Melanoma Surveillance Research Articles

Surveillance and Follow-up Examinations in Cutaneous Melanoma

The main goal of follow-up examinations of patients with cutaneous melanomas is early diagnosis of developing recurrent or second tumors. Timely recognition of recurrence has a relevant effect on the prognosis. In 80% of the cases recurrences are diagnosed for the first time in the course of follow-up when follow-up procedures are carried out systematically. Most recurrences are discovered during a physical examination. Sonographic examination of the lymph nodes is also a very sensitive method which can lead to the diagnosis of locoregional recurrences before they are palpable. Further image-producing techniques are not necessary for surveillance of primary tumors. In contrast to former recommendations, new research indicates that less extensive diagnostic procedures are sufficient in primary tumor stages, especially when the tumor thickness of the melanoma is less than 1 mm. Consequently, costs can be reduced considerably without additional risk to the patient.

Early detection of melanoma: the best strategy for a favorable prognosis

Of all the skin tumors, cutaneous melanoma represents the greatest challenge for secondary prevention and early detection aimed at finding early curable disease. Melanoma is a highly malignant tumor with an alarming increase in incidence over the last few decades, among the highest in cancer, that is directly related to a rise in the mortality rate. The current lifetime risk is 1 in 71 Americans.1 These statistics compel physicians to make the utmost effort to detect melanomas at an early, treatable stage when simple excision can provide a cure. Most melanomas develop in the skin and are clinically classified into four major subtypes, with recent identification of additional variants (Table 1). Melanoma can arise in any melanocyte-containing tissue, including the uveal tract, central nervous system, and mucosal surfaces, including the oral cavity, vulva, vagina, nasopharynx, paranasal sinuses, tracheobronchial tree, anal canal, and urinary tract. Frequently neglected are subungual melanomas, which are often mistaken for benign or traumatic conditions of the nailbed; they occur at a higher frequency in African Americans, who have 12% of all subungual melanomas in contrast to 1% of cutaneous melanomas.2 Malignant melanoma is very rare before the age of 20, accounting for 2% of cases,1 of which 0.3%–0.4% are prepubertal melanomas.1 Childhood melanoma is divided into five categories based on the mode of occurrence3: development from healthy skin, accounting for most cases; transformation from a giant congenital nevus, accounting for a third of the cases4,5; transplacental transmission from mother to fetus; transformation of a pre-existing nevus; and associated conditions like xeroderma pigmentosum, albinism, or dysplastic nevus syndrome. Melanoma is the second most common cancer in men aged 30–49 years and the fourth most common cancer in men aged 50–59.6 It is the most common cancer in women aged 25–29 and second only to breast cancer in women aged 30–35 years.7 The overall incidence is highest in New Zealand and Australia, exceeding 55 per 100,000.8 These rates have risen sharply with a more modest increase in the mortality rate, mainly due to a substantial increase in melanoma surveillance that has led to identification of early, curable melanomas and reduction in the emergence of advanced disease and melanoma-related mortality.9 Melanoma incidence and mortality rates are influenced by gender and geography. In Europe, melanoma occurs at a higher frequency among women than men, whereas in Australia and America the incidence is slightly higher in men.10 Mortality rate is higher in southern than in northern European countries and rose 3% per year for men and 1% for women for each year from 1976 to 19876 (Table 2). Large studies have shown a female survival advantage over men of 22% and a disease-free survival advantage at 5 years of 17% for woman over men.11 This survival advantage was most commonly seen in early stages of the disease and was often lost in advanced disease. The most pronounced discrepancy occurred in the progression of the disease to stage III, while there was no evident survival advantage at further progression to stage IV. This indicates that female sex steroids could slow the tumor progression at early stages of the disease.12 With regard to hormone status, the female advantage was equally strong in preand post-menopausal periods in some studies13 but restricted to premenopausal women in other studies.14 Despite widespread research, the basis for the female survival advantage is still not established. It has been suggested that estrogenic compounds reduce the invasion of human melanoma cells through fibronectin, as opposed to androgenic compounds, which seem to have no anti-invasive capacities.12,15 How estrogenic compounds affect melanoma cell invasion through fibronectin remains to be determined. Another known effect of estradiol, progesterone, and dihydrotestosterone is their ability to inhibit interleuFrom the Department of Dermatology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address correspondence to Sarah Brenner, MD, Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizman St., Tel Aviv 64239, Israel. E-mail address: derma@tasmc.health.gov.il

Multiple primary melanoma revisited.

