Journal of Cancer Education
ISSN: 0885-8195 (Print) 1543-0154 (Online) Journal homepage: http://www.tandfonline.com/loi/hjce20
Malignant melanoma as a model for cancer education and prevention William A. Robinson MD, PhD To cite this article: William A. Robinson MD, PhD (1990) Malignant melanoma as a model for cancer education and prevention, Journal of Cancer Education, 5:2, 85-89 To link to this article: http://dx.doi.org/10.1080/08858199009528044
Published online: 01 Oct 2009.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=hjce20 Download by: [University of Calgary]
Date: 06 August 2017, At: 10:18
J. Cancer Education. Vol. 5, No. 2, pp. 85-89, 1990 Printed in the U.S.A. Pergamon Press plc
0885-8195/90 $3.00 + .00 © 1990 American Association for Cancer Education
MALIGNANT MELANOMA AS A MODEL FOR CANCER EDUCATION AND PREVENTION 1989 Harvey Lecture American Association for Cancer Education
Downloaded by [University of Calgary] at 10:18 06 August 2017
WILLIAM
A.
ROBINSON,
Cutaneous malignant melanoma (MM) was once a relatively uncommon disease occurring primarily in outdoor workers. The last 50 years have seen a dramatic increase in the incidence of MM due, as we shall see, to increasing sun exposure primarily from changes in clothing habits and lifestyles that have occurred over this time period. Current estimates suggest that by the year 2000, 1 in 90-100 Caucasians will develop MM over their lifetime.1 Based upon today's statistics, 20%-30% of these patients will ultimately die of the disease.2 Thus, MM represents a major public and personal health problem for the 1990s and beyond. This is perhaps the most dramatic change that has occurred in any cancer over the past 50 years and has caught the medical community and public by surprise. As a medical student the only case of MM that I saw was during an autopsy, and this is true of most other physicians of my generation. Currently, physicians in all specialities, but particularly those in the primary care disciplines, are faced with an increasing number of persons presenting with suspicious lesions, many of whom will be diagnosed as having malignant melanoma. Many of these physicians lack the background and knowledge of the disease to allow them to adequately deal with the problem. Urgent measures are needed to educate both the professional community and public about
MD, PhD*
the cause of MM, its early diagnosis and treatment. The disease represents an important, but unfortunate, model for serving these goals in cancer education and prevention. Unlike most human cancers, the cause of the rapid rise in the incidence of MM is clear. It is the result of increasing exposure to ultraviolet light in the form of sunshine that has occurred from clothing habit and lifestyle changes that have occurred during the latter half of the current century. The data supporting this contention is incontrovertible.3'4'5-6 This includes the fact that death rates from MM increase as the amount of ultraviolet light increases in various geographic locations. The disease is particularly prevalent, for example, in the southwestern United States, the Hawaiian Islands and Australia, and less common in England and the northeastern United States. Further, it has been shown that migration of Caucasian populations from areas of low ultraviolet light to areas where there is an abundance of sunshine markedly increases the likelihood of development of MM.6 Finally, it is clear that MM occurs primarily in areas of the body that are exposed to the sun.2 For example, in males MM is most common on the back, neck, and shoulders, presumably because males are more likely to remove their shirts out of doors and have shorter hair. In women, by contrast, MM occurs most frequently on the lower and upper extremities. Various other factors have been suggested as possibly contributing to the rising incidence of the disease including ozone depletion, exposure to fluorescent lighting, and sunspot activity. While these may play minor roles in
*Professor of Medicine, Head, Melanoma Research Clinic, University of Colorado Health Sciences Center, Denver, Colorado. Reprint requests to: W. A. Robinson, MD, Head, Melanoma Research Clinic, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262.
