Dysplastic nevi and other risk markers for melanoma

Risk markers for cancer are genetic or behavioral attributes that are statistically associated with increased incidence of cancer. Risk may be assessed either in case-control studies, or in cohort studies in which individuals with particular attributes are followed and cancer risk is determined by direct observation. Both of these methods have been used to determine the major risk markers for melanoma. The single most important risk marker is the presence on the skin of dysplastic nevi. Dysplastic nevi may be regarded as intermediate lesions of tumor progression, in that approximately 30% of melanomas arise in association with a precursor nevus, which is most commonly dysplastic. However, paradoxically, because they are vastly more numerous than melanoma, most dysplastic nevi are stable lesions that do not progress. Additional important melanoma risk factors include a family and/or personal history of melanoma. A third major category of risk markers includes indicators of acute and chronic exposure to the sun, including freckles, actinic skin damage, and a history of sunburn. Evaluation of these markers in oncological patients and their first-degree relatives can identify a population of individuals whose risk for melanoma ranges from several-fold to more than 100-fold greater than that of random population members. Efforts directed at early diagnosis in these individuals can result in recognition of melanomas in their early, curable stages.     

Prognostic significance and surgical management of lymph node metastasis in gastric cancer

Eight patient case vignettes are presented to illustrate the possible relationship between melanoma and pregnancy. We pose 10 questions regarding the risk and prognosis and answer them based on information in the medical literature. Key conclusions are that there is no evidence that the risk for melanoma is influenced by pregnancy; there is no evidence that abortion in pregnant women diagnosed with melanoma is therapeutic for the mother or necessary to prevent melanoma in the fetus; although as a group, pregnant women diagnosed with melanoma may have a somewhat worse prognosis compared with nonpregnant controls, this difference disappears when patients are matched for factors including age, location and depth of primary, or stage of disease; and there is still a concern that pregnant women may present with more invasive or advanced disease due to hormonal or growth factor effects or delays in diagnosis because changes are attributed to pregnancy.     

Influence of sun exposures during childhood and during adulthood on melanoma risk. EPIMEL and EORTC Melanoma Cooperative Group. European Organisation for Research and Treatment of Cancer

Sun exposure in both childhood and adult life represents the main environmental risk determinant for cutaneous melanoma. However, little is known about the joint effects of sun exposure during early and later life on melanoma risk. A case-control study in Belgium, Germany and France conducted in 1991-1992 suggests that the melanoma risks attached to indicators related to sun exposure appear to combine their effects in an additive way. We therefore constructed composite indices of sun exposure during childhood and during adulthood, assuming additive combinations of melanoma risk associated with each indicator of sun exposure. Logistic regression modeling showed that the melanoma risk associated with a given level of sun exposure during adulthood increased with higher sun exposure during childhood, but the increase in risk was higher than the simple addition of melanoma risk associated with sun exposure during childhood or adulthood. In turn, high sun exposure during childhood constituted a significant risk factor for melanoma only if there was substantial sun exposure during adult life. We thus suggest that sun exposure during childhood and during adulthood would be interdependent as far as their impact on melanoma risk is concerned. Our results support the hypothesis by which the important contribution of sun exposure during childhood in melanoma occurrence is not properly assessed by retrospective epidemiologic studies. Sun avoidance during childhood would have a greater impact on melanoma risk than sun avoidance during adulthood.     

Atypical mole syndrome: a brief overview for the primary care physician

Early detection of melanoma and identification of potential markers or precursor lesions can substantially improve survival. Several risk factors have been identified in the pathogenesis of this potentially lethal cancer. Numerous reports in the literature have confirmed a subset of persons with an increased risk of developing melanoma. These patients are identified by a distinctive clinical phenotype depicted by unusually appearing melanocytic nevi (moles) in association with an increased number of total body nevi. They may have a family history of atypical moles or melanoma. In order to facilitate the recognition of such individuals by the non-dermatologist, a brief overview and salient features of the atypical mole syndrome are presented.     

