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Abstract

Introduction

No cohort study has thus far attempted to address the relationship between DMN numbers and melanoma risk, the cost effectiveness of surveillance compared with prophylactic excision or the occurrence of non-melanoma skin cancer in subjects with DMN. Only one study has assessed the association of incident melanomas with preexisting naevi and the role of the patient versus the clinician in detection.¹⁰ No cohort study has been undertaken in an area of high background melanoma incidence such as Australia. In this study we followed a cohort of 278 Australian patients with DMN using baseline skin surface photography to address these issues.  

Methods

The entry criterion of five DMN was based on the results of an earlier study that suggested to us that this number of DMN is associated with sufficient melanoma risk to justify entry to a screening programme.¹ A systematic set of 14 baseline photographs of the skin surface was utilised. A clinical photographer (APH) worked with us in designing the views and did the photography. The photographic method used anatomical site definitions to define standard views of recogniseable body regions rather than using standard magnifications (Figure 1). This approach reduced the number of views necessary to cover the skin surface whilst providing adequate magnification. All patients were at least 18 years of age and had been followed for at least 12 months. The mean duration of follow-up was 42 months. 154 patients were female and 108 male. Mean age was 37 years. 65 (23%) had a family history of melanoma, 54 (19%) had a past history of melanoma and 9 (3%) had both. None were from melanoma prone families (as defined by a history of 2 or more affected first degree relatives)

Figure 1: View of posterior thighs showing at initial visit.
Click pictures for a larger view.

Figure 2: View of posterior thighs at review visit 2 years later showing enlargement and darkening of a pigmented lesion on the right upper medial leg. Histopathology of this lesion showed level II superficial spreading melanoma, measuring 0.49 mm in maximum tumour thickness and arising in a preexisting dysplastic compound naevus.

Figure 3: Macroscopic view of the changing lesion evident in Figures 1 and 2.

Figure 4: Skin surface microscopy (epiluminescence microscopy) of the lesion.
At entry to the study subjects were advised about their high risk status and three monthly self examination was recommended. The clinical features of early melanoma were discussed. Appropriate sun protection measures were described.

DMN were diagnosed clinically according to criteria defined in a previously published study.¹⁴ A naevus was considered clinically dysplastic if it had a macular component and showed at least three of the following five clinical features: ill-defined border, irregularly distributed pigmentation, background erythema, size greater than 5 mm, and irregular border. An exact count was made of the number of DMN and a range of DMN numbers recorded: 1 - 4, 5 - 10, 11 - 20, 21 - 50, > 50. The total number of MN was estimated and a range of total MN numbers recorded: < 20, 21 - 50, 51 - 100, 101 - 500, > 500.

Patients were reviewed at 6 to 12 month intervals. Total body cutaneous examination was performed at each patient visit and the patient's pigmented lesions compared with baseline photographs. Excisional biopsies were performed for any lesions that were clinically suspicious for melanoma and were not done routinely for histological confirmation of the presence of dysplastic naevi. All histopathology was examined at a single private pathology laboratory in Melbourne (Dorevitch Pathology). All melanomas arising during the study were reviewed by one pathologist (GM). Melanomas detected at the initial visit were excluded from the analysis.  

Results

Table 1 and Table 2 show the distribution of numbers of dysplastic naevi and total numbers of naevi in the cohort of 278 patients and the change in melanoma incidence with increasing numbers of DMN and total naevi. For an Australian population the total numbers of naevi were not remarkable (61% had 100 naevi or less) but there were extraordinarily large numbers of DMN (59% had more than 10 DMN). Melanoma incidence correlated more closely with increasing numbers of DMN than with increasing total numbers of naevi. Subjects with 21 to 50 DMN developed melanomas at a rate of 3.3% per year.

The 20 incident melanomas were all superficial spreading in type. 12 were invasive and 8 were in situ . All the invasive lesions were less than 0.6 mm and level II except one amelanotic melanoma that showed a desmoplastic component and invaded to 1.0 mm in thickness and reached level IV. Using the criteria of Clark et. al. 15 were classified as radial growth phase lesions, 4 as vertical growth phase and one was classified separately as desmoplastic.¹⁶ The melanomas were widely scattered over the skin surface with 6 on the upper limbs, 4 on the upper back, 4 on the lower limbs, 3 on the chest, 2 on the abdomen and 1 on the head.

