Introduction

Skin cancer is the most common type of cancer. Among its various forms, mucosal melanoma is a rare and aggressive variant that develops from melanocytes, also known as cells that produce the skin’s pigment melanin, in mucous membranes that are shielded from the sun.¹ 

In both humans and animals, melanin is a naturally occurring chemical that controls the colour of hair, skin, and eyes. Melanocytes can migrate beneath the basal cell layer of the epithelium, which is the superficial skin tissue, at various anatomic districts in addition to under the epidermis to populate all areas of the skin. Melanocytes are mostly found in the heart, brain, and inner ear, though they are normally present in almost all tissues, albeit to varying degrees.²

Of all melanomas, mucosal melanoma accounts for 1.3% to 1.4% of all melanoma cases, with 25 to 50% ocurring in the head and neck region. In 1885, Lincoln Rufus Pratt wrote the first account of a mucosal melanoma case in English literature.³ Notably, 1.3% of melanomas in Caucasians are mucosal, but 11.8% of melanomas in dark-skinned people are mucosal.

Compared to cutaneous melanomas, mucosal melanomas are typically detected at a later, more severe stage since the tumours are hidden and can be challenging to find early. This subtype of melanoma t has a diverse genetic profile with different oncogenic drivers and a lower somatic mutational burden.⁴ Mucosal melanoma, which makes up 1% of all occurrences of melanoma, is one of the most aggressive subtypes and, as such, has a worse prognosis than typical cutaneous melanoma.

Changes in the shape, colour, size, or feel of a melanoma are often the earliest signs of the disease. Mucosal melanoma (MM), which makes up 1% of all occurrences of melanoma, is one of the most aggressive subtypes and, as such, has a worse prognosis than typical cutaneous melanoma ⁵ 

This worse prognosis in mucosal melanoma may be caused by several factors, including the limited understanding of mucosal melanocytes’ biology and the risk factors associated with the incidence of mucosal melanoma. 

Although UV exposure is a known risk factor for cutaneous melanoma, it is still unclear which mutagens cause mucosal melanoma to form.² Although any mucosal epithelium can give rise to mucosal melanomas, the head and neck region (31–55%), vulvovaginal (18–40%), and anorectal (17–24%) regions are the most frequently affected. Primary mucosal melanoma has been reported in the cervix, stomach, small and large intestine, esophagus, and urinary system on rare occasions. The exact risk factors that lead to the development of mucosal melanoma are still unknown.⁶

Overview of mucosal melanoma and its distinct features

Different genetic profiles are present in mucosal melanomas than in cutaneous melanomas. C-KIT signalling is a crucial regulator of cell proliferation, survival, and migration, and is also involved in hematopoiesis, pigmentation, and gastrointestinal motility. C-KIT gene mutations, although are less common in cutaneous melanomas, are often present in them. The receptor tyrosine kinase (RTK) that 3c-kit, a canonical proto-oncogene, encodes reacts to stem cell factor (SCF).⁷

In comparison to CM, it is further distinguished by a comparatively low tumour mutational burden (TMB). Specifically, MM has a mutation rate that is more than ten times lower than CM, which has one of the highest rates of somatic neoplastic mutations with an average of over 80,000 non-synonymous single-nucleotide variations (nsSNVs) per tumour. This difference may explain the molecular reason for discordant clinical responses to immunotherapy that are observed in Asian people, where mucosal melanoma represents a substantial fraction of all diagnosed melanomas, versus white Caucasian people.⁸ 

With whole-genome/exome sequencing, the mutational profile of mucosal melanoma is different from that of cutaneous melanoma. Current NGS-based studies, meta-analyses, and systematic reviews have demonstrated that mucosal melanoma is characterised by a lower burden of somatic mutations and lack of either UV-induced mutational signatures or oncogenic fusion gene transcripts that are typically detected in cutaneous melanoma.³ 

It has been shown that mutations in genes such as SF3B1, SPRED1, and CTNNB1 are frequently present in mucosal melanomas.SF3B1 gene, which codes for a spliceosome component. Mutations in SF3B1 are linked to alternative mRNA splicing and are thought to be a key factor in the pathophysiology of mucosal melanoma and other hematologic malignancies. One of the most important steps in the posttranscriptional regulation of gene expression is the removal of noncoding sections, or introns, and the SF3B1 gene belongs to this group.⁹ 

Some mucosal melanomas also include mutations in the SPRED1 gene. The RAS/MAPK signalling pathway is negatively controlled by SPRED1, whose inactivation can cause dysregulated cell growth and survival. Ras signalling is strictly regulated; illnesses like cancer, developmental abnormalities (referred to as RASopathies), and learning difficulties are caused by overactive Ras signalling.¹⁰

Mutations in mucosal melanomas have been linked to the β-catenin protein, which is encoded by the CTNNB1 gene. The formation and progression of melanoma are linked to the Wnt/β-catenin signalling system, which can be activated by mutations in CTNNB1.

Identification of key mutations through genomic studies

Important mutation hotspots, population-level variations in mutation spectra, and relationships between the distribution of mutations linked to cancer and the topography of the genome have all been found through genomic investigations. These discoveries deepen our knowledge of the processes of mutation that underlie human genetic diversity and illness.

