Clinical Features Associated With Individuals at Higher Risk of Melanoma: A Population-Based Study

Key Points

Question  Does age at diagnosis and body site of melanoma differ according to patient risk factors?

Findings  In this population-based study of 2727 patients with melanoma, the average age at diagnosis was lower for patients with a family history (56 years) or with many nevi (59 years) compared with those without risk factors (65 years). Melanoma more commonly occurred on the trunk for those with many nevi, on the limbs for those with a family history, and on the head and neck for those with a previous melanoma.

Meaning  A person’s melanoma risk factors might be useful in tailoring skin self-examination and surveillance programs.

Importance  The identification of a subgroup at higher risk of melanoma may assist in early diagnosis.

Objective  To characterize melanoma patients and the clinical features associated with their melanomas according to patient risk factors: many nevi, history of previous melanoma, and family history of melanoma, to assist with improving the identification and treatment of a higher-risk subgroup.

Design, Setting, and Participants  The Melanoma Patterns of Care study was a population-based observational study of physicians’ reported treatment of 2727 patients diagnosed with an in situ or invasive primary melanoma over a 12-month period from October 2006 to 2007 conducted in New South Wales. Our analysis of these data took place from 2015 to 2016.

Main Outcomes and Measures  Age at diagnosis and body site of melanoma.

Results  Of the 2727 patients with melanoma included, 1052 (39%) were defined as higher risk owing to a family history of melanoma, multiple primary melanomas, or many nevi. Compared with patients with melanoma who were at lower risk (ie, without any of these risk factors), the higher-risk group had a younger mean age at diagnosis (62 vs 65 years, P < .001), but this differed by risk factor (56 years for patients with a family history, 59 years for those with many nevi, and 69 years for those with a previous melanoma). These age differences were consistent across all body sites. Among higher-risk patients, those with many nevi were more likely to have melanoma on the trunk (41% vs 29%, P < .001), those with a family history of melanoma were more likely to have melanomas on the limbs (57% vs 42%, P < .001), and those with a personal history were more likely to have melanoma on the head and neck (21% vs 15%, P = .003).

Conclusions and Relevance  These findings suggest that a person’s risk factor status could be used to tailor surveillance programs and education about skin self-examination.

Cutaneous melanoma incidence is increasing in predominantly European populations.¹ Australia’s incidence is among the highest in the world,² and for young Australian adults aged 15 to 44 years, melanoma is the most common malignant abnormality and one of the leading causes of cancer death.³

Australian⁴ and international⁵ clinical practice guidelines for management of cutaneous melanoma recommend that people at higher risk of melanoma consider having regular surveillance and be educated about skin self-examination and appropriate sun protection. Number of nevi, family history of melanoma, and a history of multiple primary melanomas are among the strongest risk factors for developing a first or subsequent melanoma.^6-8 Further characterization of individuals with these risk factors, and of the clinical features associated with their melanomas, may assist in the identification and treatment of this higher-risk subgroup and could improve our understanding of the etiological heterogeneity of melanoma.

The Melanoma Patterns of Care study documented the characteristics and treatment of people diagnosed with melanoma in New South Wales (NSW), Australia, over a 12-month period. We aimed to describe patient and melanoma characteristics, including age at diagnosis, histopathological tumor characteristics, and body site of the melanoma for those identified as having either many nevi, or a family or personal history of melanoma (ie, higher-risk patients), and to compare these characteristics to those of lower-risk patients without these risk factors.

The Melanoma Patterns of Care study was a population-based, observational study based on physicians’ reported treatment of melanoma patients residing in NSW, Australia, with a new histopathologically confirmed primary in situ, invasive cutaneous, or unknown primary site melanoma (ICD-O-3 site codes C44.0 to C44.9 and C80.9; morphology codes 8720-8790 /2 or /3)⁹ reported to the NSW Central Cancer Registry in the 12 months from 23 October 2006. New South Wales is the most populous state in Australia and includes about one-third of the Australian population. Patients’ demographic information and degree of spread of the melanoma was obtained from the Registry. Ethics approval was granted by Human Research Ethics Committees of The University of Sydney and the Cancer Institute NSW. Informed consent was waived because the data obtained from the cancer registry for this study was consistent with the aims of the New South Wales Cancer Registry.