The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma

Melanocyte stimulating hormone (MSH) plays an important role in determining the cutaneous response to ultraviolet radiation and may also influence melanoma progression. We have previously shown that variants of the melanocortin receptor present on melanocytes, MC1R, are associated with sun sensitivity and red hair in a UK population and therefore now consider the gene as a candidate for melanoma susceptibility. We have compared the frequency of known MC1R variants in the second and seventh transmembrane domains in 43 melanoma cases and 44 controls. MC1R variants were more common in cases than controls (chi 2 = 6.75, 1 d.f.; P = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91 (95% c.l.: 1.48-10.35), and a population risk attributable to carriers of 34.6% (95% c.i. 10.7-52.1%). The Asp84Glu variant was only present in melanoma cases and appears to be of particular significance. The contribution of variant MC1R alleles was largely independent of skin type. Variants of the MC1R gene are likely to be causally associated with the development of melanoma.     

Black-white differences in risk for cutaneous, ocular, and visceral melanomas

Fair-skinned individuals have a much higher risk of cutaneous and ocular melanomas than dark-skinned individuals, possibly reflecting a protective effect of melanin against sun exposure. There are some reasons to believe that the effect of sunlight exposure is indirect (i.e., sunlight stimulates growth factor production, which then stimulates melanocytic proliferation, leading to melanoma). Visceral melanomas are extremely rare, and little is known about them. This study used US data on 25,184 melanoma cases to investigate the White-Black ratio for visceral melanoma and did not find a disproportionality similar to that for cutaneous and ocular melanomas. The findings support the hypothesis that the sunlight effect on melanoma is primarily direct.     

Incidence of surgically treated uveal melanoma by race and ethnicity

OBJECTIVE: The purpose of the study was to determine the race- and ethnicity-specific incidence of histologically confirmed uveal melanoma. DESIGN: The study design was a retrospective study of histologically confirmed cases of primary uveal melanoma submitted to the Florida Cancer Data System (FCDS). MAIN OUTCOME MEASURES: Race-, gender-, and Hispanic-specific incidence rates of uveal melanoma were measured. Calculations are based on Florida census data and Hispanic population estimates from the University of Florida Bureau of Economic and Business Research. RESULTS: From 1981 through 1993, 873 histologically confirmed uveal melanomas were reported to the FCDS. Four melanomas occurred in black non-Hispanics, 47 in white Hispanics, and none in black Hispanics. The relative risk of uveal melanoma for blacks compared to non-Hispanic whites was 0.03 (95% confidence interval, 0.01-0.08). Non-Hispanic white men had 72 times the risk of uveal melanoma compared to black men; non-Hispanic white women experienced a 22-fold risk compared to black women. White Hispanics were less likely to develop uveal melanoma than white non-Hispanics (relative risk, 0.36; 95% confidence interval, 0.27-0.48). CONCLUSION: The risk of uveal melanoma in blacks is exceptionally low. The reason for lower risk of uveal melanoma in white Hispanics than in white non-Hispanics is not known but could be related to the protective effects associated with dark skin pigmentation or may be because of unknown cultural-environmental exposures or socioeconomic factors.     

Melanoma and occupation: results of a case-control study

OBJECTIVES: Associations between occupational exposures and the occurrence of cutaneous melanoma were examined as part of a large population based case-control study of 19 cancer sites. METHODS: Cases were men aged 35 to 70 years old, resident in Montreal, Canada, with a new histologically confirmed cutaneous melanoma (n = 103). There were two control groups, a randomly selected population control group (n = 533), and a cancer control group (n = 533) randomly selected from among subjects with other types of cancer in the large study. Odds ratios for the occurrence of melanoma were calculated for each exposure circumstance for which there were more than four exposed cases (85 substances, 13 occupations, and 20 industries) adjusting for age, ethnicity, and number of years of schooling. RESULTS: Significantly increased risk of melanoma was found for exposure to four substances (fabric dust, plastic dust, trichloroethylene, and a group containing paints used on surfaces other than metal and varnishes used on surfaces other than wood), three occupations (warehouse clerks, salesmen, and miners and quarrymen), and two industries (clothing and non-metallic mineral products). CONCLUSIONS: Most of the occupational circumstances examined were not associated with melanoma, nor is there any strong evidence from previous research that any of those are risk factors. For the few occupational circumstances which were associated in our data with melanoma, the statistical evidence was weak, and there is little or no supporting evidence in the scientific literature. On the whole, there is no persuasive evidence of occupational risk factors for melanoma, but the studies have been too small or have involved too much misclassification of exposure for this conclusion to be definitive.     

