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Advances in Understanding Spontaneously Occurring Melanoma in Animals

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A special issue of Veterinary Sciences (ISSN 2306-7381). This special issue belongs to the section "Veterinary Biomedical Sciences".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 71335

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Special Issue Editors

Dr. Louise van der Weyden

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Guest Editor

Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Interests: oncology; cancer; metastasis; cancer genetics; cancer genomics; comparative oncology; comparative genomics; animal models of cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Kelly Lisa Bowlt Blacklock

E-Mail Website
Guest Editor

The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
Interests: veterinary clinical soft tissue surgery; veterinary surgical education; veterinary infection control; naturally occuring canine oral melanoma

Special Issue Information

Dear Colleagues,

Melanoma is a tumour that arises from the uncontrolled proliferation of melanocytes (pigment‐producing cells), found in the skin (cutaneous melanoma), in the mucosal surfaces (mucosal melanoma), the eye (ocular melanoma), and leptomeninges (leptomeningeal melanoma). Although all these subtypes are derived from melanocytes, the aetiology, pathogenesis, genetic landscape and biological behaviour of each are very different.

There are numerous case reports of animals that spontaneously develop melanoma, ranging from fish and snakes to birds and mammals. There has also been significant research into the commonly occurring forms of melanoma that affect dogs (canine oral melanoma) and cats (feline ocular melanoma).

This issue aims to look at the advances that have been made in terms of understanding melanoma in animals—the genetic and epigenetic landscape of the tumour, antigen expression by the tumour, intratumoral immune composition, mechanisms of resistance? Has this translated to new treatment options/regimes, the identification of prognostic indicators or biomarkers, and improved survival outcomes? Do we have any new tools to help us understand melanoma?

This issue aims to publish original research works, reviews or case reports that explore our understanding of spontaneous melanoma in animals.

Dr. Louise van der Weyden
Dr. Kelly Lisa Bowlt Blacklock
Guest Editors

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Keywords

animal
spontaneous
melanoma
genetics
immune composition
treatment
prognostic markers
biomarkers
outcome/survival
resistance

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 176 KiB

Open AccessEditorial

Advances in Understanding Spontaneously Occurring Melanoma in Animals

by Kelly L. Blacklock and Louise van der Weyden

Vet. Sci. 2023, 10(3), 210; https://doi.org/10.3390/vetsci10030210 - 10 Mar 2023

Cited by 2 | Viewed by 2483

Abstract

Melanoma is a tumour that arises from the uncontrolled proliferation of melanocytes (pigment-producing cells) found in the skin (cutaneous melanoma and digital melanoma), mucosal surfaces (oral melanoma), and the eye (ocular melanoma) [...] Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

Research

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10 pages, 1384 KiB

Open AccessArticle

Pilot Study: Assessing the Expression of Serum Lactate Dehydrogenase and Peripheral Leukocyte Ratios in Canine Oral Malignant Melanoma

by Ben Murray and Kelly L. Bowlt Blacklock

Vet. Sci. 2022, 9(8), 421; https://doi.org/10.3390/vetsci9080421 - 9 Aug 2022

Cited by 2 | Viewed by 2204

Abstract

Measurement of blood biomarkers such as lactate dehydrogenase (LDH) and peripheral leukocyte ratios have been shown to be of prognostic value in human melanoma patients. Previous veterinary studies have demonstrated that changes in these values are detectable in multiple canine cancer patients. However, to the authors’ knowledge, no studies have yet demonstrated an increase in LDH in canine oral malignant melanoma patients, nor has the effect of metastasis on LDH levels been explored. This retrospective pilot study included 18 dogs, of which 10 were healthy controls, 5 OMM patients with metastasis and 3 without metastasis. Serum LDH was measured and pre-treatment peripheral leucocyte ratios were calculated. LDH was measurable within all patient groups and a statistically significant difference in LDH levels was detected between patients with OMM and healthy controls (p < 0.05); however, no significant difference was detected between patients with or without metastatic disease. This study suggests that serum LDH levels are significantly increased in dogs with OMM compared to healthy controls, paving the way for further research to investigate the prognostic value of this biomarker. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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14 pages, 1149 KiB

Open AccessArticle

Molecular Genetic Investigation of Digital Melanoma in Dogs

by David Conrad, Alexandra Kehl, Christoph Beitzinger, Thomas Metzler, Katja Steiger, Nicole Pfarr, Konrad Fischer, Robert Klopfleisch and Heike Aupperle-Lellbach

