Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growthphase melanoma

The CDKN2A (p16(INK4 alpha)) cell cycle-inhibitory gene has been associated with development of familial melanoma, Additionally, recent studies indica te that p16 alterations occur freqluently in sporadic melanomas, To investi gate whether differences in p16 expression are associated with tumor cell p roliferation, tumor progression, and patient survival, ne examined the immu nohistochemical staining of p16 protein in a consecutive series of 202 vert ical growth phase melanomas and 68 corresponding metastases and compared th e results with Ki-67 expression, p53 expression, clinicopathological variab les, and survival data, Forty-five percent of the primary tumors showed abs ent or minimal nuclear staining for p16 protein. These cases were significa ntly associated with high Ki-67 expression (P < 0,0001), ulceration (P = 0, 001), and vascular invasion (P = 0,03), Further loss of p16 expression was observed in metastatic lesions (77% were negative; P < 0,0001), Absent/mini mal nuclear p16 staining significantly predicted poor patient survival (log -rank test, P = 0,0003), with 37% and 67% estimated 10-year survival rates for cases with absent or present p16 expression, respectively. In multivari ate analysis, p16 staining was an independent prognostic factor (hazard rat io, 2.5; 95% confidence interval, 1.5-4.2; P = 0,0008), along with p53 expr ession, Ki-67 expression, anatomical site, Clark's level of invasion, and v ascular invasion. Our findings indicate that loss of nuclear p16 protein ex pression in vertical growth phase melanomas is associated with increased tu mor cell proliferation (Ki-67) and independently predicts decreased patient survival. Cases without p53 expression had improved survival.