Are young adults checking their skin for melanoma?

This study examined the prevalence and predictors of self screening for melanoma in a large sample of young New Zealanders. A self-report questionnaire was administered to a sample of 909, 21-year-olds to investigate if young adults check their skin for changes in lesions which could be melanoma, and to identify the factors which influence this behaviour and any subsequent help seeking. Fifty-three per cent reported checking their skin in the past year, with 20% noticing a change in a mole or freckle. Forty-five per cent of those who noticed a change sought medical advice. The most common reason for not seeking advice was cost. Women were more likely that men to have checked their skin, to have noticed a change and to have sought medical advice. In addition to gender, tendency to self check was also associated with knowledge of melanoma and perceived risk of melanoma. These results are discussed in light of the current debate regarding skin cancer screening. This study fills a gap in the literature regarding self screening for melanoma in young adults and identifies ways in which future prevention campaigns might be modified to address the concerns of this age group.     

Sunlamp use and the risk of cutaneous malignant melanoma: a population-based case-control study in Connecticut, USA

BACKGROUND: The relationship between cutaneous malignant melanoma and sunlamp use is examined in a Caucasian population in Connecticut, United States. METHODS: Cases were diagnosed between 15 January 1987 and 15 May 1987 with a first primary cutaneous melanoma. Controls were obtained from the general population, frequency matched to cases by sex and age, through random digit dialling of Connecticut telephone numbers. RESULTS: Of all study subjects, 141 (23%) cases and 95 (19%) controls reported ever having used sunlamps. The crude odds ratio (OR) for developing malignant melanoma after ever having used sunlamps was 1.30 (95% confidence interval [CI]: 0.97-1.74). This was reduced to 1.13 (95% CI: 0.82-1.54) after further adjusting for cutaneous phenotype and recreational sun exposure. Those who used more than one type of sunlamp had a threefold higher risk for melanoma compared to never users. Subgroup analyses showed that sunlamp use was associated with a greater increase in risk for melanoma among those who used sunlamps at home and those who were first exposed to sunlamps prior to 1971. The first use of sunlamps before the age of 25 showed somewhat higher risk for melanoma compared to first use later in life. CONCLUSION: The current study provides limited evidence that use of sunlamps increases the risk of melanoma. For future studies, it is crucial that type of sunlamp, year of first use and amount of exposure are all taken into account. The association between melanoma and tanning with both UV-A and UV-B lamps and tanning under sunlamps early in life merits further investigation.     

The risk of subsequent primary carcinoma of the pancreas in patients with cutaneous malignant melanoma

BACKGROUND: Carcinoma of the pancreas is the fifth leading cancer in the U.S. and has the poorest survival rate of the major malignancies. Recent studies have reported an increased risk of carcinoma of the pancreas in malignant melanoma-prone kindreds and have suggested a link between malignant melanoma and pancreas carcinoma and mutations in the p16INK4 gene. This study evaluates the risk of carcinoma of the pancreas in a population-based cohort of patients with malignant melanoma. METHODS: The malignant melanoma patients were identified from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The cohort was followed within the SEER system to ascertain the occurrence of subsequent microscopically confirmed primary carcinoma of the pancreas from January 1973 through December 1993. The time of follow-up was expressed as person-years of observation. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated. RESULTS: There were 43,781 malignant melanoma patients providing 263,528 person-years of follow-up. A nearly 2-fold increased risk of subsequent carcinoma of the pancreas in patients diagnosed with malignant melanoma before age 50 years was observed (SIR = 1.76; 95% CI = 0.80-3.34) and the greatest estimated risk occurred in young white females (SIR = 2.27; 95% CI = 0.73-5.30). CONCLUSIONS: These results provide some evidence in support of observations in recent studies that not only a family history of malignant melanoma but also malignant melanoma diagnosed at an early age may be associated with the subsequent development of carcinoma of the pancreas. Further research with larger numbers of melanoma patients is necessary to explore these potential associations.     