Vet. Sci. 2022, 9(2), 56; https://doi.org/10.3390/vetsci9020056 - 30 Jan 2022

Cited by 8 | Viewed by 6230

Abstract

Canine digital melanoma, in contrast to canine oral melanoma, is still largely unexplored at the molecular genetic level. The aim of this study was to detect mutant genes in digital melanoma. Paraffin-embedded samples from 86 canine digital melanomas were examined for the BRAF V595E variant by digital droplet PCR (ddPCR), and for exon 11 mutations in c-kit. Furthermore, exons 2 and 3 of KRAS and NRAS were analysed by Sanger sequencing. Copy number variations (CNV) of KITLG in genomic DNA were analysed from nine dogs. The BRAF V595E variant was absent and in c-kit, a single nucleotide polymorphism was found in 16/70 tumours (23%). The number of copies of KITLG varied between 4 and 6. KRAS exon 2 codons 12 and 13 were mutated in 22/86 (25.6%) of the melanomas examined. Other mutually exclusive RAS mutations were found within the hotspot loci, i.e., KRAS exon 3 codon 61: 2/55 (3.6%); NRAS exon 2 codons 12 and 13: 2/83 (2.4%); and NRAS exon 3 codon 61: 9/86 (10.5%). However, no correlation could be established between histological malignancy criteria, survival times and the presence of RAS mutations. In summary, canine digital melanoma differs from molecular genetic data of canine oral melanoma and human melanoma, especially regarding the proportion of RAS mutations. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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Review

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11 pages, 589 KiB

Open AccessReview

The Use of Oncept Melanoma Vaccine in Veterinary Patients: A Review of the Literature

by MacKenzie A. Pellin

Vet. Sci. 2022, 9(11), 597; https://doi.org/10.3390/vetsci9110597 - 28 Oct 2022

Cited by 12 | Viewed by 9605

Abstract

The Oncept melanoma vaccine is xenogeneic DNA vaccine targeting tyrosinase. It is USDA approved for treatment of stage II to III canine oral melanoma and is also used off-label for melanomas arising in other locations and in other species. While the vaccine appears safe, the published data is mixed as to whether it provides a survival benefit, and the use of the vaccine is somewhat controversial in the veterinary oncology community. In this paper, the published literature describing the use of Oncept is reviewed and evaluated. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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47 pages, 493 KiB

Open AccessReview

Treatment of Canine Oral Melanomas: A Critical Review of the Literature

by Paolo Pazzi, Gerhard Steenkamp and Anouska J. Rixon

Vet. Sci. 2022, 9(5), 196; https://doi.org/10.3390/vetsci9050196 - 19 Apr 2022

Cited by 18 | Viewed by 7058

Abstract

Critical appraisal of the available literature for the treatment of canine oral malignant melanoma (OMM) is lacking. This critical review aimed to evaluate the current literature and provide treatment recommendations and possible suggestions for future canine OMM research. PubMed, Web of Science and Google Scholar were searched in June 2021, for terms relevant to treatment of OMM. Inclusion and exclusion criteria were applied and information on clinical response and outcome extracted. Eighty-one studies were included. The overall level of evidence supporting the various canine OMM treatment options was low. The majority of studies included confounding treatment modalities and lacked randomization, control groups and consistency in reporting clinical response and outcomes. Within these limitations, surgery remains the mainstay of therapy. Adjunctive radiotherapy provided good local control and improved median survival times (MST), chemotherapy did not offer survival benefit beyond that of surgery, while electrochemotherapy may offer a potential alternative to radiotherapy. Immunotherapy holds the most promise in extending MST in the surgical adjunctive setting, in particular the combination of gene therapy and autologous vaccination. Prospective, randomized, double-blinded clinical trials, with a lack of confounding factors and reporting based on established guidelines would allow comparison and recommendations for the treatment of canine OMM. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

