Evaluation of the prognostic significance of perirenal fat invasion and tumor size in patients with pT1-pT3a localized renal cell carcinoma in a comprehensive multicenter study of the CORONA project. Can we improve prognostic discrimination for patients with stage pT3a tumors?

BACKGROUND: The current TNM system for renal cell carcinoma (RCC) merges perirenal fat invasion (PFI) and renal vein invasion (RVI) as stage pT3a despite limited evidence concerning their prognostic equivalence. In addition, the prognostic value of PFI compared to pT1-pT2 tumors remains controversial. OBJECTIVE: To analyze the prognostic significance of PFI, RVI, and tumor size in pT1-pT3a RCC. DESIGN, SETTING, AND PARTICIPANTS: Data for 7384 pT1a-pT3a RCC patients were pooled from 12 centers. Patients were grouped according to stages and PFI/RVI presence as follows: pT1-2N0M0 (n=6137; 83.1%), pT3aN0M0 + PFI (n=1036; 14%), and pT3aN0M0 (RVI ± PFI; n=211; 2.9%). INTERVENTION: Radical nephrectomy or nephron-sparing surgery (NSS) (1992-2010). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer-specific survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional-hazards regression models, as well as sensitivity and discrimination analyses, were used to evaluate the impact of clinicopathologic parameters on cancer-specific mortality (CSM). RESULTS AND LIMITATIONS: Compared to stage pT1-2, patients with stage pT3a RCC were significantly more often male (59.4% vs 53.1%) and older (64.9 vs 62.1 yr), more often had clear cell RCC (85.2% vs 77.7%), Fuhrman grade 3-4 (29.4% vs 13.4%), and tumor size >7 cm (39.1% vs 13%), and underwent NSS less often (7.5% vs 36.6%; all p<0.001). According to multivariate analysis, CSM was significantly higher for the PFI and RVI ± PFI groups compared to pT1-2 patients (hazard ratio [HR] 1.94 and 2.12, respectively; p<0.001), whereas patients with PFI only and RVI ± PFI did not differ (HR 1.17; p=0.316). Tumor size instead enhanced CSM by 7% per cm in stage pT3a (HR 1.07; p<0.001) with a 7 cm cutoff yielding the highest prediction accuracy. CONCLUSIONS: Since the prognostic impact of PFI and RVI on CSM seems to be comparable, merging both as stage pT3a RCC might be justified. Enhanced prognostic discrimination of stage pT3a RCC appears to be possible by applying a tumor size cutoff of 7 cm within an alternative staging system. PATIENT SUMMARY: Prognosis prediction for patients with localized renal cell carcinoma up to stage pT3a can be enhanced by including tumor size with a cutoff of 7 cm as an additional parameter in the TNM classification system.

CD57 expression in incidental, clinically manifest, and metastatic carcinoma of the prostate.

OBJECTIVES: CD57 is normally found on NK-cells, but little is known about its expression in prostatic tissue. METHODS: We investigated CD57 expression by immunohistochemistry using tissue microarrays containing 3262 prostate cancers (PCa), lymph node metastases, and benign prostatic tissue. The results were compared with clinical and pathological parameters. RESULTS: Overall, 87% of PCa showed a moderate or strong expression of CD57. There was no significant difference to corresponding benign prostatic tissue. CD57 was increasingly lost from incidental over clinically manifest cancers to metastases. It correlated significantly with Gleason grade and pT-category, but not with PSA tissue expression. Loss of CD57 expression was an independent risk factor for PSA recurrence after prostatectomy in a multivariate Cox regression analysis. In standard sections, CD57 expression was heterogeneous, especially in large, high-grade PCa. CONCLUSIONS: There is a peculiar expression of CD57 in PCa and benign prostatic tissue. CD57 loss is associated with tumor dedifferentiation and tumor size. However, the use of this marker for prognostic purposes is hampered by its heterogeneous expression.

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.