85
Downloaded by [University of Calgary] at 10:18 06 August 2017
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W. A. ROBINSON
the overall picture, they are relatively insignificant when compared to simple exposure to the sun. Persons at highest risk for the development of MM in the past were mainly engaged in outdoor occupations, particularly agriculture and the building trades. As demonstrated by ourselves and others, however, recent years have seen dramatic shifts in the demographic profile of people developing malignant melanoma (Table 1). Studies by our group and others in Australia and the British Isles have shown that persons at highest risk are professional, managerial, and executive indoor workers who spend large amounts of time outdoors in leisure activities .7p8>9 It is unclear why such groups are at highest risk for the development of MM. It has been speculated that this may be the result of high dose, intermittent exposure to ultraviolet light and, in particular, the risk of repeated sunburning. In our series, only 4% of patients with malignant melanoma were occupied in agricultural or other outdoor occupations. The reasons behind this are unclear. This may result from the fact that agricultural outdoor workers, in this state, come from ethnic groups that are at lower risk for the development of the disease because of skin pigmentation or that chronic exposure to the sun, rather than high dose intermittent exposure, may be protective and beneficial. This becomes an important consideration when the question of suntan parlors is raised. The question is frequently asked whether exposure to ultraviolet A radiation, which is the primary form of UV from tanning parlors, may contribute to or prevent the development of MM. This question has not
Table 1. Demographic and phenotypic characteristics of persons at highest risk for development of cutaneous malignant melanoma — Fair skin Caucasian — Indoor occupation — Frequent outdoor leisure time — Blue or green eyes — Brown or blonde hair — Numerous moles
been answered due in part to the lack of good animal models to study the disease. It is clear that exposure of the skin to sun early in life predisposes one to the subsequent development of malignant melanoma, and it may be that repeated sunburns and high dose ultraviolet exposure in childhood may be the most important factor in the subsequent development of the disease. In addition to defining the demographic characteristics of persons at highest risk for the development of MM, we and others have also defined the phenotypic characteristics of persons developing the disease.2 Malignant melanoma occurs almost exclusively in Caucasians, most of whom are fair-skinned, have nonbrown eyes and brown or blond hair. It is a common misconception that most persons who develop MM have red hair. In a study conducted in our Melanoma Research Clinic, the most common hair color was light to medium brown. Only 12% of the patients in our study group had red hair. While this is a higher incidence of red hair than found in the general population, it is clear that most patients developing the disease do not have red hair. In the early part of this century, it was felt that most malignant melanomas arose de novo. It is now clear that most malignant melanomas, in fact, develop from preexisting nevi, as noted above, primarily in sun-exposed sites. In a study conducted by us, 70% of patients indicated that their MM began in a preexisting nevus.2 This is probably the result of an actual change in the disease over time rather than a change in recognition. The melanocytes in nevi are derived embryologically from the neuroectoderm, migrating up through the dermis to the dermal/epidermal junction, during puberty, under physiologic controls that are as yet undefined. At birth the average person has only 1-3 pigmented nevi. In puberty, nevi begin to appear, reaching an average 30-40 between the ages of 20 and 30, and then slowly begin to disappear with old age.10-11 Thus, malignant melanoma is uncommon before puberty. The distribution of benign nevi in the various sexes also,
Downloaded by [University of Calgary] at 10:18 06 August 2017
Malignant melanoma as a model
interestingly, conforms to areas of sun exposure. Thus, in males nevi are most common on the back, neck, and trunk, while in women they are more common on the lower and upper extremities. Exactly how exposure to ultraviolet light influences this distribution of neval development remains unclear. The classic junctional or compound nevus is easily recognized as a flat, uniformly brown, sharply circumscribed pigmented area usually less than 6 mm in diameter. As neoplastic changes occur, affected nevi begin to increase in diameter, develop variegated color ranging from hypo-' pigmented areas to blue, black, pink, and brown, and often develop irregular, notched borders. The most common complaint, and earliest symptom noted by most patients, is itching of a preexisting nevus (Table 2). Ulceration, bleeding, and pedunculation are late developments. The earliest changes can be easily recognized, and we recommend strongly that any nevus about which a patient or health care provider is concerned be removed by surgical excision, with an adequate 1-2 mm border down to the fat and examined histologically. Too often, in our clinic, we hear the story that the patient has shown a nevus repeatedly to a primary care physician, and because it does not have the classic features of advanced malignant melanoma, little attention is paid to it. As will be noted below, early surgical removal of any suspicious lesion is the key to the treatment of this disease. The mechanisms whereby ultraviolet light induces neoplastic degeneration have not been determined and are under intense investigation by ourselves and others. Various postulated mechanisms include direct DNA damage, alteration of the immune system, free radical production, and excess production of mela-
Table 2. The most common symptoms and signs of malignant change in a nevus — Itching — Change in color — Increase in size — Development of an irregular/notched border
87
