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Current Topics in Cutaneous Melanoma

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2015) | Viewed by 87980

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Dr. Chyi-Chia Richard Lee

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Laboratory of Pathology, National Cancer Institute, Building 10, Room 2S235J, 10 Center Drive, Bethesda, MD 20892, USA
Interests: melanoma; skin cancers; dermatopathology; skin pathology; melanocytic skin lesions
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Dear Colleagues,

In regard to the diagnoses of melanoma, possible topics of interest include: histopathology and diagnostic reporting of cutaneous melanoma, diagnostic markers (immunohistochemistry and molecular methods, such as PCR, FISH, array CGH), dermatoscopy as a clinical diagnostic tool (including digital dermatoscopy), whole body skin examination with digital photography, imaging studies, etc. In regard to the treatment of melanoma, possible topics of interest may include: surgery, the therapeutic and prognostic value of lymph node dissection, chemotherapy (interferon), radiotherapy, tumor vaccines, cellular therapy (tumor infiltrating lymphocytes), gene therapy (i.e., educating T-cells that target tumor cells), etc.

Dr. Chyi-Chia Richard Lee
Guest Editor

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Keywords

melanoma
melanocytic tumors
melanocytic nevi
dermatopathology
cutaneous melanoma

Published Papers (13 papers)

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Research

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1193 KiB

Open AccessArticle

Conditional Melanoma Cancer Survival in the United States

by Ray M. Merrill and Simone Bateman

Cancers 2016, 8(2), 20; https://doi.org/10.3390/cancers8020020 - 02 Feb 2016

Cited by 15 | Viewed by 5390

Abstract

Beyond relative survival, which indicates the likelihood that patients will not die from causes associated with their cancer, conditional relative survival probabilities provide further useful prognostic information to cancer patients, tailored to the time already survived from diagnosis. This study presents conditional relative survival for melanoma patients in the United States, diagnosed during 2000–2008 and followed through 2012. Analyses are based on 62,803 male and 50,261 female cases in population-based cancer registries in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Five-year relative survival estimates are presented for melanoma patients who have already survived one, two, three, four, or five years after the initial diagnosis. Five- and ten-year relative survival decreases with age, stage at diagnosis, and is lower among males, Blacks, and Hispanics. Five-year conditional relative survival improves with each year already survived. The potential for improvement in five-year conditional relative survival is greatest for older age, males, Blacks, Hispanics, and in later staged cases. For local disease, five-year conditional relative survival was significantly lower in ages greater than 65 years and in Blacks. It was significantly higher in females, non-Hispanics, and married individuals. Age had a greater inverse relationship with five-year survival in later staged disease. A similar result occurred for females and married individuals. In contrast, non-Hispanics had better five-year survival if diagnosed with local or regional disease, but not distant disease. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessArticle

Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma

by Amrita Dasgupta and Meena Katdare

Cancers 2015, 7(3), 1586-1604; https://doi.org/10.3390/cancers7030852 - 14 Aug 2015

Cited by 4 | Viewed by 6900

Abstract

Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessArticle

Treatment of Regional Metastatic Melanoma of Unknown Primary Origin

by Elke J. A. H. Van Beek, Alfons J. M. Balm, Omgo E. Nieweg, Olga Hamming-Vrieze, Peter J. F. M. Lohuis and W. Martin C. Klop

Cancers 2015, 7(3), 1543-1553; https://doi.org/10.3390/cancers7030849 - 10 Aug 2015

Cited by 8 | Viewed by 5138

Abstract

(1) Background: The purpose of this retrospective study was to evaluate the recurrence and survival rates of metastatic melanoma of unknown primary origin (MUP), in order to further refine current recommendations for the surgical treatment; (2) Methods: Medical data of all MUP patients registered between 2000 and 2011, were analyzed. Seventy-eight patients were categorized in either lymph node (axilla, groin, head-and neck) or subcutaneous MUP. Axillary node MUPs were generally treated with dissections of levels I-III, inguinal node MUPs with combined superficial and deep groin dissections, and head-and-neck node MUPs with neck dissections to various extents, based on lymph drainage patterns. Subcutaneous lesions were excised with 1–2 cm margins. The primary outcome was treatment outcomes in terms of (loco)regional recurrence and survival rates; (3) Results: Lymph node MUP recurred regionally in 11% of patients, with an overall recurrence rate of 45%. In contrast, subcutaneous MUP recurred locally in 65% of patients with an overall recurrence rate of 78%. This latter group had a significantly shorter disease-free interval than patients with lymph node MUP (p = 0.000). In the entire study population, 5-year and 10-year overall survival rates were 56% and 47% respectively, with no differences observed between the various subgroups; (4) Conclusion: The relatively low regional recurrence rate after regional lymph node dissection (11%) supports its current status as standard surgical treatment for lymph node MUP. Subcutaneous MUP, on the contrary, appears to recur both locally (65%) and overall (78%) at a significantly higher rate, suggesting a different biological behavior. However, wide local excision remains the best available option for this specific group. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessArticle

Claudin11 Promoter Hypermethylation Is Frequent in Malignant Melanoma of the Skin, but Uncommon in Nevus Cell Nevi

by Sara K. Walesch, Antje M. Richter, Peter Helmbold and Reinhard H. Dammann

Cancers 2015, 7(3), 1233-1243; https://doi.org/10.3390/cancers7030834 - 07 Jul 2015

Cited by 22 | Viewed by 4824

Abstract

Epigenetic inactivation of tumor-related genes is an important characteristic in the pathology of human cancers, including melanomagenesis. We analyzed the epigenetic inactivation of Claudin 11 (CLDN11) in malignant melanoma (MM) of the skin, including six melanoma cell lines, 39 primary melanoma, 41 metastases of MM and 52 nevus cell nevi (NCN). CLDN11 promoter hypermethylation was found in 19 out of 39 (49%) of the primary MM and in 21 out of 41 (51%) of the MM metastases, but only in eight out of 52 (15%) of NCN (p = 0.001 and p = 0.0003, respectively). Moreover, a significant increase in the methylation level of CLDN11 from primary melanomas to MM metastases was revealed (p = 0.003). Methylation of CLDN11 was significantly more frequent in skin metastases (79%) compared to brain metastases (31%; p = 0.007). CLDN11 methylation was also found in five out of six MM cell lines (83%) and its promoter hypermethylation correlated with a reduced expression. Treatment of MM cell lines with a DNA methylation inhibitor reactivated CLDN11 transcription by its promoter demethylation. In summary, CLDN11 proved to be an epigenetically inactivated tumor related gene in melanomagenesis, and analysis of CLDN11 methylation level represents a potential tool for assisting in the discrimination between malignant melanoma and nevus cell nevi. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessArticle

Oncogenic BRAF(V600E) Induces Clastogenesis and UVB Hypersensitivity

by Dennis A. Simpson, Nathalay Lemonie, David S. Morgan, Shobhan Gaddameedhi and William K. Kaufmann

Cancers 2015, 7(2), 1072-1090; https://doi.org/10.3390/cancers7020825 - 17 Jun 2015

Cited by 1 | Viewed by 7182

Abstract

The oncogenic BRAF(V600E) mutation is common in melanomas as well as moles. The roles that this mutation plays in the early events in the development of melanoma are poorly understood. This study demonstrates that expression of BRAF(V600E) is not only clastogenic, but synergizes for clastogenesis caused by exposure to ultraviolet radiation in the 300 to 320 nM (UVB) range. Expression of BRAF(V600E) was associated with induction of Chk1 pS280 and a reduction in chromatin remodeling factors BRG1 and BAF180. These alterations in the Chk1 signaling pathway and SWI/SNF chromatin remodeling pathway may contribute to the clastogenesis and UVB sensitivity. These results emphasize the importance of preventing sunburns in children with developing moles. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessArticle

A Possible Association between Melanoma and Prostate Cancer. Results from a Case-Control-Study

by Alina Goldenberg, Shang I. Brian Jiang and Philip R. Cohen

Cancers 2015, 7(2), 670-678; https://doi.org/10.3390/cancers7020670 - 15 Apr 2015