Current status of melanoma vaccines

BACKGROUND: Malignant melanoma is increasing worldwide faster than any other cancer and the American lifetime risk is estimated to reach 1 in 75 by the year 2000. Active specific immunotherapy with vaccines is evolving as a promising new modality in the treatment of malignant melanoma. OBJECTIVE: To present a concise and understandable summary of the key molecular and clinical concepts of melanoma vaccines currently under investigation, the history that led to their development, and their anticipated clinical response. METHODS: The recent advances in the field of melanoma immunobiology and the newest experiment vaccines are reviewed. RESULTS: There is no effective melanoma vaccine that successfully treats or prevents melanoma. However, their use has been associated with regression or delayed disease progression in some cases. The minority of patients who do have a major clinical response to vaccine therapy experience an improvement in survival. Even in those patients in whom melanoma vaccines cannot improve survival, the paucity of severe side effects has provided a quality of life superior to standard multiagent chemotherapy. CONCLUSION: Melanoma vaccines are relatively safe immunotherapeutic modalities for the management of malignant melanoma. The clinical effectiveness of melanoma vaccines is unclear and adequately controlled studies need yet to be performed. Current melanoma vaccines manipulate antigen presentation networks and combine the best cellular and antibody antitumor immune response effective in mediating tumor protective immunity; these combination vaccines hold the most promise. The ideal melanoma vaccine will ultimately prevent melanoma.     

Molecular genetics of familial cutaneous melanoma

PURPOSE: A family history of melanoma is a significant risk factor for the disease, and recently several loci that determine susceptibility to the development of melanoma have been identified. The most important of these is p16/CDKN2A. We attempted to determine the degree to which the p16/CDKN2A gene has been implicated in the development of melanoma, and to identify other genetic factors that play a role as well. METHODS: We reviewed the literature published since the isolation of p16/CDKN2A and identified 13 studies that report the status of the gene in melanoma samples and 12 reports that examine p16/CDKN2A in melanoma kindreds. We also reviewed associated studies on CDK4 and RB1 involvement in melanoma, and examined the role of p16/CDKN2A in other inherited cancers. RESULTS: The evidence strongly implicates p16/CDKN2A in determining predisposition to malignant melanoma. Overall, approximately 20% of families that have been studied show mutations in the gene. However, because of clustering of sporadic cases in families, and potentially because of technical factors, this is likely an underestimate of the proportion of the genetic predisposition for melanoma that is due to p16/CDKN2A mutation. Rare families carry a mutated CDK4 gene that is also responsible for inherited melanoma. CONCLUSION: The gene p16/CDKN2A is an important determinant of melanoma risk. A commercial test is presently available to assess the status of this locus. However, because of uncertainties regarding the interpretation of the results of p16/CDKN2A genetic testing, we do not recommend routine clinical use of this test at this time.     

Memory and intelligence in lateralized temporal lobe epilepsy and schizophrenia

The relation between use of sunscreens, different host factors and malignant melanoma was investigated in a population-based, matched case-control study of malignant melanoma in the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, between 1 July 1988 and 30 June 1990. In total, 400 melanoma patients and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire regarding different epidemiologic variables, including questions on use of sunscreens and different constitutional factors. The use of sunscreens was not found to protect against developing malignant melanoma. Instead, an unexpected relation between the use of sunscreens and the risk of developing malignant melanoma was seen (odds ratio (OR) 1.8 for almost always vs never using sunscreens). A tentative dose-response relation was found. Virtually the same ORs were seen in both sexes. Furthermore, persons younger than 50 years had a higher OR than persons older than 50 years. When different melanoma presentation sites were considered, lesions of the trunk were associated with sunscreen use in females (adjusted OR = 3.7 for almost always vs never using sunscreens), while lesions of the extremity or head and neck were associated with sunscreen use in males (adjusted OR = 3.2 for almost always vs never using sunscreens). Raised naevi on the left arm and freckling were shown to be the major constitutional risk factors (OR = 3.9 for more than three naevi vs none and OR = 1.4, respectively). The results were essentially unaltered in a histopathologically re-examined material. Further investigations are needed in order to form a basis for melanoma prevention.     

