Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin have no independent prognostic relevance for cancer-specific survival in surgically treated squamous cell carcinoma of the penis.

UNLABELLED: What's known on the subject? and what does the study add?: Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between different Broders' grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet. Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders' grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of 82% for CSS. OBJECTIVE: To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically treated squamous cell carcinoma of the penis (SCCP). PATIENTS AND METHODS: A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. After conducting a central histopathological review, the staining profiles of Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin were evaluated for their correlation with conventional histopathological criteria and their prognostic relevance for predicting CSS in a multivariable Cox proportional hazards regression model (median [interquartile range] follow-up 33 [6-63] months). RESULTS: Staining evaluation showed high interobserver agreement (92-96%). Ki-67 and MCM2 displayed a significant positive correlation with histological tumour grade, lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade. The 5-year CSS for the entire study cohort was 62%. Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036). In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS. The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898). CONCLUSIONS: At present, conventional histopathological criteria remain the most powerful predictors of CSS in surgically treated SCCP. Due to overlapping staining profiles, Ki-67, MCM2 and geminin, either singly or in various combinations, failed to immunohistochemically refine the boundaries between Broders' grading categories. Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated SCCP. Further studies are needed to clarify the currently contradictory predictive role of proliferation-associated biomarkers in terms of predicting nodal involvement in SCCPs.

Diagnostic and prognostic impact of peritumoral stromal remodeling in patients with surgically treated invasive penile squamous cell cancer.

Stromal remodeling (SR), characterized by focal loss of CD34(+) fibrocytes paralleled by a gain of α-smooth muscle actin (α-SMA)-positive myofibroblasts, has been reported in several cancer types. However, the role of SR in invasive penile squamous cell cancer (PSC) has not been investigated so far. We compared 90 surgically treated PSCs (study group) and 55 control specimens (33 foreskins and 22 differentiated penile intraepithelial neoplasias) for the presence of stromal CD34(+) fibrocytes and α-SMA-positive myofibroblasts scored by independent raters. Multivariate proportional hazards regression analysis was used to assess the impact of staining profiles on cancer-specific mortality of the 90 PSCs (median follow-up, 32 months; interquartile range, 6-64). The incidence of SR differed significantly between study and control group specimens (51.1% versus 9.1%; P < .001). Five years postsurgically, 24% and 46% of the study patients without and with SR had succumbed to their PSC (P = .010). After adjusting for the age at the time of surgery, type of surgery, tumor size, Broders' grade, pT stage, and nodal status, study patients with SR showed 3.76-fold increased cancer-specific mortality (95% confidence interval, 1.3-10.5; P = .012). Our findings suggest that SR might have prognostic as well as some limited differential diagnostic value in terms of delineating invasive PSC from preinvasive lesions. However, our preliminary data clearly need to be validated by larger advanced studies in the future.

Periostin expression correlates with pT-stage, grading and tumour size, and independently predicts cancer-specific survival in surgically treated penile squamous cell carcinomas.

AIMS: Overexpression of periostin, a secreted cell adhesion molecule, has been reported to enhance invasion and angiogenesis in squamous cell carcinomas (SCCs) derived from different anatomic sites. We studied the so far neglected periostin expression profiles in penile SCCs and evaluated its association with pertinent clinicopathologic variables. METHODS: Paraffin-embedded tissues from 89 patients with surgically treated penile SCCs were subjected to a central histopathologic review performed by one pathologist. Then, tissue microarray technique was employed for periostin immunostaining which was evaluated by two independent raters. Kappa (κ)-statistics were used to assess interobserver variability. Spearman correlations as well as uni- and multivariable Cox proportional hazards analysis were applied to assess the association between periostin expression and clinicopathologic parameters. Mean postsurgical follow-up was 31.5 months (IQR 6-66). RESULTS: Periostin expression was recorded in 39/89 penile SCCs (44%). K-statistics disclosed substantial interobserver agreement for epithelial and stromal staining evaluation (K-values 0.76 vs 0.83, p values <0.001). High periostin expression in either stroma or tumour epithelia showed a significant positive correlation with tumour size, histologic grade and pT-stage. In the multivariable Cox models including pT-stage, pN status, grading and the patients' age at the time of surgery, periostin expression independently predicted cancer-specific survival (CSS). CONCLUSIONS: Immunohistochemically, periostin is not infrequently expressed in penile cancer, and might become a valuable tool to independently predict CSS after surgical treatment. Further studies should clarify the so far unresolved usefulness of periostin to be employed as a possible molecular target in antineoplastic therapy in metastasised penile SCCs.