Expression of Nectin-4 in Chromophobe Renal Cell Carcinoma in a multicenter cohort - early prognostic and therapeutic considerations.

INTRODUCTION: Nectin-4 is a member of the nectin family and a calcium-independent immunoglobuline-like transmembrane protein that contributes to tumor growth and angiogenesis in malignant tumors. A Nectin-4 directed antibody drug conjugate, Enfortumab vedotin-ejf, has recently been approved for treatment in urothelial cancer and is currently under investigation in other tumor entities such as breast, lung, and prostate cancer. In non-clear cell renal cell carcinoma (RCC) vascular endothelial growth factor (VEGF)-directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. However, due to the rarity of disease treatment recommendations for chromophobe RCC (chRCC) are limited and new therapeutic agents urgently needed. In this study, we investigated the expression and prognostic impact of Nectin-4 in a large cohort of chRCC. METHODS: patients who underwent renal surgery due to chRCC were recruited. Clinical data was retrospectively evaluated. Tumor specimen were analyzed for Nectin-4 expression by immunohistochemistry. RESULTS: 81 chRCC patients were eligible for analysis. In 15 (18.5 %) samples tumors were positive for Nectin-4. No significant associations were found for Nectin-4 expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis disclosed a 5 year- overall survival for Nectin-4-negative and Nectin-4-positive tumors of 91.8% versus 100.0% (p=0.316, log rank). CONCLUSIONS: In chRCC a small subset of tumors expresses Nectin-4 potentially amenable to Nectin-4 directed treatment. Expression of Nectin-4 is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC further studies with larger cohorts are warranted.

Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging: Diagnostic Pathways and Metabolites for Renal Tumor Entities.

BACKGROUND: Correct tumor subtyping of primary renal tumors is essential for treatment decision in daily routine. Most of the tumors can be classified based on morphology alone. Nevertheless, some diagnoses are difficult, and further investigations are needed for correct tumor subtyping. Besides histochemical investigations, high-mass-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can detect new diagnostic biomarkers and hence improve the diagnostic. PATIENTS AND METHODS: Formalin-fixed paraffin embedded tissue specimens from clear cell renal cell carcinoma (ccRCC, n = 552), papillary renal cell carcinoma (pRCC, n = 122), chromophobe renal cell carcinoma (chRCC, n = 108), and renal oncocytoma (rO, n = 71) were analyzed by high-mass-resolution MALDI fourier-transform ion cyclotron resonance (FT-ICR) MSI. The SPACiAL pipeline was executed for automated co-registration of histological and molecular features. Pathway enrichment and pathway topology analysis were performed to determine significant differences between RCC subtypes. RESULTS: We discriminated the four histological subtypes (ccRCC, pRCC, chRCC, and rO) and established the subtype-specific pathways and metabolic profiles. rO showed an enrichment of pentose phosphate, taurine and hypotaurine, glycerophospholipid, amino sugar and nucleotide sugar, fructose and mannose, glycine, serine, and threonine pathways. ChRCC is defined by enriched pathways including the amino sugar and nucleotide sugar, fructose and mannose, glycerophospholipid, taurine and hypotaurine, glycine, serine, and threonine pathways. Pyrimidine, amino sugar and nucleotide sugar, glycerophospholipids, and glutathione pathways are enriched in ccRCC. Furthermore, we detected enriched phosphatidylinositol and glycerophospholipid pathways in pRCC. CONCLUSION: In summary, we performed a classification system with a mean accuracy in tumor discrimination of 85.13%. Furthermore, we detected tumor-specific biomarkers for the four most common primary renal tumors by MALDI-MSI. This method is a useful tool in differential diagnosis and biomarker detection.

Ultrasound-based "CEUS-Bosniak"classification for cystic renal lesions: an 8-year clinical experience.

