UPDATED JULY 2017
1. GENERAL INFORMATION
1.1 What is the disease and how is it treated?
What is small bowel cancer?
Malignant melanomas of the mucosa (MM) are aggressive cancer with a very poor prognosis. They represent a group of cancers originating from cells (melanocytes) located mostly in the epidermis and dermis of the skin, but also in the eyes and mucosal surfaces.
The most common sites of MM are the head and neck (nasal cavity, paranasal sinuses, and oral cavity).
How does mucosal melanoma manifest itself?
Nasal obstruction and discharge, bleeding from the nose (epistaxis), and facial pain are early signs and symptoms of tumours growing in the sinonasal tract. As for the oral cavity, darker areas (nevi) may appear.
What are the causes of mucosal melanoma?
The exact causes of mucosal melanoma are not known. Some lifestyle factors can increase the risk of developing this cancer: cigarette smoking is of concern for oral lesions, while it has been suggested that workers exposed to formaldehyde may be at risk for sinonasal mucosal melanoma.
Is it a frequent disease?
Malignant melanomas of the mucosa are very rare cancers: every year 1.5 new cases are diagnosed per 1 million persons, but the tumour becomes more frequent in the elderly: over 65 years of age, new diagnoses increase to 6.3 per 1 million persons per year.
How is it diagnosed?
Early diagnosis is not simple because these cancers are rare, located in areas that are not easily accessible, and they are often asymptomatic (there are no symptoms) in the first phases of growth.
This is why MM is frequently discovered by chance, and often when the disease has already progressed.
How is it treated?
Patients are treated with therapies that can counteract the effect of cellular alteration and mutation. Some clinical trials have tested adjuvant therapies, such as chemotherapy and high-dose interferon.
2. WHAT IS IT, HOW DOES IT OCCUR, HOW IS IT DIAGNOSED?
2.1 What is mucosal melanoma?
Mucosal melanoma is a rare malignancy, involving areas covered by mucosal tissue. The mucosa of the nasal cavity, paranasal sinuses, and oral cavity are the most common locations. People commonly think of melanocytes as being located only in the epidermis and dermis of the skin. But it is not rare to find these cells in other body structures, such as the eyes and the mucosal surface of the head and neck region, where their function is still unknown, although – according to a few studies – they may have an antimicrobial and immunological function. Like melanocytes in other parts of the body, these can transform into cancerous cells, resulting in the development of mucosal melanoma.
Mucosal melanoma may present as multiple lesions with different degrees of pigmentation. Tumours without pigmentation are rare, but not exceptional.
2.1.1 Disease stats
Each year, in Europe, 1.5 persons out of 1 million are diagnosed with MM (incidence). The disease is unusual in people under the age of 65, while incidence in people over 65 years old increases to 6.3 cases per million persons.
Incidence of MM is slightly but significantly higher in women than in men.
The occurrence of the disease is highest in the North (2.2) and lowest in the East of Europe (0.7).
MM is an aggressive cancer, with a very poor prognosis. In Europe, among the cases diagnosed in the years 2000-2007, 63% of patients were still alive 1 year after diagnosis, 30% after 3 years, and 20% after 5 years. In the same period (1999-2007) survival at 5 years did not improve despite numerous technological developments in surgery and therapies.
2.2 Risk factors
Sun radiation, a major risk factor for cutaneous melanoma, is unlikely to be implicated in mucosal melanomas, which occur on sun-shielded surfaces. Additionally, there are no obvious identified risk factors, not even family history. Association with viruses is unlikely, since several studies did not show a link between mucosal melanomas and human papillomaviruses, human herpesviruses, or polyomavirus.
Some occupational and lifestyle factors have been suggested to increase or decrease the risk.
- Pigmented oral lesions are more prevalent among smokers.
- Patients have a long history of mucosal pigmentation, which is considered an early phase of invasion of the underlying tissues.
- Exposure to formaldehyde was suggested to be a risk factor for sinonasal mucosal melanoma, since some cases were reported among workers subject to industrial or professional exposure to this substance.
- Genetic studies have identified several gene alterations that seem to be associated with disease susceptibility. Frequently, expression of factors playing an important role in the regulation of proliferation, differentiation, growth, and survival of melanocytes is increased in mucosal melanoma.
