Metallothionein-overexpression as a prognostic factor for progression and survival in melanoma. A prospective study on 520 patients

Background Metallothioneins (MTs) are ubiquitous proteins with high affinity for heavy metal ions, e. g. zinc, copper and cadmium. In the last decade it has been shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and radiotherapy, and with a poor prognosis. Objectives To examine the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Methods In a prospective cohort study 760 patients with primary cutaneous melanoma were investigated over 5 years (1993 - 98) by using a monoclonal antibody (E9) against MT on routinely fixed and paraffin-embedded tissues. In total, 520 patients were able to be followed up for progression of their disease or death due to melanoma and were included for statistical analysis ( Fisher's exact test, Mantel - Haenszel chi(2) test, Kaplan-Meier curves). MT data, progress-free interval and overall survival were compared univariately and multivariately with other prognostic factors, e.g. Breslow thickness, Clark level, ulceration, localization, age and gender (Cox regression analysis). Results The immunohistochemical overexpression of MT in tumour cells (cut-off level > 10% of all tumour cells) in patients with primary melanoma (156 of 520; 30%) was associated with a higher risk for progression of the disease (33 of 45; 73%) and reduced survival (24 of 30; 80%) than MT-negative lesions [364 of 520 (70%), 12 of 45 (27%) and six of 30 (20%), respectively (P < 0.0001)]. Similarly, Kaplan-Meier tumour-free survival and overall survival curves for the comparison of MT-positive and MT-negative tumours gave highly significant advantages for the MT-negative group. In a univariate analysis ( comparison with Breslow thickness: relative risk 2.9, 95% confidence interval, CI 1.46 - 5.76, P = 0.0023 for progression; relative risk 4.19, 95% CI 1.73 - 10.19, P = 0.0015 for survival), as well as in a multivariate analysis with other prognostic markers, MT overexpression turned out to be a highly significant and independent factor for prognosis in primary melanoma. Conclusions MT overexpression in primary melanoma is associated with an increased risk for disease progression. This marker is independent from Breslow thickness and helps to identify those thin melanomas (< 1.5 mm) that are at increased risk of progression. Moreover, the immunohistochemical staining of paraffin material is a cheap, easy and widely available technique to gain these results.