JOURNAL OF INSURANCE MEDICINE VOLUME 26, No. 2 SUMMER 1994

MALIGNANT UPDATE 1993

CHARLES W. LYNDE, MD, FRCP(C) Acting Head of Toronto Western Hospital Assistant Professor of Medidne University of Toron to President Lynde Center for Dermatology

Introduction: Statistics of incidence among women. Malignant melanoma is the number one cancer in white women age 25-29, second There has been a dramatic increase in the incidence of most prevalent in women age 30-35, second only to melanoma throughout the world. breast cancer. This rate of increase in the incidence of this disease is not just a specific flare or matter of more In the United States the incidence of melanoma has cases suddenly being reported. almost tripled in the past four decades growing faster than that of any other cancer. It now ranks number eight Melanoma counts for only 5% of the cases of skin can- to all types. No major change in diagnostic criteria can cers but counts for the majority of deaths. explain this rapid increase. Approximately 32,000 Americans developed melanoma in 1991 and 6,500 died While the numbers of people getting melanoma has yet of it. In terms of the life time risk, in 1935 it was one in to show much positive change, there are changes in the 1,500 and it is now felt that by the year 2,000, 1 to 75 to 5-year survival rate for those who have the illness. In 90 Americans will develop melanoma of which I in 300 British Columbia, between 1970-74 for example, the will die. 5-year survival rate for men was 65%, by 1984 it in- creased to 82%. The survival rate for women during the In terms of Canadian statistics, they are comparable, our same period increased to 88% from 80%. Similarly, in population being approximately a tenth of the U.S. the U.S., while the death rate has continued to increase population. Approximately 3,100 new cases of malig- with increased incidence 5 years, survival has more nant melanoma will be diagnosed in 1993 in Canada than doubled from 40% in the 1940’s to over 80% in the with 540 deaths resulting from this condition. 1980’s.1’2 The increase in survival is felt to be attribut- able to early diagnosis on the part of physicians and the Overall the incidence of malignant melanoma (Canada) public. is now 9 per 100,000 population although incidence varies from a high of 14 per 100,000 in British Columbia Unlike many other forms of cancer which affect primar- to I per 100,000 in Newfoundland. (By comparison, the ily older people, melanoma frequently affects young incidence of lung cancer is now 73 per 100,000.) While people. The median age for patients with melanoma is the mortality rate for melanoma is increasing, it is hold- in the low 40’s. Thus, diagnosis and cure of cutaneous ing steady and even appears to be decreasing among melanoma in young individuals can lead to dramati- women. In the U.S., of the 6,800 deaths in 1993, 4,200cally increased life extension unachievable in cancers (62%) will be in men and 2,600 (38%) will be in women.that primarily affect older individuals. This is felt to be partly as result of women being more health conscious and taking better overall care of them- Epidemiology selves. The precise causation of is unknown, al- This tells us that men are still one of the main groups though epidemiologic and case control studies suggest we have to address to let them know that they are the sunlight is the most important environmental factor in ones who are dying disproportionately from this dis- the pathogenesis of melanoma with radiation in the ease. ultraviolet B range proposed to be the critical compo- nent. Malignant melanoma has the fastest growing incidence rate of all cancers among men, the third fastest increase