2.3 What are the symptoms?
MM symptoms vary greatly in relation to the site of origin. Nasal obstruction and discharge, bleeding from the nose, and facial pain characterize the sinonasal tract. Other complaints, like an abnormal protrusion of the eyeball, a paralysis or weakness of eye muscles, headache, skin infiltration and ulceration, are less frequently encountered and are commonly associated with advanced-stage disease.
Oral MM generally presents as excessively pigmented lesions, with a wide range of colours varying from black, brown, and grey to reddish or white, even though in 10%-30% of cases oral lesions may be colourless.
Rare cases of laryngeal MM may cause hoarseness, sore throat, and dysphagia. Pharyngeal lesions may cause haemorrhage, dysphagia, and/or dyspnoea.
Any suspected and unexplained sores or sores that won’t heal need to be reported to the physician.
Mucosal melanoma can be diagnosed through endoscopy, which is able to highlight polypoid, fleshy, and multiple lesions, frequently with different degrees of pigmentation.
Due to greater accessibility for inspection, lesions arising in the oral cavity may be diagnosed earlier and more easily.
If a mucosal melanoma is suspected, the most important test is a biopsy of the involved tissue. The tissue analysis, in addition to a morphological assay, helps to identify mixed cells, which are more aggressive and associated with a higher prevalence of vascular invasion and metastasis. Stains of tissues may help distinguish mucosal melanomas from other malignancies and from cutaneous melanoma.
Further tests may include imaging techniques. Among them, magnetic resonance imaging (MRI), that detects images of the internal organs of the body with magnetic waves, is to be preferred. The combination of high spatial and contrast resolution obtained with 3D MRI sequences allows a more accurate delineation of deep tumour extension.
2.4.1 Do these tests involve any risks for patients?
Generally, these exams are well tolerated. Endoscopy and biopsy may require the use of a local or general anaesthetic.
MRI may require the injection of a dye (or contrast medium) in order to obtain clearer images.
3. HOW IS MUCOSAL MELANOMA TREATED?
3.1 Which therapies are currently employed?
The type of treatment for MM depends on different factors related both to the disease (cancer stage [see paragraph 4 below], presence of metastases) and to the patient (general health, age, comorbidities).
Surgery is the first line treatment for most MMs. Medical therapies also can be employed to cure the disease, to control or slow down the growth of cancer, and to control/relieve symptoms (palliative care).
The fact is that MM is a very aggressive neoplasm with a high tendency to recur despite treatments, and even aggressive surgery does not seem to improve survival.
Surgery is considered the mainstay of treatment for most MMs of the head and neck region, even though the anatomical complexity of the region and proximity to vital structures make it difficult to achieve radical excision of the tumour, the surgery’s main goal. Moreover, despite radical surgery, a relevant proportion of patients with head and neck MM will suffer from recurrent disease, with various combinations of local, regional, and distant relapse.
Endoscopic techniques, which avoid the external wide resections performed in the past, have gained ground in the treatment of MMs, especially of those located in the sinonasal tract.
But in the presence of oral or maxillary lesions endoscopy may not be possible, and a more traditional surgery should be performed. Different approaches tailored according to the site of origin and local extension of the lesion with different types of reconstruction are available.
3.3 Medical treatments
After decades of little progress, a host of new treatment options have been produced for patients with melanoma. Since 2011, several new treatments for advanced melanoma have been approved. In particular, targeted therapies and immunotherapies, seem to provide good options for mucosal melanoma patients.
3.3.1 Targeted therapy
The use of appropriately targeted agents is one therapeutic strategy; howeveer; because of the rarity of metastatic mucosal melanoma, clinical data are limited. Despite the toxicity, this regimen showed a dramatic impact on the disease in terms of response rate.
The new therapies aim to target altered molecular pathways and mutated genes in mucosal melanoma. This association of treatment efficacy with a specific molecular subgroup of melanoma has important implications. Targeted therapy is systemic, which means that the drugs reach parts of the body through the bloodstream.
Cancer experts have found that combining two drugs may treat advanced melanoma more effectively than either medication on its own, for certain patients.
