Higher Fuhrman Nuclear Grade Research Articles

Predictors of disease recurrence in high-risk non-metastatic renal cell carcinoma patients post-surgical resection A single-center, retrospective study.

Approximately 20-40% of kidney cancer patients treated for localized disease experience post-surgical recurrence. Several prognostic models exist to help clinicians determine the risk of distant recurrence, but these models vary in criteria and endpoints. We aimed to examine the recurrence rate and clinicopathologic factors as predictors of recurrence in high-risk renal cell carcinoma (RCC) patients. We conducted a single-center, retrospective chart review of pT3 RCC patients who underwent a nephrectomy between January 2000 and December 2015. Patients registered in clinical trials for adjuvant therapy and those with fewer than three years of followup were excluded. Kaplan-Meier survival analysis and univariate and multivariate Cox regression were performed to identify the rate and predictors of disease recurrence. Eighty-eight pT3 RCC patients were included, and 39 patients had recurrence with a median of 23.5 months (range 1.6-127.5). Nine patients had disease recurrence beyond 58 months. Kaplan-Meier log-rank tests identified patients with negative surgical margins and low Fuhrman nuclear grades had greater recurrence-free survival. Univariate Cox regression revealed positive surgical margins, high Fuhrman nuclear grade, and large tumor sizes were significant predictors. In the multivariate Cox regression model, high Fuhrman nuclear grade and positive surgical margins were significant predictors of recurrence. Disease recurrence occurred in 44% of pT3-staged patients. High Fuhrman nuclear grade and positive surgical margins were associated with time to recurrence. Physicians should use prognostic models to facilitate conversations about disease recurrence and continue to monitor high-risk patients beyond the recommended five-year followup period. We recommend monitoring pT3 resected patients for up to 10 years post-surgery.

To Study the Association of Cyclin D1 Expression with Fuhrman’s Nuclear Grading in Renal Cell Carcinoma

Background: In adults, renal cell cancer (RCC) consists of tumors arising from the renal parenchyma and renal pelvis. Renal parenchyma cancer is mainly renal cancer i.e. adenocarcinoma. Renal pelvis malignancy is mainly transitional cell type. Presently, prognostic markers for renal cell cancer are tumor stage and nuclear grade. Aim: To observe the expression of cyclinD1 in different variants of RCC and to associate cyclinD1 expression with Fuhrman nuclear grades of RCC. Results: Out of 93 patients, 54(58.1%) were of more than 40 years of age, with M: F ratio of 1: 1. Clear cell RCC was the most common histological type i.e. 72out of 93(77.4%) biopsies. Low grades RCC were 50 out of 93(53.8%) and High grade RCC were in 43 out of 93(46.6%) biopsies and out of these 43 high grade RCC 23(24.7%) were found to invade surrounding tissue. As far as CyclinD1 expression score was concerned, 60 out of 93(64.4%) biopsies were found to have score 1 and 2 with no and upto30% +ve cells and 33(35.5%) biopsies were of score 3 and 4 with 30-60% and >60% positive cells respectively. In this study, 28 out of 93(30.2%) biopsies of low Fuhrman’s nuclear grade showed cyclin D1 score 3 and 4 respectively. Conclusion: In our study cyclin D1 protein was over expressed in low grade RCC showing that high protein levels may be related with the disease progression in patients of RCC. Cyclin D1 protein expression in future can be used as adjuvant to Fuhrman’s nuclear grading and will increase the predictive accuracy of the current disease progression models for RCC. Keywords: CyclinD1, RCC, Low and High Fuhrman nuclear grade

Coexpression of lymphocyte-activation gene 3 and programmed death ligand-1 in tumor infiltrating immune cells predicts worse outcome in renal cell carcinoma.