nocyte stimulating hormone in phenotypically susceptible individuals.12 With the development of neoplasia, cell division results in both lateral and downward growth of cells. The lateral growth leads to the visual characteristics noted above, but it is the downward growth through the dermis and eventually into the fat, blood vessels, and lymphatics in and underneath the skin that is the most important factor determining spread. The levels of downward growth have been defined by Clark and Breslow13-1* as the most important prognostic indicators of potential metastases. In the system described by Clark, Level I melanomas are those confined to the epidermal/dermal junction, Level II when cells are present in the papillary dermis, Level III when extension has occurred into the upper reticular dermis, Level IV into the lower reticular dermis, and Level V into the fat underneath the dermis. In our Melanoma Research Clinic, the majority of patients present with level III and IV melanomas, with the latter comprising 47% of the total. For these patients the likelihood of microscopic metastases at diagnosis is in the order of 4O(7o-5O%. These cannot be detected by any known means at the present time. The median time from resection of the primary lesion until the detection of metastatic deposits in other organs is 4 years, and instances of 10-20 years are not uncommon. This long time lag often lulls the patient and health care provider into a false sense of security. It is important that all patients with a diagnosis of malignant melanoma be placed on regular follow-up schedule with systematic evaluation. It is beyond the scope of the present discourse to go into the various ramifications of width of excision of the primary lesions, lymph node dissection, and staging of patients at diagnosis. Excellent discussions of these sometimes contentious points can be found elsewhere.15-16 The most common sites of metastases are the lungs, liver, and brain, but melanoma is notorious for metastasizing to virtually any and every organ in the body. Once metastases have occurred, no treatment has been shown to be of consistent long-term benefit, and the
Downloaded by [University of Calgary] at 10:18 06 August 2017
88
W. A. ROBINSON
vast majority of patients will eventually succumb to the disease, with a median survival of one year. Recent years have seen significant advances in the treatment of metastatic disease but, in general, the outlook remains dismal. With current multidrug chemotherapy regimens, response rates of 20-40% have been achieved.17 Alpha interferon, interleukin 2 combined with lymphokine activated killer cells, and tumor infiltrating lymphocytes have yielded similar response rates, but most are short-lived.18'19 Ourselves and others are also investigating the use of antimelanoma monoclonal antibodies linked with ricin Achain toxin, with an occasional dramatic response.20 Multimodality therapies combining these various approaches are under intense investigation by a large number of investigators throughout the world (Table 3). Despite the advances that have been made in the treatment of metastases outside the brain, little progress has been made in the treatment of central nervous system (CNS) involvement. Seventy percent or greater of patients with metastatic disease will eventually develop brain metastases, and the currently available modalities have had little effect on this devastating complication.21 In the past year we have undertaken a study of the administration of the pineal derived hormone melatonin to patients with advanced disease, including those with CNS metastases. To date only 27 patients have been treated on a dose-escalating protocol using this agent. The results, while quite preliminary, have seen two patients with CNS metastases regress with melatonin. This protocol is being expanded to further determine both the mechanism of action of melatonin in
Table 3. Modalities currently under study for the treatment of advanced malignant melanoma — Multidrug chemotherapy —The interferons — Interleukin-2 — Lymphokine activated killer cells — Monoclonal antibodies — Melatonin
this regard and its further use in patients with advanced disease. We have also taken, and reported, an aggressive neurosurgical approach for the treatment of brain metastases in malignant melanoma with encouraging results when combined with therapy to treat systemic involvement in other areas.22 What is most clear from all of the therapeutic studies, however, is that primary prevention and understanding of the disease will, in the long haul, be the most important factor in stemming the tide currently facing us. Thus, we have a cancer which is occurring in near epidemic proportions with a clearcut cause in demographically and phenotypically definable populations which is easily recognized visually, preventable and curable in its early stages. Malignant melanoma, therefore, represents an ideal model for professional and public cancer education. The public must be made aware of the deadly danger of excessive exposure to sunshine, to understand that the disease develops primarily in moles, and the changes that are likely to occur in them as neoplasia develops. Physicians and other health care providers should include skin screening as a routine part of all examinations, particularly in high risk populations, and must be made aware of who the latter are, how nevi develop, and the risk of leaving potentially dangerous moles in place. The professional community must also take the lead in patient and public education. The task will not be a simple one. Health, in many ways, has become synonymous with outdoor activities and a tanned look. Education must begin in childhood about the dangers of sun exposure, and the public must be made aware that ultraviolet light doesn't simply cause wrinkling and aging of the skin—it may mean death. Changes in clothing habits, lifestyles, and the use of sun screens and blocks are all essential ingredients of the formula to be put forward, together with early recognition and removal of potentially malignant nevi. Pale skin and a few scars hopefully will become the beauty marks of the future. The dark side of the sun looming over us is malignant melanoma.
