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Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 11029

Special Issue Editor

Dr. Barbara Corti

E-Mail Website
Guest Editor
Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria Policlinico di Sant’Orsola, University of Bologna, 40139 Bologna, Italy
Interests: melanoma; atypical Spitz tumor; squamous cell carcinoma; Merkel cell carcinoma; skin adnexal neoplasms; skin soft tissue tumors; histology; diagnosis; immunohistochemistry; genetics; molecular alterations; next generation sequencing

Special Issue Information

Dear Colleagues,

The new strategies for the diagnosis and treatment of cutaneous melanoma have been the focus of attention of an increasing number of scientific investigations in the last few decades. The annual incidence and morbidity of cutaneous melanoma are constantly increasing worldwide and there is a continuous need for improvement of diagnostic and therapeutic strategies.  The diagnosis of cutaneous melanoma is still mainly performed by the pathologists with the histological exam rendered on hematoxylin and eosin slides but an everyday increasing understanding of molecular biology and the pathogenesis of this tumour led to the development of new diagnostic and prognostic-therapeutic tools, which all the professional figures (surgical pathologist, dermatologist, oncologist, molecular biologist) involved in the management of this deadly disease should know. Specific immunohistochemical markers and molecular alterations represent novel diagnostic, prognostic and therapeutic targets for cutaneous melanoma. The work highlighting and defining new immunohistochemical markers (p21, p53, PRAME, double stains), genetic alterations (CDKN2A, TP53, NTRK, PRKAR1A) and tumour microenvironment (PD-L1) in cutaneous melanoma adds to the enormous body of well-knowledge in delineating the current strategies for the diagnosis and therapy of cutaneous melanoma. Original studies, reviews and research papers that highlight the current concepts and advances in diagnosis and treatment of cutaneous melanoma are welcomed.

Dr. Barbara Corti
Guest Editor

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Keywords

  • cutaneous melanoma
  • histology
  • histological diagnosis
  • immunohistochemical markers
  • immunohistochemistry
  • PRAME
  • double stains
  • genetics
  • molecular alterations
  • genetic techniques
  • fluorescence in situ hybridization (FISH)
  • next generation sequencing (NGS)
  • therapy
  • immunotherapy
  • chemotherapy
  • PD-L1
  • anti PD-1/PD-L1

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Published Papers (5 papers)

