ABSTRACT
PURPOSE: The DNA replication licensing machinery is integral to the control of proliferation, differentiation, and maintenance of genomic stability in human cells. We have analyzed replication licensing factors (RLF), together with DNA ploidy status, to investigate their role in progression of penile squamous cell carcinoma and to assess their utility as novel prognostic tools. EXPERIMENTAL DESIGN: In a cohort of 141 patients, we linked protein expression profiles of the standard proliferation marker Ki67 and the RLFs Mcm2 and geminin to clinicopathologic variables, ploidy status, and clinical outcome. RESULTS: Increased Ki67, Mcm2, and geminin levels were each significantly associated with arrested tumor differentiation (P < 0.0001) and aneuploidy (P < or = 0.01). Accelerated cell cycle progression was linked to increasing tumor size, stage, and depth of invasion. Aneuploid tumors significantly correlated with tumor grade (P < 0.0001). Biomarker expression and DNA ploidy status were significant predictors of locoregional disease progression [Mcm2 (P = 0.02), geminin (P = 0.02), Ki67 (P = 0.03), and aneuploidy (P = 0.03)] in univariate analysis. Importantly, aneuploidy was a strong independent prognosticator for overall survival (hazard ratio, 4.19; 95% confidence interval, 1.17-14.95; P = 0.03). Used in conjunction with conventional pathologic information, multiparameter analysis of these variables can stratify patients into low- or high-risk groups for disease progression (Harrell's c-index = 0.88). CONCLUSIONS: Our findings suggest that RLFs and tumor aneuploidy may be used as an adjunct to conventional prognostic indicators, identifying men at high risk of disease progression. Our results also identify the DNA replication initiation pathway as a potentially attractive therapeutic target in penile squamous cell carcinoma.
Subject(s)
Aneuploidy , Carcinoma/genetics , Carcinoma/therapy , Gene Expression Regulation, Neoplastic , Penile Neoplasms/genetics , Penile Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Cell Cycle , Cell Cycle Proteins/biosynthesis , Cohort Studies , Geminin , Gene Expression Profiling , Humans , Ki-67 Antigen/biosynthesis , Male , Middle Aged , Minichromosome Maintenance Complex Component 2 , Nuclear Proteins/biosynthesis , Ploidies , Treatment OutcomeABSTRACT
OBJECTIVES: To evaluate the role of radical surgical debridement and excision with a vertical rectus abdominis myocutaneous (VRAM) flap reconstruction in patients with advanced penile cancer and subcutaneous metastatic disease, as the quality of life in such patients is extremely poor, multimodal treatments often fail and the outlook for the patient is limited with the development of uncontrollable disease. PATIENTS AND METHODS: Four patients with advanced penile cancer presenting with fungating, cutaneous tumour deposits received palliative surgical resections for abdominal and inguinal disease. A VRAM flap was used in all cases to achieve tissue coverage. RESULTS: All grafts were viable and the mean inpatient stay was 14 days. There were no immediate complications after surgery; patient satisfaction and symptom relief was excellent. CONCLUSIONS: Aggressive palliative resection with a VRAM can dramatically improve the patients' quality of life in advanced penile cancer, permitting disease control with satisfactory cosmesis. However, a multidisciplinary approach involving both the urological reconstructive and plastic surgeon is essential.