Does the width of the surgical margin of safety or premalignant dermatoses at the negative surgical margin affect outcome in surgically treated penile cancer?

AIMS: To evaluate the prognostic impact of the width of negative surgical margins (NSM) and associated and preinvasive lesions at the NSM in patients with penile squamous cell cancer (PSC). METHODS: Enrolling 87 patients with NSM who underwent surgery for PSC, the archived margin slides and entirely wax-embedded surgical margins were retrieved from the pathology files. After step sections were cut, margins were stained with antibodies against CK5/6, p16, p53 and Ki-67 and subjected to in situ hybridisation for high-risk human papillomavirus (HPV). All NSM were histologically examined for squamous hyperplasia (SH), lichen sclerosus (LS) and subtypes of penile intraepithelial neoplasia (PeIN). Then, histological findings were correlated with cancer-specific mortality (CSM, median follow-up 34 months; IQR 6-70). RESULTS: All NSM were negative for high-risk HPV and exhibited SH (p16 and p53 negative, Ki-67 variably positive), LS (p16 negative, variable p53 and Ki-67 positivity) and differentiated PeIN (dPeIN; p16 negative, Ki-67 positive, variable p53 positivity) in 28 (32%), 30 (34%) and 22 (25%) cases, respectively, whereas PeIN subtypes other then dPeIN did not occur. Pathological tumour stage was the only independent predictive parameter with respect to CSM in the multivariable analysis (p=0.001). CONCLUSIONS: SH, LS and dPeIN are frequent histological findings at the NSM of surgically treated PSC. However, neither the width of the NSM nor dPeIN, LS or SH at the NSM influences prognostic outcome.

Prognostic effect of sarcomatoid dedifferentiation in patients with surgically treated renal cell carcinoma: a matched-pair analysis.

BACKGROUND: The aim of this study was to assess the prognostic relevance of SD in patients with RCC. PATIENTS AND METHODS: Among 8126 RCC patients surgically treated at 12 academic centers (members of the Collaborative Research on Renal Neoplasms Association [CORONA] project), 316 patients (3.9%) had SD with sarcomatoid areas comprising at least 10% of the tumor tissue. After propensity score-based matched-pair analysis, 281 with and 281 matched RCC patients without SD remained available for direct comparison of cancer-specific survival (CSS). Median follow-up was 36.5 months (interquartile range, 15-82). Uni- and multivariable Cox proportional hazards regression analyses were performed to assess the prognostic value of parameters. RESULTS: In univariable analysis, there was no difference in CSS between patients with or without SD (1 and 5 years CSS, 79% vs. 83% and 59% vs. 64%, respectively; hazard ratio, 1.21; P = .16). Multivariable analysis in patients with SD identified metastatic dissemination at the time of surgery, pT-stage, nodal status, and tumor size as independent predictors of CSS. This study was limited by its retrospective multicenter design and lack of central histopathological review. CONCLUSION: Sarcomatoid dedifferentiation was not an independent predictor of CSS in surgically treated RCC patients in the present matched-pair series. Because pathology reports form the basis on which study specimens are selected for further studies, which are clearly needed to advance our understanding of the prognostic value of SD in RCC, it is imperative that pathologists reliably report on absence or presence and the estimated percentage of a coexisting sarcomatoid component.

C-MET is expressed in the majority of penile squamous cell carcinomas and correlates with polysomy-7 but is not associated with MET oncogene amplification, pertinent histopathologic parameters, or with cancer-specific survival.

