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Background: A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b ( 10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. Objective: Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. Design, setting, and participants: Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. Intervention: Patients underwent either radical or partial nephrectomy. Measurements: Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. Results and limitations: In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS (p for trend < 0.0001). However, the substratification of pT1 tumors did not retain an independent predictive role. The major limitations of the study are retrospective design, lack of central pathologic review, and the small number of patients included in some substages. Conclusions: The recently released seventh edition of the primary tumor staging system for kidney tumors is a powerful predictor of CSS. However, some of the substages identified by the classification have overlapping prognoses, and other substages include patients with heterogeneous outcomes. The few modifications included in this edition may have not resolved the most critical issues in the previous version. (C) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.

AIMS: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a high-grade, aggressive tubulopapillary carcinoma, arising predominantly in the setting of the hereditary leiomyomatosis-RCC syndrome of familial uterocutaneous leiomyomatosis and deficiency of FH. In contrast, succinate dehydrogenase (SDH)-deficient RCC is a lower-grade oncocytic carcinoma with cytoplasmic flocculence/vacuolation and inclusions, arising mostly in individuals harbouring germline mutations of subunit B of the SDH complex (SDHB). Herein we aim to report the clinicopathologic features of a novel form of FH-deficient RCC showing a low grade oncocytic morphology, reminiscent of SDH-deficient RCC. METHODS AND RESULTS: These distinctive, low-grade oncocytic neoplasms, with solid, nested and focally tubular architecture (2-90 mm), arose in four males (aged 11-41 years). Uniform cytology of polygonal cells, with flocculent, vacuolated eosinophilic cytoplasm with scattered inclusions, fine chromatin, and inconspicuous nucleoli, was apparent. Despite these features suggestive of SDH-deficient RCC, each tumour was confirmed as an FH-deficient carcinoma with retained SDHB expression. One case showed a synchronous, anatomically separate, typical high-grade FH-deficient RCC; one other showed such a tumour at nephrectomy 4 years later. No progression has been noted at 3 and 7 years in the cases with only the SDH-like lesions; the two cases with separate, typical FH-deficient RCCs progressed. CONCLUSIONS: In summary, we characterize a novel oncocytic type of FH-deficient RCC with a striking resemblance to SDH-deficient RCC, posing a diagnostic challenge and raising concerns about sampling and multifocality for syndrome-associated cases under surveillance protocols.

OBJECTIVES To investigate cancer-related outcomes and prognostic factors of papillary renal cell carcinoma (pRCC) in a large multicentre data set. Oncological outcome and prognostic factors of pRCC have been limitedly evaluated in comparison with the most common RCC subtype, clear cell RCC. PATIENTS AND METHODS From a multicentre retrospective database, including 5463 patients who were surgically treated for RCC at 16 Italian academic centres between 1995 and 2007, 577 patients with pRCC were identified. Univariable and multivariable Cox regression models were performed to identify prognostic factors predictive of recurrence-free survival (RFS) and cancer-specific survival (CSS) after surgery. RESULTS At a median (interquartile range) follow-up of 39.2 (21.7-72) months, 81 (14%) patients had experienced disease progression and 63 (11%) patients had died from disease; the 5-year RFS estimate was 85.5%. In multivariable analysis, pathological N stage (pooled P < 0.001), M stage (hazard ratio, 2.9; P = 0.007) and Fuhrman nuclear grade (pooled P = 0.039) were all independent predictors of RFS; the 5-year CSS estimate was 87.9%. In Cox multivariable analysis, an independent predictive role was reconfirmed for mode of presentation (pooled P = 0.038), pathological N stage (pooled P < 0.001), M stage (hazard ratio, 2.4; P = 0.049) and Fuhrman nuclear grade (pooled P = 0.037). CONCLUSIONS Patients with pRCC have a low risk of tumour recurrence and cancer-related death after surgery. Fuhrman nuclear grade was found to be a stronger predictor of both RFS and CSS, whereas only a non-statistically significant trend was found for the 2009 pathological T stage.