16 pages, 4966 KiB

Open AccessReview

Diagnosis and Prognosis of Canine Melanocytic Neoplasms

by Rebecca C. Smedley, Kimberley Sebastian and Matti Kiupel

Vet. Sci. 2022, 9(4), 175; https://doi.org/10.3390/vetsci9040175 - 6 Apr 2022

Cited by 21 | Viewed by 9535

Abstract

Canine melanocytic neoplasms have a highly variable biological behavior ranging from benign cutaneous melanocytomas to malignant oral melanomas that readily metastasize to lymph nodes and internal organs. This review focuses on the diagnosis and prognosis of canine melanocytic neoplasms. While pigmented melanocytic neoplasms can be diagnosed with fine-needle aspirates, an accurate prognosis requires surgical biopsy. However, differentiating amelanotic spindloid melanomas from soft tissue sarcomas is challenging and often requires immunohistochemical labeling with a diagnostic cocktail that contains antibodies against Melan-A, PNL-2, TRP-1, and TRP-2 as the current gold standard. For questionable cases, RNA expression analysis for TYR, CD34, and CALD can further differentiate these two entities. The diagnosis of amelanotic melanomas will be aided by submitting overlying and/or lateral flanking epithelium to identify junctional activity. Wide excision of lateral flanking epithelium is essential, as lentiginous spread is common for malignant mucosal melanomas. Combining histologic features (nuclear atypia, mitotic count, degree of pigmentation, level of infiltration, vascular invasion; tumor thickness and ulceration) with the Ki67 index provides the most detailed prognostic assessment. Sentinel lymph nodes should be evaluated in cases of suspected malignant melanomas using serial sectioning of the node combined with immunohistochemical labeling for Melan-A and PNL-2. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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23 pages, 4999 KiB

Open AccessReview

Chromatophoromas in Reptiles

by Colleen F. Monahan, Michael M. Garner and Matti Kiupel

Vet. Sci. 2022, 9(3), 115; https://doi.org/10.3390/vetsci9030115 - 4 Mar 2022

Cited by 10 | Viewed by 5633

Abstract

Chromatophoromas are neoplasms that arise from pigment cells of reptiles, amphibians, and fish. They include melanophoromas (melanomas), iridophoromas, and xanthophoromas. Most chromatophoromas develop spontaneously, but genetic and environmental factors may also play a role in their oncogenesis. The diagnosis is typically through histologic examination. Immunohistochemistry and electron microscopy can be helpful for diagnosing poorly differentiated and/or poorly pigmented neoplasms. Aggressive surgical excision is the current treatment of choice. This review describes the clinical presentation, gross appearance, diagnostic applications, clinical behavior, and treatment of chromatophoromas in reptiles. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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13 pages, 3457 KiB

Open AccessEditor’s ChoiceReview

Feline Uveal Melanoma Review: Our Current Understanding and Recent Research Advances

by David Kayes and Benjamin Blacklock

Vet. Sci. 2022, 9(2), 46; https://doi.org/10.3390/vetsci9020046 - 26 Jan 2022

Cited by 9 | Viewed by 11118

Abstract

Melanocytic neoplasia is the most common form of ocular tumour in cats, accounting for 67% of cases in an analysis of 2614 cases of primary ocular neoplasia. Feline diffuse iris melanoma (FDIM) is by far the most common form of ocular melanocytic neoplasia, with limbal melanomas and atypical melanoma (melanoma affecting the choroid or ciliary body) infrequently recognised. Early lesions begin as flat areas of pigmentation of the iris, known as iris melanosis. This melanosis is a precursor lesion that can become FDIM when pigmented cells infiltrate the anterior iris stroma, commonly alongside a transition in cell morphology. The differentiation between FDIM and benign iris melanosis is only recognisable though histologic examination, with no in vivo means of identifying the malignant transformation. The behaviour of FDIM is variable and difficult to predict. Some FDIM lesions have a more benign progression and can slowly grow or remain static for years without affecting the ocular or systemic health of the individual, whilst other tumours behave aggressively, invading the ocular structures and significantly affecting the life expectancy of cats through metastatic disease. This makes management and timely enucleation of these cases challenging in practice. This article aims to review our current knowledge of FDIM. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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22 pages, 1149 KiB

Open AccessReview

A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

by Laura Hardwick

Vet. Sci. 2021, 8(11), 286; https://doi.org/10.3390/vetsci8110286 - 22 Nov 2021

Cited by 8 | Viewed by 3510

Abstract

Canine oral melanoma (COM) is a highly aggressive tumour associated with poor prognosis due to metastasis and resistance to conventional anti-cancer therapies. As with human mucosal melanoma, the mutational landscape is predominated by copy number aberrations and chromosomal structural variants, but differences in study cohorts and/or tumour heterogeneity can lead to discordant results regarding the nature of specific genes affected. This review discusses somatic molecular alterations in COM that result from single nucleotide variations, copy number changes, chromosomal rearrangements, and/or dysregulation of small non-coding RNAs. A cross-species comparison highlights notable recurrent aberrations, and functionally grouping dysregulated proteins reveals unifying biological pathways that may be critical for oncogenesis and metastasis. Finally, potential therapeutic strategies are considered to target these pathways in canine patients, and the benefits of collaboration between science, medical, and veterinary communities are emphasised. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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11 pages, 2182 KiB