PURPOSE: Renal cysts comprise benign and malignant entities. Risk assessment profits from CT/MRI imaging using the Bosniak classification. While Bosniak-IIF, -III, and -IV cover complex cyst variants, Bosniak-IIF and -III stand out due to notorious overestimation. Contrast-enhanced ultrasound (CEUS) is promising to overcome this deficit but warrants standardization. This study addresses the benefits of a combined CEUS and CT/MRI evaluation of renal cysts. The study provides a realistic account of kidney tumor boards' intricacies in trying to validate renal cysts. METHODS: 247 patients were examined over 8 years. CEUS lesions were graded according to CEUS-Bosniak (IIF, III, IV). 55 lesions were resected, CEUS-Bosniak- and CT/MRI-Bosniak-classification were correlated with histopathological diagnosis. Interobserver agreement between the classifications was evaluated statistically. 105 lesions were followed by ultrasound, and change in CEUS-Bosniak-types and lesion size were documented. RESULTS: 146 patients (156 lesions) were included. CEUS classified 67 lesions as CEUS-Bosniak-IIF, 44 as CEUS-Bosniak-III, and 45 as CEUS-Bosniak-IV. Histopathology of 55 resected lesions revealed benign cysts in all CEUS-Bosniak-IIF lesions (2/2), 40% of CEUS-Bosniak-III and 8% of CEUS-Bosniak-IV, whereas malignancy was uncovered in 60% of CEUS-Bosniak-III and 92% of CEUS-Bosniak-IV. Overall, CEUS-Bosniak-types matched CT/MRI-Bosniak types in 58% (fair agreement, κ = 0.28). CEUS-Bosniak resulted in higher stages than CT/MRI-Bosniak (40%). Ultrasound follow-up of 105 lesions detected no relevant differences between CEUS-Bosniak-types concerning cysts size. 99% of lesions showed the same CEUS-Bosniak-type. CONCLUSION: The CEUS-Bosniak classification is an essential tool in clinical practice to differentiate and monitor renal cystic lesions and empowers diagnostic work-up and patient care.

Immunohistochemical expression of the hepatocyte growth factor in chromophobe renal cell carcinoma.

BACKGROUND: The prognostic value of Hepatocyte growth factor (HGF) in non-clear cell renal cell carcinoma (RCC) is still unclear. The aim of this study is to evaluate the prognostic impact of HGF expression in a large cohort of chromophobe RCC (chRCC). METHODS: Patients who underwent renal surgery due to chRCC were recruited. Clinical data was retrospectively evaluated. Tumor specimen were analyzed for HGF expression by immunohistochemistry. RESULTS: 81 chRCC patients were eligible for analysis, thereof 37 (45.7%) patients were positive for HGF. No significant associations were found for HGF expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in 5-year overall survival (OS) for patients with HGF- compared to HGF+ tumors (95.0% versus 90.9%; p = 0.410). CONCLUSIONS: In chRCC HGF expression is not associated with parameters of aggressiveness or survival.

Growth Arrest-Specific 6 in Chromophobe Renal Cell Carcinoma.

BACKGROUND: Overexpression of tumor-associated growth arrest-specific protein 6 (Gas6) is found in many tumor entities. The prognostic value of Gas6 in renal cell carcinoma (RCC), especially in non-clear cell RCC, is still unclear. AIM: The aim of the study was to evaluate the prognostic impact of Gas6 expression in a large cohort of patients with chromophobe RCC (chRCC). MATERIAL AND METHODS: Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for Gas6 expression by immunohistochemistry. RESULTS: Eighty-one chRCC patients were eligible for analysis; of these, 24 (29.6%) patients were positive for Gas6. No significant associations were found for Gas6 expression and clinical attributes in patients with chRCC. The Kaplan-Meier analysis revealed no differences in 5-year overall survival for Gas6- compared to Gas6+ (89.6% vs. 100.0%; p = 0.288) tumors. CONCLUSION: In chRCC, Gas6 expression is not associated with survival and other parameters of aggressiveness. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.

Trophoblast Cell Surface Antigen 2 (Trop2) in Chromophobe Renal Cell Carcinoma.

BACKGROUND: Overexpression of tumor-associated calcium signal transducer 2 (Trop2) is found in many tumor entities. The prognostic value of Trop2 in renal cell renal carcinoma (RCC), especially in nonclear cell RCC, is still unclear. AIM: The aim of this study was to evaluate the prognostic impact of Trop2 expression in a large cohort of patients with chromophobe (ch)RCC. MATERIALS AND METHODS: Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for Trop2 expression by immunohistochemistry. RESULTS: Eighty-one chRCC patients were eligible for analysis, of these 24 (29.6%) patients were positive for Trop2. No significant associations were found for Trop2 expression and clinical attributes in patients with chRCC. The Kaplan-Meier analysis revealed no differences in 5-year overall survival for Trop2- compared to Trop2+ (89.6% vs. 100.0%; p = 0.288). CONCLUSION: In chRCC, Trop2 expression is not associated with survival and other parameters of aggressiveness. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.

Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study.

PURPOSE: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure. METHODS: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter. RESULTS: The study proved that intravesical instillation of the 213Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment. CONCLUSION: Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

Intraoperative frozen section monitoring during nerve-sparing radical prostatectomy: evaluation of partial secondary resection of neurovascular bundles and its effect on oncologic and functional outcome.

PURPOSE: Intraoperative frozen sections (IFS) of the prostate have demonstrated to be effective in reducing positive surgical margins (PSM) and biochemical recurrence (BCR). The aim of this study was to assess partial secondary resection of neurovascular bundles (NVB) and report for the first time corresponding functional results. METHODS: A total of 500 consecutive patients were included in this prospective series. All patients underwent open nerve-sparing radical prostatectomy. Intraoperatively, both posterolateral aspects of the prostate were sent for IFS. In case of PSM, additional tissue was partly resected from the prostatic bed along the NVB. BCR was the oncologic endpoint (PSA ≥ 0.2 ng/ml). The impact of IFS on PSM and BCR-free survival, and the effect of secondary partial resection of NVB on continence and erectile function (EF) recovery were analyzed by Kaplan-Meier analyses. RESULTS: Twenty-nine patients were excluded because of neoadjuvant treatment/lymph node positive disease. PSM were detected in 137/471 patients (29.1%). After secondary resection, 127/137 patients (92.7%) converted to definitive negative surgical margins (NSM). Out of 137 patients, ten (7.3%) showed persistent PSM. False-negative rate was 3.3% (11/334). Out of 471 patients, two (0.4%) showed PSM outside the IFS area. Overall, final PSM rate was 4.9% (23/471). Five-year BCR-free survival did not differ significantly in patients with primarily and converted NSM. Continence and EF recovery after 12 months were 95.8 versus 94.3%, and 65.7 versus 56.1%, respectively (all p > 0.05). CONCLUSION: IFS are highly effective in reducing PSM and avoiding compromised oncologic outcome. Partial secondary resection of the NVB ensures ns status and consequently preserves continence and EF.

Evaluation of Computed Tomography for Lymph Node Staging in Bladder Cancer Prior to Radical Cystectomy.

OBJECTIVES: To retrospectively evaluate the value of CT for lymph node (LN) staging in bladder cancer. METHODS: Two uroradiologists reviewed CT scans of 231 patients who underwent radical cystectomy and pelvic lymphadenectomy according to a predefined 12-field template. A 5-step model was used to grade the radiological likelihood of a LN to represent malignant spread based on size, configuration and structure as well as regional clustering. Statistical analyses were performed both on patient- and field-based levels. RESULTS: LN metastases were found in 59 of 231 patients (25.5%). On a patient-based level, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 52.6, 93.6, 73.2, 85.6 and 83.4%, respectively. Using the field-based approach, a total of 1,649 anatomical fields were evaluable, of which 114 fields showed malignancy (6.9%). On a field basis, sensitivity, specificity, PPV, NPV and accuracy were 30.2, 98, 51.5, 94.5 and 93.3%, respectively. Concerning local staging (pT category), the overall accuracy was 78%; overstaging occurred in 6% and understaging in 16%. CONCLUSIONS: In line with prior studies, the sensitivity of CT imaging for the detection of LN metastases was low, while high values for specificity were achieved. This was further underlined by analyzing standardized anatomical fields. Concerning local staging, postoperative changes after TURB-T rarely led to overstaging.

Supremacy of modern morphometry in typing renal oncocytoma and malignant look-alikes.

In the era of tumour type-specific therapies, the correct typing of renal tumours is of prime importance. As immunotyping and genotyping approaches are laborious and fall short of standardization, we used whole-scale computer-assisted morphometry instead. Three different types of renal tumours with different prognoses and therapies, notoriously prone to mistyping, were analysed . The sample of 335 tumours included clear cell renal cell carcinoma, chromophobe renal cell carcinoma and renal oncocytoma. The sample was analysed using H&E stains of tissue microarrrays in combination with an image-scanning software. Nuclear and cytoplasmic features were registered with the aid of computer-assisted morphometry. Features included shape, texture, colour and colour intensity for different cell compartments, e.g. nuclei and cytoplasm. The software passed several training steps for final validation. Using morphometry, we were able to classify the three renal tumour types correctly, with a 100 % specificity compared to the WHO typing. Nuclear features dominated the typing of chromophobe renal cell carcinoma, whereas cytoplasmic features were the leading classificators for renal oncocytoma. The grading of clear cell renal cell carcinoma attained a specificity of 80 %. In conclusion, modern morphometry may serve as a tool for typing renal epithelial tumours and additionally draws the attention to future nuclear research in chromophobe renal cell carcinoma.