ObjectivesLymphocyte-activation gene 3 (LAG-3) represents a potential immune checkpoint target for cancer treatment. We investigated LAG-3 expression and its prognostic value in patients with surgically treated clear cell renal cell carcinoma (RCC) and correlated LAG-3 expression with programmed cell death ligand 1(PD-L1).MethodsWe evaluated LAG-3 and PD-L1 expression using immunohistochemistry on tissue microarrays incorporating 134 primary excision specimens of clear cell RCC (ccRCC). The patients were analyzed as two groups: the whole cohort and those with metastatic RCC (mRCC). The cancer genome atlas (TCGA) data analysis of LAG-3 was done through UALCAN web servers.ResultsUsing the UALCAN cancer transcriptional data analysis, we found that LAG-3 was overexpressed in ccRCC. LAG-3 expression was significantly correlated with PD-L1 expression in the whole cohort and in the mRCC group (all, p < 0.05). Both LAG-3⁺ RCC and PD-L1⁺ RCC presented with a higher TNM stage and higher Fuhrman nuclear grade (all, p < 0.05). PD-L1⁺/LAG-3⁺ RCC and PD-L1⁻/LAG-3⁺ RCC showed poorer cancer-specific survival (CSS) than PD-L1⁻/LAG-3⁻ RCC (all, p = 0.01). Similarly, PD-L1⁺/LAG-3⁺ mRCC and PD-L1⁻/LAG-3⁺ mRCC showed poorer CSS than PD-L1⁻/LAG-3⁻ mRCC (all, p < 0.05). Multivariate analysis showed that PD-L1⁺/LAG-3⁺ mRCC (hazard ratio: 3.19; 95% CI: 0.77–13.67; p = 0.033) was a predictor of poor CSS.ConclusionBoth LAG-3⁺ and PD-L1⁺ RCC have adverse pathological features, and their coexpression predicts worse clinical outcomes. Our findings suggest LAG-3 blockade in combination with programmed cell death 1/PD-L1 blockade as a potential therapeutic approach for RCC.

Can we Predict Preoperative Tumor Aggressivity with Hemogram Parameters in Renal Cell Carcinoma? a Novel Calculation Method.

We aim to investigate the prognostic significance of the hemoglobin X lymphocyte / neutrophil ratio (HLNR) and hemoglobin x lymphocyte / platelet ratio (HLPR) with tumor aggressivity in patients with renal cell carcinoma. We retrospectively analyzed 127 patients' data who had diagnosed as renal cell carcinoma between 2008 and 2019 in Suleyman Demirel University Hospital. Tumor and patient characteristics, hemoglobin, neutrophil, lymphocyte, platelet values HLNR and HLPR were calculated in preoperative hemogram parameters. The relationship between tumor pathological stage, Fuhrman nuclear grade and tumor necrosis with HLPR and HLNR analyzed with statistically. There was a negative correlation between pathologic stage, Fuhrman nuclear grade and tumor necrosis with HLNR. P values are 0.003, 0.012 and 0.015 respectively. HLNR was lower in patients with high pathologic stage, high Fuhrman nuclear grade and accompanying tumor necrosis positiveness. There was a negative correlation between pathologic stage, Fuhrman nuclear grade and tumor necrosis with HLPR. P values are 0.001, 0.014 and 0.047 respectively. HLPR was lower in patients with high pathologic stage, high Fuhrman nuclear grade and accompanying tumor necrosis positiveness. High pathological stage, high Fuhrman nuclear grade and existence of tumor necrosis are associates with preoperative low HLNR and low HLPR in renal cell carcinoma patients. They can be used as prognostic markers in patients with renal mass preoperatively.

S100A8 Expression May Have a Prognostic Value in CCRCC Reflecting TNM Staging and Fuhrman Nuclear Grade.

S100A8 is a chemoattractant known to be associated with metastatic niche formation. Herein, we evaluated the prognostic value of S100A8 in patients with clear cell renal cell carcinoma (CCRCC). A total of 152 CCRCC patients who have undergone nephrectomy were enrolled. The expression of S100A8 was assessed immunohistochemically using tissue microarray (TMA) blocks of CCRCC. Using statistical analysis, the relationship between S100A8 expression and clinicopathological factors was evaluated. Among 152 TMA cores, 21 (6.9%) showed higher S100A8 expression. S100A8 expression was significantly increased in cores of patients with higher T stage (≥2, p<0.001) and higher Fuhrman nuclear grade (≥3, p<0.001). Multivariate analysis confirmed that high expression of S100A8 was significantly correlated to poor disease-free survival (hazard ratio, 2.601; 95% confidence interval (CI), 1.020-6.628; p-value=0.045). S100A8 expression may have a prognostic value in CCRCC reflecting TNM staging and Fuhrman nuclear grade.

