Left-Sided Excess in the Laterality of Cutaneous Melanoma

An unequal distribution of cancer laterality, particularly in paired organs, has long been documented and generally thought to be related to asymmetries in organ size or behavioral factors such as handedness.¹ Recently in a large series patients with cancers in the left testis, right lung, and left ovary were found to have a significantly better survival than those with contralateral cancers.² Apart from anecdotal assertions and very sparse data that suggest asymmetrical differences in the frequency of cutaneous melanoma and photodamage,^3,4 melanoma laterality has, to our knowledge, never been specifically studied. Investigation of laterality could thus contribute to a better understanding of cancer etiology and prognosis.

As part of a larger study,⁵ the laterality of 2143 first cutaneous melanomas was retrieved and clinically validated using a standardized body chart that allowed unequivocal marking of the location of the lesion.⁶ After excluding cases with unspecified laterality (n = 228 [11%]) or those on the midline (n = 254 [12%]), 1661 melanomas diagnosed between 1995 and 2002 in 5 Swiss population-based tumor registries (Neuchâtel, St Gallen/Appenzell, Vaud, Valais, and Ticino) were investigated. Results were expressed as left to right (L/R) ratios and stratified by cancer registration area, sex, age group, and subsite. Exact 2-sided 95% confidence intervals (95% CIs) were computed assuming that laterality was binomially distributed.

This series included 890 left-sided and 771 right-sided melanomas, yielding an L/R ratio of 1.15 (95% CI: 1.05-1.27). The excess of left-sided lesions was consistently observed across all populations, sexes, age groups, body site, and categories of Breslow thicknesses (Table), although it only occasionally reached statistical significance. The upper limbs was the site with the greatest left-sided excess (27%). Left to right ratios higher than 1 were systematically found for clinical characteristics such as tumor behavior (invasive and in situ), skin type, and morphological type (data not shown).

This multicentric study suggests a moderate but consistently higher frequency of melanoma on the left side of about 15%. Four main potential explanations were identified and explored: chance finding, recording bias, differential sun exposure, and bilateral asymmetry in the number of melanocytes or tumor biological behavior.

Although chance finding cannot be excluded, we believe it is an unlikely explanation for our observation. The pattern was similar for every variable studied and, for instance, the probability of observing simultaneously an excess L/R ratio in all 5 populations was about 3% (1 in 32). The detailed site was thoroughly cross-validated from textual and pictorial support.⁶

Two nonmethodological explanations for a left-sided excess of melanoma can be speculated. Traveling in a motor vehicle is probably the only frequent human activity that results in side-specific UV exposure depending on the individual position in the car. Swiss drivers sit on the left side of the car and, until the recent availability of air conditioning, their left arm was more likely to be sun exposed through an open window, particularly in summertime. The largest left-sided excess observed for the upper limbs (an L/R ratio of 1.27, 95% CI: 1.05-1.54,Table) and the greater L/R ratio for men (an L/R ratio of 1.38, P = .02, data not shown) than women (an L/R ratio of 1.18, P = .22, data not shown) at this site supports this assumption and the known greater propensity for men to drive. Reports of a left-sided excess of facial photodamage lesions commensurate with time spent driving in the United States⁴ and the commoner occurrence of solar keratoses on the right upper limb among Australian men,³ where drivers sit on the right side of vehicles, concurred with our findings. This hypothesis, however, only partly explains our results, since it cannot account for the left-sided excess of melanomas observed at other body sites.

Several aspects in embryogenesis occur in asymmetric fashion. An asymmetry in the distribution of melanocytes favoring the left body side might occur when these cells migrate from the neural crest during embryonic development. This assumption could be challenged and eventually supported by investigating the laterality of nonmelanocytic skin cancers from the Vaud Cancer Registry database⁷ since L/R ratios computed for squamous and basal cell carcinomas registered over a 10-year period (1995-2004) were 1.03 (1286:1244) and 1.00 (2946:2939), respectively (F.L., oral communication, September 2007). An asymmetric development of the angiolymphatic system might lead to a higher progression of left-sided melanoma, which is compatible with our concomitant increase in L/R ratios and melanoma thickness.

This largest study to date to explore melanoma laterality suggests that an asymmetric, melanocytic distribution or, to a lesser extent, a differential sun exposure are plausible etiological explanations for the observed left-sided excess of melanomas but not of other types of skin cancers.

Correspondence: Dr Bulliard, Unité d'épidémiologie du cancer, Institut universitaire de médecine sociale et préventive, rue du Bugnon 17, 1005 Lausanne, Switzerland (Jean-Luc.Bulliard@chuv.ch).

Financial Disclosure: None reported.

Additional Contributions: Practitioners are gratefully acknowledged for taking the time to complete the survey questionnaires. We are indebted to T. Fisch, MD, and D. De Weck, MD, as well as the staff of the cancer registries of Neuchâtel, St Gallen/Appenzell, Vaud, Valais, and Ticino, for their valuable collaboration. We also thank C. La Vecchia, MD, for his most helpful comments.