The “doctor providing initial care following diagnosis” for this study was the referring physician on the diagnostic pathology report on which the cancer registration was based. It is mandatory for pathologists in NSW to notify every newly diagnosed cancer to the Central Cancer Registry. For each new melanoma reported during this period, the physician providing initial care was contacted by the study team and asked to complete a questionnaire regarding the treatment of their patient. Physicians to whom the initial physician referred a melanoma patient were also contacted by the study team and asked to complete a questionnaire. eFigure 1 in the Supplement describes this process. While all invasive melanomas were captured and followed during the study period, questionnaire responses were only sought for the first 450 notifications of in situ melanomas, to minimize workload. Trained field workers assisted with completion of questionnaires using patient records, when requested by physicians with large numbers of patients.

Questionnaires were completed for 2758 (71%) of 3869 of patients diagnosed with melanoma during the study period. Thirty-one (1%) patients for whom risk status was not completed were excluded from this analysis. Of the remaining 2727 patients, 1052 (39%) were defined as higher risk if they had one or more of: multiple primary melanoma (physicians were asked “Did the patient have a personal history of melanoma?”), or a family history of melanoma in a blood relative, or many nevi; and 1675 (61%) patients were defined as lower risk (eFigure 1 in the Supplement). Body site of the melanoma was categorized as head and neck (face, scalp, ears, neck), trunk, upper limbs (including shoulders), and lower limbs (including hips). For 22 patients who were diagnosed with multiple primary melanomas during the study period, the thickest lesion was chosen for analysis. Postcode of residence was used to derive socioeconomic status, based on the Index of Relative Social-Economic Disadvantage¹⁰ that ranks social and economic well-being, and to derive an index of remoteness based on the Rural, Remote and Metropolitan Areas classification.¹¹ The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist was used to guide the reporting of this study.¹²

Analysis of variance F tests, χ² tests, t tests, and Wilcoxon rank sum tests were used to compare groups defined by risk factors. Linear regression was used to test for 2-way interactions. All analyses were conducted using SAS (version 9.3, SAS Institute Inc), with statistical significance inferred at P < .05.

Information was collected from clinicians for 71% of patients diagnosed with melanoma during the study period. The age distribution of study patients was virtually identical to that of all melanomas registered by the Cancer Registry during the study period, but our sample had a slightly higher proportion of females (39% in those surveyed, 36% in those not surveyed), and a slightly lower proportion of melanomas that were 4 mm or larger (5% vs 7%).

Table 1 describes the 1052 patients classified as higher risk, the 1675 lower-risk patients, and the characteristics of their melanomas. Having many nevi (62%) was the most common risk factor in the high-risk group, followed by personal history (42%) and family history (28%). Higher-risk patients had, on average, a higher proportion of superficial spreading melanomas than lower-risk patients (49% vs 45%), fewer lentigo maligna melanomas (12% vs 15%, P = .007), and a lower proportion of melanomas larger than 1 mm thick (29% vs 32%, P < .001). The higher-risk group had a younger mean age at diagnosis (62 years vs 65 years, P < .001), with 25% of patients younger than 50 years compared with 16% of lower-risk patients. A difference in mean age at diagnosis between higher- and lower-risk patients was observed for females (55.9 years vs 63.3 years, P < .001) but not for males (65.1 vs 65.3 years, P = .79). However, a lower mean age of diagnosis for higher-risk patients compared with lower-risk patients was consistent across all body sites and histological subtypes except lentigo maligna melanoma (eTable 1 in the Supplement). There were similar proportions of men and women in the higher-risk and lower-risk groups, and they had similar socioeconomic status and proportions of urban to rural locations of residence.