Compare Fuhrman Nuclear and Chromophobe Tumor Grade on Chromophobe RCC.

BackgroundChromophobe renal cell carcinoma (chRCC) has a favorable prognosis. Due to irregular nuclei and nuclear pleomorphism, chRCC has a high Fuhrman nuclear grade (FNG). The chromophobe tumor grade (CTG) is a novel three-tier grading system that has been reported to be a better prognosticator than the traditional FNG. We compared the two nuclear grading systems in terms of patients’ clinical outcomes.Patients and MethodWe performed this retrospective chart review of all patients with chRCC from 2000 to 2017. All pathologic features and CTG and FNG results were re-evaluated.ResultEighteen patients’ records were reviewed with a mean follow-up of 70.6 months. The nuclear grading distribution was as follows: FNG 2, 56%; FNG 3, 39%; FNG 4, 5%; CTG 1, 78%; CTG 2, 17%; and CTG 3, 6%. Only one patient died. This patient had adrenal invasion, lung metastasis, sarcomatoid change and tumor necrosis, and the tumor was graded as FNG 4 and CTG 3. Overall survival was associated with both FNG and CTG.ConclusionChromophobe RCC was associated with a low rate of cancer-specific death and sarcomatoid differentiation. Both FNG and CTG were associated with overall survival.

CT-based machine learning model to predict the Fuhrman nuclear grade of clear cell renal cell carcinoma

To predict the Fuhrman grade of clear cell renal cell carcinoma (ccRCC) with a machine learning classifier based on single- or three-phase computed tomography (CT) images. Patients with pathologically proven ccRCC from February 1, 2009 to September 31, 2018 who were not treated were retrospectively collected for machine learning-based analysis. The texture features were extracted and ranked from precontrast phase (PCP), corticomedullary phase (CMP), nephrographic phase (NP) and three-phase CT images, and open-source gradient boosting from the decision tree library of CatBoost was used to establish a machine learning classifier to differentiate low- from high-grade ccRCC. The performances of machine learning classifiers based on features from single- and three-phase CT images were compared with each other. A total of 231 patients with 232 pathologically proven ccRCC lesions were retrospectively collected. 35, 36, 41, and 22 Features were extracted and ranked from PCP, CMP, NP, and three-phase CT images, respectively. The machine learning model based on three-phase CT images [area under the ROC curve (AUC) = 0.87] achieved the best diagnostic performance for differentiating low- from high-grade ccRCC, followed by single-phase NP (AUC = 0.84), CMP (AUC = 0.80), and PCP images (AUC = 0.82). Machine learning classifiers can be promising noninvasive techniques to differentiate low- and high-Fuhrman nuclear grade ccRCC, and classifiers based on three-phase CT images are superior to those based on features from each single phase.

Neutrophil-to-Lymphocyte Ratio Predicts Pathological Renal Sinus Fat Invasion in Renal Cell Carcinomas of ≤7 cm with Presumed Renal Sinus Fat Invasion.

PurposeComputed tomography (CT) is the most useful diagnostic modality for staging renal cell carcinoma (RCC). However, CT is limited in its ability to predict renal sinus fat invasion (SFI). Here, we aimed to evaluate whether preoperative neutrophil-to-lymphocyte ratio (NLR) could predict pathological SFI in patients with RCC of ≤7 cm for whom preoperative imaging reveals potential renal SFI.Materials and MethodsWe reviewed the medical records of 1311 patients who underwent extirpative renal surgery for non-metastatic RCC of ≤7 cm between November 2005 and December 2014. After excluding patients with no SFI in preoperative imaging, unavailable preoperative data, and morbidity affecting inflammatory markers, a total of 476 patients were included in this study. Multivariate logistic regression analysis was used to evaluate predictors of pathological SFI.ResultsWe implemented a cut-off value of 1.98, which was calculated by ROC analysis to obtain high (≥1.98) and low (<1.98) NLR groups. A total of 93 patients with pathological SFI had larger clinical tumor size, higher preoperative NLR, larger pathological tumor size, more frequent renal vein involvement, and higher Fuhrman nuclear grade. Multivariate analysis indicated that high NLR [odds ratio (OR) 2.032, p=0.004], clinical tumor size (OR 1.586, p<0.001), and collecting system involvement on preoperative imaging (OR 3.957, p=0.011) were significantly associated with pathological SFI in these tumors.ConclusionPreoperative high NLR was associated with pathological SFI in patients with RCC of ≤7 cm and presumed SFI on preoperative imaging. Greater surgical attention is needed to obtain negative margins during partial nephrectomy in these patients.

Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma

The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ≥1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan–Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.

Clear Cell Renal Cell Carcinoma: Machine Learning-Based Quantitative Computed Tomography Texture Analysis for Prediction of Fuhrman Nuclear Grade.

To evaluate the performance of quantitative computed tomography (CT) texture analysis using different machine learning (ML) classifiers for discriminating low and high nuclear grade clear cell renal cell carcinomas (cc-RCCs). This retrospective study included 53 patients with pathologically proven 54 cc-RCCs (31 low-grade [grade 1 or 2]; 23 high-grade [grade 3 or 4]). In one patient, two synchronous cc-RCCs were included in the analysis. Mean age was 57.5 years. Thirty-four (64.1%) patients were male and 19 were female (35.9%). Mean tumour size based on the maximum diameter was 57.4 mm (range, 16-145 mm). Forty patients underwent radical nephrectomy and 13 underwent partial nephrectomy. Following pre-processing steps, two-dimensional CT texture features were extracted using portal-phase contrast-enhanced CT. Reproducibility of texture features was assessed with the intra-class correlation coefficient (ICC). Nested cross-validation with a wrapper-based algorithm was used in feature selection and model optimisation. The ML classifiers were support vector machine (SVM), multilayer perceptron (MLP, a sort of neural network), naïve Bayes, k-nearest neighbours, and random forest. The performance of the classifiers was compared by certain metrics. Among 279 texture features, 241 features with an ICC equal to or higher than 0.80 (excellent reproducibility) were included in the further feature selection process. The best model was created using SVM. The selected subset of features for SVM included five co-occurrence matrix (ICC range, 0.885-0.998), three run-length matrix (ICC range, 0.889-0.992), one gradient (ICC = 0.998), and four Haar wavelet features (ICC range, 0.941-0.997). The overall accuracy, sensitivity (for detecting high-grade cc-RCCs), specificity (for detecting high-grade cc-RCCs), and overall area under the curve of the best model were 85.1%, 91.3%, 80.6%, and 0.860, respectively. The ML-based CT texture analysis can be a useful and promising non-invasive method for prediction of low and high Fuhrman nuclear grade cc-RCCs. • Based on the percutaneous biopsy literature, ML-based CT texture analysis has a comparable predictive performance with percutaneous biopsy. • Highest predictive performance was obtained with use of the SVM. • SVM correctly classified 85.1% of cc-RCCs in terms of nuclear grade, with an AUC of 0.860.