We assessed c-MET expression and oncogene amplification in a cohort enrolling 92 surgically treated penile squamous cell carcinomas (PSCCs). A tissue microarray was constructed for c-MET immunohistochemistry (IHC) and chromogenic silver in situ hybridization (SISH). Two independent pathologists evaluated IHC by employing the breast cancer scoring rules, and scored the presence of MET oncogene amplification and/or polysomy-7. Eighty study cases (87%) showed c-MET expression. No study case had MET oncogene amplification, but 42 patients (45.7%) had polysomy-7. Polysomy-7 showed a significant positive correlation with c-MET expression (ρ=0.323, p=0.002). Neither c-MET expression nor polysomy-7 was associated with histopathologic parameters or with cancer-specific survival (median post-surgical follow-up 32 months). Our data suggest that the majority of PSCCs exhibit c-MET expression which is not associated with oncogene amplification, but might be attributable to polysomy-7. Further studies should investigate the expression and activation of downstream molecules functionally involved in c-MET pathway signaling, and clarify the so far unresolved role of c-MET inhibitors as potential targeted therapies in PSCCs with metastatic dissemination.

Impact of clinical and histopathological parameters on disease specific survival in patients with collecting duct renal cell carcinoma: development of a disease specific risk model.

PURPOSE: Collecting duct renal cell carcinoma is a rare, aggressive histological subtype of renal cell carcinoma. Since few groups have evaluated the oncological prognosis in these patients based on clinical and pathological parameters, we assessed parameters prognostic for disease specific mortality. MATERIALS AND METHODS: From a cohort of 14,047 patients with renal cell carcinoma we retrieved the records of 95 with collecting duct renal cell carcinoma at a total of 16 European and American centers of the CORONA (Collaborative Research on Renal Neoplasms Association) and SATURN (Surveillance and Treatment Update Renal Neoplasms) projects, and another 2 centers. Multivariable Cox regression analysis was applied to determine the influence of parameters on disease specific mortality. Median followup was 48.1 months (IQR 24-103). RESULTS: The disease specific survival rate at 1, 2, 5 and 10 years was 60.4%, 47.3%, 40.3% and 32.8%, respectively. American Society of Anesthesiologists (ASA) score 3-4, tumor size greater than 7 cm, stage M1, Fuhrman grade 3-4 and lymphovascular invasion independently predicted disease specific mortality. Based on these parameters, patients were divided into 26 (27%) at low, 13 (14%) at intermediate and 56 (59%) at high risk with a 5-year disease specific survival rate of 96%, 62% and 8%, respectively (bootstrap corrected c-index 0.894, 95% CI 0.820-0.967, p <0.001). CONCLUSIONS: While patients with collecting duct renal cell carcinoma are commonly diagnosed at advanced stage and have poor prognosis after surgery, a subset has excellent survival. Histopathological features can help risk stratify patients based on the described, highly accurate risk model to predict disease specific mortality, facilitating patient counseling and risk based clinical decision making for adjuvant therapy and clinical trial inclusion.

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.

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.

Inherent grading characteristics of individual pathologists contribute to clinically and prognostically relevant interobserver discordance concerning Broders' grading of penile squamous cell carcinomas.

INTRODUCTION: We assessed the reproducibility and prognostic impact of the Broders' grading system (BGS) in a cohort of 147 patients with surgically treated penile squamous cell carcinomas. MATERIALS AND METHODS: Conventionally stained histology slides were graded according to the BGS in two rounds by two study pathologists. Reproducibility was assessed using ĸ statistics. Multivariable analyses were calculated to predict cancer-specific survival (CSS). The 'mean grade' per pathologist per round was calculated by allocating grade points to each study case (G1-G4: 1-4 points) and dividing the sum of all grade points by the number of cases examined. RESULTS: The BGS showed substantial interobserver variation (59-87% with ĸ = 0.38-0.69) but almost perfect intraobserver reproducibility (91% with ĸ = 0.86 and 96% with ĸ = 0.94, respectively). The 'mean grade' per pathologist remained nearly constant in both rounds of examination (differences ≤0.05 grade points) but differed between the two pathologists (up to 0.4 grade points). In multivariable analyses, the prognostic impact of the BGS in terms of CSS was strongly pathologist-dependent. CONCLUSIONS: Clinically and prognostically relevant interobserver discordance concerning the BGS seems, at least in part, to be attributable to inherent 'aggressive' versus 'reserved' grading characteristics of individual pathologists.

Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis?

AIMS: Penile, vulvar and anal squamous cell carcinomas (SCCs) share histomorphological overlap and are prone to lymphatic dissemination into inguinal nodes. Anal SCCs might derive from the anorectal zone (ARZ), anal transitional zone, squamous zone or from perianal skin. These anatomically distinct zones differ in terms of their embryological development. We sought to investigate the role of caudal-related homeobox 2 (CDX2), a homeobox gene implicated in the development and anterior/posterior pattern specification from duodenum to rectum including the ARZ, in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with histologically confirmed inguinal lymph node metastasis. METHODS: By immunohistochemistry (IHC) employing a panel of antibodies directed against CK5/6, CK7, CK20, p63, p16, CEA and CDX2, we compared 89 penile, 11 vulvar and eight anal SCCs with respect to their staining profiles. Moreover, anal SCCs were subjected to in situ hybridisation (ISH) for high-risk human papillomavirus (HPV) subtypes. RESULTS: By IHC, CDX2 expression was observed in 2/8 anal SCCs (25%) while being absent from all penile and vulvar SCCs examined. High-risk HPV subtypes were detected by ISH in all anal SCCs examined, which were uniformly p16-positive by IHC. CONCLUSIONS: CDX2 might be valuable in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with inguinal lymph node metastasis. However, despite its favourable specificity, the diagnostic benefit achieved by this observation is limited by the low sensitivity.

Protein gene product 9.5 is diagnostically helpful in delineating high-grade renal cell cancer involving the renal medullary/sinus region from invasive urothelial cell carcinoma of the renal pelvis.

The classification of poorly differentiated carcinomas involving the renal medullary/sinus region might be challenging on conventional histomorphologic grounds alone. However, delineation of high-grade renal cell carcinomas such as collecting duct (Bellini) carcinoma from urothelial cell carcinoma of the renal pelvis is critical, as it conveys important therapeutic implications. We assessed the so far neglected differential diagnostic role of protein gene product 9.5, a neuropeptide involved in intracellular proteolysis, in terms of differentiating invasive urothelial cell carcinomas of the renal pelvis from high-grade renal cell carcinomas infiltrating the renal medullary/sinus region. To this aim, 21 invasive urothelial cell carcinomas of the renal pelvis and 27 high-grade renal cell carcinomas (8 renal cell carcinomas with sarcomatoid dedifferentiation and 5 type 1 and 7 type 2 papillary renal cell carcinomas as well as 7 collecting duct carcinomas) were stained with antibodies directed against protein gene product 9.5, CD10, vimentin, CEA, p63, CK5/6, CK7, CK20, PAX2, PAX8, CD117 (c-Kit), AE1/3, α-methyl CoA racemase, actin, and desmin. Briefly, strong protein gene product 9.5 expression was observed in 6 (86%) of 7 collecting duct carcinomas, 8 (67%) of 12 papillary renal cell carcinomas, and 2 (25%) of 8 renal cell carcinomas with sarcomatoid dedifferentiation. Conversely, none of the 21 urothelial cell carcinomas investigated showed protein gene product 9.5 expression. Our findings suggest that protein gene product 9.5, particularly if used in conjunction with p63 and CK5/6, might be helpful in differentiating high-grade renal cell carcinomas from urothelial cell carcinomas of the renal pelvis, whereas its specificity with respect to the histologic subtyping of renal cell carcinomas seems to be low. However, because of the limited number of study cases enrolled in our investigation, our findings need to be validated in the future.

Scoring the percentage of Ki67 positive nuclei is superior to mitotic count and the mitosis marker phosphohistone H3 (PHH3) in terms of differentiating flat lesions of the bladder mucosa.