Higher-risk patients were less likely than lower-risk patients to have a melanoma situated on the head and neck (17% vs 23%) and more likely to have a melanoma diagnosed on the trunk (37% vs 34%) and limbs (46% vs 43%) (P = .002) (Table 1). The relative tumor density was calculated using the method described by Pearl and Scott,¹³ which takes into account the proportion of skin surface area for each body site. According to their formula, a relative density of 1 indicates a uniform distribution of melanomas over the surface of the body, values above 1 indicate an excess concentration and values less than 1 indicate a lower concentration of melanomas at a particular body site. The body site with the highest concentration of melanomas relative to its skin surface area was the head and neck area region (relative tumor density 1.80 for higher-risk patients and 2.58 for lower-risk patients), followed by the upper limbs (1.48 and 1.32, respectively), trunk (1.13 and 1.03, respectively), and lower limbs (0.48 and 0.45, respectively).

The pattern of melanomas on different body sites also differed by sex (Table 2). In each risk group, males were more likely than females to have melanoma on the trunk and head and neck, and less likely to have melanoma on the upper and lower limbs (P < .001).

Among higher-risk patients, those with many nevi were more likely to have melanoma on the trunk (41% vs 29%, P < .001), those with family history were more likely to have melanoma on the limbs (57% vs 42%, P < .001), and those with a personal history were more likely to have melanomas on the head and neck (21% vs 15%, P = .003) (Table 3). Lentigo maligna melanoma was more common for patients with a previous primary melanoma (22%) compared with those with a family history (9%) or many nevi (10%).

Patients with a family history of melanoma or with many nevi were more likely to be diagnosed at a younger age than those with a personal history of melanoma (Table 3). Fifteen percent of patients with a family history of melanoma were younger than 40 years at diagnosis compared with 9% of patients without a family history. About half (54%) of patients who had no prior melanoma history were younger than 60 years at diagnosis. The mean age at diagnosis was 56 years for patients with a family history, 59 years for those with many nevi, and 69 years for those with a previous melanoma. These differences in age at diagnosis according to risk factor were observed regardless of the body site of the melanoma (eTable 2 in the Supplement). For patients with many nevi or a personal history of melanoma, the mean age at diagnosis was lowest for melanoma on the lower limbs, followed by the upper limbs, then trunk, then the head and neck (P < .01). Patients with a family history of melanoma also followed this pattern but the differences were not statistically significant.

In this large population-based study, those classified as being at higher risk of developing melanoma had a younger mean age at diagnosis, were less likely to have a melanoma on their head and neck region, and were less likely to have a lentigo maligna melanoma subtype compared with lower-risk patients. However, these characteristics differed according to the type of risk factor; presence of many nevi, family history, or a personal history of melanoma.

The younger age at diagnosis for patients with a family history or many nevi is consistent with a genetic predisposition to melanoma.^14-16 Although men and women had a different distribution of melanomas on different body sites, when compared with lower-risk patients, those at higher risk consistently had a greater concentration of melanomas on the trunk and limbs, body sites that receive more intermittent sun exposure. The finding that patients with head and neck melanomas had significantly fewer nevi than patients with melanomas on the trunk has also been observed in other studies.^17-19 These findings provide some support for the divergent pathways model of melanoma etiology, which proposes one pathway associated with more continuously sun-exposed sites, such as the face and neck, and a second pathway related to a genetic predisposition (eg, those with a family history or many nevi) characterized by melanomas developing on intermittently exposed body sites, such as the trunk and limbs and requiring less sun exposure for melanomagenesis to occur.^17,19 One study²⁰ found that patients with multiple primary melanomas or a family history of melanoma had fewer nevus-associated melanomas than patients with high nevus counts. For these reasons, people with many nevi may be most likely to benefit from sequential digital dermoscopy and total body photography for ongoing surveillance.^21,22 Improving patient awareness of their skin to recognize changes may also aid in early melanoma detection and improve outcomes.²³ Education about skin self-examination could be tailored to a person’s risk factors, such as highlighting areas on the body where melanoma is most likely to occur, and emphasizing that melanomas do not always originate from a nevus.

The lentigo maligna melanoma histological subtype is typically associated with melanomas on the head and neck, chronic sun exposure, and older age²⁴ and in the present study this subtype was more common among lower-risk patients and those with a personal history of melanoma. Lentigo maligna melanoma was the histological subtype with the highest mean age at diagnosis, and it was the only subtype that had a greater mean age at diagnosis for higher-risk patients (71.9 years) than lower-risk patients (70.7 years).

