevi is limited. In this study, we aimed to compare the findings of a single ophthalmologic examination between the group of patients with multiple atypical nevi with at least one histopathologically proven dysplastic nevus and another group without atypical nevi. We examined the eyes of 110 patients with multiple atypical nevi with at least one histopathologically proven dysplastic nevus (47 had the diagnosis of dysplastic nevus syndrome type A, B, C, D1 or D2) for any lesion and compared the results with a control group consisted of 110 gender, age and skin-type matched patients without atypical nevi no ocular melanoma was detected in any of the groups. The frequency of the conjunctival nevi, iris nevi, choroidal nevi and conjunctival acquired melanosis were similar in both groups. Iris freckles were detected more frequently in the study group. Conjunctival racial hyperpigmentation was detected more frequently in the control group (P < .05). In this study, any significant difference in the distribution of the ocular lesions with any risk of malignancy in the study and control groups was not observed. However, considering the limitations of the study, there may still be a need of regular ophthalmic examination for the patients with atypical nevi in case of having high risk factors for developing melanoma.

Optic disc dose reduction in ocular brachytherapy using 125 I notched COMS plaques: A simulation study based on current clinical practice.

PURPOSE: Although notched Collaborative Ocular Melanoma Study (COMS) plaques have been widely used, optic disc dose reduction by notched COMS plaques has not been discussed in the literature. Therefore, this study investigated optic disc dose reduction in ocular brachytherapy using 125 I notched COMS plaques in comparison with optic disc dose for 125 I standard COMS plaques. METHODS: For this simulation study, an in-house brachytherapy dose calculation program was developed using MATLAB software by incorporating the American Association of Physicists in Medicine Task Group-43 Update (AAPM TG-43U1) dosimetry formalism with a line source approximation in a homogeneous water medium and COMS seed coordinates in the AAPM TG 129. Using this program, optic disc doses for standard COMS plaques (from 12 to 22 mm in diameter in 2 mm increments) and notched COMS plaques with one seed removed (Case #1, from 12 to 22 mm) and with two seeds removed (Case #2, from 14 to 22 mm) were calculated as a function of tumor margin-to-optic disc distance (DT) for various tumor basal dimensions (BDs) for prescription depths from 1 to 10 mm in 1 mm intervals. A dose of 85 Gy for an irradiation time of 168 h was prescribed to each prescription depth. Then absolute and relative optic disc dose reduction by notched COMS plaques (Cases #1 and #2) was calculated for all prescription depths. RESULTS: Optic disc dose reduction by notched COMS plaques (Cases #1 and #2) had five unique trends related to maximum optic disc dose reduction and corresponding optimal DT for each BD in each plaque. It increased with increasing prescription depth. CONCLUSIONS: The results presented in this study would enable the clinician to choose an adequate plaque type among standard and notched 125 I COMS plaques and a prescription depth to minimize optic disc dose.

Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing.

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. These malignancies derive from melanocytes in the uveal tract or conjunctiva. The genetic profiles of these different entities differ from each other. In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes. Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described. The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well. The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are. Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment.

Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know.

Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients.

The Role of Immune Checkpoint Blockade in Uveal Melanoma.

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

Natural killer cells and pigment epithelial-derived factor control the infiltrative and nodular growth of hepatic metastases in an Orthotopic murine model of ocular melanoma.

BACKGROUND: Metastases account for 90% of all cancer-related deaths, becoming a therapeutic problem. Approximately 50% of all uveal melanoma (UM) patients will develop metastases, mainly in the liver. Post-mortem analyses of livers from metastatic UM patients showed two different metastatic growth patterns: infiltrative and nodular. The infiltrative pattern exhibits tumor infiltration directly to the hepatic lobule and minimal angiogenesis. The nodular pattern shows clusters of tumor cells around the portal venules that efface the liver parenchyma. We recently demonstrated Natural Killer (NK) cells play a pivotal role in the control of hepatic metastases and the pigment epithelial-derived factor (PEDF) controls angiogenesis in the liver using our established ocular melanoma animal model. In this study we investigated the role of NK cells and PEDF in the development of metastatic growth patterns, as this can contribute to the development of novel therapeutics specific towards each growth pattern. METHODS: We utilize our established ocular melanoma animal model by inoculation of B16-LS9 melanoma cells into C57BL/6 J mice (WT), anti-asialo GM1-treated C57BL/6 J mice (NK-depleted), and PEDF-/- C57BL/6 J mice. Three weeks after inoculation we evaluated the metastatic growth patterns and stratified them based of the numbers of tumor cells. To evaluate angiogenesis the mean vascular density (MVD) was calculated. The immune compartment of the liver was analyzed by flow cytometry. RESULTS: Our in vivo work showed two distinct metastatic growth patterns, the infiltrative and nodular, recapitulating the post-mortem analyses on human liver tissue. We discovered NK cells control the infiltrative growth. In contrast, PEDF controlled anti-angiogenic responses, showing higher MVD values compared to NK-depleted and WT animals. The myeloid lineage, comprised of monocytes, macrophages, and myeloid-derived suppressor cells, was reduced in the absence of NK cells or PEDF. CONCLUSIONS: Our animal model recapitulates the metastatic growth patterns observed in the human disease. We demonstrated a role for NK cells in the development of the infiltrative growth pattern, and a role for PEDF in the development of the nodular pattern. The understanding of the complexity associated with the metastatic progression has profound clinical implications in the diagnostic and disease-management as we can develop and direct more effective therapies.