Abstract 1549: LAPTM5 in clear cell renal cell carcinoma

Abstract Lysosomal-associated multispanning membrane protein 5 (LAPTM5) is membrane protein that mostly expressed in immune cells and hematopoietic cells. Recently, it has been demonstrated that LAPTM5 expression levels are decreased in several cancer cells by inducing regression of Hela cells and neuroblastomas. However, its exact role in cancer has yet to be defined. Furthermore, the clinical effect of LAPTM5 expression in cancer has not been reported so far. Thus, we investigated the association between LAPTM5 expression and its clinicopathological characteristics in 112 cases of clear cell renal cell carcinoma using tissue microarrays by immunohistochemical staining. Tumors were classified into four grades based on the staining intensity: 0 = no staining, +1 = weak, +2 = intermediate, and +3 = strong. The staining intensity was classified into LAPTM5-negative group or LAPTM5-positive groups. (0; negative, +1 ~ +3; positive). Of all 112 cases, 9 cases showed LAPTM5-negative, while 93 cases showed LAPTM5-positive: +1 (35 cases), +2 (28 cases), and +3 (30 cases). LAPTM5-positivity was significantly associated with decreased tumor recurrence. In addition, recurrence-free survival (RFS) (p = 0.010), cancer-specific survival (CSS) (p = 0.022), and overall survival (OS) (p = 0.022) were significantly decreased in the LAPTM5-negative group. Univariate analysis indicated that tumor size (HR = 3.44; 95% CI, 1.000-11.836), Fuhrman nuclear grade (HR = 1.863; 95% CI, 1.169-2.971), and negative LAPTM5 expression (HR = 3.173; 95% CI, 1.249-8.064) significantly affected the RFS of clear cell renal cell carcinoma patients. Moreover, CSS and OS were significantly affected by Fuhrman nuclear grade (HR = 2.177; 95% CI, 1.261-3.757 and HR = 1.673, 95% CI, 1.062-2.635, respectively) and negative LAPTM5 expression (HR = 3.398; 95% CI, 1.110-10.405 and HR = 2.826; 95% CI, 1.136-7.031, respectively). Multivariate analysis showed that a high Fuhrman nuclear grade and negative LAPTM5 expression were significant independent risk factors. Based on these results, loss of LAPTM5 was associated with poor oncological outcomes; this suggests that LAPTM5 might be a useful prognostic marker in patients with clear cell renal cell carcinoma. Citation Format: Hyewon Ryu, Solbi Kim, Nayoung Kim, Jin-Man Kim, Hyo Jin Lee. LAPTM5 in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1549.

Evaluation of programmed cell death protein 1 (PD-1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma

ABSTRACT Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have shown activity in patients with advanced renal cell carcinoma (RCC). However, the role of PD-1 expression in tumor-infiltrating lymphocytes (TILs) as a biomarker for poor outcome is not clear. In this study, we evaluated the prognostic value of TIL PD-1 expression in patients with clear cell RCC (ccRCC). 82 patients who underwent nephrectomy for localized or metastatic ccRCC and followed up for at least four years were searched from our database and retrospectively enrolled. Their fixed primary tumor specimens were stained with anti-PD-1 (NAT105). The specimens were classified as negative or positive for PD-1 expression, and the positive specimens were further scored in 10% increments. 37 (45.12%) patients were negative (<1% stained), 26 (31.71%) patients were low (<10 and 10%), and 19 (23.17%) patients were high (20–50%) for PD-1 expression. The prognostic value of TIL PD-1 expression was evaluated by univariate Cox proportional hazards regression on overall and recurrence-free survivals. Higher TIL PD-1 expression was not associated with increased risk of death (P = 0.336) or with increased risk of recurrence (P = 0.572). Higher primary tumor stage was associated with increased risk of recurrence (P = 0.003), and higher Fuhrman nuclear grade was associated with increased risk of death (P <0.001) and with increased risk of recurrence (P <0.001). Our study shows that TIL PD-1 expression by immunohistochemistry (IHC) does not correlate with poor clinical outcome in patients with ccRCC and is inferior to established prognosticating tools.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0–300): intensity of c-Met staining (0–3) x % of positive cells (0–100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Prognostic role of myoferlin expression in patients with clear cell renal cell carcinoma.

