Therapeutics in Dermatology
A reference textbook in dermatology
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Cutaneous melanoma

11 May 2012, by GROB J.-J. , RICHARD M.-A. & GAUDY-MARQUESTE C.

Melanoma is a malignancy of pigment-producing cells, melanocytes, in the skin. It has several distinguishing features:

– for at least the past 20 years, its incidence has risen more steeply than that of other cancers, although some of this rise is attributable to changes in the way melanoma is defined;

– their visibility should make possible to detect most melanomas at an early stage but this is far from the case at the present time;

– their ability to metastasise for a very low initial tumour mass. The risk of metastasis from a melanoma 2 to 4 mm thick is already high since almost half of these patients die within 10 years. This is further proof of the importance of an early diagnosis;

– the unpredictable course of the super-acute and virtually chronic forms, which we are unable to identify immediately;

– a lack of modern, non-invasive, reliable and validated prognostic markers, to the extent that we are still reliant on the Breslow thickness index and the presence of tumour cells in the first draining lymph node (measured by biopsying the sentinel node) for our assessment of the risk of progression;

– their complex immunogenicity and relationship with the immune system which could explain some recurrences arising more than 10 years after excision and the appeal of immunotherapy, although the last decade has taught us that immunotherapy is difficult to employ, whether for prevention or as a curative method.

Until the present time, patients with metastatic melanoma have been managed with chemotherapy, which has well-known limits (the response rate with the most effective treatments is 10 to 15 percent, with little or no impact on survival), or inclusion in clinical trials testing experimental treatments. Major progress has been made in the treatment of metastatic melanoma with the recent development of two new treatments which have, for the very first time, shown benefits on survival: immune synapse treatments, particularly anti-CTLA4 antibodies (ipilimumab), and targeted molecular therapies such as the BRAF inhibitors (vemurafenib) which have just been granted a marketing authorisation. Tests are on-going with numerous other molecules and the currently limited therapeutic arsenal looks set to expand in the near future.

The earlier a melanoma is diagnosed, the better its prognosis. Clinical detection of a melanoma, whether during screening or a routine clinical exam, is complex because these tumours can be difficult to distinguish from other pigmented lesions such as atypical naevi, especially during their early stages. The diagnostic algorithms most frequently applied are the American Cancer Society’s "ABC" rule [1], and the "7 point check list" used in the United Kingdom [2]. The progressive nature of the lesion must also be taken into account [3]. In routine practice, dermatologists take a more global approach, naturally checking the appearance of the lesions both against images stored in their memory and the patient’s other naevi [4]. A pigmented lesion is all the more suspicious when it looks different from the others present (ugly duckling sign) [5]. Examination of the lesion under the dermascope will provide further diagnostic information.

Histological analysis of a clinical suspect lesion after it has been removed (a) confirms the diagnosis of melanoma, (b) allows the margins to be checked to ensure that they are free of residual tumour and (c) provides information helping to establish the prognosis: maximum thickness on Breslow scale, Clark level of invasion, existence or absence of ulceration, presence and extent of regression and mitotic index.

There are generally accepted to be four major types of melanoma with different clinical appearances, histopathological profiles and modes of progression: the spreading superficial melanoma (SSM), the nodular melanoma, the acral lentiginous melanoma and the lentigo malignant melanoma. Each of these melanomas has its own epidemiological characteristics and prognosis, linked in part to their different growth patterns with rapid growth signifying a more aggressive nature. Recent gene mutation studies indicate that molecular classification of tumours – more accurate in terms of prognosis and therapy - will soon be possible.

There are generally three main phases in the development of a melanoma: primary melanoma, regional lymph node invasion and then disseminated disease. A cure is possible in the first two stages of the disease. It is not known exactly how the disease spreads. However, tumour cells are often found in the sentinel (draining) nodes of patients with primary melanoma but no clinical lymph node invasion, and in the circulation of patients whose malignancy was believed to be confined to the lymph nodes. This discrepancy between clinical and laboratory findings requires further comment:

– there is clearly spread beyond the visible disease;

– and yet in spite of this, and apparently paradoxically, primary melanoma can be cured by a minor surgical procedure; regional lymph node invasion can also be cured by simple dissection of the affected nodes although there is a high risk of metastasis in the short term. This strongly suggests that not all the tumour cells migrating from the initial tumour will give rise to a clinically aggressive metastasis;

– there are therefore discrepancies between the classification systems based purely on clinical findings and those founded on the results of samples systematically removed from the sentinel node (see below) since, depending on the evaluation system used, there is potential for the same patient to be considered as presenting with/being free from regional involvement.

The AJCC classification is the most widely used system [6] (Table I).

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