Research Article: Melanoma: What Are the Gaps in Our Knowledge?

Date Published: June 3, 2008

Publisher: Public Library of Science

Author(s): Jonathan L Rees

Abstract: Jonathan Rees outlines a number of puzzling gaps that remain in our knowledge of the etiology of non-acral melanomas.

Partial Text: Cutaneous malignant melanoma (MM) falls into two main groups, based on aetiology [1–3]. First, a small minority of patients have acral MM, in which the disease occurs on the palms and soles. The incidence of acral MM is similar in people with widely different skin colours (and hence with different amounts of skin melanin), and at different latitudes. The palms and soles have a thick epidermis, and so few harmful photons of ultraviolet radiation (UVR) will penetrate to the germinative layers. Acral melanomas are therefore not believed to be causally related to UVR, and their aetiology remains a mystery. They will not be discussed further in this article.

First, although MM is related to UVR exposure, the body site distribution of MM does not match the distribution of some other sun-related cancers, such as squamous cell carcinoma (SCC) of the skin [6,7]. SCC is most common on the backs of the hands, the face, and the scalps of bald men: these are the sites that receive the highest cumulative dose of UVR. By contrast, when the body site distribution of MM is mapped out, we see that sites such as the shoulders and back in men, and lower legs in women, show relatively higher rates of MM. I say relatively because obviously the different body sites differ in surface area, but the point is that we see a difference between SCC and melanoma on the basis of the same human anatomy. If the amount of UVR received is to explain MM aetiology, then we need to factor in some other modifying hypothesis. Perhaps the pattern of exposure is important, with sites that are intermittently exposed behaving differently from those that are continually exposed. It is this line of argument that contributed to the hypothesis that acute episodes of “sunburning” (rather than cumulative dose of UVR) may be important [3,6,8].

In the early part of the 20th century, the clinical picture of melanoma was of a highly malignant tumour that presented late and carried a high mortality at five years of about 80% [1]. Then, as is still largely the case today, there was no curative treatment for metastatic disease. Judged in terms of absolute tumour mass MM appears to metastasise early and, in the absence of insights into how to treat metastatic disease, the mantra has been to detect melanoma early before it has metastasised. Although we have no evidence for the value of population screening for MM, over the last century greater access to health care and increasing knowledge and concern about MM led to patients presenting earlier with lesions that might be MM [3]. Rather than a five-year death rate of 80% or greater, we now see a survival rate at five years of 80% or more [2]. It would seem natural to attribute the increased survival of patients with MM to the increased detection of early disease.

The combination of increasing incidence of a disease with a reduction in case fatality has led to other hypotheses [9]. In the 1990s, based on examination of epidemiological trends in Australia, Burton and Armstrong [12] argued that dramatic increases in thin melanomas (in terms of Breslow thickness) and no reduction in the number of thick MMs suggested that many lesions being detected were (in their words) “non-metastasising MM”. The argument was that on top of the real increases in MM capable of metastases, increased sampling led to lesions that were biologically more benign being histopathologically classed as MM—a scenario familiar to students of other human cancers such as breast and prostate. This scenario is also seen in the skin with non-melanoma cancers: actinic keratoses, lesions with multiple genetic changes that were once thought to be the hallmark of cancer, regress without any treatment in most cases [13]. The more you look for squamous cell carcinomas, the more actinic keratoses you biopsy.



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