The drugs most used are the BRAF mutation inhibitors dabrafenib (Tafinlar) and vemurafenib (Zelboraf), the MEK inhibitor trametinib (Mekinist), and KIT inhibitors.
Mucosal melanoma can be considered as a strongly immuno-modulated tumour. Immunotherapy includes treatments able to stimulate the patient’s immune system to detect and react against cancer cells. In normal conditions, the immune system protects the body from the outside world, attacking infections caused by viruses and bacteria and destroying abnormal cells, such as cancer cells.
Immunotherapy options include:
- Ipilimumab, a monoclonal antibody that helps strengthen the immune system by promoting the function and growth of T cells. Although ipilimumab has been shown to improve the overall survival of patients with cutaneous melanoma, its efficacy in patients with mucosal melanoma remains unknown because of the variable response to treatment.
- Nivolumab and pembrolizumab, which help make cancer cells more vulnerable to attack by the body’s own immune system, promoting the tumour-killing effects of T cells. These drugs are particularly recommended for patients with unresectable or metastatic melanoma, but specific data regarding the subgroup of mucosal melanoma patients have not been reported.
Studies evaluating the efficacy of other immunotherapy agents have been recently set, to assess the longest progression-free survival rate.
Radiotherapy is recommended as standard option for patients who refuse surgery or who have an inoperable/unresectable tumour.
This approach may also be used during surgery, by delivering high doses of radiation directly to cancer cells, or after surgery, to reduce the chance of the cancer coming back (adjuvant radiotherapy).
Radiotherapy is recommended as individualized local treatment and also as standard palliative treatment of symptomatic metastatic disease.
Although useful in controlling inoperable cancers and relieving symptoms, radiotherapy seems not to contribute to the prolongation of survival.
Patients could take advantage by the combination of surgery and radiotherapy.
3.5 Side effects related to therapies
Surgery can likely leave large defects, since it may be extensive and destructive due to the important structures in the region of the neck and head.
After radiotherapy, the most common side effects are skin changes, like sunburn to the skin surrounding the mouth/neck.
Immunotherapy most common side effects are fatigue, fever, chills, nausea, and reactions at the site of the infusion. But ipilimumab and nivolumab can give rise to more serious adverse effects, such as pneumonitis, colitis, hepatitis and pancreatitis, skin rashes, and endocrine disorders, that can be controlled with immunosuppressive drugs (i.e., corticosteroids, antihistamines).
Common side effects of targeted therapies include fevers, rash, joint pain, and nausea. They could also have dermatologic side effects.
The association of various therapies has more side effects than giving either treatment alone, but it may also reduce the risk that the cancer will grow back after treatment.
4. STAGING OF MUCOSAL MELANOMA
The stage of a tumour indicates its extension and its spread beyond its site of origin (metastasis). It is important in order to choose the most appropriate treatment.
A universal staging system for mucosal melanoma does not exist. There are several systems depending on each site. However, in the 7th edition of the American Joint Committee on Cancer (AJCC), the classic TNM staging system was adopted for melanomas of the head and neck, although it is still necessary to create appropriate staging systems for mucosal melanomas of other regions, in order to facilitate comparisons of the results of different institutions, and help define the best therapy.
4.1 TNM classification
Originally conceived for epithelial cancer, TNM also has a prognostic value in head, neck ,and sinonasal mucosal melanomas. Similarly to skin melanoma, its intent is to focus on depth of infiltration rather than involvement of single subsites. Moreover, this staging system is not site-dependent, thus confirming that mucosal melanoma is a very aggressive disease, regardless of the site of origin.
4.1.1 TNM staging
It is the most commonly used system, where:
- T refers to the size or position of the primary tumour (where the cancer first starts in the body);
- N refers to which lymph nodes are affected, if any;
- M refers to metastatic disease (when the cancer has spread to other parts of the body).
4.1.2 Number staging
In this system staging is identified with numbers, from 1 (small cancers that have not spread) to 4 (advanced cancers with metastases).
In order to give more detailed information about cancer size and spread, stage numbers may be followed by lowercase letters.