Non-invasive dynamic assessment of conjunctival melanomas by photoacoustic imaging.

This study describes non-invasive photoacoustic imaging to detect and monitor the growth of conjunctival melanomas in vivo. Conjunctival melanomas were induced by injection of melanotic B16F10 cells into the subconjunctival space in syngeneic albino C57BL/6 mice. Non-invasive in vivo photoacoustic tomography was performed before, and after tumor induction up to 2 weeks. Spectral unmixing was performed to determine the location and to assess the distribution of melanin. The melanin photoacoustic signal intensity was quantified from the tumor-bearing and control eyes at all timepoints. For postmortem validation, total tumor and melanotic tumor volumes were measured using H&E stained tumor sections and were compared to in vivo photoacoustic imaging measurements. Photoacoustic imaging non-invasively detected eyes bearing conjunctival tumors of varying sizes. The melanin signal was detected as early as immediately following injection of melanotic tumor cells. Changes in tumor size over time were assessed with changes in the volume and intensity of the melanin signal. Four growing tumors and one regressing tumor were observed. Three tumors without significant change in signal intensity over time were observed, showing variable growth. Photoacoustic melanin signal on the last day of in vivo imaging correlated with postmortem total tumor volume (R2 = 0.81) and melanotic tumor volume (R2 = 0.80). The results of our study show that actively growing conjunctival melanomas can be quantified in a non-invasive manner using in vivo photoacoustic tomography. The photoacoustic melanin signal intensity correlated with total and melanotic tumor volume. This novel in vivo imaging platform may help to assess new treatment modalities to manage ocular tumors.

Conservative management of suspicious melanocytic lesions of the iris.

PURPOSE: The diagnosis of iris melanoma can be difficult, with no established diagnostic criteria currently available. Careful monitoring of patients with suspicious iris lesions is one approach to managing these tumors. We determined the risk of malignant transformation and melanoma-related mortality in patients under observation to evaluate the validity of this management approach. METHODS: This was a retrospective chart review of patients with suspicious iris lesions diagnosed at Massachusetts Eye and Ear Infirmary (MEE) between 1975 and 2014. All patients with an initial diagnosis of suspicious iris lesion followed and/or treated after malignant transformation at the MEE in this 39-year period were included in the cohort. Rates of malignant transformation and melanoma-related mortality were calculated. Treatment outcomes after proton beam irradiation were evaluated in patients who developed iris melanomas during observation. RESULTS: Two hundred thirty-four patients had a diagnosis of suspicious iris lesion (median follow-up, 5.8 years). Malignant transformation occurred in 16 (6.8%) patients with suspicious lesions during the observation period (median follow-up, 9.9 years). All patients diagnosed with iris melanomas were treated with proton beam irradiation (PBI). Complications after treatment included cataract (18.8%), secondary glaucoma (6.3%), and neovascular glaucoma (12.5%). Two of 16 patients (12.5%) who developed iris melanomas died of metastatic melanoma 32.6 months and 10 years after treatment with PBI. Both cases had been followed regularly to monitor for malignant transformation of their suspicious lesions (8.2 years and 3.2 years before melanoma diagnosis, respectively). CONCLUSIONS: These data suggest that suspicious iris lesions have low malignant potential, and a conservative approach to the management of these lesions is appropriate. Survival does not appear to be compromised with an observational approach, and there is potential for preservation of good visual function because vision-threatening treatments can be avoided.

Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma.