ObjectivesIn patients with cancer, myoferlin protein hyperexpression has been correlated with poor patient prognosis. Here, we evaluated myoferlin expression in patients with clear cell renal cell carcinoma (ccRCC) and investigated the prognostic significance of myoferlin expression in these patients.Materials and MethodsOne hundred and fifty-two patients with ccRCC who underwent treatment at Gyeongsang National University Hospital, Korea, between January 2000 and December 2009 were enrolled. Immunohistochemical analysis was performed on tissue microarray blocks produced from surgical specimens. Surgical specimen cancerous cells were graded as showing myoferlin hyperexpression or hypoexpression by comparison with intratumoral endothelial cells. Disease-free survival was evaluated using Kaplan-Meier analysis. Cox regression analysis was used to determine the relationships between myoferlin expression levels, risk factors, and prognosis.ResultsSeventy-one of 304 cores exhibited myoferlin hyperexpression. T stage was not associated with myoferlin hyperexpression, whereas a high Fuhrman nuclear grade was significantly associated with myoferlin hyperexpression. Kaplan-Meier analysis revealed that patients with T stage >2, Fuhrman nuclear grade >2, and those with myoferlin hyperexpression had poorer disease-free survival compared to those with lower T stage, lower Fuhrman nuclear grade, and myoferlin hypoexpression (all p <0.001). Furthermore, myoferlin hyperexpression was significantly associated with disease-free survival on Cox regression analysis (hazard ratio, 4.604; 95% confidence interval, 1.893–11.199; p = 0.001).ConclusionMyoferlin expression could be a potential prognosticator in patients with ccRCC, and might be a useful marker for oncologic surveillance in such patients.

Loss of CD15 expression in clear cell renal cell carcinoma is correlated with worse prognosis in Chinese patients.

To explore the role of CD15 expression in the prognosis of clear cell renal cell carcinoma (ccRCC) in Chinese patients. The study included 301 patients who had undergone surgery for localized ccRCC. All paraffin-embedded tumor sections were collected to make a set of tissue microarrays. CD15 expression was assessed by immunohistochemistry. The relationship between CD15 expression and survival parameters, clinicopathology features was assessed. Kaplan-Meier and Cox proportional hazards model were utilized to determine the correlation between CD15 expression and overall survival (OS). The median follow-up time was 54.6 months (range, 3-121 months). The positive rate of CD15 expression was 81.7% (246/301). The cut-off value of CD15 expression was defined as the maximum for Youden index by plotting the receiver operating characteristic curve for survival status. As the threshold was 0.5, all cases were divided into two groups: positive expression group and negative expression group. In correlation analysis, loss of CD15 expression was correlated with female gender, higher Fuhrman nuclear grade, with sarcomatoid differentiation, with necrosis, and with vascular invasion. Kaplan-Meier analysis indicated that the OS time of patients with loss of CD15 expression was shorter than that of patients with positive CD15 expression (P = 0.013). CD15 is a significant prognostic factor in clear cell renal cell carcinoma.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma (ccRCC) and its association with PD-L1 expression.

4573 Background: Preclinical models show that c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). The relationship between c-Met and PD-L1 in human ccRCC is not well characterized. We compared c-Met expression between primary and metastatic sites in ccRCC tissues and evaluated the association with PD-L1 expression. Methods: Pairedprimary and metastatic samples from 45 ccRCC patients were included. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab, VARI) and calculated by a combined score (CS, 0-300) as: intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression was previously assessed by IHC (PMID: 26014095). c-Met expression (average c-Met CS) between paired primary and metastatic samples were compared using Wilcoxon signed-rank test. Associations of c-Met expression with PD-L1 expression (+/-) and other clinical features were assessed with Wilcoxon rank-sum tests. Results: Our cohort included 45 primary ccRCCs and 54 corresponding metastases. c-Met expression was higher in metastatic sites compared to primary (c-Met CS: 55 vs. 28, p=0.0003) and was numerically-greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression was associated with higher FNG and T-stage in both primary and metastatic sites (Table). Conclusions: Higher c-Met expression in metastases compared to paired primary tumors in our cohort of ccRCC suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. Although the observation of higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination trials. [Table: see text]

Size and Volumetric Growth Kinetics of Renal Masses in Patients With Renal Cell Carcinoma