Malignant melanoma as a model
Downloaded by [University of Calgary] at 10:18 06 August 2017
SUMMARY Cutaneous malignant melanoma is one of the most rapidly increasing and highly fatal cancers in the world today. Current estimates suggest that 1 in 90-100 Caucasians will develop MM by the year 2000, and 20%-30% will eventually die of the disease. The cause of the epidemic of malignant melanoma is clearly increasing exposure to the sun from lifestyle and clothing habits that have changed over the past 50 years. The disease occurs primarily in preexisting nevi in sun-exposed sites in specific high risk populations who can be, and have been, defined. These are primarily middle- and upper middle-class Caucasians with blue eyes, brown or blonde hair, and fair skin, with predominantly indoor occupations who spend, or have spent, considerable time outdoors in leisure and other activities. The presence of a clearly definable cause (exposure to the sun) in specific risk groups, the ease of early detection by simple means, and the devastating outcome of late diagnosis make malignant melanoma an ideal model for teaching the basic tenets of cancer causation, development, and prevention to the public and professionals alike.
REFERENCES 1. Kopf AW, Rigel DS, Friedman RJ: The rising incidence and mortality rate of malignant melanoma. J Dermatol Surg Oncol 8:760-761, 1982. 2. Rifkin RM, Thomas MR, Mughal TI, et al: Malignant melanoma—Profile of an epidemic. West J Med 149:43-46, 1988. 3. Elwood JM, Lee JA, Walter SD, et al: Relationship of melanoma and other skin cancer mortality to latitude and ultraviolet radiation in the United States and Canada. Int J Epidemiol 3:325-332, 1974. 4. Teppo L, Pakkanen M, Hakulinen T: Sunlight as a risk factor of malignant melanoma of the skin. Cancer 41:2018-2027, 1978. 5. Crombie IK: Variation of melanoma incidence with latitude in North America and Europe. Br J Cancer 40:774-781, 1979. 6. Elwood JM, Hislop TG: Solar radiation in the etiology of cutaneous malignant melanoma in Caucasians. Natl Cancer Inst Monogr 62:167-171, 1982. 7. Cooke KR, Skegg DCG, Fraser J: Socio-economic
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status, indoor and outdoor work, and malignant melanoma. Int J Cancer 34:57-62, 1984. 8. Lee JA, Strickland D: Malignant melanoma: Social status and outdoor work. Br J Cancer 41:757-763, 1980. 9. Robinson WA, Ferguson J, Robinson JF: Malignant melanoma, the dark side of the sun, at 40° north. Transactions of the Menzies Foundation 15:121-125, 1989. 10. Greene MH, Clark WH Jr, Tucker MA, et al: Acquired precursors of cutaneous malignant melanoma: The familial dysplastic nevus syndrome. N Engl J Med 312:91-97, 1985. 