Introduction to mucosal melanoma

Mucosal melanoma is a rare and aggressive form of melanoma arising from the melanocytes in mucosal membranes. These membranes line various body cavities, including the nasal passages, oral cavity, gastrointestinal tract, and genitourinary tract.¹ Unlike cutaneous melanoma, which develops on the skin, mucosal melanoma originates in areas not exposed to sunlight.² 

• Approximately 40-55% of all mucosal melanomas arise around the head and neck³
• About 25-30% occur in the anorectal region⁴
• Roughly 20% are found in the female genital tract⁴
• The remaining cases are distributed among other mucosal sites, such as the urinary tract and oesophagus³

Mucosal melanoma is a rare subtype of melanoma, which accounts for approximately 1.3% of all melanoma cases worldwide.³ The global incidence is estimated to be around 0.03% of all new cancer diagnoses.³

The prevalence of mucosal melanoma varies slightly by geographic region and ethnicity.  In Western countries, mucosal melanoma represents about 1-2% of all melanoma cases.³ In Asia and Africa, where cutaneous melanoma is less common, mucosal melanoma accounts for a higher proportion of melanoma cases, ranging from 9% to 23%.³ People with darker skin tones, such as African Americans, Hispanics, and Asians, are more likely to develop mucosal melanoma.⁴ The five-year survival rate for mucosal melanoma is only about 25%, compared to 80% for cutaneous melanoma.⁵

Challenges in treating mucosal melanoma

Treating mucosal melanoma presents several challenges. Firstly, its hidden locations often lead to late diagnosis, by which time the cancer has frequently metastasised.¹ Secondly, mucosal melanoma is often amelanotic, meaning it lacks the pigmentation that typically helps identify melanoma, further complicating early detection.¹ Additionally, the aggressive nature of the disease and its tendency to recur after treatment makes management difficult.¹ Current treatment options include surgery, radiation, and systemic therapies, but the prognosis remains poor, necessitating ongoing research into more effective treatment.²

 What is targeted therapy? 

Targeted therapies are drugs designed to identify and attack specific molecules in cancer cells. These molecules often include particular proteins and genetic mutations that regulate cell growth and apoptosis (cell death).⁶

Unlike traditional chemotherapy, targeted therapies operate differently. They are more precise in their action and focus specifically on cancer cells. In contrast, chemotherapy affects all rapidly dividing cells, healthy or cancerous.⁶ Targeted therapies can inhibit the division of cancer cells, thereby preventing the cancer from growing and spreading. Chemotherapy, on the other hand, primarily works by destroying existing cancer cells.⁶

Symptoms of mucosal melanoma 

Head and Neck Mucosal Melanoma¹

• Mouth ulcers
• Unexplained nosebleeds
• Lump in the neck, jaw, or mouth
• Mouth pain or difficulty talking
• Visible lesions inside the mouth

Anorectal Mucosal Melanoma¹

• Bleeding from the anus
• Feeling of a growth or protrusion from the anus
• Constipation
• Pain or discomfort in the anal area

Vulvovaginal Mucosal Melanoma¹

• Unexplained vaginal bleeding
• The feeling of a mass inside the vagina
• Visible lesions on the vulva
• Pain or discomfort in the vaginal area

General Symptoms¹

• Malaise
• Fatigue
• Bleeding
• Diarrhea
• Constipation
• Nosebleeds
• Skin discoloration
• Itching
• Discharge
• Ulcers
• Anosmia (loss of smell)
• Hyposmia (reduced sense of smell)
• Skin irritation
• Canker sores
• Bloody stools
• Bloody urine
• Gum disease
• Rosacea

Molecular characteristics of mucosal melanoma

Common genetic alterations:

1. BRAF mutations

Mutations in the BRAF gene lead melanoma cells to generate proteins that promote the growth of cancer cells. Approximately 50% of melanoma skin cancers exhibit a BRAF mutation.⁶ BRAF mutations are less frequent in mucosal melanomas compared to cutaneous melanomas. 

Approximately 6% of mucosal melanomas harbour BRAF-V600 mutations, significantly lower than the 35-50% rate observed in cutaneous melanomas.⁷ However, mucosal melanomas have more non-canonical BRAF mutations (e.g., L505H, G469A, L597R, and T599I), leading to weaker MAPK activation than BRAF-V600.⁷

2. NRAS mutations

NRAS mutations are among the significantly mutated genes in mucosal melanomas, which occur in about 8.7% of cases.⁸ While less common than in cutaneous melanomas, NRAS mutations still play a role in the pathogenesis of some mucosal melanomas.