BACKGROUND AND OBJECTIVES: Ocular melanoma has a predilection for liver metastases. Systemic treatment is ineffective and the optimal regional therapy approach is poorly defined. Isolated hepatic perfusion (IHP) with melphalan has emerged as a viable treatment option, however a subset of patients are not candidates for this treatment. We therefore sought to determine if melphalan could be safely administered via the hepatic artery for these patients. METHODS: A retrospective review of patients treated with hepatic artery infusion (HAI) of melphalan was undertaken. All patients had contraindications to IHP and were without other therapy options. Melphalan infusion was repeated every four weeks with consideration for dose escalation in the absence of toxicity or significant disease progression. RESULTS: Fourteen patients were treated with HAI of melphalan from 2010 to 2015. All patients had hepatic dysfunction or prohibitive tumor volume precluding IHP. There were no procedure-related complications. Three patients (21%) died within 30 days and the median survival was 2.9 months. Elevated baseline bilirubin > 2.5 mg/dL was associated with worse overall survival (0.93 vs 6.3 months, P < 0.05). CONCLUSION: HAI of melphalan is safe and feasible for patients with metastatic ocular melanoma. Further study to determine the optimal utilization of this treatment approach is warranted.

Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy-From Animal Models to Clinical Trials.

The focus of the present review is to investigate the role of melanin in the radioprotection of melanoma and attempts to sensitize tumors to radiation by inhibiting melanogenesis. Early studies showed radical scavenging, oxygen consumption and adsorption as mechanisms of melanin radioprotection. Experimental models of melanoma in hamsters and in gerbils are described as well as their use in biochemical and radiobiological studies, including a spontaneously metastasizing ocular model. Some results from in vitro studies on the inhibition of melanogenesis are presented as well as radio-chelation therapy in experimental and clinical settings. In contrast to cutaneous melanoma, uveal melanoma is very successfully treated with radiation, both using photon and proton beams. We point out that the presence or lack of melanin pigmentation should be considered, when choosing therapeutic options, and that both the experimental and clinical data suggest that melanin could be a target for radiosensitizing melanoma cells to increase efficacy of radiotherapy against melanoma.

Metastatic Melanoma of the Optic Nerve Sheath.

A 23-year-old man with a history of metastatic melanoma developed painful vision loss to counting fingers with enhancement of optic nerve on contrast-enhanced magnetic resonance imaging (MRI) and received a diagnosis of optic neuritis from an outside hospital. Despite empiric corticosteroid therapy, the patient worsened and developed secondary central retinal vein occlusion with further deterioration of vision. Repeat MRI demonstrated optic nerve sheath (ONS) involvement suggestive of optic perineuritis (OPN) and an ONS biopsy confirmed a rare case of isolated metastatic melanoma. Our case highlights the clinical and radiographic features that can mimic OPN and delay diagnosis and treatment.

[Treatment of metastatic progression following the synchronous occurrence of cutaneous and ocular primary melanomas]. / Metasztatikus progresszió kezelése primer cutan és ocularis melanoma szinkrón elofordulását követoen.

The incidence rates of cutaneous melanoma in non-Hispanic whites show an increasing tendency with age. While uveal melanoma in general is a rare disease, representing only 4% of all melanomas with an incidence rate of 0.6 per 100 000, it is still the most frequent malignancy of the eye. Synchronous occurrence of ocular and cutaneous melanoma is an exceptional rarity, due to the distinct genetic background of the diseases. We report the case of a 80-year-old man who underwent total excision of a cutaneous melanoma in 2008. In 2013, he was diagnosed with uveal melanoma as part of a routine work-up for reduced vision. The uveal melanoma was treated by brachytherapy. In 2015, liver metastases were suspected by routine ultrasonography. Core biopsy was carried out, and the histology confirmed melanoma metastases. The molecular analysis of the cutaneous lesion showed gain of function mutation of the BRAF V600 K gene, while we found a wild-type BRAF gene in the metastatic lesion. Based on the recommendation of the oncoteam, hepatic intra-arterial Epirubicin-Platidiam therapy was introduced. He received 11 doses of intra-arterial chemotherapy (IAC), in 21 cycles. IAC was well tolerated without any catheter-related complications or toxicities. Partial regression of the hepatic metastases were documented in February 2016. After completing the eleventh cycle of intrahepatic chemotherapy, the disease remained in complete remission for over a year. The parallel occurrence of cutaneous and ocular melanoma is rare, however, the metastatic progression in such cases make the selection of optimal medical therapy challenging. The distinct genetic background of two melanoma types may help the identification of the source of the metastatic lesions, in order to guide the treatment decisions. Orv Hetil. 2018; 159(16): 642-647.