11. Sigg C, Pelloni F: Frequency of acquired melanonevocytic nevi and their relationship to skin complexion in 939 schoolchildren. Dermatologica 179:123-128, 1989. 12. Ghanem G, Lienard D, Hanson P, et al: Increased serum alpha-melanocyte stimulating hormone (alpha-MSH) in human malignant melanoma. Eur J Cancer and Oncol 22:535-536, 1986. 13. Clark WH Jr, From Bernardino EA et al: The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 29:705-727, 1969. 14. Breslow A: Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 172:902-908, 1970. 15. Balch CM: The role of elective lymph node dissection in melanoma: Rationale, results, and controversies. J Clin Oncol 6:163-172, 1988. 16. Pritchard DJ, Sim FH: Surgical management of malignant melanoma of the trunk and extremities. Mayo Clinic Proceedings 64:846-851, 1989. 17. McClay EF, Mastrangelo MJ, Sprandio JD, et al: The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma. Cancer 63:1292-1295, 1989. 18. Robinson WA, Mughal TI, Thomas MR, et al: Treatment of metastatic malignant melanoma with recombinant inteferon alpha 2. lmmunobiol 172:275-282, 1986. 19. Kradin RL, Lazarus DS, Dubinett SM, et al: Tumorinfiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet, March 18:577580, 1989. 20. Gonzalez R, Salem P, Bunn PA Jr, et al: Single dose murine monoclonal antibody-ricin A chain immunotoxin in the treatment of metastatic melanoma: A phase I trial. In preparation, 1990. 21. Robinson WA, Jobe K, Stevens R: Central nervous system metastases in malignant melanoma. In Nathanson L (ed) Basic and Clinical Aspects of Malignant Melanoma. Boston: Marinas Nijhoff Pub, 1987, pp. 155-163. 22. Brega K, Robinson WA, Winston K, et al: Surgical treatment of brain metastases in malignant melanoma. Cancer, Accepted for publication, 1990.
ISSN: 0885-8195 (Print) 1543-0154 (Online) Journal homepage: http://www.tandfonline.com/loi/hjce20
Malignant melanoma as a model for cancer education and prevention William A. Robinson MD, PhD To cite this article: William A. Robinson MD, PhD (1990) Malignant melanoma as a model for cancer education and prevention, Journal of Cancer Education, 5:2, 85-89 To link to this article: http://dx.doi.org/10.1080/08858199009528044
Published online: 01 Oct 2009.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=hjce20 Download by: [University of Calgary]
Date: 06 August 2017, At: 10:18
J. Cancer Education. Vol. 5, No. 2, pp. 85-89, 1990 Printed in the U.S.A. Pergamon Press plc
0885-8195/90 $3.00 + .00 © 1990 American Association for Cancer Education
MALIGNANT MELANOMA AS A MODEL FOR CANCER EDUCATION AND PREVENTION 1989 Harvey Lecture American Association for Cancer Education
Downloaded by [University of Calgary] at 10:18 06 August 2017
WILLIAM
A.