Incidence of cutaneous melanoma continues to increase in the Caucasian population worldwide. Approximately 5% of melanoma patients develop additional primary melanoma. This rate is significantly higher than the estimated lifetime risk of an individual for developing the disease (1.4%). These features suggest that a genetic predisposition may underlie multiple primary melanomas (MPMs). Prior studies had identified CDKN2A mutations in a few MPM individuals. The objectives of this study were to determine the frequency of family history of melanoma in MPM cases, to characterize other clinical features including history of other cancer, and to determine the association with functional CDKN2A mutations. This study used a case series design. All living patients who had been seen in the Pigmented Lesion Clinic at the University of Pennsylvania and who had more than one primary invasive malignant melanoma or an invasive primary followed by an in situ melanoma were eligible for participation. Individuals with MPM frequently had a family history of melanoma, dysplastic nevi (DN), and/or another cancer including basal cell carcinoma (BCC), and squamous cell carcinoma breast cancer, and a personal history of DN, and basal cell carcinoma. Germline mutations in CDKN2A gene were identified in 8 of 96 MPM cases (8.3%, 95% confidence interval, 6.7-9.9%). These data indicate that the presence of MPM is associated with a modest incidence of a family history of melanoma, DN, or BCC and a small association with CDKN2A mutations. Therefore, in addition to the MPM index case, other family members can benefit from screening and regular surveillance for melanoma, DN, and BCC.

Suppression of immune surveillance in melanoma

Numerous reports of IL-10 cytokine secretion by tumor infiltrating cells indicate there is suppression of immune surveillance within the milieu of many melanomas. In this paper we have outlined the suppressor system that best fits the published data. The regulatory system is composed of CD4+ T-lymphocytes which have been activated and programmed to secrete Th2 cytokines. Initially these cells do not secrete cytokines, but subsequently they enter an IL-10 secretory phase as a result of T-T cell interaction. After activation, Th1 programmed T-cells express MHC class II molecules and B7 second signals. When these Th1 T-cells express MHC II molecules containing ‘self’ polypeptides coupled with faulty B7-H1 second signals they are subject to inactivation by Th2 T-cells. If this system can be inactivated, immunotherapy of melanoma will be more successful. If an antigen can be discovered that stimulates sensitized Th2 T-cells without stimulating Th1 T-cells, this antigen, followed with cyclophosphamide, can be used to destroy the Th2 T-cells in the course of both active and passive immunotherapy. Solubilized MHC II molecules with appropriate ‘self’ polypeptides should qualify as such an antigen. We postulate such an antigen can be prepared using poliovirus 1 (Sabin) to lyse melanoma tissue cultures.

Genetic and environmental influences in the development of multiple primary melanoma.

To identify risk factors and the prognosis associated with the development of multiple primary melanoma (MPM). Case-comparison studies of subjects with MPM and single primary melanoma. Sequencing of CDKN2A in germline DNA. Population-based study of patients with invasive melanoma in Scotland between 1979 and 1996. For mortality studies, 108 patients with MPM and 216 single melanoma controls matched for age, sex, site, and tumor thickness. For risk factor studies, 48 patients with MPM and 48 single melanoma controls matched as above. For CDKN2A analysis, a sample of 23 subjects with MPM. The development of MPM was found not to be an independent prognostic factor. The risk of MPM was greatest in those with a family history of melanoma, with large numbers of benign nevi, and the presence of clinically or histologically atypical nevi. Germline mutations of CDKN2A were present in 6 of 23 patients with MPM and in 5 cases consisted of the base pair substitution Met53Ile. The importance of MPM should be addressed in melanoma follow-up protocols. Those patients at greatest risk can be identified by a family history of melanoma and their mole pattern. Germline mutations in CDKN2A occur in both familial and sporadic MPM and further studies are required to determine the value of analysis of this gene in melanoma surveillance. Patients should be informed that the development of MPM does not adversely affect their prognosis.