A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b (< or =10 cm vs >10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. OBJECTIVE: Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. DESIGN, SETTING, AND PARTICIPANTS: Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. INTERVENTION: Patients underwent either radical or partial nephrectomy. MEASUREMENTS: Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. RESULTS AND LIMITATIONS: In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS (p for trend

Study Type - Outcomes (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? About 80% of RCCs have clear cell histology, and consistent data are available about the clinical and histological characteristics of this histological subtype. Conversely, less attention has been dedicated to the study of non-clear cell renal tumours Specifically, published data show that chromophobe RCC (ChRCC) have often favourable pathological stages and better nuclear grades as well as a lower risk of metastasizing compared with clear cell RCC (ccRCC). Patients with ChRCC were shown to have significantly higher cancer-specific survival (CSS) probabilities compared with ccRCC. However, an independent prognostic role of RCC histotype was not confirmed in some large multicenter series and only a few studies have focused on the oncological outcomes of ChRCC. The present study is one of the few to evaluate cancer-related outcomes of ChRCC and represents to our knowledge the largest series of ChRCCs. Consequently, the present findings may assist in elucidating the natural history of surgically treated ChRCC. The present study confirms that ChRCCs have good prognosis and a low tendency to progress and metastasize. Only 1.3% of patients presented with distant metastases at diagnosis, and the 5- and 10-year CSS were 93% and 88.9%, respectively. However, although ChRCCs are generally characterised by an excellent prognosis, we observed that patients with locally advanced or metastatic cancers as well as those with sarcomatoid differentiation have a poor outcome. The study also investigated prognostic factors for recurrence-free survival (RFS) and CSS for this RCC histotype. The definition of outcome predictors can be useful for patient counselling, planning of follow-up strategies, and patient selection for clinical trials. In the present study, gender, clinical T stage, pathological T stage, and presence of sarcomatoid differentiation were significantly associated with RFS and CSS at multivariable analysis. We also identified N/M stage as an independent predictor of CSS. Notably, as Fuhrman grade was not an independent predictor of cancer-related outcomes, the present study confirms that this histological variable is not a reliable prognostic factor for ChRCC. OBJECTIVES: To investigate cancer-related outcomes of chromophobe renal cell carcinoma (ChRCC) in a large multicentre dataset. To determine prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS) for this RCC histological type. PATIENTS AND METHODS: In all, 291 patients with ChRCC were identified from a multi-institutional retrospective database including 5463 patients who were surgically treated for RCC at 16 Italian academic centres between 1995 and 2007. Univariable and multivariable Cox regression models were used to identify prognostic factors predictive of RFS and CSS after surgery for ChRCC. RESULTS: At a median follow-up of 44 months, 25 patients (8.6%) had disease recurrence and 18 patients (6.2%) died from disease. The 5-year RFS and CSS rates were 89.3% and 93%, respectively. Gender (P= 0.014), clinical T stage (P= 0.017), pathological T stage (P= 0.003), and sarcomatoid differentiation (P= 0.032) were independent predictors of RFS at multivariable analysis. For CSS, there was an independent prognostic role for gender (P= 0.032) and T stage (P= 0.019) among the clinical variables and for T stage (P= 0.016), N/M stage (P= 0.023), and sarcomatoid differentiation (P= 0.015) among the pathological variables. CONCLUSIONS: Patients with ChRCC have a low risk of tumour progression, metastasis, and cancer-specific death. Patient gender, clinical and pathological tumour stage, and sarcomatoid differentiation are significant predictors of RFS and CSS for ChRCC.

Monosomy of chromosome 17 may affect the assessment of HER2 amplification. Notably, the prevalence ranges from 1% up to 49% due to lack of consensus in recognition. We sought to investigate the impact of monosomy of chromosome 17 to interpretation of HER2 gene status. 201 breast carcinoma were reviewed for HER2 gene amplification and chromosome 17 status. FISH analysis was performed by using double probes (LSI/CEP). Absolute gene copy number was also scored per each probe. HER2 FISH test was repeated on serial tissue sections, ranging in thickness from 3 to 20 µm. Ratio was scored and subsequently corrected by monosomy after gold control test using the aCGH method to overcome false interpretation due to artefactual nuclear truncation. HER2 immunotests was performed on all cases. 26/201 cases were amplified (13%). Single signals per CEP17 were revealed in 7/201 (3.5%) cases. Five out of 7 cases appeared monosomic with aCGH (overall, 5/201, 2.5%) and evidenced single signals in >60% of nuclei after second-look on FISH when matching both techniques. Among 5, one case showed amplification with a pattern 7/1 (HER2/CEP17>2) of copies (3+ at immunotest); three cases revealed single signals per both probes (LSI/CEP=1) and one case revealed a 3:1 ratio; all last 4 cases showed 0/1+ immunoscore. We concluded that: 1) monosomy of chromosome 17 may be observed in 2.5% of breast carcinoma; 2) monosomy of chromosome 17 due to biological reasons rather than nuclear truncation was observed when using the cut-off of 60% of nuclei harboring single signals; 3) the skewing of the ratio due to single centromeric 17 probe may lead to false positive evaluation; 4) breast carcinomas showing a 3:1 ratio (HER2/CEP17) usually show negative 0/1+ immunoscore and