Clinical prognosticators of survival in patients with urothelial carcinoma of the bladder and lymph node metastases after cystectomy with curative intent.

INTRODUCTION: Patients with lymph node-positive urothelial carcinoma of the bladder generally have a poor prognosis. Nevertheless, long-term survival in up to 30% of patients is reported. In the absence of established prognostic molecular markers, an assessment of the prognosis with clinical parameters is mandatory. PATIENTS AND METHODS: All patients from one high-volume center with a curatively intended cystectomy for lymph node-positive urothelial carcinoma were evaluated. Patients' overall and cancer-specific survival were correlated with clinicopathological parameters. Pathological lymph node staging was performed with both the 2002 and 2010 TNM classification of the AJCC. RESULTS: Lack of a perioperative chemotherapy (p < 0.001), higher numbers of positive nodes (p = 0.002), a higher lymph node density (p = 0.003), a higher pathological T stage (p = 0.006) and urinary diversion with an ileal conduit compared to an ileal neobladder (p = 0.023) were prognostic of a shorter overall survival while the number of removed lymph nodes showed no significant association with survival. Both with the 2002 and 2010 TNM classifications patients staged pN1 had a longer overall survival and time to cancer-specific death in comparison to patients with more extensive lymph node disease. According to the 2002 classification, there was a significant survival difference between patients with lymph node metastases in regional and distant lymph nodes. DISCUSSION: Patients with a low lymph node density and an early pT stage present with the best prognosis among LN positive patients. The value of perioperative chemotherapy is emphasized. Which lymph node metastases are to be considered regional or distant remains a matter of debate.

The role of claudin-6 in chromophobe renal cell carcinoma.

BACKGROUND: The prognostic value of Claudin-6 (CLDN6) in non clear cell renal cell carcinoma (RCC) is still unclear. AIM: To evaluate the prognostic impact of CLDN6 expression in a large cohort of chromophobe RCC (chRCC). MATERIAL AND METHODS: Patients who underwent renal surgery due to chRCC were recruited. Clinical data were retrospectively evaluated. Tumor specimens were analyzed for CLDN6 expression by immunohistochemistry. RESULTS: 81 chRCC patients were eligible for analysis, thereof 10 (12.3%) patients were positive for CLDN6. No significant associations were found for CLDN6 expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in overall survival (OS) for patients with CLDN6⁻ compared to CLDN6⁺ tumors (87.0% versus 62.5%; p=0.174). CONCLUSION: In chRCC CLDN6 expression is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC further studies with larger cohorts are warranted.

MALDI Mass Spectrometry Imaging-Prognostic Pathways and Metabolites for Renal Cell Carcinomas.

High mass resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is a suitable method for biomarker detection for several tumor entities. Renal cell carcinoma (RCC) is the seventh most common cancer type and accounts for more than 80% of all renal tumors. Prognostic biomarkers for RCC are still missing. Therefore, we analyzed a large, multicenter cohort including the three most common RCC subtypes (clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC)) by MALDI for prognostic biomarker detection. MALDI-Fourier-transform ion cyclotron resonance (FT-ICR)-MSI analysis was performed for renal carcinoma tissue sections from 782 patients. SPACiAL pipeline was integrated for automated co-registration of histological and molecular features. Kaplan-Meier analyses with overall survival as endpoint were executed to determine the metabolic features associated with clinical outcome. We detected several pathways and metabolites with prognostic power for RCC in general and also for different RCC subtypes.

[Virtual skills-training in urology : Teaching at the Technical University of Munich during the COVID-19-pandemic]. / Virtueller Praktikumstag Urologie : Studentenunterricht an der Technischen Universität München in Zeiten der COVID-19-Pandemie.