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Research

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12 pages, 11403 KiB  
Article
Standardized Computer-Assisted Analysis of 5-hmC Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas
by Elias A. T. Koch, Carola Berking, Ramona Erber, Michael Erdmann, Franklin Kiesewetter, Stefan Schliep and Markus V. Heppt
Int. J. Mol. Sci. 2023, 24(19), 14711; https://doi.org/10.3390/ijms241914711 - 28 Sep 2023
Cited by 1 | Viewed by 938
Abstract
5-Hydroxymethylcytosine (5-hmC) is an important intermediate of DNA demethylation. Hypomethylation of DNA is frequent in cancer, resulting in deregulation of 5-hmC levels in melanoma. However, the interpretation of the intensity and distribution of 5-hmC immunoreactivity is not very standardized, which makes its interpretation [...] Read more.
5-Hydroxymethylcytosine (5-hmC) is an important intermediate of DNA demethylation. Hypomethylation of DNA is frequent in cancer, resulting in deregulation of 5-hmC levels in melanoma. However, the interpretation of the intensity and distribution of 5-hmC immunoreactivity is not very standardized, which makes its interpretation difficult. In this study, 5-hmC-stained histological slides of superficial spreading melanomas (SSM) and dysplastic compound nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. Receiver operating characteristic/area under the curve (ROCAUC) and t-tests were performed. A p-value of <0.05 was used for statistical significance, and a ROCAUC score of >0.8 was considered a “good” result. In total, 92 5-hmC-stained specimens were analyzed, including 42 SSM (45.7%) and 50 DN (54.3%). The mean of 5-hmC-positive cells/mm2 for the epidermis and dermo-epidermal junction and the entire lesion differed significantly between DN and SSM (p = 0.002 and p = 0.006, respectively) and showed a trend towards higher immunoreactivity in the dermal component (p = 0.069). The ROCAUC of 5-hmC-positive cells of the epidermis and dermo-epidermal junction was 0.79, for the dermis 0.74, and for the entire lesion 0.76. These results show that the assessment of the epidermal with junctional expression of 5-hmC is slightly superior to dermal immunoreactivity in distinguishing between DN and SSM. Full article
(This article belongs to the Special Issue Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma)
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9 pages, 2219 KiB  
Communication
Standardized Computer-Assisted Analysis of PRAME Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas
by Elias A. T. Koch, Michael Erdmann, Carola Berking, Franklin Kiesewetter, Rafaela Kramer, Stefan Schliep and Markus V. Heppt
Int. J. Mol. Sci. 2023, 24(7), 6388; https://doi.org/10.3390/ijms24076388 - 28 Mar 2023
Cited by 3 | Viewed by 2124
Abstract
PRAME (PReferentially expressed Antigen in MElanoma) is a cancer testis antigen that is frequently expressed in melanoma compared to benign melanocytic proliferations and nevi. However, the interpretation of the intensity and distribution of PRAME immunostaining is not standardized a lot, which makes interpretation [...] Read more.
PRAME (PReferentially expressed Antigen in MElanoma) is a cancer testis antigen that is frequently expressed in melanoma compared to benign melanocytic proliferations and nevi. However, the interpretation of the intensity and distribution of PRAME immunostaining is not standardized a lot, which makes interpretation difficult. PRAME-stained histological slides of superficial spreading melanomas (SSM) and dysplastic nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. t-tests and ROC AUCs were performed with SPSS. A p-value of <0.05 was used for statistical significance, and a ROC AUC score of >0.8 was considered a good result. A cut-off score was defined in an evaluation cohort and subsequently analyzed in an independent validation cohort. In total, 81 PRAME-stained specimens were included. The evaluation cohort included 32 (50%) SSM and 32 (50%) DN, and the mean of PRAME-positive cells/mm2 for the entire lesion was 455.3 (SD 428.2) in SSM and 60.5 (SD 130.1; p < 0.001) in DN. The ROC AUC of PRAME-positive cells of the entire lesion was 0.866, and in the epidermis it was 0.901. The defined cut-off score to distinguish between DN and SSM was 97.67 cells/mm2. In the validation cohort, 16 out of 17 cases (94.1%) were correctly classified by the cut-off score. The computer-aided assessment of PRAME immunostaining is a useful tool in dermatopathology to distinguish between DN and SSM. Lesions with a moderate expression and indifferent morphologic features will remain a challenge for dermatopathologists. Full article
(This article belongs to the Special Issue Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma)
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18 pages, 6899 KiB  
Article
Integrin Targeting Enhances the Antimelanoma Effect of Annexin V in Mice
by Jingyi Zhu, Xiangning Li, Wenling Gao and Jian Jing
Int. J. Mol. Sci. 2023, 24(4), 3859; https://doi.org/10.3390/ijms24043859 - 15 Feb 2023
Cited by 3 | Viewed by 2120
Abstract
Malignant melanoma, an increasingly common form of skin cancer, is a major threat to public health, especially when the disease progresses past skin lesions to the stage of advanced metastasis. Targeted drug development is an effective strategy for the treatment of malignant melanoma. [...] Read more.
Malignant melanoma, an increasingly common form of skin cancer, is a major threat to public health, especially when the disease progresses past skin lesions to the stage of advanced metastasis. Targeted drug development is an effective strategy for the treatment of malignant melanoma. In this work, a new antimelanoma tumor peptide, the lebestatin–annexin V (designated LbtA5) fusion protein, was developed and synthesized by recombinant DNA techniques. As a control, annexin V (designated ANV) was also synthesized by the same method. The fusion protein combines annexin V, which specifically recognizes and binds phosphatidylserine, with the disintegrin lebestatin (lbt), a polypeptide that specifically recognizes and binds integrin α1β1. LbtA5 was successfully prepared with good stability and high purity while retaining the dual biological activity of ANV and lbt. MTT assays demonstrated that both ANV and LbtA5 could reduce the viability of melanoma B16F10 cells, but the activity of the fusion protein LbtA5 was superior to that of ANV. The tumor volume growth was slowed in a mouse xenograft model treated with ANV and LbtA5, and the inhibitory effect of high concentrations of LbtA5 was significantly better than that of the same dose of ANV and was comparable to that of DTIC, a drug used clinically for melanoma treatment. The hematoxylin and eosin (H&E) staining test showed that ANV and LbtA5 had antitumor effects, but LbtA5 showed a stronger ability to induce melanoma necrosis in mice. Immunohistochemical experiments further showed that ANV and LbtA5 may inhibit tumor growth by inhibiting angiogenesis in tumor tissue. Fluorescence labeling experiments showed that the fusion of ANV with lbt enhanced the targeting of LbtA5 to mouse melanoma tumor tissue, and the amount of target protein in tumor tissue was significantly increased. In conclusion, effective coupling of the integrin α1β1-specific recognition molecule lbt confers stronger biological antimelanoma effects of ANV, which may be achieved by the dual effects of effective inhibition of B16F10 melanoma cell viability and inhibition of tumor tissue angiogenesis. The present study describes a new potential strategy for the application of the promising recombinant fusion protein LbtA5 in the treatment of various cancers, including malignant melanoma. Full article
(This article belongs to the Special Issue Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma)
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Review