We created the first nomograms to predict cancer specific survival probabilities of patients with squamous cell carcinoma of the penis, clustering prognostic information from the most commonly used clinical and pathological variables.We retrospectively collected clinical and pathological data from 175 patients who had undergone surgery for squamous cell carcinoma of the penis from 1980 to 2002 at 11 urological centers in northeastern Italy. A logistic regression model was used to construct the nomogram.At a median followup of 24 months, 101 patients (57.7%) were alive and disease-free while 74 (42.3%) died of penile cancer. According to multivariate analyses, 2 models predictive of cancer specific survival probability were generated. The first model was based on the pathological findings of the primary tumor after penectomy and on the clinical stage of groin lymph nodes, while the second model included the pathological data of the primary tumor and groin lymph nodes. The concordance index was 0.728 for the first model and 0.747 for the second. Calibration appeared to be good in both models.In this article we propose 2 models to predict the 5-year cancer specific survival probabilities of patients with squamous cell carcinoma of the penis. Both models showed good discriminating power and calibration in predicting patient 5-year cancer specific survival. These nomograms could improve the quality of prognostic data provided to patients and support physicians in planning treatment.

Abnormalities of the locus chromosome 3p and the entire chromosome 3 are involved in the cancerogenesis of clear cell renal carcinoma and may be detected by interphase fluorescence in situ hybridization (interphase FISH). We observed a variable detection rate of chromosome 3p/3 abnormalities in different series of clear cell renal carcinoma. Therefore, we focused on problematic issues when performing analysis on routinely available formalin-fixed and paraffin embedded tissue. A group of studies encountered a single approach to chromosome 3p detection, by using probe/s to map different codes of the short arm 3p without a control of the entire chromosome 3. Deletion of chromosome 3p and monosomy of chromosome 3 ranged from 38% to 100% in clear cell renal carcinoma. Cut-off values for the threshold were chosen randomly or obtained by calculation of the mean value plus 1 or 2 or 3 standard deviations. Loss of chromosome 3p was assessed either as the percentage of single signals on the total number of nuclei, or applying a double approach with corrections of control chromosome 3. Moreover, cut off values were sometimes arbitrarily corrected with the findings from normal adjacent renal parenchyma. A consensus of experts in the field is needed in order to define the best methodological approach and the appropriate threshold in assessment 3p deletion when interphase FISH is performed in clear cell renal carcinoma. This harbours relevant diagnostic and therapeutic implications, at light also of targeted therapies recently available to clear cell renal carcinoma.

The chemokine receptor CXCR4 and CD133, putative stem cell markers, were previously described in renal cancer (RCC). To evaluate the biological and prognostic role of CD133 and CXCR4 in RCC the expression was evaluated through qPCR and immunoblotting in human renal cancer cell lines (786-O, A498, ACHN, CAKI-1, SN12C, TK10, UO31) and patients biopsies. Renal cancer cells and surgical biopsies expressed functional CXCR4 while CD133 was not detectable. CXCR4 and CD133 expression was then evaluated in 240 renal cancer patients through immunohistochemistry. CXCR4 and CD133 were low in 19.1% and 59.6%; intermediate in 20% and 17.9%; high in 60.8% and 22.5% of the cases, respectively. CXCR4 was overexpressed in tumours (p= 0.02), while CD133 was over expressed in healthy tissues (p= 0.04). Disease free survival Kaplan Meier plots suggest that prognosis is unfavourable for patients whose primary tumours express CXCR4 (p= 0.0199) but nor CD133 (p= 0.151) neither the concomitant CXCR4-CD133 (p=0.848) high expression affected prognosis. Analysis of prognostic factors suggests that age, clinical presentation, AJCC stage and CXCR4 had a significant prognostic value at the univariate analysis. The CXCR4 predictive ability was confirmed at the multivariate analysis while no prognostic role was identified for CD133.Thus concomitant CD133 and CXCR4 evaluation is not worth in RCC patient while the CXCR4 prognostic role encourage CXCR4 antagonists as promising therapeutic option.