AIMS: To systematically compare different approaches for evaluating mucosal proliferative activity regarding their diagnostic role for delineating flat lesions of the bladder mucosa. METHODS: 32 carcinoma in situ (CIS) and 31 flat non-CIS conditions (low-grade dysplasia and reactive atypia) of the bladder mucosa were assessed by two independent pathologists in two rounds in terms of their proliferative activity assessed by the mitotic counts on H&E-stained sections (mitoses per mm(2)) and immunohistochemically using the MIB-1 antibody and the mitosis marker phosphohistone H3 (PHH3). Two different approaches for immunoscoring (percentage of stained nuclei vs dichotomised height of mucosal staining considering lower half vs full-thickness marker expression) were applied. κ statistics were used to evaluate interobserver and intraobserver reproducibility. RESULTS: Scoring the percentage of Ki67 expressing cell nuclei seems to be superior to dichotomisation of the height of mucosal staining as well as to PHH3 immunostaining and conventional mitotic counts in terms of delineating CIS from flat non-CIS conditions. This approach shows substantial (κ=0.62-0.65; p<0.001) interobserver and substantial to almost perfect (κ=0.67-0.83; p<0.001) intraobserver reproducibility. CONCLUSIONS: The MIB-1 antibody is a useful adjunct in the differential diagnosis of conventionally challenging flat lesions of the bladder mucosa. In particular, 16% or more Ki67 positive cell nuclei favours CIS over flat non-CIS conditions, whereas 15% or less Ki67 positive cell nuclei is supportive of non-CIS conditions. However, due to some important limitations of MIB-1 staining, the MIB-1 antibody should be used as a component of a panel.

p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study.

PURPOSE: We assessed the prognostic role of p16(INK4a) expression in penile cancer with respect to cancer specific survival. MATERIALS AND METHODS: Based on a multi-institutional collaboration wax embedded tissues from 92 surgically treated patients, including 27 with total and 65 with partial penectomy, were retrospectively evaluated. After a central histopathological review by 1 pathologist a tissue microarray was constructed for p16(INK4a) immunostaining. Two independent pathologists evaluated p16(INK4a) expression, which was correlated with cancer specific survival. The κ statistic was used to assess interobserver variability. Univariate and multivariate Cox proportional hazards analysis was applied to assess the independent effects of prognostic factors on cancer specific survival during a median postoperative followup of 32 months (IQR 6-66). RESULTS: The κ statistic revealed excellent interobserver agreement (κ 0.934, p <0.001). Two and 5-year cancer specific survival rates for the entire study cohort were 86% and 74%, respectively. The 2 and 5-year rates for patients without and with p16(INK4a) expression differed significantly (73% and 57% vs 95% and 85%, respectively, p = 0.011). Univariate analysis revealed p16(INK4a) expression as a significant prognostic factor with respect to cancer specific survival (p = 0.018). Multivariate analysis identified koilocytosis (HR 0.24, 95% CI 0.07-0.83, p = 0.024), p16(INK4a) expression (HR 0.44, 95% CI 0.23-0.84, p = 0.013), and histological stage (HR 3.54, 95% CI 1.88-6.67, p <0.001) and grade (HR 2.47, 95% CI 1.00-6.09, p = 0.049) as independent prognostic factors for cancer specific survival. CONCLUSIONS: Results show that p16(INK4a) seems to be a prognostic parameter for primary invasive penile cancer with excellent interobserver reproducibility. At pathology laboratories without antibodies against p16(INK4a) conventional histological determination of koilocytosis by the pathologist also appears to provide important prognostic information for cancer specific survival.

Should we abstain from Gleason score 2-4 in the diagnosis of prostate cancer? Results of a German multicentre study.