Seven of the 20 melanomas detected in follow-up showed histological evidence of an associated benign naevus. Naevoid remnants evident histologically were intradermal in 4 and showed features of dysplastic naevi in 3. Nine of the 20 melanomas evolved as a change in a preexisting pigmented lesion that had been evident on baseline photos. In two of these nine the preexisting pigmented lesion was likely to have been a de novo melanoma. One of these patients had a stable pigmented lesion on her right chest over a 6 year period. It was excised when it began to enlarge and darken and was found to be level II, 0.6 mm thick melanoma without histological evidence of any associated naevus. A second patient had a tiny, 2 mm lesion on his chest at his first visit. At his initial review visit, 6 months later, this had enlarged slightly and become more angular in shape. Histologically this was a level I melanoma with no associated naevus. It is unlikely that these early melanomas had replaced a preexisting naevus.

The patients who developed melanoma were more likely to have had a previous melanoma (P=0.001) and to have a family history of melanoma (P=0.05) than those who did not. Five (31%) of 16 patients who developed melanomas had a family history and 7 (44%) had a past history of melanoma.. The percentage of patients in each risk group who developed melanoma are shown in Table 1.

Eleven of the 20 melanomas were detected at follow-up visits by comparison with the baseline photographs. These eleven patients were unaware of the changing lesion and in most of these lesions the change would not have been apparent to the clinician without the use of photographs. Seven melanomas were detected by the patient as a change on self examination and 2 were observed by the patients partner between follow-up visits.

Four of the 20 were amelanotic melanomas and did not fulfil the normal diagnostic criteria for melanoma. Nonetheless one of these was detected by the patient on self examination.

The mean time from commencement of follow-up to diagnosis of melanoma was 36 months (+/- 12 months) with a range of 11 to 75 months.

A total of 1554 patient consultations were required for the 278 patients to detect 20 melanomas (78 for each melanoma detected). 210 biopsies were performed for changes observed during follow-up in 104 patients (10 for each melanoma detected). Not all changes in pigmented lesions lead to a biopsy. If melanoma could be confidently ruled out on clinical examination and skin surface microscopy the lesion was simply rephotographed. Histopathological diagnoses on these biopsies are shown in Table 4. Changing dysplastic naevi were by far the predominant source of clinically suspicious change and we do not know how many of these may have progressed to melanoma if they had not been removed.

Nineteen nonmelanoma skin cancers were detected prospectively during follow up in this group of patients and removed. 16 were basal cell carcinomas and there was one squamous cell carcinoma, one keratoacanthoma and one Bowen's disease.  

Discussion

The age adjusted incidence of melanoma reported here of 1835/100,000 person years is somewhat higher than that reported in other studies (692 - 709/100,000 person years).^8,10 This may be explained by the relatively large numbers of DMN in our patients (Table 1) and by the higher background rate of melanoma in Australia (other studies were from the USA and UK). Our study did not examine a cohort of control patients, however, the cohort study of Marghoob et al did include a control population.¹¹ This study demonstrated a 10 year cumulative risk of 10.7% among 287 patients with at least one large naevus, one atypical naevus and 100 total naevi. This risk compared with a 0.62% 10 year risk among 831 controls selected from patients requiring annual dermatological follow-up for other reasons.

We have intentionally continued to use the word "dysplastic" rather than "atypical". These naevi have been studied because they are believed to be associated with melanoma risk. There are other naevi that are clinically atypical and that are not linked with melanoma risk. Examples are naevus spilus, blue naevus and halo naevus. We prefer the term "dysplastic" because it clearly does not embrace these other atypical naevi.