4.1.3 Other terms
The following are other commonly used terms:
- “early” or “local”: a cancer that has not spread;
- “locally advanced”: a cancer that has begun to spread into surrounding tissues or nearby lymph nodes;
- “local recurrence”: the cancer has come back in the same area after treatment;
- “secondary”, “advanced”, “widespread”, “metastatic”: the cancer has spread to other parts of the body.
The speed at which the tumour may progress is related to the appearance of cancer cells under the microscope. These morphologic characteristics are defined by “grades”.
A low-grade cancer is made of cells looking very like normal cells, growing slowly and less likely to spread. Highly abnormal cells, that tend to grow quickly and spread, are typical of high-grade cancer.
5.1 General information
Prognosis indicates the likelihood that treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. Generally, it is referred to as the percentage of survival at 5 or 10 years since the start of treatment: this indicates the percentage of patients that are still alive after 5 or 10 years since the beginning of therapy, as demonstrated in large studies.
It is important to remember that these statistics are indicative: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.
5.2 Prognosis of mucosal melanoma
The prognosis of patients with head and neck mucosal melanoma remains dismal, since this tumour has a very high propensity to relapse, regardless of resection width and adjuvant treatment administered.
Local, regional, and distant failures are observed in up to 81% of patients. Overall, 18% of patients have lymphatic metastases at presentation, with no significant difference between oral and sinonasal lesions. The brain and lungs are the preferential sites of distant localization, whereas multiple organ involvement may be detected in up to one-third of cases.
In Europe, among the cases diagnosed in the years 2000-2007, 63% of the patients were still alive at 1 year after diagnosis, but after 3 years this percentage decreased to 30%. In fact, most recurrences occur within the first 3 years. At 5 years, survival had an average rate of 20%, but these value varied with age: five-year survival was 23% in patients aged 25-64 years of age and 19% in patients >65 years of age.
Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, no increased survival advantage was seen for mucosal melanoma.
6. WHAT TO DO AFTER TREATMENT
6.1 General information
After completing treatment, the oncologist will plan a series of subsequent visits and additional tests to monitor the effects of treatment and make sure that cancer does not recur. It is important for patients to contact their oncologist immediately in case of new symptoms or side effects, even beyond the already scheduled appointments that are part of the planned follow-up care schedule.
Frequency of the medical examination is not standardized, because subjects affected by melanoma can relapse up to 5 years after diagnosis; even relapses in the period exceeding 10 years after surgical intervention are documented.
A specialist visit per year for the rest of a patient’s life is recommended, as the risk of developing another neoplasm is estimated to be between 4% and 8%.
In patients with melanoma with deep invasion, clinical examination and imaging techniques should be carried to evaluate the tumour stage.
7. WHAT TO ASK DOCTORS
• May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
• What leaflets, books, or websites could I read to learn more about mucosal melanoma?
• Is there a patient association I could contact?
• Do you have special advice regarding nutrition?
• Does mucosal melanoma run in families? Are my children at risk of getting mucosal melanoma?
Diagnosis and exams
• What tests are you going to do?
• What are you looking for?
• What should I do in preparation for a CT scan or MRI?
• How long will the exam take?
• Is it painful?
• Will I be asleep?
• Should someone be with me?
• Are CT or MRI dangerous because of radiation exposure?
• Is biopsy painful? Is it performed under general or local anaesthesia?
• How long will it take to confirm diagnosis?
• Do I need a highly specialized centre?
• What type of treatment do I need?
• Is there any choice of treatments?
• What are the risks and benefits of the treatments?
• What are the side effects?
• How can I help to reduce the side effects?
• What signs should I recognize so that I can tell the doctor and ask if the approach needs to be changed?
• Is surgery performed under general or local anaesthesia? Will it be painful? What should I do before and after surgery?
• What are the possible side effects of therapy? Will I lose my hair? Will I have nausea and vomiting?
• During treatment should I take special precautions or change my habits?
• Is there any behaviour I could adopt to improve my prognosis?
• What late effects could treatments have?
• What supportive therapy is suggested during the treatment?
• How will my treatment affect me?
• Will I ever get back to normal, or will I have long term effects?
• Will I need a special diet? Is there anything I shouldn’t eat?
• Will I be able to go back to work?
• Could the cancer recur?