3. KIT mutations

KIT mutations are more prevalent in mucosal melanomas. Studies have shown that KIT is mutated in approximately 19.1% of mucosal melanomas, making it one of this subtype's most frequently altered genes. KIT mutations are particularly important as they may be more easily targeted with specific inhibitors.⁸

Advances in targeted therapies 

The key principles of targeted therapy include:⁹

• Specificity: Targeting specific molecules involved in cancer cell growth and survival
•  Reduced toxicity: Aiming to minimise damage to healthy cells
• Cytostatic action: Often blocking tumour cell proliferation rather than directly killing cells
• Personalised approach: Using biomarkers to select patients likely to respond to a given therapy

Mechanisms of action of targeted therapies

1. Tyrosine kinase inhibitors (TKIs)

TKIs are small molecule drugs that can enter cells easily and target specific enzymes called tyrosine kinases. These enzymes play crucial roles in cell signalling pathways that regulate cell growth and division. By inhibiting these kinases, TKIs can block cancer cell growth and survival.¹⁰ 

Examples include:¹⁰

• Imatinib (Gleevec): Targets BCR-ABL fusion protein in chronic myelogenous leukaemia 
• Erlotinib: Targets EGFR in non-small cell lung cancer
• Sunitinib: Multi-targeted TKI used in renal cell carcinoma and gastrointestinal stromal tumours

• Immune checkpoint inhibitors

These are monoclonal antibodies that target proteins involved in immune system regulation. Blocking these checkpoint proteins enhances the immune system's ability to recognise and attack cancer cells⁹. 

Examples include:⁹

• PD-1 inhibitors (e.g., pembrolizumab, nivolumab)
• PD-L1 inhibitors (e.g., atezolizumab, durvalumab)
• CTLA-4 inhibitors (e.g., ipilimumab)

• Other molecular targets

Targeted therapies can also focus on various other molecular mechanisms involved in cancer development and progression:¹⁰

• Angiogenesis inhibitors: Target blood vessel formation (e.g., bevacizumab)
• Proteasome inhibitors: Disrupt protein degradation (e.g., bortezomib)
• PARP inhibitors: Interfere with DNA repair mechanisms (e.g., olaparib)
• CDK4/6 inhibitors: Block cell cycle progression (e.g., palbociclib)
• mTOR inhibitors: Inhibit a key signalling pathway (e.g., everolimus)

These targeted therapies interfere with specific molecular pathways crucial for cancer cell survival, growth, and metastasis. 

Specific targeted therapies for mucosal melanoma 

BRAF and MEK inhibitors

Efficacy and clinical trials:

Approximately 6% of mucosal melanomas have BRAF V600 mutations, compared to 35–50% of cutaneous melanomas.¹¹ Due to this low rate, BRAF inhibitors have limited efficacy in mucosal melanomas.

Combination therapies:

The combination of BRAF and MEK inhibitors is less widely used in mucosal melanomas than in cutaneous melanomas due to the lower frequency of BRAF mutation.¹¹

KIT inhibitors

Imatinib and others:

A tyrosine kinase inhibitor called imatinib targets KIT mutations. KIT mutations are more prevalent in mucosal melanomas (approximately 19.1%).¹¹

Clinical outcomes and case studies:

KIT inhibitors have shown some efficacy in mucosal melanomas with KIT mutations.

Clinical trials are ongoing to assess the role of KIT inhibitors in mucosal melanomas.¹¹

PD-1 and PD-L1 inhibitors

Nivolumab, pembrolizumab, and others:

Immunotherapy, particularly PD-1 inhibitors, has shown some efficacy in mucosal melanomas.¹¹

Response rates and survival benefits:

A pooled analysis suggested that combination immunotherapy (anti-PD-1 plus anti-CTLA-4) might improve survival outcomes compared to single-agent immunotherapy in mucosal melanomas. However, results are inconsistent across different studies, and combination immunotherapy is associated with higher rates of adverse events.¹¹

Emerging targets and experimental therapies

Novel targets under investigation:

SF3B1 mutations, CDK4 amplifications, and CDKN2A gene deletions are potential targets currently under investigation in clinical trials¹¹.

Early-phase clinical trials:

Several combination strategies are being evaluated in clinical trials, including:¹¹

• Immunotherapy combined with radiotherapy.
• Immunotherapy combined with antiangiogenic drugs.
• Novel compounds targeting other signalling pathways.