To examine radiological growth patterns as an indicator of renal tumor aggressiveness, we studied about the growth kinetics of small renal mass (SRM, ≤4 cm) and possible associated factors for high Fuhrman nuclear grade (≥3). From January 1999 to May 2013, 112 cases (111 patients) diagnosed as renal cell carcinoma after surgical treatment were reviewed retrospectively. Patients who had at least two preoperative contrast-enhanced computed tomography scans more than 6 months apart were included. The mean age was 59 years and mean computed tomography follow-up duration was 20 months. Median tumor size and tumor volume at diagnosis were 1.45 cm and 1.80 cm(3), respectively. Median linear growth rate (LGR) was 0.28 cm/year. Median volumetric growth rate was 0.75 cm(3)/year and median volume doubling time was 1.41 years. Tumor growth rate was not different to histologic type (P = .271). High LGR was a significant factor associated with high Fuhrman grade in multivariate analysis (odds ratio 3.877, 95% confidence interval 1.715-8.765). Volumetric growth rate (P <.001) and volume doubling time (P = .004) were positive correlation with initial mass size, but not LGR (P = .764). In our growth kinetics study, generally small renal mass grew slowly. High LGR could be a risk factor for high-grade tumor (Fuhrman grade ≥3).

Nuclear expression and clinical significance of phosphohistidine phosphatase 1 in clear-cell renal cell carcinoma.

To explore expression and clinical relevance of phosphohistidine phosphatase 1 (PHPT1) in clear-cell renal cell carcinoma. Patients with clear-cell renal cell carcinoma who underwent radical or nephron-sparing nephrectomy were enrolled. Correlations between PHPT1 expression and demographic and clinical characteristics were analysed prospectively. In total, 122 patients (78 male/44 female) were included. In normal kidney tissue, PHPT1 expression was observed only in the proximal tubule. High PHPT1 expression levels were associated with larger tumour size, higher Fuhrman nuclear grade and advanced pathological tumour-node-metastasis (pTNM) stage compared with low PHPT1 expression levels. Patients with low PHPT1 expression showed better overall survival and progression-free survival compared with those with high PHPT1 expression. In addition, multivariate analysis showed that nuclear grade and pTNM stage were independent predictors of progression-free survival and overall survival in patients with clear-cell renal cell carcinoma. PHPT1 expression was also an independent predictor of overall survival but not progression-free survival. PHPT1 was expressed in the epithelium of proximal tubuli and nuclei of clear-cell renal cell carcinoma tissue samples. High levels of 14 kDa phosphohistidine phosphatase protein were negatively associated with overall survival and progression-free survival in patients with clear-cell renal cell carcinoma.

Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma.

PD-L1 expression in primary clear-cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11 of 53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (P = 0.51). Tumor cell PD-L1 positivity was associated with higher T stage (P = 0.03) and higher Fuhrman nuclear grade (P < 0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (P < 0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (P = 0.82). The heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as a predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, because PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false-negative results, these areas should be specifically selected for assessment.

High expression of APRIL correlates with poor prognosis in clear cell renal cell carcinoma

IntroductionThe members of the Tumor Necrosis Factor Superfamily (TNFSF), including A PRoliferation Inducing Ligand (APRIL), have been studied in RCC and other tumors. In this study, we investigated the expression of APRIL in resected clear cell renal cell carcinoma (CCRCC) samples by immunohistochemistry (IHC) and analyzed its association with the clinicopathologic characteristics and prognosis of the patients. MethodsWe examined 206 CCRCC samples from patients who underwent radical or partial nephrectomy at Seoul National University Hospital between 1999 and 2002. Tissue microarray (TMA) blocks were made, and immunohistochemical staining for APRIL expression was performed. ResultsWe classified the IHC results as high expression or low expression. Of the 206 cases, 89 cases (43.2%) were classified as showing high expression, and 117 cases (56.8%) showed low expression. The high expression of APRIL was significantly correlated with higher Fuhrman nuclear grade and higher pathologic stage (p=0.000 and 0.004), and we observed that the high expression of APRIL was significantly correlated with the overall survival of the patients (p=0.045) and cancer-specific survival (p=0.020), but was not correlated with disease-free survival (p=0.106). In multivariate analysis adjusted for Fuhrman nuclear grade and pathologic stage, the high expression of APRIL was not an independent prognostic factor for CCRCC, as determined by overall survival (p=0.830) and cancer-specific survival (p=0.792). ConclusionsWe found that the high expression of APRIL in CCRCCs was correlated with high Fuhrman nuclear grade, high pathologic stage, and poor overall and cancer-specific survival of the patients. However, it did not correlate with disease-free survival and was not an independent prognostic factor.