247 VOLUME 26, NO. 2 SUMMER 1994 MALIGNANT MELANOMA UPDATE 1993

The incidence of melanoma in whites generally corre- compounded by the phenotype of the population. Rates lates inversely with latitude; i.e., rates are higher closer of melanoma are relatively low in persons with outdoor to the equator and progressively lower in areas near the occupations, but much higher in middle class people poles. In the Eastern Australia Mole Stud~ Jason Rivers, with high recreational exposure. Except for ma- et al,3 recruited a total of 1,123 caucasian children be-ligna; melanoma does not regularly occur on skin most tween the ages of 6-15 years old in three cities along a exposed to the sun, such as the face. One would also latitude gradient Melbourne 38 S, Sydney 34 S, Towns- have to explain mucosal melanoma. Equally aside from ville 19 S. For each child the age, sex, eye and hair color, one single report, studies using ultraviolet light alone skin reflectance, response to sun exposure, ability to tan, have failed to induce melanoma regularly in animals. and place of residence were determined. Each student The body of evidence supports the risk of melanoma was examined by one of three trained medical ob- depends more on the intermittent exposure to the sun, servers, and the total number of moles greater than 2 especially earl in life than on simple cumulative expo- mm were recorded for all body sites excluding the sure. One has to think about the increased recreational genitalia and scalp. The average number of moles for exposure to the sun, the depletion of the earth’s ozone the entire cohort was 44. Older children and those with layer increasing ultraviolet penetration to the earth and blue eyes, light hair, fair skin, many freckles, and a the increased use of sunbeds and tanning parlors. tendency to painful burns with peeling, and an inability to tan had significantly more moles than children with- Loraine Marrett, et al4 in 583 case controls in southern out these features. As well, the number of moles in- Ontario have further identified that people with a large creased as one lived closer to the equator. This latter number of nevi, who have red or blond hair, having a factor remained a significant independent risk factor history of freckling in response to sun exposure and after controlling for age and phenotypic characteristics. burn with no tan after repeated sun exposure are par- These results indicate that in the Australian population ticularly at high risk. Interestingl)~ in their study it was at very high risk for melanoma, school children have also suggested that exposure to fluorescent lighting very large numbers of melanocytic nevi. The geo- may also be a risk factor. Other studies have found this, graphic variation in mole counts would support a solar but dismissed it as a confounding factor. ultraviolet radiation role in the causation of these le- sions. The phenotypic characteristics that predispose In the past, melanoma was notorious for its poor prog- one to the development of moles in childhood are simi- nosis. The current 5-year survival rate of 80% is a great lar to those that increase one’s risk for melanoma in later improvement over the 50% rate in 1950. Nevertheless, life. the overall mortality rate has increased by 150%, driven up by the rising incidence rate. Other investigators have linked blistering sunburns in childhood or adolescence with increased rates of mela- We Wish to Win the War on Melanoma in later life. Whites, especially those with a ten- dency to bum rather than tan when exposed to sunlight, Several advances have dramatically improved our abil- have higher rates of melanoma than nonwhites. Migra- ity to diagnose and treat melanoma. tion studies by other investigators suggest that child- hood or adolescence represents a critical period for 1) Recognition of Melanoma ultraviolet burn. Australian children less than age 15 who migrated to Britain maintained high rates of ma- The first was to recognize that melanoma has distinct lignant melanoma, whereas children from England who clinical features: The great physician Hippocrates rec- came to Australia after age 15 had low rates of malig- ognized and described melanoma, and since then vari- nant melanoma. ous names, including melano sarcoma, melano carcinoma, Kaposis melano sarcoma, have been used to Xeroderma pigmentosa, a rare autosomal recessive dis- describe this tumor. order characterized by deficient repair of ultraviolet B damaged DNA shows a greater than 100-fold higher It really wasn’t until the 1960"s or 70"s that we began to rate of skin cancer and, in particular, primary melano- understand this tumor, recognizing its melanocytic ori- nlas. gin and began to classify it and recognize its distinct clinical features. Not all evidence readily links ultraviolet light to mela- noma, however. In some countries the incidence of ma- Cutaneous melanoma is a visible tumor and therefore lignant melanoma, i.e. Europe, does not rise with perhaps more easily discovered in an asymptomatic increasing proximity to the equator, but this may be phase than any other type of cancer. The early detection

248 JOURNAL OF INSURANCE MEDICINE VOLUME 26, No. 2 SUMMER 1994

and recognition of malignant melanoma is the key to possible cure! This often starts as a tan macule that extends peripher- Melanoma writes its message in the skin with its own ally and darkens and eventually develops a black nod- ink and is there for all to see. ule. The growth is extremely slow and insidious and often occurs over 5-20 years. It is found equally in men The ABCD rule has been established for the possible and women usually in their 60/70 decade, most fre- diagnosis of melanoma in any pigmented lesion. The A quently on the face and particularly on sun damaged stands for asymme~t, B for border irregularity, C for skin. It represents 5% of all melanomas. color variegation, often in a dark blue color, D for di- ameter being greater than 0.6 cm.