BACKGROUND AND INTRODUCTION: The COVID-19 pandemic presents the challenge for medical education to teach practical skills without practical training. To provide an alternative to hands-on training during the COVID-19 lockdown, we created a virtual curriculum to teach practical skills using videos combined with online exams on a virtual e­learning platform. The goal was to convey different theoretical and practical aspects of urology. MATERIALS AND METHODS: The videos were produced by department employees using a predefined concept. The students had access to the virtual curriculum via the university's Moodle e­learning platform. To assess the success of training, participating students had to pass an online exam about the curriculum's contents, followed by an evaluation of the course. RESULTS: A total of 164 participants took part in the virtual curriculum. The overall evaluation and feedback was very positive. The acceptance of the virtual alternative to hands-on teaching was high. DISCUSSION: The virtual curriculum offered a fast and contactless alternative to the regular hands-on teaching.

KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy.

BACKGROUND: Lymph-node (LN) metastasis in prostate cancer (PC) is a main risk factor for tumor recurrence after radical prostatectomy (RP). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP. METHODS: The expression of kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostate-specific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2) and transient receptor potential cation channel subfamily M member 8 (TRPM8) was assessed using qPCR. We analyzed LNs from 111 patients (intermediate PC, n = 32 (29%); high-risk PC, n = 79 (71%)) who underwent RP and extended pelvic lymph-node dissection without neoadjuvant treatment. RESULTS: Overall, 2411 LNs were examined by molecular and histopathologic examination. Histopathology detected 69 LN metastases in 28 (25%) patients. KLK2 and KLK3 diagnostically performed best and classified all pN1-patients correctly as molecular node-positive (molN1/pN1). The concordance on LN level was best for KLK3 (96%). KLK2, KLK3, KLK4, PSMA, TMPRSS2, and TRPM8 reclassified 27 (24%), 32 (29%), 29 (26%), 8 (7%), 13 (12%), and 23 (21%) pN0-patients, respectively, as node-positive (pN0/molN1). On multivariable cox regression analysis molecular LN status (molN1 vs. molN0) using KLK3 (HR 4.0, p = 0.04) and TMPRSS2 (HR 5.1, p = 0.02) were independent predictors of bRFS. Median bRFS was shorter in patients with only molecular positive LNs (molN1/pN0) for KLK3 (24 months, p = 0.001) and for TMPRSS2 (12 months, p < 0.001) compared to patients with negative nodes (molN0/pN0) (median bRFS not reached). CONCLUSIONS: For diagnostic purposes, KLK3 showed highest concordance with histopathology for detection of LN metastases in PC patients undergoing RP. For prognostic purposes, KLK3 and TMPRSS2 expression were superior to histopathologic LN status and other transcripts tested for molecular LN status. We suggest a combined KLK3/TMPRSS2 panel as a valuable diagnostic and prognostic tool for molecular LN analysis.

Molecular lymph node staging for bladder cancer patients undergoing radical cystectomy with pelvic lymph node dissection.

OBJECTIVE: Presence of lymph node (LN) metastasis in bladder cancer (BCa) is a main risk factor for tumor recurrence after radical cystectomy (RC). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than standard histopathology. The aim of the present study was to establish molecular LN analysis in BCa patients undergoing RC with lymph node dissection (LND) and to determine its ability to predict tumor recurrence. PATIENTS AND METHODS: Five transcripts with overexpression in BCa (FXYD3, KRT17, KRT20, SPINK1, UPKII) were evaluated for molecular LN analysis. We included 76 BCa patients from the prospective, randomized surgical phase-III trial (LEA AUO AB 25/02, NCT01215071) investigating extended vs. limited LND at RC. The primary endpoint was recurrence-free survival (RFS). As control, 136 LNs from 45 patients without BCa were analyzed to determine a threshold for pathologic gene expression. RESULTS: About 1,319 LNs were investigated with molecular and histopathologic examination. Histopathology detected 39 LN metastases in 17 (22%) patients. Of the tested genes FXYD3 performed best and classified all pN+-patients correctly as node-positive (pN+/molN+). In addition, FXYD3 reclassified 43 histopathologic negative LNs and 7 (9%) pN0-patients as molecular node-positive (pN0/molN+). Molecular and histopathologic LN status (pN0/molN0 vs. pN0/molN+ vs. pN+/molN+) was significantly associated with locally advanced disease (P = 0.006) and poor RFS (P < 0.001). Median RFS was not reached in LN-negative patients (pN0/molN0), 45 months (95%CI 8-83) in exclusively molecular positive patients (pN0/molN+) and 9 months (95%CI 5-13) in patients with histopathologic and molecular positive LNs (pN+/molN+). CONCLUSIONS: Molecular LN analysis with FXYD3 identified additional LN metastases in histopathologic negative LNs and identified patients with elevated risk of tumor recurrence after RC. Thus, molecular LN analysis improves LN staging and might serve as a tool to guide adjuvant treatment.