ROBINSON,
Cutaneous malignant melanoma (MM) was once a relatively uncommon disease occurring primarily in outdoor workers. The last 50 years have seen a dramatic increase in the incidence of MM due, as we shall see, to increasing sun exposure primarily from changes in clothing habits and lifestyles that have occurred over this time period. Current estimates suggest that by the year 2000, 1 in 90-100 Caucasians will develop MM over their lifetime.1 Based upon today's statistics, 20%-30% of these patients will ultimately die of the disease.2 Thus, MM represents a major public and personal health problem for the 1990s and beyond. This is perhaps the most dramatic change that has occurred in any cancer over the past 50 years and has caught the medical community and public by surprise. As a medical student the only case of MM that I saw was during an autopsy, and this is true of most other physicians of my generation. Currently, physicians in all specialities, but particularly those in the primary care disciplines, are faced with an increasing number of persons presenting with suspicious lesions, many of whom will be diagnosed as having malignant melanoma. Many of these physicians lack the background and knowledge of the disease to allow them to adequately deal with the problem. Urgent measures are needed to educate both the professional community and public about
MD, PhD*
the cause of MM, its early diagnosis and treatment. The disease represents an important, but unfortunate, model for serving these goals in cancer education and prevention. Unlike most human cancers, the cause of the rapid rise in the incidence of MM is clear. It is the result of increasing exposure to ultraviolet light in the form of sunshine that has occurred from clothing habit and lifestyle changes that have occurred during the latter half of the current century. The data supporting this contention is incontrovertible.3'4'5-6 This includes the fact that death rates from MM increase as the amount of ultraviolet light increases in various geographic locations. The disease is particularly prevalent, for example, in the southwestern United States, the Hawaiian Islands and Australia, and less common in England and the northeastern United States. Further, it has been shown that migration of Caucasian populations from areas of low ultraviolet light to areas where there is an abundance of sunshine markedly increases the likelihood of development of MM.6 Finally, it is clear that MM occurs primarily in areas of the body that are exposed to the sun.2 For example, in males MM is most common on the back, neck, and shoulders, presumably because males are more likely to remove their shirts out of doors and have shorter hair. In women, by contrast, MM occurs most frequently on the lower and upper extremities. Various other factors have been suggested as possibly contributing to the rising incidence of the disease including ozone depletion, exposure to fluorescent lighting, and sunspot activity. While these may play minor roles in
*Professor of Medicine, Head, Melanoma Research Clinic, University of Colorado Health Sciences Center, Denver, Colorado. Reprint requests to: W. A. Robinson, MD, Head, Melanoma Research Clinic, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262.
85
Downloaded by [University of Calgary] at 10:18 06 August 2017
86
W. A. ROBINSON
the overall picture, they are relatively insignificant when compared to simple exposure to the sun. Persons at highest risk for the development of MM in the past were mainly engaged in outdoor occupations, particularly agriculture and the building trades. As demonstrated by ourselves and others, however, recent years have seen dramatic shifts in the demographic profile of people developing malignant melanoma (Table 1). Studies by our group and others in Australia and the British Isles have shown that persons at highest risk are professional, managerial, and executive indoor workers who spend large amounts of time outdoors in leisure activities .7p8>9 It is unclear why such groups are at highest risk for the development of MM. It has been speculated that this may be the result of high dose, intermittent exposure to ultraviolet light and, in particular, the risk of repeated sunburning. In our series, only 4% of patients with malignant melanoma were occupied in agricultural or other outdoor occupations. The reasons behind this are unclear. This may result from the fact that agricultural outdoor workers, in this state, come from ethnic groups that are at lower risk for the development of the disease because of skin pigmentation or that chronic exposure to the sun, rather than high dose intermittent exposure, may be protective and beneficial. This becomes an important consideration when the question of suntan parlors is raised. The question is frequently asked whether exposure to ultraviolet A radiation, which is the primary form of UV from tanning parlors, may contribute to or prevent the development of MM. This question has not
Table 1. Demographic and phenotypic characteristics of persons at highest risk for development of cutaneous malignant melanoma — Fair skin Caucasian — Indoor occupation — Frequent outdoor leisure time — Blue or green eyes — Brown or blonde hair — Numerous moles