Open AccessReview

Comparative Review of Malignant Melanoma and Histologically Well-Differentiated Melanocytic Neoplasm in the Oral Cavity of Dogs

by Won Suk Kim, Arathi Vinayak and Barbara Powers

Vet. Sci. 2021, 8(11), 261; https://doi.org/10.3390/vetsci8110261 - 2 Nov 2021

Cited by 9 | Viewed by 5286

Abstract

Oral malignant melanoma (OMM) is the most common neoplasm of the canine oral cavity. It is characterized by its aggressive local disease as well as its high rate of lymphatic invasion and distant metastasis. OMM carries a poor prognosis, with most patients succumbing to the disease due to progression of the neoplasm. Histopathologically, OMM is characterized by significant nuclear atypia, a mitotic index of greater than 4/10 hpf, and evidence of vascular invasion or metastasis. Clinically, these lesions can become locally invasive, causing lysis of bones and severe inflammation of the surrounding soft tissue. With time, these lesions can spread to the regional lymph node and to the lungs and other organs. Prognosis can vary depending on the size of the primary tumor, regional node involvement, and distant metastatic disease; however, multiple studies report a relatively short median survival time ranging from less than 4 months to 8 months. Histologically well- differentiated melanocytic neoplasms (HWDMN) are a variant of OMM and sometimes referred to as canine oral melanocytic neoplasms of low malignant potential. Unlike OMM, patients with HWDMN have longer survival times. Histopathologically, HWDMNs have well-differentiated melanocytes with a low mitotic index of 3 or less per 10 hpf and minimal nuclear atypia. HWDMNs have better prognosis with a mean survival time of up to 34 months. This article is a comparative review of OMM and its less aggressive counterpart. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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Other

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8 pages, 1123 KiB

Open AccessCase Report

Multimodal Treatment of a Canine Lingual Melanoma Using a Combination of Immunotherapy and a Tyrosine Kinase Inhibitors

by Alexander Berry, Alison Hayes, Luca Schiavo and Jane Dobson

Vet. Sci. 2022, 9(2), 54; https://doi.org/10.3390/vetsci9020054 - 29 Jan 2022

Cited by 3 | Viewed by 3249

Abstract

A 9-year-old female neutered Miniature Schnauzer was diagnosed with a lingual malignant melanoma on the basis of incisional biopsy and histopathology. The patient was initially given a guarded prognosis of a few months’ survival as surgical treatment options were declined by the owner. In order to control the disease a combination treatment of immunotherapy and tyrosine kinase inhibitors was initiated. The mass showed a marked and sustained reduction in size, whilst preserving quality of life for the patient, with a survival at the time of writing of 15 months since diagnosis. This experience suggests that combination therapy for oral malignant melanoma using immunotherapy and tyrosine kinase inhibitors may be successful in some patients and warrants further investigation. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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8 pages, 4636 KiB

Open AccessCase Report

Metastatic Cutaneous Melanoma in a White African Lioness (Panthera leo)

by Louise van der Weyden, Peter Caldwell, Liesl van Rooyen, Emily P. Mitchell and Nicolize O’Dell

Vet. Sci. 2021, 8(8), 154; https://doi.org/10.3390/vetsci8080154 - 1 Aug 2021

Cited by 1 | Viewed by 3347

Abstract

Malignant melanomas tend to be locally destructive, aggressive tumours commonly associated with recurrence and/or metastasis. In this report, a 13-year-old captive white African lioness (Panthera leo), with a recent history of intermittent bouts of lethargy and inappetence, presented with a distended abdomen (due to ascites) and a small, round crusty lesion on the ear. An abdominal ultrasound showed the presence of masses on the liver and an exploratory laparotomy revealed multiple pale lesions on the liver and omentum. Histopathology revealed sheets of pleomorphic neoplastic cells compressing the non-neoplastic liver tissue. Similar neoplastic cells had multifocally expanded and effaced omentum adipose tissue, as well as formed a well-circumscribed mass in the ear sample, extending from close to the epidermis to the lateral and deep margins of the section. All three tissue samples had a high mitotic index (15 per 10 HPF), and critically, in the ear sample, there were rafts of neoplastic cells in the lymphatics, indicating lymphovascular invasion. Immunohistochemistry for the melanoma marker, PNL-2, showed strong positivity in all three tissue samples. Thus, the diagnosis was of malignant melanoma with metastasis to the liver and omentum. This is the first report of metastatic cutaneous melanoma in a lion. Full article

(This article belongs to the Special Issue Advances in Understanding Spontaneously Occurring Melanoma in Animals)

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