Cited by 7 | Viewed by 5938

Abstract

Melanoma and prostate cancer are the fifth and first most common cancers in men within the United States, respectively. The association between the two cancers lies in the mutual androgen-dependence. However, the relationship between prostate cancer history and melanoma development remains to be further elucidated. We aim to determine the odds of history of prostate cancer among men with melanoma as compared to time-frame, clinic, and provider-matched controls without melanoma within a single academic surgical center. We present a case-control study comparing men treated for melanoma and non-melanoma cancer by a single provider between 2010 and 2014 within an academic dermatologic surgical center. Overall, there were nine cases of prostate cancer among the melanoma group and two cases amongst the controls—a statistically significant difference in both uni- and multivariable analyses (p = 0.057 [95% CI 1, 23.5], p = 0.042 [95% CI 1.1, 129], respectively). Body mass index, alcohol use, and skin type II were significant risk factors for melanoma (p = 0.011 [95% CI 1, 1.3], 0.005 [95% CI 1.4, 7], 0.025 [95% CI 1.1, 3.3], respectively). There were more immunosuppressed controls (p = 0.002); however, the melanoma patients had a significantly longer duration of immunosuppression (11.6 vs. 1.9 years, p < 0.001 [95% CI 0.03, 0.5]). Melanoma screenings for men should include questions on prostate cancer history. Prostate cancer patients may benefit from more frequent and comprehensive melanoma screening. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Review

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Open AccessReview

Melanoma and the Unfolded Protein Response

by Erin K. Sykes, Swetlana Mactier and Richard I. Christopherson

Cancers 2016, 8(3), 30; https://doi.org/10.3390/cancers8030030 - 27 Feb 2016

Cited by 35 | Viewed by 8573

Abstract

The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and poor outcome in melanoma patients. The proliferative burden of cancer induces stress and activates several cellular stress responses. The UPR is a tightly orchestrated stress response that is activated upon the accumulation of unfolded proteins within the ER (endoplasmic reticulum). The UPR is designed to mediate two conflicting outcomtes, recovery and apoptosis. As a result, the UPR initiates a widespread signaling cascade to return the cell to homeostasis and failing to achieve cellular recovery, initiates UPR-induced apoptosis. There is evidence that ER stress and subsequently the UPR promote tumourigenesis and metastasis. The complete role of the UPR has yet to be defined. Understanding how the UPR allows for adaption to stress and thereby assists in cancer progression is important in defining an archetype of melanoma pathology. In addition, elucidation of the mechanisms of the UPR may lead to development of effective treatments of metastatic melanoma. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

Updates in Therapy for Advanced Melanoma

by Bhavana P. Singh and April K. S. Salama

Cancers 2016, 8(1), 17; https://doi.org/10.3390/cancers8010017 - 15 Jan 2016

Cited by 43 | Viewed by 7339

Abstract

Cutaneous melanoma is one of the most aggressive forms of skin cancer, and is correlated with a large proportion of skin cancer-related deaths. Therapy for cutaneous melanoma has advanced greatly through careful identification of therapeutic targets and the development of novel immunotherapeutic approaches. The identification of BRAF as well as other driver mutations, have allowed for a specialized approach to treatment. In addition, immune checkpoint inhibition has dramatically changed the treatment landscape over the past 5–10 years. The successful targeting of CTLA-4, as well as PD-1/PD-L1, has been translated into meaningful clinical benefit for patients, with multiple other potential agents in development. Systemic therapy for cutaneous melanoma is becoming more nuanced and often takes a multifaceted strategy. This review aims to discuss the benefits and limitations of current therapies in systemic melanoma treatment as well as areas of future development. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy

by Stuart J Gallagher, Jessamy C Tiffen and Peter Hersey

Cancers 2015, 7(4), 1959-1982; https://doi.org/10.3390/cancers7040870 - 25 Sep 2015

Cited by 33 | Viewed by 8076

Abstract

The treatment of melanoma has been revolutionized by new therapies targeting MAPK signaling or the immune system. Unfortunately these therapies are hindered by either primary resistance or the development of acquired resistance. Resistance mechanisms involving somatic mutations in genes associated with resistance have been identified in some cases of melanoma, however, the cause of resistance remains largely unexplained in other cases. The importance of epigenetic factors targeting histones and histone modifiers in driving the behavior of melanoma is only starting to be unraveled and provides significant opportunity to combat the problems of therapy resistance. There is also an increasing ability to target these epigenetic changes with new drugs that inhibit these modifications to either prevent or overcome resistance to both MAPK inhibitors and immunotherapy. This review focuses on changes in histones, histone reader proteins and histone positioning, which can mediate resistance to new therapeutics and that can be targeted for future therapies. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

Therapy for BRAFi-Resistant Melanomas: Is WNT5A the Answer?

by Chandra Prakash Prasad, Purusottam Mohapatra and Tommy Andersson

Cancers 2015, 7(3), 1900-1924; https://doi.org/10.3390/cancers7030868 - 17 Sep 2015

