Risk Factors And Etiology Of Mucosal Melanoma

Introduction

Definition and overview of mucosal melanoma

Melanomas are a sneaky type of cancer originating from pigment cells called melanocytes. While most melanomas begin in the skin, they can also develop in other body parts where pigment cells are found. These include ocular melanomas (in the eye), mucosal and leptomeningeal melanomas, and rare cases of melanoma in internal organs.

Mucosal melanoma, a rare type of melanoma, begins in the mucous membranes of the body, such as the mouth, nose, throat, anus, or genital areas. Unlike cutaneous melanoma, which develops on the skin, mucosal melanoma presents unique challenges.

Roughly half of the mucosal melanomas manifest in the head and neck, affecting areas such as the mouth, nose, sinuses, large airways, and the oesophagus. The remaining cases most commonly occur in the lower large intestine, women's reproductive organs, and the urinary tract.

Mucosal melanoma tends to be diagnosed at a more advanced stage than cutaneous melanoma, posing significant treatment difficulties. It is also more aggressive and carries a poorer prognosis compared to cutaneous melanoma

Most mucosal melanomas are found in hidden areas, and the lack of early and specific signs means they are often diagnosed late, which affects the prognosis. Understanding the causes and risk factors of mucosal melanomas is limited due to their rarity, and there are no established protocols for staging and treatment.¹

Importance of understanding risk factors and aetiology

Knowing the risk factors and causes of mucosal melanoma is crucial for maintaining good health. This knowledge helps doctors detect the condition early and provide personalised prevention advice. Understanding these factors also helps predict the aggressiveness of the cancer and guides treatment decisions, potentially leading to better outcomes for patients. Furthermore, this understanding drives research into new treatments and informs public health efforts, aiming to protect those at risk better and improve overall healthcare strategies.

Risk factors

The risk factors for the development of mucosal melanomas are unknown. These melanomas arise on sun-unexposed surfaces, so the usual risk factor of sun exposure for cutaneous melanoma is unlikely to be involved. Remember these important risk factors: formaldehyde exposure is linked to sinonasal mucosal melanoma, while oral mucosal melanoma is associated with cigarette smoking. Recent genetic studies have shown that different melanoma subtypes carry different mutations, highlighting that these tumours may represent distinct biological entities. Understanding the differences among melanocytes in various tissues is vital for melanoma development.¹

Demographic factors

Mucosal melanomas are rare compared to cutaneous melanoma, representing only about 1.4% of all melanomas. While the incidence of cutaneous melanoma is increasing, the incidence of mucosal melanoma is believed to remain stable. In the US, there are 2.2 cases of mucosal melanoma per million per year, compared to 153.5 cases of cutaneous melanoma. Mucosal melanomas have been found to occur at higher rates among women than men. This female predominance is mainly caused by higher rates of genital tract melanomas among women.

The incidence of mucosal melanomas is higher in older people, with over 65% of patients being older than 60 years. Rates of mucosal melanomas are approximately twice as high among whites than among blacks. The difference in rates is not as noticeable as with cutaneous melanoma, but it is similar to that of conjunctival melanoma. Cutaneous melanoma has higher rates in coastal and southern states in the US, but the same was not observed for mucosal melanoma.¹

Genetic predisposition

Researchers are still uncertain about the exact causes of mucosal melanoma. Melanomas are tumours that develop from melanocytes, cells responsible for producing melanin—the pigment that gives colour to skin, hair, and eyes and helps protect against sun damage. What's puzzling is that melanocytes, which protect against sunlight, are found in mucosal areas rarely exposed to sunlight.

However, researchers have identified two genetic mutations that may contribute to some cases of mucosal melanoma. These mutations—KIT and BRAF—are somatic, meaning they occur during a person's lifetime:

KIT: KIT genes control the growth rate of specific cells, including melanocytes. When these genes mutate, they produce a protein that signals cells to grow and divide faster. KIT mutations are found in 7% to 17% of all mucosal melanomas and in about 30% of cases affecting the vagina and vulva.

