Melanoma is a severe form of skin cancer. Prevention and early diagnosis are essential. Surgery and medicines have helped improve patients' lives. Further research offers the hope of even better treatments for this increasingly common disease.
Melanoma is a malignancy of pigment-producing cells, also known as melanocytes (from the Greek words “melas“ meaning black or dark and “kytos“ meaning hollow, container or cell). The cells are predominantly located in the basal layer of the skin and produce melanin to protect the body from ultraviolet light, under the control of the melanocyte-stimulating hormone (MSH). Melanocytes can also be found in the eyes and ears, in the gastrointestinal tract, in the thin lining that surrounds the brain and the spinal cord, and in several mucous membranes.
The development of melanoma appears to be related to several risk factors. Primary cutaneous melanoma may develop in precursor melanocytic skin areas, although more than 60 per cent of cases are believed not to arise from a pre-existing pigmented lesion. Risk factors include fair complexion, intense sun exposure and repeated sunburns during childhood, an increased number of moles, the presence of a changing mole, a family history of melanoma, and older age. Melanoma is extremely rare prior to puberty.
Four major subtypes have been identified. These include superficial spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), and acral lentiginous melanoma (ALM). SSM is the most common, occurring in 60-70 per cent of patients and is mostly seen in individuals aged 30-50 years. NM occurs in about 20 per cent of patients and grows rapidly over weeks to months. It may ulcerate and bleed with minor trauma. The LMM subtype accounts for some ten per cent of cases. It is typically located on sun-damaged skin of fair-skinned older individuals and grows slowly over 5-20 years. ALM is the least common subtype, accounting for five per cent of cases. It occurs on the palms, the soles or beneath the nail plate, and, because of delays in diagnosis, may be associated with a worse prognosis.
A changing mole is the most common warning sign for melanoma. Variation in colour and an increase in diameter, height, or asymmetry of borders of a pigmented lesion are noted by more than 80 per cent patients at the time of diagnosis. Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common, but warrant an evaluation.
Melanoma accounts for only four per cent of all skin cancers; however, it is the cause of nearly 80 per cent of skin cancer–related deaths. It is primarily a malignancy of white individuals. African Americans develop melanoma approximately one-twentieth as frequently as white people. Worldwide, 160,000 new cases were estimated to have occurred in 2002, with 41,000 deaths reported. Of the 160,000 cases, women were slightly more affected (male-to-female ratio: 0.97:1). Conversely, in the 41,000 fatal outcomes, the male-to-female ratio was found to be 1.2:1.
Over the last 50 years, melanoma incidence has continued to increase worldwide, with the highest numbers in Australia and New Zealand (38 cases per 100,000 men and 30 cases per 100,000 women). About 60,000 new cases a year are diagnosed in Europe. The incidence is slightly higher in women than men, at about 7 and 6 per 100,000 per year respectively, and higher in northern than in southern Europe. This compares with 7 cases per 100,000 men and 12 cases per 100,000 women in North America.
Early detection is the best means of reducing mortality. Patients have higher survival rates in industrialised countries (85 per cent) than in developing countries (40 per cent). Educational efforts have resulted in earlier diagnosis, treatment, and potential cure of thinner lesions. To adjust treatment and to assess patient prognosis, a melanoma staging system is in place. It incorporates tumour thickness and anatomic level of invasion for stages I and II in localised cutaneous disease. Stage III involves the regional lymph nodes, while stage IV takes metastases into account, in distant skin, lymph nodes, intestines, skeleton or the central nervous system.
Surgery is the primary mode of therapy for localised cutaneous melanoma. Lymphatic mapping and sentinel (first draining) node biopsy have effectively solved the dilemma of whether to perform regional removal of lymph nodes in patients with melanomas thicker than 1mm. Sentinel node status is the prognostic factor for recurrence and a powerful predictor of survival.
The biological response modifiers interferon (IFN) alfa-2b and interleukin (IL)-2 are used as adjuvant therapy for melanoma of stages II and III. Controlled clinical trials have shown a beneficial effect on relapse-free survival and five years overall survival. Metastatic disease responds poorly to the usual treatments. Two out of 30 medicines tested, an imidazole carboxamide derivative and nitrosourea compounds have shown response rates greater than ten per cent. Complete responses are very rare.
In a phase 2 trial with patients suffering from metastatic melanoma, investigators are studying the effect of a triple therapy; two chemotherapeutic agents – a platinum compound and a taxoid derivative – which are applied together with a modified dipeptidyl boronic acid molecule. The latter sensitises tumour cells by blocking some of the enzymes needed for cell growth.
An imidazotetrazine derivative which has been approved to treat aggressive brain cancer, is being tested in a phase 2 comparative trial to ascertain if the extended schedule of the medicine is a more effective treatment than another single agent, usually given to patients suffering from lymphomas.
Another research group is studying the combination therapy of IL-2, with two cytostatics plus colony stimulating factor to see if patients will show improved response rates. Clinical trials are exploring the effects of IL-21 as monotherapy in advanced (stage IV) melanoma.
In a phase 3 clinical trial, scientists are looking into safety and efficacy of an antiCTLA-4 monoclonal antibody (Mab) combined with a melanoma peptide vaccine in previously treated stage III or IV disease. Eligible patients are those who relapsed or did not tolerate treatment due to toxicity.
A phase 1/2 clinical trial is investigating the safety and efficacy of a human Mab directed against integrins – a family of trans-membrane receptors which engage cells with their environment – alone and in combination with DTIC. Participants are patients with stage IV melanoma.
Several phase 3 studies are ongoing to assess the adjuvant effect of high-dose IFN alfa-2b therapy in patients with stage II or III melanoma.
Stages of melanoma
• Stage 0
The melanoma cells are found only in the outer layer of the skin.
• Stage I
The tumour is between 1and 2 mm thick. The outer layer of skin may appear scraped. The melanoma cells have not spread to nearby lymph nodes.
• Stage II
The tumour is between 1 and 2mm thick. There is ulceration of the skin. The melanoma cells have not spread to nearby lymph nodes.
• Stage III
The melanoma cells have spread to one or more nearby lymph nodes or to tissues just outside the original tumour, but not to any lymph nodes.
• Stage IV
The melanoma cells have spread to other organs, to lymph nodes, or to skin areas far away from the original tumour.
A human cellular enzyme called Poly-ADP ribose polymerase (PARP) allows tumour cells to become resistant to chemotherapeutic agents, by repairing the deoxyribonucleic acid (DNA) damage and tumour killing effects. In a phase 1/2 trial in patients with stage III and IV disease, scientists study, whether by blocking PARP, cancers may be more sensitive to chemotherapy.
Patients with stage IV ocular melanoma have very few available treatment options and an overall poor prognosis. In a phase 2 clinical trial, investigators are evaluating the safety and efficacy of a novel anti-angiogenic and immunomodulating agent which has activity against solid tumours.
More than 20 trials are running to assess the effect of different adjuvant vaccines prepared from melanoma peptides, including biological immune response modifiers, colony stimulating factors and other cytokines, which may enhance the body’s immune response to kill tumour cells.
Knowledge about melanoma and how to treat it keeps improving. Research has established that a gene known as c-myc controls the growth of melanocytes. When damage through ultra-violet light occurs, control is lost, resulting in cell growth at an abnormally fast rate which may lead to melanoma. There are findings that inhibition of the synthesis of c-myc protein can cause growth arrest of melanoma cells, e.g. by ribonucleic acid (RNA) binding molecules which specifically attach to the c-myc RNA. Blocking c-myc may pave the way for new approaches in combination with newly found adjuvant vaccines, immune response modifiers and chemotherapeutics.