Cited by 18 | Viewed by 6258

Abstract

In recent years, scientists have advocated the use of targeted therapies in the form of drugs that modulate genes and proteins that are directly associated with cancer progression and metastasis. Malignant melanoma is a dreadful cancer type that has been associated with the rapid dissemination of primary tumors to multiple sites, including bone, brain, liver and lungs. The discovery that approximately 40%–50% of malignant melanomas contain a mutation in BRAF at codon 600 gave scientists a new approach to tackle this disease. However, clinical studies on patients have shown that although BRAFi (BRAF inhibitors) trigger early anti-tumor responses, the majority of patients later develop resistance to the therapy. Recent studies have shown that WNT5A plays a key role in enhancing the resistance of melanoma cells to BRAFi. The focus of the current review will be on melanoma development, signaling pathways important to acquired resistance to BRAFi, and why WNT5A inhibitors are attractive candidates to be included in combinatorial therapies for melanoma. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

Vitamins and Melanoma

by Irene Russo, Francesca Caroppo and Mauro Alaibac

Cancers 2015, 7(3), 1371-1387; https://doi.org/10.3390/cancers7030841 - 24 Jul 2015

Cited by 22 | Viewed by 5922

Abstract

A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus on the role played by vitamins in melanoma with particular regard to vitamin A, D, K, E and C. Given that vitamin supplementation is easy, convenient, and readily accepted by patients, in the future the use of vitamins in chemoprevention and therapy of melanoma could be encouraged if supported by pre-clinical and clinical evidence. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

The Role of Regional Therapies for in-Transit Melanoma in the Era of Improved Systemic Options

by Emmanuel Gabriel and Joseph Skitzki

Cancers 2015, 7(3), 1154-1177; https://doi.org/10.3390/cancers7030830 - 01 Jul 2015

Cited by 25 | Viewed by 4857

Abstract

The incidence of melanoma has been increasing at a rapid rate, with 4%–11% of all melanoma recurrences presenting as in-transit disease. Treatments for in-transit melanoma of the extremity are varied and include surgical excision, lesional injection, regional techniques and systemic therapies. Excision to clear margins is preferred; however, in cases of widespread disease, this may not be practical. Historically, intralesional therapies were generally not curative and were often used for palliation or as adjuncts to other therapies, but recent advances in oncolytic viruses may change this paradigm. Radiation as a regional therapy can be quite locally toxic and is typically relegated to disease control and symptom relief in patients with limited treatment options. Regional therapies such as isolated limb perfusion and isolated limb infusion are older therapies, but offer the ability to treat bulky disease for curative intent with a high response rate. These techniques have their associated toxicities and can be technically challenging. Historically, systemic therapy with chemotherapies and biochemotherapies were relatively ineffective and highly toxic. With the advent of novel immunotherapeutic and targeted small molecule agents for the treatment of metastatic melanoma, the armamentarium against in-transit disease has expanded. Given the multitude of options, many different combinations and sequences of therapies can be offered to patients with in-transit extremity melanoma in the contemporary era. Reported response and survival rates of the varied treatments may offer valuable information regarding treatment decisions for patients with in-transit melanoma and provide rationale for these decisions. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

Sarcoidosis in Melanoma Patients: Case Report and Literature Review

by Bryce D. Beutler and Philip R. Cohen

Cancers 2015, 7(2), 1005-1021; https://doi.org/10.3390/cancers7020821 - 15 Jun 2015

Cited by 36 | Viewed by 10009

Abstract

Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated sarcoidosis. In addition, we not only review the literature describing characteristics of other melanoma patients with sarcoidosis, but also the features of melanoma patients with antineoplastic therapy-associated sarcoidosis. Sarcoidosis has been described in 80 melanoma patients; sufficient information for analysis was provided in 39 of these individuals. In 43.6% of individuals (17 out of 39), sarcoidosis was directly associated with melanoma; in 56.4% of oncologic patients (22 out of 39), sarcoidosis was induced by antineoplastic therapy that had been administered for the treatment of their metastatic melanoma. The discovery of melanoma preceded the development of sarcoidosis in 12 of the 17 (70.5%) individuals who did not receive systemic treatment. Pulmonary and/or cutaneous manifestations of sarcoidosis were common among both groups of patients. Most patients did not require treatment for sarcoidosis. Melanoma patients—either following antineoplastic therapy or without systemic treatment—may be at an increased risk to develop sarcoidosis. In antineoplastic therapy naive melanoma patients, a common etiologic factor—such as exposure to ultraviolet light—may play a role in their developing melanoma and sarcoidosis. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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