BRAF: BRAF genes regulate proteins that manage melanocyte growth. Mutated BRAF genes alter these proteins' instructions, causing cells to multiply uncontrollably and potentially develop into cancerous tumours. BRAF mutations occur in 3% to 15% of all mucosal melanomas.

These genetic findings provide insights into how mucosal melanoma develops, although much remains to be understood about its origins and risk factors.

Environmental factors and other risk factors 

Depending on the specific body area where the disease occurs, different risk factors may contribute to developing mucosal melanoma. 

For mucosal melanoma in the head and neck, risk factors include:

• Poorly fitting dentures
• Smoking
• Exposure to environmental carcinogens

For mucosal melanoma in the anus, possible risk factors include:

• Human immunodeficiency virus (HIV)

For mucosal melanoma in the vagina, potential risk factors include:

• Genetic predisposition
• Viruses
• Exposure to certain chemicals
• Chronic inflammatory disease

It's important to note that while these factors can increase the risk of developing mucosal melanoma, the exact causes of the disease are still unknown.

Aetiology

Understanding what causes mucosal melanoma (MM) is essential. MM differs from cutaneous melanoma (CM), mainly linked to UV radiation. MM develops on mucous membranes where there is little UV exposure. Genetic mutations and environmental factors both play a role in MM's development.

Genetic mutations are critical in the development of MM. Mutations in genes like SF3B1, KIT, and PTEN activate crucial signalling pathways for tumour growth. SF3B1 mutations, for example, disrupt splicing mechanisms, leading to abnormal gene transcripts and possibly contributing to cancer in MM. These mutations show the molecular differences between MM and CM.

It is also essential where MM develops. Unlike CM, which develops on sun-exposed skin, MM develops in sun-shielded areas. Factors like chronic irritation caused by dentures or mechanical stress, smoking, and chronic infections may create a favourable environment for tumour formation in mucosal tissues.

MM's genetic makeup and behaviour differ from CM's. While CM's mutations are linked to UV exposure, MM's mutations, such as SF3B1 and KIT, are more prevalent. This requires targeted therapies specific to MM.

It is essential to understand what causes MM to develop effective treatment strategies. Targeted therapies, like SF3B1 or KIT inhibitors, promise to improve outcomes for MM patients. Understanding the role of environmental factors and their interaction with genetic mutations could help prevent and detect MM early.

In conclusion, MM's causes involve genetic mutations, anatomical factors, and potential environmental influences. Continued research into these factors is necessary to develop effective therapies and improve outcomes for MM patients facing this aggressive cancer.²

Clinical considerations

Diagnosis

Mucosal melanoma is diagnosed similarly to skin melanoma, usually with a physical examination and a biopsy. During a biopsy, a small piece of the affected area is removed and examined under a microscope for signs of cancer. Additional tests may be ordered to determine the stage of the cancer. These tests, which may include ultrasounds, CT scans, MRI scans, PET scans, and blood chemistry tests, help doctors understand the severity of the disease and plan the appropriate treatment. Staging systems for mucosal melanoma depend on where it starts; there's no consensus on a specific staging system. The stages of skin melanoma consider the thickness of the melanoma, whether it is ulcerated or bleeding, its spread to nearby tissues or lymph nodes, and its spread to other parts of the body.

Symptoms and clinical presentation 

Mucosal melanoma often doesn't show early symptoms. A dentist can discover it during a regular check-up if there's an ulcer or discolouration in the mouth. Vaginal cancer may be detected during a routine Pap test. Anal cancer may be found during an anal Pap test or digital rectal exam (DRE). Mucosal melanomas are often diagnosed at advanced stages when noticeable symptoms have developed.

Melanoma usually looks like a dark and uneven spot on the skin or mucous membrane. However, the signs can vary depending on where the melanoma is.