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22 pages, 2466 KiB  
Review
Exploring the Complex and Multifaceted Interplay between Melanoma Cells and the Tumor Microenvironment
by Magdalena Kuras
Int. J. Mol. Sci. 2023, 24(18), 14403; https://doi.org/10.3390/ijms241814403 - 21 Sep 2023
Cited by 5 | Viewed by 2139
Abstract
Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our [...] Read more.
Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our understanding of melanoma biology has increased profoundly, and disease management for patients with disseminated disease has improved due to the emergence of immunotherapy and targeted therapy. However, a significant fraction of patients relapse or do not respond adequately to treatment. This can partly be explained by the complex signaling between the tumor and its microenvironment, giving rise to melanoma phenotypes with different patterns of disease progression. This review focuses on the key aspects and complex relationship between pathogenesis, genetic abnormalities, tumor microenvironment, cellular plasticity, and metabolic reprogramming in melanoma. By acquiring a deeper understanding of the multifaceted features of melanomagenesis, we can reach a point of more individualized and patient-centered disease management and reduced costs of ineffective treatments. Full article
(This article belongs to the Special Issue Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma)
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18 pages, 4155 KiB  
Review
Cutaneous Melanomas: A Single Center Experience on the Usage of Immunohistochemistry Applied for the Diagnosis
by Costantino Ricci, Emi Dika, Francesca Ambrosi, Martina Lambertini, Giulia Veronesi and Corti Barbara
Int. J. Mol. Sci. 2022, 23(11), 5911; https://doi.org/10.3390/ijms23115911 - 25 May 2022
Cited by 19 | Viewed by 3123
Abstract
Cutaneous melanoma (cM) is the deadliest of all primary skin cancers. Its prognosis is strongly influenced by the stage at diagnosis, with early stages having a good prognosis and being potentially treatable with surgery alone; advanced stages display a much worse prognosis, with [...] Read more.
Cutaneous melanoma (cM) is the deadliest of all primary skin cancers. Its prognosis is strongly influenced by the stage at diagnosis, with early stages having a good prognosis and being potentially treatable with surgery alone; advanced stages display a much worse prognosis, with a high rate of recurrence and metastasis. For this reason, the accurate and early diagnosis of cM is crucial—misdiagnosis may have extremely dangerous consequences for the patient and drastically reduce their chances of survival. Although the histological exam remains the “gold standard” for the diagnosis of cM, a continuously increasing number of immunohistochemical markers that could help in diagnosis, prognostic characterization, and appropriate therapeutical choices are identified every day, with some of them becoming part of routine practice. This review aims to discuss and summarize all the data related to the immunohistochemical analyses that are potentially useful for the diagnosis of cM, thus rendering it easier to appropriately applicate to routine practice. We will discuss these topics, as well as the role of these molecules in the biology of cM and potential impact on diagnosis and treatment, integrating the literature data with the experience of our surgical pathology department. Full article
(This article belongs to the Special Issue Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma)
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