Malignant melanoma

Family physicians should be aware of the early signs of malignant melanoma, as well as measures that can be taken to prevent the disease. Etiologic factors for melanoma include sunburns, particularly those occurring early in life, giant congenital nevi, dysplastic nevi and the presence of numerous nevi. The four major subtypes of melanoma are lentigo maligna, superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma. Diagnosis is based on excisional, incisional or punch biopsy. The crude five-year survival rate for malignant melanoma is 81 percent, but survival depends on stage of disease, anatomic site, the patient's age and sex, histologic factors and clinical subtype. Surgical excision is the usual treatment for primary melanoma. Surgery, radiation therapy and chemotherapy are used in the management of metastatic disease, but the prognosis following the development of metastases remains poor. Family physicians can affect survival rates by improving early detection, promoting patient awareness and self-examination, and encouraging regular physical examination of patients who are at increased risk of melanoma.     

Health risks

The health risks associated with ozone depletion will principally be those due to increased ultraviolet B (UV-B) radiation in the environment, i.e., increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). Quantitative risk estimates are available for some of the UV-B-associated effects, e.g., cataract and skin cancer; however, the data are insufficient to develop similar estimates for effects such as immunosuppression and the toxicity of alternatives. Ocular damage from UV exposures includes effects on the cornea, lens, iris, and associated epithelial and conjunctival tissues. The most common acute ocular effect of environmental ultraviolet radiation (UVR) is photokeratitis. Also known as snowblindness in skiers, this condition also occurs in other outdoor recreationists. Chronic eye conditions likely to increase with ozone depletion include cataract, squamous cell carcinoma, ocular melanoma, and a variety of corneal/conjunctival effects, e.g., pterygium and pinguecula. Suppression of local (at the site of UV exposure) and systemic (at a distant, unexposed site) immune responses to a variety of antigens has been demonstrated in both humans and animals exposed to UV-B. In experiments with animals these effects have been shown to worsen the course/outcome of some infectious diseases and cancers. There is reasonably good evidence that such immunosuppression plays a role in human carcinogenesis; however, the implications of such immunosuppression for human infectious diseases are still unknown. In light-skinned populations, exposure to solar UVR appears to be the most important environmental risk factor for basal and squamous cell carcinomas and cutaneous melanoma. Originally it was believed that total accumulated exposure to UVR was the most important environmental factor in determining risk for these tumors. Recent information now suggests that only squamous cell carcinoma risk is related to total exposure. In the cases of both basal cell carcinoma and melanoma, new information suggests that increases in risk are tied to early exposures (before about age 15), particularly those leading to severe sunburns. Testing of a number of the chlorofluorocarbon (CFC) alternatives indicates that most of these chemicals have low acute toxicity, and low to moderate chronic toxicity. Some chemicals that were originally proposed as alternatives have been dropped from consideration because these tests raised concerns about toxicity and/or manufacturing difficulties. In one instance, high accidental occupational exposure was associated with liver damage, underlining the need for care in the use of these substitutes. Recent quantitative risk estimates have been developed for cataract, melanoma, and all skin cancers combined. These estimates indicate that under the Montreal Adjustments, cataract and skin-cancer incidence will peak mid-century at additional incidences of just under 3 per 100,000 and about 7 per 100,000, respectively.     