Side effects and management 

Common side effects of targeted therapies:

• BRAF and MEK inhibitors:¹²
  • Skin toxicities: rash, photosensitivity, hyperkeratosis, squamous cell carcinoma, keratoacanthomas
  • Gastrointestinal: nausea, diarrhoea
  • Fatigue
  • Arthralgia
  • Pyrexia (fever)
• KIT inhibitors:¹²
  • Edema
  • Nausea
  • Fatigue
  • Skin rash
• Immunotherapy (PD-1 and CTLA-4 inhibitors)¹²
  • Skin reactions: rash, pruritus, vitiligo
  • Gastrointestinal: diarrhoea, colitis
  • Endocrine disorders: thyroiditis, hypophysitis
  • Pneumonitis
  • Hepatitis

Strategies for managing adverse effects:

• Early recognition and intervention¹³
  • Regular dermatological evaluations
  • Monitoring of blood work and imaging studies
• Supportive care¹³
  • Topical treatments for skin toxicities
  • Antihistamines for pruritus
  • Antidiarrheal medications for gastrointestinal symptoms
• Dose modifications or treatment interruptions¹³
  • Temporary discontinuation of therapy for severe side effects
  • Dose reductions when restarting treatment
• Corticosteroids¹³
  • Used for managing immune-related adverse events from immunotherapy
• Multidisciplinary approach¹³
  • Collaboration between oncologists, dermatologists, and other specialists

Impact on patient quality of life:

• Physical impact¹⁴
  • Skin toxicities can cause discomfort and affect appearance
  • Fatigue and gastrointestinal symptoms may interfere with daily activities
• Psychological impact¹⁴
  • Anxiety related to side effects and treatment efficacy
  • Body image concerns due to skin changes
• Treatment adherence¹⁴
  • Side effects may lead to treatment discontinuation or non-compliance
• Long-term effects¹⁴
  • Some side effects may persist after treatment cessation
  • Regular follow-up is necessary to monitor for late-onset toxicities
• Patient education¹⁴
  • Providing information about potential side effects and management strategies
  • Empowering patients to report symptoms early

Future directions

Innovations in drug development:

• Novel molecular targets:
  • SF3B1 mutations, CDK4 amplifications, and CDKN2A gene deletions are potential targets currently under investigation in clinical trials¹¹
  • Targeting the MAPK pathway, PI3K/AKT pathway, cell cycle regulation, telomere maintenance, and RNA maturation process are areas of active research¹⁵
• Improved drug delivery systems:
  • Developing nanoparticle-based drug delivery systems to enhance targeted therapy efficacy and reduce side effects¹¹

Personalised medicine approaches:

• Molecular profiling:
  • To better understand the genetic profile of mucosal melanoma and find possible treatment targets, researchers are doing whole genome and whole exome sequencing¹¹
  • Development of biomarkers for early detection and diagnosis of mucosal melanoma¹
• Patient-specific treatment strategies:
  • Tailoring treatment is based on individual genetic alterations, such as KIT inhibitors for mucosal melanomas associated with KIT gene mutations¹⁶

Potential for combination therapies:

• Immunotherapy combinations:
  • Ongoing clinical trials investigating the combination of nivolumab and Ipilimumab have shown promising response rates and survival results¹¹
• Targeted therapy with immunotherapy:
  •  Exploration of combining VEGFR inhibitors with anti-PD1 antibodies, such as the LEAP-003 trial of pembrolizumab combined with Lenvatinib¹¹
• Multi-modal approaches:
  • Investigation on combinations of immunotherapy with radiotherapy or antiangiogenic drugs
  • A phase 2 trial of Camrelizumab (anti-PD1 antibody) in combination with Anlotinib (multitargeted tyrosine kinase inhibitor) and nab-paclitaxel as first-line treatment for mucosal melanoma¹¹

Summary

Overall, mucosal melanoma remains an aggressive disease with limited therapeutic options. Ongoing research and clinical trials are focusing on combination strategies and novel targets to improve outcomes for patients with this rare subtype of melanoma.¹¹ While targeted therapies and immunotherapies have improved outcomes for melanoma patients, managing their side effects is crucial for maintaining quality of life and ensuring treatment adherence. A proactive side effect management approach involving healthcare providers and patients is essential for optimising treatment outcomes.¹⁴ Future research in mucosal melanoma treatment is focused on developing more effective targeted therapies, improving personalised medicine approaches, and exploring innovative combination strategies. The rarity of mucosal melanoma presents challenges in conducting large-scale clinical trials, emphasising the importance of cooperative data collection and international collaboration to advance treatment options for this aggressive disease.¹¹