Variations in the mutation spectrum between groups have been found through analyses of worldwide human genetic variation, indicating past modifications in genomic mutation processes. For instance, populations from Europe and South Asia have been found to have a higher frequency of TCC → TTC mutations. The mutation TCC → TTC itself has a particular functional impact.¹¹ 

Since mutation rates can differ both within and between genomes, DNA sequencing technologies are making it possible to estimate mutation frequencies and distributions with greater accuracy. Most mutations have minimal or insignificant consequences, but a tiny percentage might have significant, even harmful, effects.²

The human genome's topography, which includes characteristics like early and late replicating regions, affects the accumulation of specific mutational fingerprints connected to functions like alcohol consumption and antiviral enzyme activity, according to a recent study by UC San Diego researchers.¹² This implies that the landscape of cancer mutations is significantly shaped by the genetic landscape.

Impact of mutations on tumour initiation, progression, and response to therapy

A sequence of mutations that inactivate tumour suppressor genes and/or change the status of proto-oncogenes is typically required for the development of tumours. The dynamics of cancer development and even the character of the disease itself can be greatly impacted by the chronological order of these mutations.¹³

Studies have demonstrated that the first mutation largely determines the likelihood of cancer onset, although both mutations are necessary for the dynamics that follow. Getting a more fit mutation before a less fit one can raise the likelihood of a tumour forming, but postpone the onset of cancer.¹³

The human genome's topography, which includes characteristics like early and late replicating regions, has also been shown through genomic research to affect the accumulation of specific mutational signatures associated with functions like alcohol consumption and antiviral enzyme activity. This shows that the distribution of mutations linked to cancer is significantly shaped by the genetic landscape.¹⁴

Moreover, many point mutations and chromosomal rearrangements can result from large-scale mutational events such as chromothripsis, chromoplexy, and kataegis in a single cellular disaster. This casts doubt on the widely held belief that cancer originates from a slow accumulation of mutations over time.¹⁵

Staging of mucosal melanoma

Mucosal melanoma staging is determined by a physical examination, imaging, and a comprehensive medical history because there are few guidelines. The American Joint Committee on Cancer (AJCC) staging strategy is commonly used, although a more effective system based on factors unique to mucosal melanoma would be desirable. Breslow depth on its own is frequently insufficient, leading to several staging arrangements. Because of this, oncologists employ a variety of techniques to stage mucosal melanoma.³ 

Clinical relevance and therapeutic implications

Certain gene mutations, such as those in FLT3, NPM1, CEBPA, and BRAF, have been demonstrated to have clinical significance in a variety of malignancies, influencing prognosis and directing therapeutic choices.

Gene mutations in FLT3, NPM1, MLL, BAALC, and CEBPA are linked to prognosis and can be used to classify people according to their risk in acute myeloid leukaemia with normal karyotype. For instance, isolated mutations in NPM1 and CEBPA suggest better results, whereas FLT3-ITD and MLL-PTD mutations are associated with a worse prognosis.¹⁶

BRAF V600E and TERT promoter mutations work together to identify the most aggressive tumours with a high probability of death in differentiated thyroid cancer. The coexistence of these two mutations indicates a decline in radioiodine avidity and a subpar response to conventional treatment.¹⁷

It has been documented that one of the mechanisms involved in carcinogenesis is multiple mutations within a single gene. Compared to cells lacking or carrying a single mutation, those with several mutations in genes such as MUC16 and PIK3CA are more susceptible to targeted therapies like regorafenib and PI3K inhibitors.¹⁸ This implies that genetic mutations may function as prognostic biomarkers for customised therapies.

In malignancies such as hepatocellular carcinoma, tumour mutational burden (TMB), which is correlated with multiple mutations, is being investigated as a possible measure for immune checkpoint inhibitor response prediction.

For prognosis, treatment selection, and the creation of tailored medicines, genomic profiling of malignancies for significant mutations is becoming more and more crucial. Certain mutations can be used to recognise severe illness, forecast how well new and conventional treatments will work, and direct individualised care plans.

Current treatment strategies and challenges in mucosal melanoma management

The cornerstone of treatment for localised disease is complete surgical resection; however, anatomical features frequently make achieving wide negative margins challenging.

To enhance local control, adjuvant radiation therapy may be utilised, particularly in individuals with extense melanomas or lymph node involvement. When compared to cutaneous melanoma, immunotherapies such as anti-PD-1 and anti-CTLA-4 drugs have demonstrated comparatively little efficacy and lower response rates. Given greater response rates, combination immunotherapy with anti-PD-1 and anti-CTLA-4 may be recommended for fit patients; nonetheless, toxicity is a concern. ¹⁹ When compared to cutaneous melanoma, immunotherapies such as anti-PD-1 and anti-CTLA-4 drugs have demonstrated comparatively little efficacy and lower response rates.

Given greater response rates, combination immunotherapy with anti-PD-1 and anti-CTLA-4 may be recommended for fit patients; nonetheless, toxicity is a concern. Mucosal melanoma has a lower mutational burden and a higher rate of copy number/structural changes than cutaneous melanoma, which may result in immunotherapy resistance. 

Due to the anatomical location and insufficient symptoms, diagnosis often occurs at an advanced stage, leading to worse outcomes.

Opportunities for personalised medicine and precision oncology approaches

Precision oncology has the potential to offer more tailored, less toxic, and more effective cancer treatments by utilizing the most recent advancements in genomes, biomarkers, and targeted medications. However, challenges remain to be addressed in terms of implementation, accessibility, and improving outcomes for each patient.

Summary

Mucosal melanoma, which is a rare and aggressive type of cancer, is marked by different molecular and clinical patterns from cutaneous melanoma. It is these molecular patterns that increase its ability to cause havoc on the health and well-being of patients. The inability to detect this type of cancer at earlier stages emphasises the need for regular checkups at health facilities.