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Issue 2, 2007
HOT TOPICS IN ONCOLOGY
Melanoma
| Publ. date: | 2007 |
| ISBN: | 978-88-89881-44-6 |
| ISSN: | 1973-9656 |
| E-ISSN: | 2036-0894 |
| DOI: | 10.4147/HTO-070200 |
Abstract
The most deadly form of skin cancer, malignant melanoma is increasing in incidence. Prevention through limiting sun exposure is effective but conflicts with popular notions about the health and beauty of a suntan. New insights emerging from the study of the cell biology of melanoma are altering our understanding of the disease and pointing to a number of potentially useful therapeutic targets. Key players in these pathways include Rho, transforming growth factor-beta, tumor necrosis factor, Stat3, Raf, and Wnt. Particularly intriguing is that when the Wnt pathway is active, the immunologic targets for melanoma that have been defined are down-regulated and the converse is also true. Absence of Wnt expression is associated with less aggressive tumor behavior and a greater likelihood of responding to immunotherapies. Thus, Wnt is a particularly interesting target for therapeutic intervention.
Clinical research in melanoma continues to show sporadic successes that provide opportunities for further exploration. Immunotherapy may be successful during lymphocyte depletion. Targeting CTLA4 (cytotoxic T-lymphocyte-associated antigen 4) appears capable of breaking self-tolerance and causing a vigorous autoimmune response against melanoma. In addition, adoptive cellular therapies, antibodies, vaccines, and other manipulations have shown some preliminary encouraging results. As a result of these developments, we may be on the verge of making substantial progress in treating melanoma.
Table of contents
Foreword
The same sun that melts the wax can harden clay
The same rain that drowns the rat can grow the hay
Amy Grant/Tom Hemby lyric from “How Can We See That Far?”
A duality is inherent in the nature of things. Too much of a good thing, even an essential thing, like water or the sun, is bad for you.
Malignant melanoma is one of a handful of cancers that is increasing in incidence worldwide. There were nearly 60,000 new cases diagnosed in the United States in 2007. A major etiologic factor in melanoma is sun exposure. However, some sun exposure is clearly healthy. The sun is a major source of vitamin D. Sun exposure has positive effects on mood and affect. It is the accumulation of UV damage to the skin from sun overexposure that poses a risk for melanoma, especially in fair-skinned persons.
Melanoma is the most dangerous of skin cancers, accounting for 75% of skin cancer deaths. The risk of melanoma is about 50% higher in people with dysplastic nevus syndrome. About 10% of patients with melanoma have an immediate family member who has had the diagnosis. About 1 person in 75 will develop melanoma at some time in their lives, men somewhat more commonly than women.
The two methods currently available for reducing deaths from melanoma are protection against sun damage of the skin and early detection of melanomas while they are localized and remain curable with surgery. Sun protection is straightforward. Cover your skin with clothing, hats, or sunscreen when you go outdoors. Avoid tanning salons. It has not been proven that those machines are less dangerous than the sun.
Early detection is not easy. Each of us normally has 10-50 moles and sometimes they are in areas that are difficult to keep track of. However, the ABCDE rules have been devised as a mnemonic to help people decide when a particular mole needs medical attention.
The A is for asymmetry. Benign melanomas are generally symmetrical. Pigmented skin lesions that are asymmetrical are potentially malignant.
The B is for border. Malignant melanomas may have an uneven border, or they may have notched or scalloped edges. Benign moles tend to have smooth and even borders.
The C is for color. Benign pigmented lesions are generally homogeneous in color, usually a shade of brown. Malignant melanomas, on the other hand, may have a variety of brown, tan, and black coloring. Red, white, and blue colors may also be present. Variegated coloring is a danger sign.
The D is for diameter. Larger size may be a sign of malignant melanoma. Benign lesions rarely grow larger than the size of a pencil eraser (~6 mm). Any lesion 6 mm in diameter or larger is potentially malignant.
The E is for elevation or evolution. A mole that has areas of different elevation or contour above the skin surface is unusual. Furthermore, any mole that grows or changes should be examined by a dermatologist as soon as a change has been discerned.
Seeking immediate attention by a dermatologist for any of the ABCDE rules can optimize efforts at early detection.
Once melanoma has spread beyond its site of origin, it becomes an extremely difficult and life-threatening problem. My own experience with melanoma patients has spanned the extremes. I had a patient with metastatic malignant melanoma who developed a headache that lasted 2 days. I decided to perform a spinal tap because of some minor almost trivial slowness in lateral gaze. The cerebrospinal fluid came out black. At autopsy a few weeks later, that patient had metastases to every organ, including the heart muscle and the spleen, unusual sites of solid tumor metastases.
On the other end of the spectrum, some patients with metastatic melanoma have enjoyed long-term disease-free survival as a consequence of some intervention, usually an IL-2-based therapy. Surprising differences have emerged in some long-term survivors. Some are restored to complete health without discernible after-effects. Occasional patients have small or large patches of vitiligo; at least one patient has lost all pigmented cells of the skin and skin appendages and has white hair. In such cases with signs of autoimmunity against melanin-containing cells, it is tempting to speculate that a therapy has somehow broken self-tolerance to melanin and an immune response was mounted against the tumor. However, this speculation is not satisfying. Melanin is not an essential component of melanomas; many are amelanotic.
The bottom line is that we do not know where melanomas are vulnerable or what cellular machinery they use to do their devastating damage. But that situation is changing rapidly. In this monograph, Michael P. O’Connell and Ashani T. Weeraratna describe some of the recent progress that has been made in understanding melanoma biology. This work has defined not just one or two, but many potential targets for a more specific therapeutic approach.
In addition to progress at the lab bench, the modicum of clinical success that has been seen in treating patients with melanoma has led to further experimental efforts in clinical research. Those efforts are also producing insights that may form the basis for therapeutic advances in melanoma. They are beautifully summarized here by Brendan D. Curti and Walter J. Urba.
We are poised to make significant advances in the treatment of melanoma based on the application of the insights emerging from both laboratory and clinical research.
ARTICLES
Novel targets in melanoma: stopping the signals that make tumors go
Michael P. O'Connell, Ashani T. Weeraratna
Immunotherapy of melanoma
Brendan D. Curti, Walter J. Urba
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Editor-in-chief
Dan L. Longo - MD
The investment in basic research over the last twenty-five years has led to an explosion of new agents and approaches to cancer treatment. The current unprecedented pace of discovery of novel targets ...
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