This population-based study had a relatively high response rate from the clinicians treating melanoma patients. The results from this study are probably most generalizable to other regions that are similar to the Australian population with regard to ambient ultraviolet radiation exposure, clothing habits, and ethnicity. Few other studies have reported specifically on these relationships of melanoma risk status with characteristics of patients and their melanomas. However, many studies of other European-origin populations show similar distributions of melanoma by body site, sex, and age, which would make similar associations with melanoma risk plausible.^19,25,26 This is not so of nonEuropean origin populations,²⁶ in which overall melanoma risk is much lower and body site distributions are quite different. The approach to high-risk people in such populations requires separate consideration.

Identification of risk factors was based on physicians’ recall and patients’ medical records. We did not assess the reliability or validity of the risk factor data obtained. Assessing validity would require contacting patients and conducting a thorough independent assessment to compare against the clinician-reported data. A supplementary study assessing the validity and interrater and intrarater reliability of such data would be valuable. There also may have been different interpretations of the risk factors. For example, the questionnaire item asked whether or not the patient had “many nevi” rather than record actual nevus count, and for family history there was no ascertainment of the number of affected relatives or their relationship to the proband, which would have enabled further categorization of risk status. Simple, validated questions are now available to measure family history in clinical settings.²⁷ In addition, other melanoma risk factors, such as hair color, skin type, previous history of keratinocytic lesions, sunburns, or smoking were not collected.

Our data indicate that individuals with many nevi or a family history of melanoma will, on average, present with melanoma at a younger age and be more likely to develop melanoma on areas normally covered by clothing (intermittently sun-exposed sites). Individuals at higher risk of developing melanoma are likely to benefit from increased surveillance including whole-body skin checks and monitoring of nevi.^28,29 The results of our study suggest that a person’s risk factor status might be used to tailor their surveillance program in terms of starting age and education about skin self-examination, or more intensive surveillance. They could be considered for incorporation into clinical practice guidelines to optimize outcomes for high-risk individuals.⁵ Risk prediction models that include these risk factors could be used to personalize prevention and screening strategies, for example by basing the surveillance starting age on a suitable 10-year absolute risk threshold.³⁰

Corresponding Author: Caroline G. Watts, MPH, Cancer Epidemiology and Prevention Research, Sydney School of Public Health, The Lifehouse, Level 6-North, 119-143 Missenden Rd, Camperdown NSW 2050, Australia (caroline.watts@sydney.edu.au).

Published Online: November 9, 2016. doi:10.1001/jamadermatol.2016.3327

Author Contributions: Mrs Watts and Mr Goumas had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Watts, Madronio, Morton, Armstrong, Curtin, Mann, Thompson, Cust.

Acquisition, analysis, or interpretation of data: Watts, Madronio, Goumas, Armstrong, Menzies, Thompson, Cust.

Drafting of the manuscript: Watts, Armstrong, Thompson.

Critical revision of the manuscript for important intellectual content: Madronio, Morton, Goumas, Armstrong, Curtin, Menzies, Mann, Thompson, Cust.

Statistical analysis: Watts, Madronio, Goumas, Cust.

Obtaining funding: Armstrong, Curtin, Mann, Thompson, Cust.

Administrative, technical, or material support: Madronio, Morton, Mann, Thompson.

Study supervision: Madronio, Morton, Armstrong, Mann, Cust.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by the Cancer Institute NSW (05/POC/1-06), with additional financial support given by the Melanoma Institute Australia and the NSW Melanoma Network. The authors are very grateful to these organizations for their financial and in-kind support, as well as The University of Sydney and the Royal Prince Alfred Hospital for their in-kind support, and to the doctors who took part in the study. Mrs Watts was supported by a PhD scholarship funded through a Cancer Institute NSW fellowship to Dr Cust, and a Sydney Catalyst Top-Up Research Scholar Award. Dr Morton was supported by a National Health and Medical Research Council Sidney Sax Fellowship (#1054216). Dr Cust was supported by a National Health and Medical Research Council Career Development Fellowship (#1063593) and a Cancer Institute NSW Career Development Fellowship (#15/CDF/1-14).

Role of the Funder/Sponsor: The funders/sponsors were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.