There are several definitions in the literature for syndromes associated with atypical or dysplastic naevi. One includes patients with a single atypical naevus, a large (> 8 mm) naevus and > 100 total naevi.¹¹ Another depends on distribution of atypical naevi on the anterior scalp, dorsae of the feet, iris or buttocks.¹⁹ DMN have been demonstrated to be independent of total naevi in their association with melanoma risk and will not always be associated with large numbers of naevi or naevi in certain locations. We prefer not to include DMN in a syndrome definition but rather to consider them as a continuous numerical variable. There is evidence from this study (Table 1) and from two case-control studies of increasing risk with increasing numbers of DMN.^1,10 The risk associated with a single DMN is likely to be small and insufficient to justify entry to this kind of follow-up regimen. It is also difficult to accurately diagnose a single naevus as being dysplastic or otherwise on clinical grounds but much more easy to identify the patient with numerous DMN.

It is also difficult to apply definitions of large numbers of naevi in different geographical locations. A recent Australian study showed a mean total count of naevi (> 2 mm in diameter) that approached 100 in 15 year old adolescents whilst this is considered to be a large number in the USA and UK.²⁰ The proportion of the Australian adult population with 5 or more dysplastic naevi has not been clearly defined. One study of 1123 Australian schoolchildren aged between 6 and 15 years showed that 2.7% had 3 or more dysplastic naevi using the same clinical definition applied here.²¹

Two thirds of the incident melanomas in this study were de novo lesions. This finding is similar to those of studies that examine the histological frequency of associated naevi with melanoma which suggest that 43 to 77% of melanomas are new lesions.^22,23,24 The predominance of de novo melanoma in these patients also supports management by surveillance of patients using baseline photographs rather than by attempts at prophylactic excision. If every one of the 5,838 DMN present in our cohort of patients had been excised at the outset, only 3 of the incident melanomas would have been prevented. Ninety-three DMN were excised in the course of the study because of changes evident in comparison with photographs and because the possibility of melanoma could not be confidently excluded. These changing DMN would seem to be the most likely pigmented lesions to develop into melanoma and it is possible that some of these would have progressed to melanoma had they been left in place.

When consultations and biopsies are costed at the Australian Government's Medicare Schedule rates for 1997 and $100.00 allowed per set of photographs the cost of diagnosing each melanoma in this study would have been $5,583. Prophylactic excision of all dysplastic naevi in this study would have cost $1,118,038 and would have prevented three melanomas at a cost of $395,038 per melanoma. This approach would not have prevented 17 of the 20 incident melanomas.

The use of baseline photographs in patients with many floridly atypical pigmented lesions provides knowledge of the stability of many lesions that would otherwise demand excisional biopsy. Baseline photographs therefore greatly reduce the number of excisions that would be otherwise necessary in managing such patients. Patients would commonly present with concern about change in a particular pigmented lesion. Reference to the photographs would most often reveal no change and the lesion would remain under observation. Only ten biopsies were necessary to detect each melanoma and less than one biopsy was necessary per subject in the course of this study.

The melanomas incident in this study were detected at an earlier stage than other melanomas that were incident in the state of Victoria in 1990. In situ melanomas comprised 45% of those seen in the DMN cohort and 33% of those seen in the state of Victoria for 1990. ¹⁵ Median tumour thickness was 0.40 mm in our cohort and 0.77 mm for the state in 1990. Mean tumour thickness for invasive melanoma in the cohort was 0.44 mm compared with 1.40 mm (95% confidence interval 1.29-1.51) for the state.

It is possible that such close surveillance leads to the detection of some melanomas that would otherwise have remained undetected and may have regressed spontaneously or failed to progress and become life threatening. Such "harvesting" of early melanomas may contribute to the very high incidence observed.

We conclude that numerous dysplastic naevi identify patients at high risk for melanoma. Baseline photography of the entire skin surface and 6 to 12 monthly surveillance provides an effective method for early detection of incident melanomas. The majority of new melanomas were de novo lesions and only three developed from 5,835 DMN. Prophylactic excision of dysplastic naevi would not have provided a satisfactory alternative to follow-up and does not provide sufficient risk reduction to justify the cost and morbidity of the procedure.  

References

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