Melanoma in pregnancy

The incidence of pregnancy complicated by melanoma of the skin, calculated from data of the Netherlands Cancer Registry, is 1 per 10,000 pregnancies. The prognosis of a melanoma is not affected by prior or subsequent pregnancy. A melanoma diagnosed during pregnancy does appear to have a more unfavourable prognosis, due not to a less favourable clinical course, but to a delay in diagnosing melanoma during pregnancy and (or) a less favourable site. When a pregnancy is complicated by malignancy, in case of a melanoma there is a higher risk of placental metastasis compared with other malignancies. In nearly 50% of the cases reported in literature of placental metastasis there was foetal involvement.     

Increased cancer mortality following a history of nonmelanoma skin cancer

CONTEXT: Cancer registries have reported an increased incidence of melanoma and certain noncutaneous cancers following nonmelanoma skin cancer (NMSC). Whether these findings were attributable to intensified surveillance, shared risk factors, or increased cancer susceptibility remains unclear. OBJECTIVE: To determine whether a history of NMSC predicts cancer mortality. DESIGN: Prospective cohort with 12-year mortality follow-up adjusted for multiple risk factors. SETTING: Cancer Prevention Study II, United States and Puerto Rico. PARTICIPANTS: Nearly 1.1 million adult volunteers who completed a baseline questionnaire in 1982. MAIN OUTCOME MEASURE: Deaths due to all cancers and common cancers. RESULTS: After adjusting for age, race, education, smoking, obesity, alcohol use, and other conventional risk factors, a baseline history of NMSC was associated with increased total cancer mortality (men's relative risk [RR], 1.30; 95% confidence interval [CI], 1.23-1.36; women's RR, 1.26; 95% CI, 1.17-1.35). Exclusion of deaths due to melanoma reduced these RRs only slightly. Mortality was increased for the following cancers: melanoma (RR, 3.36 in men, 3.52 in women); pharynx (RR, 2.77 in men, 2.81 in women); lung (RR, 1.37 in men, 1.46 in women); non-Hodgkin lymphoma (RR, 1.32 in men, 1.50 in women); in men only, salivary glands (RR, 2.96), prostate (RR, 1.28), testis (RR, 12.7), urinary bladder (RR, 1.41), and leukemia (RR, 1.37); and in women only, breast (RR, 1.34). All-cause mortality was slightly increased (adjusted men's RR, 1.03 [95% CI, 1.00-1.06]; women's RR, 1.04 [95% CI, 1.00-1.09]). CONCLUSIONS: Persons with a history of NMSC are at increased risk of cancer mortality. Although the biological mechanisms are unknown, a history of NMSC should increase the clinician's alertness for certain noncutaneous cancers as well as melanoma.     

Cutaneous melanoma in women: anatomic distribution in relation to sun exposure and phenotype

An analysis of the relationship between the anatomic site of cutaneous melanoma, sun exposure, and phenotype was conducted in 355 women with histologically confirmed superficial-spreading melanoma and in 935 control subjects. The most frequent site for superficial-spreading melanoma was the leg. However, when major sun-related and phenotype risk factors were examined by site, risk ratios were lowest for melanomas that occurred on the leg. A history of frequent sunburns during elementary or high school, increased number of self-assessed large nevi, and blond hair were more strongly associated with melanoma sites other than the leg. Tumors on the trunk were more likely than tumors at other sites to be associated with histological evidence of a preexisting nevus. Results of this work indicate that associations between melanoma phenotypic factors may differ by anatomic site.     

4-iodotamoxifen aziridine, a new affinity labeling agent for the rapid detection of estrogen receptor isoforms

During the past few years significant progress has been made in the treatment of cutaneous melanoma. These developments often involve the use of interferon-alpha (IFNalpha). Promising results have been reported in high risk patients using adjuvant treatment with high dose IFNalpha. A confirmatory trial of high dose IFNalpha and several adjuvant trials using low or intermediate dose IFNalpha are ongoing, and currently a standard regimen cannot be defined. High response rates have been reported in patients with metastatic disease with combination chemoimmunotherapy schedules. Randomized trials have to be performed in order to demonstrate a survival benefit over less toxic regimens. In this paper the current status of IFNalpha in the treatment of cutaneous melanoma is reviewed.