been answered due in part to the lack of good animal models to study the disease. It is clear that exposure of the skin to sun early in life predisposes one to the subsequent development of malignant melanoma, and it may be that repeated sunburns and high dose ultraviolet exposure in childhood may be the most important factor in the subsequent development of the disease. In addition to defining the demographic characteristics of persons at highest risk for the development of MM, we and others have also defined the phenotypic characteristics of persons developing the disease.2 Malignant melanoma occurs almost exclusively in Caucasians, most of whom are fair-skinned, have nonbrown eyes and brown or blond hair. It is a common misconception that most persons who develop MM have red hair. In a study conducted in our Melanoma Research Clinic, the most common hair color was light to medium brown. Only 12% of the patients in our study group had red hair. While this is a higher incidence of red hair than found in the general population, it is clear that most patients developing the disease do not have red hair. In the early part of this century, it was felt that most malignant melanomas arose de novo. It is now clear that most malignant melanomas, in fact, develop from preexisting nevi, as noted above, primarily in sun-exposed sites. In a study conducted by us, 70% of patients indicated that their MM began in a preexisting nevus.2 This is probably the result of an actual change in the disease over time rather than a change in recognition. The melanocytes in nevi are derived embryologically from the neuroectoderm, migrating up through the dermis to the dermal/epidermal junction, during puberty, under physiologic controls that are as yet undefined. At birth the average person has only 1-3 pigmented nevi. In puberty, nevi begin to appear, reaching an average 30-40 between the ages of 20 and 30, and then slowly begin to disappear with old age.10-11 Thus, malignant melanoma is uncommon before puberty. The distribution of benign nevi in the various sexes also,
Downloaded by [University of Calgary] at 10:18 06 August 2017
Malignant melanoma as a model
interestingly, conforms to areas of sun exposure. Thus, in males nevi are most common on the back, neck, and trunk, while in women they are more common on the lower and upper extremities. Exactly how exposure to ultraviolet light influences this distribution of neval development remains unclear. The classic junctional or compound nevus is easily recognized as a flat, uniformly brown, sharply circumscribed pigmented area usually less than 6 mm in diameter. As neoplastic changes occur, affected nevi begin to increase in diameter, develop variegated color ranging from hypo-' pigmented areas to blue, black, pink, and brown, and often develop irregular, notched borders. The most common complaint, and earliest symptom noted by most patients, is itching of a preexisting nevus (Table 2). Ulceration, bleeding, and pedunculation are late developments. The earliest changes can be easily recognized, and we recommend strongly that any nevus about which a patient or health care provider is concerned be removed by surgical excision, with an adequate 1-2 mm border down to the fat and examined histologically. Too often, in our clinic, we hear the story that the patient has shown a nevus repeatedly to a primary care physician, and because it does not have the classic features of advanced malignant melanoma, little attention is paid to it. As will be noted below, early surgical removal of any suspicious lesion is the key to the treatment of this disease. The mechanisms whereby ultraviolet light induces neoplastic degeneration have not been determined and are under intense investigation by ourselves and others. Various postulated mechanisms include direct DNA damage, alteration of the immune system, free radical production, and excess production of mela-
Table 2. The most common symptoms and signs of malignant change in a nevus — Itching — Change in color — Increase in size — Development of an irregular/notched border
87
nocyte stimulating hormone in phenotypically susceptible individuals.12 With the development of neoplasia, cell division results in both lateral and downward growth of cells. The lateral growth leads to the visual characteristics noted above, but it is the downward growth through the dermis and eventually into the fat, blood vessels, and lymphatics in and underneath the skin that is the most important factor determining spread. The levels of downward growth have been defined by Clark and Breslow13-1* as the most important prognostic indicators of potential metastases. In the system described by Clark, Level I melanomas are those confined to the epidermal/dermal junction, Level II when cells are present in the papillary dermis, Level III when extension has occurred into the upper reticular dermis, Level IV into the lower reticular dermis, and Level V into the fat underneath the dermis. In our Melanoma Research Clinic, the majority of patients present with level III and IV melanomas, with the latter comprising 47% of the total. For these patients the likelihood of microscopic metastases at diagnosis is in the order of 4O(7o-5O%. These cannot be detected by any known means at the present time. The median time from resection of the primary lesion until the detection of metastatic deposits in other organs is 4 years, and instances of 10-20 years are not uncommon. This long time lag often lulls the patient and health care provider into a false sense of security. It is important that all patients with a diagnosis of malignant melanoma be placed on regular follow-up schedule with systematic evaluation. It is beyond the scope of the present discourse to go into the various ramifications of width of excision of the primary lesions, lymph node dissection, and staging of patients at diagnosis. Excellent discussions of these sometimes contentious points can be found elsewhere.15-16 The most common sites of metastases are the lungs, liver, and brain, but melanoma is notorious for metastasizing to virtually any and every organ in the body. Once metastases have occurred, no treatment has been shown to be of consistent long-term benefit, and the