The Melanoma Epidemic: More Apparent Than Real?

To examine inconsistencies between the growth in incidence of melanoma and more modest changes in melanoma-related mortality, we reviewed the medical literature on the incidence of melanoma diagnosis and associated mortality and on the changes in diagnosis and mortality over time. Increases in melanoma surveillance activity have been associated with increases in the diagnosis of thin melanomas, but the incidence of advanced tumors has changed minimally. The large increases in diagnosis of melanoma without commensurate increases in advanced tumors and mortality are not compatible with presumed malignant behavior of thin melanomas. Increased intensity of melanoma surveillance may artificially increase the incidence of melanoma by harvesting histologically "malignant" but biologically benign tumors. Little available evidence suggests the presence of an actual increase in the frequency of biologically malignant tumors. Attempts to increase screening intensity for melanoma may result in further increases in diagnosis of melanomas. Nevertheless, limitations in histopathologic diagnostic techniques will continue to hinder efforts at early identification of those at risk for death from melanoma without diagnosing melanoma in large numbers of patients with biologically benign pigmented skin tumors.

Total body photography for melanoma surveillance

Total body photography for melanoma surveillance

Accelerated detection with prospective surveillance for cutaneous malignant melanoma in high-risk groups

In 1983 a classification scheme was proposed for patients with atypical naevi, according to their personal and family history of melanoma and atypical naevi. To assess the predictive value of these features we undertook prospective surveillance of patients at high risk of primary melanoma. We followed up 116 patients each with 3 or more clinically atypical naevi for at least 5 years. Patients are examined and naevi are photographed every 3-6 months; lesions showing disturbing change are excised for histopathology. Among 85 patients with no personal or family history of melanoma, 5 invasive (level 2 or deeper) melanomas developed during 583 person-years of follow up. The expected number of invasive melanomas in this population would be 0·054; the increased risk is significant (p<0·001; relative risk 92 [95% Cl 30-216]). There was a similarly increased risk of new melanoma also among 24 patients with atypical naevi plus a history of previous melanoma (observed 2, expected 0·022, p<0·001; relative risk 91 [11-328]). By comparison, no second melanoma developed among 25 patients with previous melanoma but a normal naevus pattern during 213 person-years of similarly intensive follow-up. The risk of melanoma was highest among 7 patients with atypical naevi and a family history of melanoma (observed 6, expected 0·009, p<0·001; relative risk 444 [121-1138]). The median thickness of surveillance-detected melanomas was 0·75 mm (range 0·40-1·05 mm) in this group. This study shows the value of clinical follow-up of high-risk patients to detect early thin melanomas.

Support for Screening for Melanoma in High-Risk Groups

These investigators assessed the value of long-term surveillance for detecting melanoma in high-risk persons. One hundred sixteen patients, each with at least 3 clinically atypical melanocytic nevi, were followed with serial photography at 3- to 6-month intervals for 5 years or more, with attention given to changing nevi. …

Wald PH, Schneider JS: Medical surveillance for melanoma at the Lawrence Livermore National Laboratory. Occup Med: State of the Art Reviews 5:607–616, 1990

Wald PH, Schneider JS: Medical surveillance for melanoma at the Lawrence Livermore National Laboratory. Occup Med: State of the Art Reviews 5:607–616, 1990

Wald PH, Schneider JS: Medical surveillance for melanoma at the Lawrence Livermore National Laboratory. Occup Med: State of the Art Reviews 5:607–616, 1990

Wald PH, Schneider JS: Medical surveillance for melanoma at the Lawrence Livermore National Laboratory. Occup Med: State of the Art Reviews 5:607–616, 1990