Correction to: Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme.

The legends of Figs. 1 and 3 in the published original version of the above article are incorrect.

Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme.

A histological grading system of chromophobe renal cell carcinoma (chRCC) is highly desirable to identify approximately 5-10% of tumors at risk for progression. Validation studies failed to demonstrate a correlation between the four-tiered WHO/ISUP grade and outcome. Previous proposals with three-tiered chromophobe grading systems could not be validated. In this study, the presence of sarcomatoid differentiation, necrosis, and mitosis was analyzed in a Swiss cohort (n = 42), an Italian cohort (n = 103), a German cohort (n = 54), a Japanese cohort (n = 119), and The Cancer Genome Atlas cohort (n = 64). All 3 histological parameters were significantly associated with shorter time to tumor progression and overall survival in univariate analysis. Interobserver variability for identification of these parameters was measured by Krippendorff's alpha coefficient and showed high concordance for the identification of sarcomatoid differentiation and tumor necrosis, but only low to medium concordance for the identification of mitosis. Therefore, we tested a two-tiered tumor grading system (low versus high grade) based only on the presence of sarcomatoid differentiation and/or necrosis finding in the combined cohorts (n = 382). pT stage, patient's age (> 65 vs ≤ 65), lymph node and/or distant metastasis, and the two-tiered grading system (low versus high grade) were significantly associated with overall survival and were independent prognostic parameters in multivariate analysis (Cox proportional hazard). This multi-institutional evaluation of prognostic parameters suggests tumor necrosis and sarcomatoid differentiation as reproducible components of a two-tiered chromophobe tumor grading system.

Molecular Lymph Node Status for Prognostic Stratification of Prostate Cancer Patients Undergoing Radical Prostatectomy with Extended Pelvic Lymph Node Dissection.

Purpose: Molecular lymph node (LN) analysis using quantitative polymerase chain reaction (qPCR) detects LN metastases with higher sensitivity than histopathology. However, the prognostic role of molecular LN status in prostate cancer patients treated with radical prostatectomy (RP) and extended pelvic LN dissection (ePLND) is unclear. To investigate the association of molecular compared with histopathologic LN status with biochemical recurrence.Experimental Design: Patients with intermediate and high-risk prostate cancer were prospectively enrolled and underwent RP with ePLND, including the obturator, internal, external, and the common iliac region. LNs ≥3 mm were bisected and examined by standard histopathology and qPCR for Kallikrein3 (KLK3) expression. Biochemical recurrence was defined by confirmed postoperative PSA > 0.2 ng/mL.Results: In 111 patients, 2,411 of 3,173 removed LNs were examined by both methods. Histopathology detected 68 LN metastases in 28 (25%) patients. Molecular analysis confirmed elevated KLK3 expression in 65 histopathologic LN metastases of all 28 pN1 patients (pN1/molN1) and additionally reclassified 224 histopathologic negative LNs and 32 (29%) pN0 patients as LN-positive (pN0/molN1).At a median follow-up of 48 months, 52 (47%) patients developed biochemical recurrence. Median biochemical recurrence-free survival was 9 months [95% confidence interval (CI), 0.0-20.1] in pN1/molN1 patients, 24 months (95% CI, 1.7-46.3) in pN0/molN1 patients and was not reached in pN0/molN0 patients (P < 0.001). On multivariable Cox regression analysis, molecular LN status [HR 4.1 (95% CI, 1.9-8.8), P < 0.001] but not histopathologic LN status [HR 1.5 (95% CI, 0.8-3.0), P = 0.198] was confirmed as independent predictor of biochemical recurrence.Conclusions: Molecular LN analysis identified pN0 patients with a high risk of biochemical recurrence and provided superior prognostic information in comparison with histopathology alone. Clin Cancer Res; 24(10); 2342-9. ©2018 AACR.