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Biologic and Prognostic Significance of Dermal Ki67 Expression, Mitoses, and Tumorigenicity in Thin Invasive Cutaneous Melanoma

From the Melanoma Program of the Abramson Cancer Center and the Center for Clinical Epidemiology and Biostatistics, Departments of Biostatistics and Epidemiology, Medicine, Pathology and Laboratory Medicine, and Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA.

Address reprint requests to Phyllis A. Gimotty, PhD, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 631 Blockley Hall, 423 Guardian Dr, Philadelphia, PA 19104-6021; e-mail: pgimotty{at}cceb.upenn.edu

PURPOSE: Tumor cell proliferation is a central feature of melanoma progression. In this study, we characterized three biomarkers of proliferation (Ki67 expression, dermal mitotic rate [MR], and tumorigenicity) in thin ( 1.00 mm) primary cutaneous melanomas and examined their association with prognosis.

PATIENTS AND METHODS: We used immunohistochemistry to determine Ki67 expression using the monoclonal antibody MIB-1 in lesions from a prospective cohort that included 396 patients with thin invasive primary melanomas seen between 1972 and 1991. A multivariate Cox proportional hazards model was used to define independent prognostic factors, and recursive partitioning was used to develop a prognostic tree identifying risk groups.

RESULTS: Dermal Ki67 expression was lower than epidermal Ki67 expression in radial growth phase (RGP) melanomas (n = 171), and dermal Ki67 expression and MR were higher in tumorigenic vertical growth phase (VGP) melanomas (n = 193) compared with RGP and nontumorigenic VGP melanomas (n = 42). Dermal Ki67 expression, MR greater than 0, growth phase, thickness, ulceration, tumor-infiltrating lymphocytes, and sex were associated with metastasis at 10 years, however, only dermal Ki67 expression, MR greater than 0, and sex were independent prognostic factors. Two high-risk groups were identified: men and women with dermal MR greater than 0 and dermal Ki67 expression 20% in tumor cells and men with MR greater than 0 and Ki67 expression less than 20%, with 10-year metastasis rates of 39% and 20%, respectively.

CONCLUSION: Proliferation slows as melanoma cells enter the dermis and then increases with the onset of tumorigenic VGP. Ki67 expression and dermal MR provide independent prognostic information that can potentially be used in risk-based management of patients.

Supported in part by Grant Nos. CA-75434, CA-25874, and CA-093372 from the National Institutes of Health and the National Cancer Institute, Bethesda MD.

Presented in part at the 93rd Annual Meeting of the American Association for Cancer Research, April 5-11, 2002, San Francisco, CA.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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