PURPOSE: The present study analysed the loss of prognostic information related to the abandonment of Gleason score (GS) 2-4 by the International Society of Urological Pathology (ISUP-2005). METHODS: Within a 10-year period prior to the modification of GS, 856 patients (mean age 64.2 years) underwent radical prostatectomy (RP). The grade of agreement between GS in biopsy and definitive histology was calculated by Kappa statistics (κ). Univariable and multivariable influence of different preoperatively available parameters on disease-free survival (DFS) were assessed. The mean follow-up period was 39 months. RESULTS: Concordance between GS in biopsy versus RP samples was 58% (κ-value 0.354) and was improved by an increased number of biopsy cores. Undergrading in biopsy was present in 38% and not significantly enhanced by an extended time-period between biopsy and RP (threshold 90 d). PSA level, clinical tumour stage, fraction of positive cores (dichotomized at 34%), cases of RP per year and institution (dichotomized at 75), and GS independently influenced DFS. An upgrading to GS ≥ 7 was found in only 5.7% of patients presenting with GS 2-4 in the biopsy. Independent from definitive histology, patients with GS 2-4 had a significantly better prognosis compared to patients with a higher GS. CONCLUSIONS: The present study shows an independent prognostic impact of GS in biopsy samples classified according to the previous classification. The elimination of GS 2-4 by the ISUP 2005 results in a considerable loss of pretherapeutic prognostic information and therefore should be questioned in particular with regard to the increasing demand for active surveillance regimens.

Expression of p53, p21 and cyclin D1 in penile cancer: p53 predicts poor prognosis.

AIMS: To evaluate the role of p53, p21 and cyclin D1 expression in patients with penile cancer (PC). METHODS: Paraffin-embedded tissues from PC specimens from six pathology departments were subjected to a central histopathological review performed by one pathologist. The tissue microarray technique was used for immunostaining which was evaluated by two independent pathologists and correlated with cancer-specific survival (CSS). κ-statistics were used to assess interobserver variability. Uni- and multivariable Cox proportional hazards analysis was applied to assess the independent effects of several prognostic factors on CSS over a median of 32 months (IQR 6-66 months). RESULTS: Specimens and clinical data from 110 men treated surgically for primary PC were collected. p53 staining was positive in 30 and negative in 62 specimens. κ-statistics showed substantial interobserver reproducibility of p53 staining evaluation (κ=0.73; p<0.001). The 5-year CSS rate for the entire study cohort was 74%. Five-year CSS was 84% in p53-negative and 51% in p53-positive PC patients (p=0.003). Multivariable analysis showed p53 (HR=3.20; p=0.041) and pT-stage (HR=4.29; p<0.001) as independent significant prognostic factors for CSS. Cyclin D1 and p21 expression were not correlated with survival. However, incorporating p21 into a multivariable Cox model did contribute to improved model quality for predicting CSS. CONCLUSIONS: In patients with PC, the expression of p53 in the primary tumour specimen can be reproducibly assessed and is negatively associated with cancer specific survival.

Different HER2 protein expression profiles aid in the histologic differential diagnosis between urothelial carcinoma in situ (CIS) and non-CIS conditions (dysplasia and reactive atypia) of the urinary bladder mucosa.

We evaluated HER2 expression profiles in 32 carcinoma in situ (CIS) and 31 non-CIS conditions (5 dysplasia and 26 reactive atypia) of the urinary bladder mucosa by applying breast cancer scoring rules. In situ hybridization was performed on tissue microarrays to assess HER2 gene amplification status. Our immunoprofiling data disclosed moderate to strong HER2 expression in CIS, including the basal layer of the urothelium, and absent to weak HER2 expression in non-CIS conditions. From the histologic differential diagnostic standpoint, immunostaining for HER2 protein represents a useful adjunct to aid in the delineation between CIS and non-CIS conditions of the bladder mucosa. Pathogenically, aberrant HER2 protein expression in CIS seems to be more commonly associated with polysomy than with gene amplification. From a therapeutic viewpoint, prospective clinical studies should investigate the potential benefit of HER2-targeted therapies in CIS, particularly in cases unresponsive to conventional therapeutic regimens.

Prostate cancer with Paneth cell-like neuroendocrine differentiation and extensive perineural invasion: coincidence or causal relationship?