Adenocarcinoma of the paraurethral glands represents a very rare neoplasm of the urinary tract. Due to the rarity of this disease, there is no standard therapeutic approach. We report a case of adenocarcinoma of the paraurethral glands in a 56-year-old woman, presenting with abnormal serous vaginal discharges. The radiologic examination revealed a 5-cm mass around the urethra, which underwent surgical resection. After surgical resection, the histology revealed a moderately differentiated adenocarcinoma, probably arising from the paraurethral glands. One month later, a pelvic recurrent mass was radiologically diagnosed; consequently, an anterior pelvic exenteration with lymph node dissection was performed. Histological examination revealed a moderately differentiated adenocarcinoma, with glandular and micropapillary architecture, with multiple lymph node metastases. The absence of modifications such as urethritis cystic glandularis on the urethral mucosa, as well as the lack of a lesion in situ, associated with the immunohistochemical expression of PAX8 and negativity for GATA3 and S100p, suggested that the adenocarcinoma originated from the paraurethral glands rather than from the urethral mucosa. Post-surgery CT scans revealed no evidence of metastatic disease. The patient received 6 courses of adjuvant chemotherapy with carboplatin and paclitaxel. One year after the pelvic exenteration, because of inguinal lymph node progression, an inguinal lymphadenectomy was performed. Four months later, a TC-PET revealed a multidistrectual lymph node and a lung micronodule disease progression. Invasive micropapillary carcinomas have been characterized as a rare distinctive variant of carcinomas in several anatomic sites and are distinguished by a marked tendency to lymphovascular invasion, justifying the association with high-stage disease and poor prognosis. In the present case, both the poor prognosis connected with micropapillary structure and the lymph node involvement, encouraged adjuvant cisplatinumbased chemotherapy.

Since target therapy with mTOR inhibitors plays an important role in the current management of clear cell renal cell carcinoma (RCC), there is an increasing demand for predictive biomarkers, which may help to select patients that are most likely to benefit from personalized treatment. When dealing with formalin-fixed paraffin-embedded (FFPE) cancer tissue specimens, several techniques may be used to identify potential molecular markers, yielding different outcome in terms of accuracy. We sought to investigate and compare the capability of three main techniques to detect molecules performing an active function in mTOR pathway in RCC. Immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) analyses were performed on FFPE RCC tissue specimens from 16 patients by using the following mTOR pathway-related: mTOR (Ser235/236), phospho-mTOR (p-mTOR/Ser2448), phospho-p70S6k (p-p70S6k/Thr389), both monoclonal and polyclonal, phospho-S6Rb (p-S6Rb) and phospho-4EBP1 (p-4EBP1/Thr37/46). No single molecule was simultaneously revealed by all three techniques. Only p-p70S6k was detected by two methods (IHC and IF) using a monoclonal antibody. The other molecules were detected exclusively by one technique, as follows: p-mTOR and polyclonal p-p70S6K by IHC, p70S6K, p-S6Rb and p-4EBP1 by WB, and, finally, mTOR by IF. We found significant differences in detecting mTOR pathway-related active biomarkers by using three common techniques such as IHC, WB and IF on RCC samples. Such results have important implications in terms of predictive biomarker testing, and need to be related to clinical end-points such as responsiveness to targeted drugs by prospective studies.

Basi scientifiche per la creazione delle linee guida per la diagnosi e il tratamento del tumore renale

The objective of the current study was to identify independent clinical and pathologic variables that were predictive of lymph node involvement in patients with squamous cell carcinoma of the penis in a multicenter series with the intent to select patients who were suitable to undergo immediate inguinal lymphadenectomy. METHODS: Data were analyzed from 175 patients who underwent surgery for penile carcinoma in 11 urologic centers participating in the Gruppo Uro-Oncologico del Nord-Est (Northeast Uro-Oncological Group) Penile Cancer Data Base. Pathologically positive lymph nodes were defined as the presence of histologically confirmed lymph node metastasis in patients who underwent either immediate or delayed inguinal and/or pelvic lymphadenectomy. Patients who had clinically positive lymph nodes with cytologically positive fine-needle aspiration results and who had not undergone lymphadenectomy were censored. RESULTS: Overall, lymph-node involvement was observed in 71 of 175 patients (