Downloaded by [University of Calgary] at 10:18 06 August 2017
88
W. A. ROBINSON
vast majority of patients will eventually succumb to the disease, with a median survival of one year. Recent years have seen significant advances in the treatment of metastatic disease but, in general, the outlook remains dismal. With current multidrug chemotherapy regimens, response rates of 20-40% have been achieved.17 Alpha interferon, interleukin 2 combined with lymphokine activated killer cells, and tumor infiltrating lymphocytes have yielded similar response rates, but most are short-lived.18'19 Ourselves and others are also investigating the use of antimelanoma monoclonal antibodies linked with ricin Achain toxin, with an occasional dramatic response.20 Multimodality therapies combining these various approaches are under intense investigation by a large number of investigators throughout the world (Table 3). Despite the advances that have been made in the treatment of metastases outside the brain, little progress has been made in the treatment of central nervous system (CNS) involvement. Seventy percent or greater of patients with metastatic disease will eventually develop brain metastases, and the currently available modalities have had little effect on this devastating complication.21 In the past year we have undertaken a study of the administration of the pineal derived hormone melatonin to patients with advanced disease, including those with CNS metastases. To date only 27 patients have been treated on a dose-escalating protocol using this agent. The results, while quite preliminary, have seen two patients with CNS metastases regress with melatonin. This protocol is being expanded to further determine both the mechanism of action of melatonin in
Table 3. Modalities currently under study for the treatment of advanced malignant melanoma — Multidrug chemotherapy —The interferons — Interleukin-2 — Lymphokine activated killer cells — Monoclonal antibodies — Melatonin
this regard and its further use in patients with advanced disease. We have also taken, and reported, an aggressive neurosurgical approach for the treatment of brain metastases in malignant melanoma with encouraging results when combined with therapy to treat systemic involvement in other areas.22 What is most clear from all of the therapeutic studies, however, is that primary prevention and understanding of the disease will, in the long haul, be the most important factor in stemming the tide currently facing us. Thus, we have a cancer which is occurring in near epidemic proportions with a clearcut cause in demographically and phenotypically definable populations which is easily recognized visually, preventable and curable in its early stages. Malignant melanoma, therefore, represents an ideal model for professional and public cancer education. The public must be made aware of the deadly danger of excessive exposure to sunshine, to understand that the disease develops primarily in moles, and the changes that are likely to occur in them as neoplasia develops. Physicians and other health care providers should include skin screening as a routine part of all examinations, particularly in high risk populations, and must be made aware of who the latter are, how nevi develop, and the risk of leaving potentially dangerous moles in place. The professional community must also take the lead in patient and public education. The task will not be a simple one. Health, in many ways, has become synonymous with outdoor activities and a tanned look. Education must begin in childhood about the dangers of sun exposure, and the public must be made aware that ultraviolet light doesn't simply cause wrinkling and aging of the skin—it may mean death. Changes in clothing habits, lifestyles, and the use of sun screens and blocks are all essential ingredients of the formula to be put forward, together with early recognition and removal of potentially malignant nevi. Pale skin and a few scars hopefully will become the beauty marks of the future. The dark side of the sun looming over us is malignant melanoma.
Malignant melanoma as a model
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SUMMARY Cutaneous malignant melanoma is one of the most rapidly increasing and highly fatal cancers in the world today. Current estimates suggest that 1 in 90-100 Caucasians will develop MM by the year 2000, and 20%-30% will eventually die of the disease. The cause of the epidemic of malignant melanoma is clearly increasing exposure to the sun from lifestyle and clothing habits that have changed over the past 50 years. The disease occurs primarily in preexisting nevi in sun-exposed sites in specific high risk populations who can be, and have been, defined. These are primarily middle- and upper middle-class Caucasians with blue eyes, brown or blonde hair, and fair skin, with predominantly indoor occupations who spend, or have spent, considerable time outdoors in leisure and other activities. The presence of a clearly definable cause (exposure to the sun) in specific risk groups, the ease of early detection by simple means, and the devastating outcome of late diagnosis make malignant melanoma an ideal model for teaching the basic tenets of cancer causation, development, and prevention to the public and professionals alike.
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