The rapid enlargement of a mole, the development of This presents a very pigmented papule or dome-shaped raised areas on a previously fiat lesion, scaling, ulcera- nodule that grows rapidly over a few months and arises tion, crusting, , itching, burning, or pain should without a radial growth phase. It represents 15% of all alert the physician to possible change within the melanomas, is two times more frequent in men and and the possibility of melanoma.5’6 occurs in sun exposed head, neck and trunk areas. This tumor arises de novo and the ABCD rule does not apply However, most melanomas are completely asympto- in this case, as the growth is so rapid. matic. Visual examination is the most reliable means of identification. Melanoma can occur anywhere on the Acral Lenfiginous Melanoma surface of the skin. It is often found on the back and other areas that are difficult for a person to inspect This presents as an irregularly enlarging macule par- themselves. Patients with melanoma may thus be un- ficularly on the tips of the toes, fingers subungually and aware that a lesion exists. Early detection by the physi- on the mucosa of the , orally in the palate, on the cian is exceedingly important. glans penis or the anal canal. It represents 10% of all melanomas. In Japanese (particularly the soles), in 2) Melanoma Subtypes Blacks, Hispanics, and American Indians, it is the com- monest type. The second advance was the recognition that melanoma can be classified into four major subtypes. Superficial Melanoma Look-Alikes spreading melanoma, , nodular melanoma and the newly described acral len- It is important to note that there are a number of skin tigenous melanoma. These subtypes are useful in offer- lesions that are seen by physicians that can mimic mela- ing prognosis and therapy. nomas. These include seborrheic keratoses, solar len- tigines, pigmented basal ceils, pyogenic granulomas, Superficial Spreading Melanoma and angiokeratomas to name but a few. With the use of oil and a magnifying lens on one’s ophthalmascope, one This is the commonest type of melanoma representing creates an epi or dermatoscope and can improve one’s over 70% of all the melanomas. The title is actually a ability to distinguish benign and malignant lesions. misnomer as this does not always stay superficial; after However, the old surgical dictum holds that, "When in a horizontal growth phase, it eventually develops a doubt, cut is out." Upon providing patholog~ one can vertical growth phase and potential metastases. It af- have a definite answer. fects adults of all ages, the median being in the fifth decade. We see this particular type of melanoma tend- 3) Precursor Lesions ing to occur at earlier and earlier ages. There is no preference for sun damaged skin; the upper back is a The third advance was the recognition of precursor favorite site in both sexes, and shin and calves in fe- lesions -- dysplastic nevi. Dysplastic nevi were first males is an extremely common site also. These melano- described in 1978.7 Dysplastic nevi are both markers for mas are often multicolored, showing many different an increased risk of melanoma and potential precursor shades of pigmentation, and patients often present be- lesions from which melanoma may develop. cause their mole appears "ugly." The horizontal growth phase is often over a year, then followed by a vertical Disagreements and precise reproducible definitions growth phase. These tumors can have extremely rapid and dinpathical correlations of dysplastic nevi have growth and metastases. hindered efforts to determine their prevalence and

249 26, No. 2 S~MM~ "].994 MAL~G~hrr M~A~O~ UPOA’r~ 1993

proper management. In general, dysplastic nevi are 4) Tumor Thickness = Prognosis larger than common nevi and have clinical features of haphazard pigmentation, irregular borders that are The fourth advance was the ability to predict patient quantitatively not as extreme as a melanoma. outcome from measurements of the primary tumor.

Dysplastic nevi were initially described in family pedi- In 1969, Clark and From were the first to link poorer gree studies. Persons with a familial prognosis with increasing levels of microinvasion into syndrome have a high risk of melanoma. In fact, ff you the dermis or subcutaneous tissue. They described five have dysplastic nevus syndrome and two or more first levels of invasion, so called Clark’s Levels 1-5. Since degree relatives with melanoma, your lifetime risk of then, in 1970, Breslow has found a better predicator with melanoma is 100%.8,9 Characteristics of familial dys- the vertical tumor thickness. With this, one can prognos- plastic nevus syndrome include a family history of ticate a 5-year survival rate with those thin lesions less melanoma or dysplastically acquired moles with char- than .76 mm having a 96% 5-year survival rate, and acteristic pathologic dysplasia, moles present in un- those over 4 mm having a survival rate of only 47%, i.e., usual places, such as a breast or pubic area, and the the thicker lesions would be more likely to develop occurrence of new moles throughout life. Between 5- metastatic disease. 10 % of the population without a family history of mela- noma have multiple dysplastic nevi. Their risk for In addition to tumor thickness, which is felt to be the melanoma is unknown, although it has been estimated best prognosticator, anatomical site also seems to play at 18% over lifetime, as compared to the general popu- a role, although which sites are at highest risk is some- lation’s risk of less than 1%. The diagnosis of dysplastic what a matter of debate. For an equivalent thickness, nevus is not difficult; the mole shows variation of out- those on the scalp, hand and feet seem to have a poorer line and color and contrasts the dermal nevi which are prognosis. well circumscribed and evenly depigmented. It is really fiat, although elevated areas in the center may occur. Older patients have a worse prognosis than younger. Women better prognosis than men, although this prob- A dysplastic nevi patient should be followed, particu- ably reflects difference in the thickness site. Histologi- larly, one with a family history of melanoma or dysplas- cally, a high mitotic rate, ulceration, large tumor tic nevi. When dysplastic nevi are found on one patient volume, DNA aneuploidy all produce a poorer progno- and another family member has had a melanoma, all sis. members of the immediate family should be thoroughly examined for lesions. Overall, in stage I, the 5-year survival rate if 79% and decreases rapidly with state II (nodal mets) being 36% The dysplastic nevus syndrome has now been called the and stage HI (distant mets) 5%. State II disease at the "atypical mole syndrome," and there have been various present time is felt to be incurable with the median classifications made in an attempt to prognosticate survival rate being less than 6 months. those at higher risk. One such recent classification is that of group ) dysplastic nevus with no family history or 5) Less Necessary personal history of melanoma, group I with a personal history of melanoma, group 2 with a family history of The fifth advance was the demonstration that less mu- melanoma and group 3 where two or more family mem- tilating surgery for melanomas is as curative as the more bers have had melanoma. radical procedures used in the past. This improvement has been helped by the prognostic system by which low Many physicians feel that only by paying particular risk patients can be treated with relatively narrow exci- attention to the subsets of patients and following them sion margins (one cm).11 closely will we be able to make some inroads in decreas- ing mortality from melanoma. Melanoma is a multidisciplinary disorder that brings together practitioners of many medical specialties: der- Giant congenital melanocytic nevi rarely can transform matologists, oncologic surgeons, plastic surgeons, into melanoma, although some people put the risk at medical oncologists, radiation medicine physicians, 6-7% lifetime risk of transformation. Others feel the risk epidemiologists, geneticists, pathologists, immunolo- is much smaller than this, and particularly in smaller gists, molecular biologists, public health officers, gen- lesions the risk is felt to be quite low. eral physicians, pediatricians, and gynecologists, all of whom bring their own unique approach to the prob- lems. Each of these groups has a role to play in the JOURNAL OF INSURANCE ME~ICINE VO~.UME 26, NO. 2 SUMMER 1994