The case of a 74-year-old man is reported who suffered from a locally advanced prostate cancer treated by neoadjuvant hormonal ablation, followed by prostatectomy. Histological examination of the prostatectomy specimen disclosed an adenocarcinoma with partial, Paneth-like, neuroendocrine differentiation. Extensive perineural tumor invasion was found with a total of 921 perineural tumor foci. Neuroendocrine differentiation of tumor cells was accentuated in perineural locations and was associated with an elevated expression of N-CAM and vimentin, and a reduced expression of E-Cadherin and Ki-67. We hypothesize that neuroendocrine differentiation may promote perineural invasion of prostate cancer cells by a "catherin-switch" and by mechanisms involving epithelial-mesenchymal transition.

Lewis(y) antigen (blood group 8, BG8) is a useful marker in the histopathological differential diagnosis of flat urothelial lesions of the urinary bladder.

BACKGROUND AND AIMS: The cell-surface carbohydrate Lewis(y) antigen (blood group 8, BG8) has recently been investigated in bladder cancer, but its role in the differential diagnosis of flat urothelial lesions of the bladder has not yet been systematically evaluated. METHODS: 30 carcinoma in situ (CIS) and 30 non-CIS conditions of the bladder mucosa (four dysplasia and 26 reactive atypia according to consensus diagnoses) were comparatively assessed in terms of their Lewis(y) antigen staining profiles by two independent clinical pathologists. RESULTS: Lewis(y) antigen expression differed significantly (p<0.001) between CIS (full thickness expression throughout the entire urothelium including the basal cell layer) and non-CIS conditions (patchy discontinuous expression restricted to individual cells scattered singly throughout the urothelial mucosa). The four dysplastic study cases showed Lewis(y) antigen expression more closely related to the staining profiles observed in most of the reactive urothelial atypia. κ statistics showed excellent inter-observer agreement between both raters in terms of Lewis(y) antigen staining evaluation (κ=0.9, p<0.001). CONCLUSIONS: The data hint at the cell-surface carbohydrate Lewis(y) antigen as a so far neglected diagnostically useful marker to aid in the histological classification of conventionally equivocal flat urothelial lesions of the bladder in contemporary surgical pathology practice.

Pathological upstaging detected in radical cystectomy procedures is associated with a significantly worse tumour-specific survival rate for patients with clinical T1 urothelial carcinoma of the urinary bladder.

OBJECTIVE: Due to their variable oncological course, clinical stage T1 (cT1) urothelial carcinomas of the bladder (UCBs) are the subject of controversial discussion with regard to indication for radical cystectomy (RC).This study aimed to evaluate the frequency and prognosis of upstaging in patients undergoing RC due to UCB. MATERIAL AND METHODS: Clinical and pathological records of 607 patients, having undergone RC for treatment of UCB in cT1N0M0, were summarized in a multi-institutional database. Cancer-specific survival (CSS) and overall survival (OS) rates were calculated. A multivariable prognostic model predicting the possibility of an upstaging in RC specimens was developed based on clinical information. RESULTS: In 210patients (35%) an upstaging (> pT1 and/or pN+) was detected in the RC specimen. Five-year CSS was 86%, 78%, 60%and 34%, respectively, for tumour stages < pT2N0 (n = 397), pT2N0 (n = 78), > pT2N0 (n = 63)and pN+ (n = 69) (p < 0.001). In a multivariable Cox regression model, pN stage, pT stage and lymphovascular invasion (LVI) revealed an independent influence on CSS (OS: pN, pT, age). An upstaging of cT1 tumours was enhanced by the criteria of G3 tumour grading and absent Tis in the transurethral resection of the bladder (TURB)specimen. Detection of LVI in RC specimens was also independently associated with an upstaging and, therefore, is recommended as a relevant prognostic parameter for the histopathological evaluation of TURB specimens. CONCLUSIONS: More than one-third of patients with cT1 tumours had an upstaging that was associated with significant prognosis deterioration. Further valid markers are required for an early identification of these patients. LVI represents such a criterion and, therefore, should be evaluated in prospectively designed trials with accurate histopathological assessment of TURB specimens.