Head and neck mucosal melanomas are usually found in the nasal or oral areas. Symptoms for these types of cancer may include frequent nosebleeds, decreased sense of smell, lesions, pain or bleeding in the mouth, discolouration, and lumps or ulcers.

Symptoms of vaginal cancer may include unusual vaginal discharge or bleeding, itching in the private area, trouble or pain when urinating, changes in bowel habits, and discolouration, lumps, or sores in the private area.

Symptoms of anal cancer may include bleeding, pain or pressure in the area, lumps or swelling, and changes in bowel habits.

Prognostic factors

Mucosal melanoma is a severe type of cancer. Doctors use surgery and other treatments to remove tumours and cancer cells, but the cancer often comes back. If you have mucosal melanoma, you might need more surgery or treatment.

As for survival rates, studies show that about 25% of people with mucosal melanoma were alive five years after diagnosis. However, the survival rates vary depending on where the cancer is located:

• Head and neck: On average, less than 30% of people were alive five years after diagnosis (ranging from 14% to 48%).
• Vulvovaginal (vagina and rectum): Around 36% of people with this type of cancer were alive five years after diagnosis.
• Anorectal (anus and rectum): Roughly 20% of people with this type were alive five years after diagnosis.

It's important to understand that these numbers are estimates and may not apply to everyone. If you have questions about your prognosis, it's best to talk to your doctor. 

Treatment implications

It's crucial to understand the treatment options for mucosal melanoma, a challenging type of cancer. Despite its difficulty to treat, there are effective methods available.

Surgery, radiation therapy, immunotherapy, and targeted therapy are standard treatments for mucosal melanoma. These approaches can be combined and tailored to ensure the best possible outcome.

Early-stage mucosal melanoma can often be completely removed through surgery, presenting the potential for remission. When combined with surgery, radiation therapy not only prevents cancer from returning but also assists in symptom management.

Immunotherapy drugs empower the immune system to combat cancer, while targeted therapy can obstruct specific pathways that melanomas exploit for growth. These treatments can be personalised based on the particular characteristics of the tumour.

Participation in clinical trials is an essential opportunity to develop new and improved treatments. As there are more effective treatment options available, chemotherapy is not the primary choice for treating melanoma.

Palliative care is a crucial consideration, as it aids in managing the side effects and symptoms of cancer and its treatment.

Future directions

The way we treat MM isn't set in stone. Surgery is often used, but it's tough because of tumour size and where it's located. Immunotherapy is common, but we're unsure about the best combos and side effects. When there are specific mutations, targeted therapies become vital. To get better at treating MM, we need more research with bigger groups of patients. This could help us improve how we understand and deal with MM.³

Summary

Mucosal melanoma, a rare subtype of melanoma, originates in the body's mucous membranes and is more aggressive and challenging to treat than cutaneous melanoma. The risk factors for mucosal melanoma are not well-understood, but potential contributors include formaldehyde exposure, cigarette smoking, and genetic mutations such as KIT and BRAF. Demographically, mucosal melanoma is more prevalent in older adults and shows a higher incidence in women, mainly due to genital tract melanomas. Genetic predispositions play a significant role, with specific mutations influencing tumour growth and development. Environmental factors like poorly fitting dentures and chronic infections may also contribute to the risk.

Diagnosing mucosal melanoma typically involves physical examinations and biopsies, with advanced imaging techniques used to determine the cancer stage. Symptoms vary depending on the tumour's location but often include discolouration, lumps, bleeding, and changes in bowel or urinary habits. Prognosis remains poor, with five-year survival rates varying by cancer location.

Current treatment options include surgery, radiation therapy, immunotherapy, and targeted therapies tailored to the individual's cancer characteristics. Participation in clinical trials is encouraged to explore new treatments. Ongoing research is essential to improve the understanding and treatment of mucosal melanoma, aiming to develop more effective therapeutic strategies and enhance patient outcomes.