evaluation of causation, early detection, prevention, nately, efforts in immunotherapy or to and treatment, and it is through synergistic multidisci- present have not been useful. plinary interaction that many of these advances have been achieved.12 Melanomas are not likely to decrease in the next decade. Melanoma is not a disease to be feared but one that can How to Win the War be detected early and cured...The war can be won.

Areas of attack to reduce melanoma mortality include REFERENCES several strategies. 1. Boring CC, Squires TS, Tong T. Cancer statistics, 1991. CA 1991;41:19-36. 1) Professional Education 2. Cutler SJ, Myers MI-I, Green SB. Trends in survival rates of patients with cancer. N Engl J Med 1975;293:122-124.

The first is professional educational awareness about 3. Rivers J, Kelly J, MacLennan R. Eastern Australia Mole Study. the nature of the problem and the clinical features for Melanoma Letter 193;Vl1(2):1. diagnosis. 4. Marrett L, King W, Waiters S, From L. Use of host factors to identify people at high risk for cutaneous melanoma. Can Med Assoc Recent research has shown that, as a screening tool, 11992;147(2):445-453. cutaneous examination by a dermatologist has a semi- 5. Mihm MC Jr, Fitzpatrick TB, Brown MM, et al. Early detection of primary cutaneous malignant melanoma" A color atlas. N Engl ]Med tivity for melanoma detection that is at least as high as 1973;289:989-996. that of the Pap smear, the stool guaiac test, and mam- 6. Friedman RJ, Rigel DS, Silverman MK, et al. Malignant mela- mography for cervical, colorectal,a nd breast cancers, noma in the 1990s: The continued importance of early detection and respectively.13 the role of physician examination and self-examination of the skin. CA 1991;41:201-226.

2) Public Awareness 7. Reimer RR, Clark WH Jr, Green MH, et al. Precursor lesions in familial melanoma" A new genetic preneoplastic syndrome. JAMA 1978;239:744-746. Individuals likewise should be aware of the problem 8. Tiersten AD, Grin CM, Kopf AW, et al. Prospec~_ive follow-up and taught self examination. Twenty percent of melano- for malignant melanoma in patients with atypical-mole (dyspiastic- mas are being detected by individuals other than the nevus) syndrome. J Dermatol Surg Oncol 1991;17:44-48. patient, such as spouses, friends, and physicians. 9. Albert I~q, Rhodes AR, Sober AJ. Dysplastic melanocytic nevi and cutaneous melanoma: Markers of increased melanoma risk for affected persons and blood relatives. ] Am Acad Dermatology 3) Prevention 1990;22:69-75. 10. Breslow A. Thickness, cross-sectional areas and depth of inva- This is a critical focus. The Canadian Dermatology As- sion in the prognosis of cutaneous melanoma. Ann Surg 1970;17~’902- sociation, American Academy of Dermatology and 908. Cancer Societies are sponsoring several sun safety pro- 11. Veronesi U, Cascinelli N, Adamus J, et al. ~ stage I primary grams particularly aimed at young children. cutaneous malignant melanoma: Comparison of excision with mar- gins of I or 3 cm. N Engl J Med 1988;318:1159-1162. It is hoped by developing good sun safety habits early 12. Sober A. Cutaneous melanoma" Opportunity for cure. CA-A in life, these habits will carry through into adolescence Cancer l fvr clinicians 1991;V41(4):197-198. and adult life. 13. Koh HK, Caruso A, Gage I, et al. Evaluation of melanoma/skin cancer screening in Massachusetts. Preliminary results. Cancer 1990;65:375-379. 4) Research

Only by ongoing research into all aspects of melanoma will we further understand this "black tumor." Unfortu-

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