We examined many histopathologic and some clinical characteristics of multiple melanomas and found that subsequent melanomas in patients with multiple melanomas were more likely than than their first melanomas to have evidence of a contiguous dysplastic nevus, to have invaded less, and to be located on the head and neck or legs.
In studying patients with multiple melanomas, it is important to ensure that the subsequent melanomas are independent primary tumors and not cutaneous metastases from an antecedent primary melanoma. Classifying cutaneous melanomas as primary or secondary solely on histologic grounds may be challenging.37
More reliable classification is based on correlation of several clinical and pathologic features, such as location, the presence of an associated precursor/in-situ lesion, lymphatic invasion and dense lymphocytic inflammation, although both primary and metastatic melanomas may share some of these characteristics. In a recent study, Orlow and colleagues38
compared the somatic mutational profiles of pairs of melanomas designated as independent primary tumors on the basis of their clinical and pathologic characteristics. They found no significant evidence of clonal origin of the two primaries in 17 of the 19 patients examined by molecular profiling using a set of highly polymorphic genetic markers. These results suggest that most second melanomas designated clinically and pathologically as independent primary tumors are indeed independent occurrences of the disease, supporting the validity of the criteria used by experienced clinicians and pathologists in distinguishing new primaries from metastases.
Pathologic features of tumors in patients with multiple melanomas have been incompletely reported to date. Most commonly, subsequent melanomas have been reported to have invaded less than preceding melanomas, both in terms of Breslow thickness20–22
and Clark level.8, 27
Studies that included in situ melanomas reported that a greater proportion of subsequent melanomas were in situ.2, 3, 20, 21, 29, 39
Although melanomas that were exclusively in situ were excluded from the present analysis, invasive subsequent melanomas were more commonly associated with an in situ component (92%) than preceding melanomas (89%) and single melanomas (88%). The high prevalence of an associated in situ component supports the proposition that the subsequent melanomas in patients with multiple melanomas in this study were primary at the site of diagnosis.
We observed a weak but significant concordance between the sites of occurrence of multiple melanoma pairs. While a significant correlation between their sites has not been reported in most studies,8, 10, 14, 16, 20, 22, 40
several studies19, 34, 39
did find site concordance ranging between 52% and 56%. Some degree of site concordance between melanomas in the same patient would be expected because the same patterns of sun exposure and sun protection underlie the occurrence of both lesions. The comparatively weak site concordance and the fact that subsequent melanomas are diagnosed synchronously (within three months) with the first melanoma in up to 60% of patients with multiple melanomas (27% of the 395 pairs in the present study – results not shown)21
highlight the need for careful and complete skin examination when assessing patients with melanoma.39, 41, 42
Moreover, the increased risk of metachronous melanomas, the long intervals (>20 years1
) within which they may be diagnosed, and the probable benefits of early diagnosis of additional melanomas and metastatic disease suggest that patients with one melanoma may benefit from regular follow up.27, 43
This suggestion is strengthened by our findings that subsequent melanomas diagnosed ≥ 3 years after a first, when perhaps clinical follow-up has become less intense or ceased, were thicker, more likely to be of nodular type and to have mitoses, than subsequent melanomas diagnosed within 3 years of the first.
In addition to the greater site concordance of multiple melanomas, subsequent melanomas were more likely than first melanomas to be on the head and neck or legs than on the upper limbs or trunk. This too might be expected, at least for the head and neck, because of the head and neck’s generally greater exposure to the sun and greater risk of melanoma per unit of surface area than other body sites, particularly in older people.44, 45
This possible association of multiple melanomas with higher sun exposure is supported by the stronger association of solar elastosis with first melanomas than single melanomas in the present study, observed associations of high sun exposure44
and lack of sunscreen use4
with an increased risk of multiple melanomas, and the finding that solar exposure at any age was associated with increased risk of developing multiple primary melanomas in the GEM study.46
Superficial spreading melanoma, lentigo maligna melanoma and nodular melanoma were, in decreasing order, the commonest histologic subtypes in each of subsequent, first and single primary melanomas in our study. Scheibner et al16
found the commonest subtypes to be superficial spreading melanoma and nodular melanoma, and that each of subsequent and first melanomas were of the same histologic type in 74% of cases, which compares with 54% in the present study. The prominence of lentigo maligna melanoma in our study probably reflects refined diagnostic criteria and better clinical recognition of this subtype of melanoma, as well as the common occurrence in Australian populations (42% of melanomas in this analysis were from the Australian GEM center – data not shown) of high solar UV exposure, which is well known to be associated with lentigo maligna melanoma.47
Ulceration has previously been shown to be less common2, 21
and regression to be more common16
in subsequent than in first melanomas. Consistently, ulceration was less common in subsequent melanomas in our study, which is in keeping with the lesser thickness of these tumors and a known correlation of ulceration with tumor thickness,48
and regression was more common, but both could have been chance differences. The difference between our findings for regression and those of Scheibner et al16
may be due to the fact that there is considerable interobserver variation in, and poor reproducibility of, the histologic assessment of regression.49, 50
Similarly to our study, dysplastic nevi have been found to occur more frequently in patients with multiple (38–63%) than single primary melanomas17, 22
and in the general population.51
These observations suggest that dysplastic nevi are markers of risk for additional melanomas. They are in keeping with results of previous studies, which have shown that the presence of clinically and histologically diagnosed dysplastic nevi,5, 33
a family history of dysplastic nevi,4
and classical atypical mole syndrome20
are associated with increased risk of multiple primary melanomas. Dysplastic nevi are also risk markers for the development of melanoma in melanoma-prone families.52–54
However, it is generally easier to detect a nevus remnant in thin melanomas (e.g. subsequent melanomas in patients with multiple melanomas) than in thick melanomas (e.g. first melanomas), as in the latter any residual nevus may have been overgrown by the invasive melanoma.
Differences in pathology between the paired melanomas in patients with multiple tumors, notably the reduced thickness and vertical growth in subsequent melanomas, are likely to reflect closer clinical surveillance and earlier diagnosis. Other differences, such as the more common occurrence of dysplastic nevi in association with subsequent melanomas, and the stronger association of subsequent melanomas with the most exposed body site (head and neck) are consistent with dysplastic nevi and sun exposure being risk factors or risk markers for and, in the case of dysplastic nevi, possible precursors to additional melanomas in patients with a cutaneous melanoma.