High-grade Clear Cell Renal Cell Carcinoma Research Articles

Alpha-methyl CoA racemase (AMACR) reactivity across the spectrum of clear cell renal cell neoplasms

a-Methylacyl coenzyme A racemase (AMACR) is traditionally considered to be a marker of papillary renal cell carcinoma. However, AMACR expression can be seen in other renal tumors. The aim of this study was to investigate AMACR immunoreactivity within the spectrum of clear cell renal cell neoplasms.Fifty-three clear cell renal epithelial tumors were used in assembling the following four cohorts: low grade (LG) clear cell renal cell carcinoma (CCRCC), high grade (HG) CCRCC, CCRCC with cystic changes, and multilocular cystic renal neoplasm of low malignant potential (MCRNLMP). Representative blocks were stained for AMACR, using two different clones (SP52 and OV-TL12/30).There were at least some AMACR immunoreactivity in 77.8 % and 68.9 % of CCRCCs (using SP52 and OV-TL12/30 clone, respectively). Moderate to strong positivity, or positivity in more than one third of the tumor (even weak in intensity) was detected in 46.7 % of CCRCCs using SP52 and in 48.9 % of CCRCC using OV-TL12/30 clone. The highest AMACR reactivity was observed in HG CCRCC (60 % by SP52 and 66.7 % by OV-TL12/30). Strong and diffuse AMACR positivity was detected in 8.9 % of all CCRCCs. AMACR immunoreactivity in MCRNLMP was 37.5 % (SP52 clone) and 25 % (OV-TL12/30 clone).We demonstrated relatively high expression rate of AMACR in CCRCC, while very variable in intensity and distribution. This finding may have diagnostic implications especially in limited samples (i.e., core biopsies), as AMACR positivity does not exclude the diagnosis of CCRCC.

Cystic Clear Cell Renal Cell Carcinoma: A Morphological and Molecular Reappraisal.

A wide variety of renal neoplasms can have cystic areas. These can occur for different reasons: some tumors have an intrinsic cystic architecture, while others exhibit pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated with low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway, and they are more frequent in patients suffering from VHL disease. The differential diagnosis of multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumor includes cystic forms, knowledge of the criteria required for a differential diagnosis is mandatory.

Tumors masquerading as type 2 papillary renal cell carcinoma: pathologists' ever-expanding differential diagnosis for a heterogeneous group of entities.

Although papillary renal cell carcinoma has historically been classified as either type 1 or type 2, data from The Cancer Genome Atlas (TCGA) has demonstrated significant genomic heterogeneity in tumors classified as "type 2 papillary renal cell carcinoma" (T2PRCC). Papillary renal cell carcinoma is expected to have a favorable clinical course compared to clear cell renal cell carcinoma (CCRCC). However, tumors with poor outcome more similar to CCRCC were included in the T2PRCC cohort studied by the TCGA. The differential diagnosis for T2PRCC includes a variety of other renal tumors, including aggressive entities such as TFE3 translocation-associated renal cell carcinoma, TFEB-amplified renal cell carcinoma, fumarate hydratase-deficient renal cell carcinoma, high-grade CCRCC, and collecting duct carcinoma. Accurate classification of these tumors is important for prognostication and selection of therapy.

Deciphering intratumor heterogeneity in clear cell renal cell carcinoma utilizing clinicopathologic and molecular platforms

Clear cell renal cell carcinoma (CCRCC) is a common renal malignancy known for its lethality and chromosome 3p aberrancies associated with loss of VHL. It has been shown that additional prognostic molecular markers exist in other transcriptional modifiers such as BAP1 and SETD2. Molecular heterogeneity has been described between primary and metastatic sites as well as genetic diversity in spatial tumor analysis; however, morphologic and proteogenomic heterogeneity information is lacking. We assessed 77 nephrectomy specimens with a diagnosis of CCRCC for morphologic architectural patterns including nodular growth patterns and variations in WHO/ISUP grade. Evaluation of highly heterogeneous areas with immunohistochemical (IHC) staining for BAP1, UCHL1, SETD2, and CAIX was performed and correlated with morphologic and histology data. Ultimately, high variability in the morphologic and histological findings matched the complexity of the IHC findings. Alterations in expression of CAIX and UCHL1 correlated with alterations in transcriptional regulators BAP1 and SETD2 within the tumor. High-grade morphology, such as eosinophilia, were areas enriched for alteration of biomarker expression. This highly complex data set of morphologic and biomarker characteristics highlights the heterogeneity of morphology amongst high-grade CCRCC tumors.

Whole exome sequencing reveals molecular mechanisms of clear cell renal cell carcinoma with sarcomatoid differentiation

Objective: To investigate the molecular mechanisms of clear cell renal cell carcinoma (CCRCC) with sarcomatoid differentiation (CCRCCS) and to explore new therapeutic targets for CCRCCS. Methods: Whole exome sequencing was performed on the carcinomatous and sarcomatoid components of five CCRCCS cases collected from January 2017 to October 2018. A highly frequent non-synonymous mutation of cadherin 23 (CDH23) was revealed by whole exome sequencing and further studied in additional samples. The sequencing of CDH23 in 40 specimens with CCRCCS and 50 specimens with CCRCC collected from January 2008 to October 2018 were conducted using Sanger sequencing. Immunohistochemistry was carried out to detect the protein expression of CDH23 in the additional 90 cases. Results: Carcinomatous and sarcomatoid components of CCRCCS shared most of the somatic single-nucleotide variants (SSNVs) as revealed through whole exome sequencing, while the sarcomatoid component had higher overall SSNVs than carcinomatous component. A highly frequent non-synonymous mutation of CDH23 (p.Arg1804Gln) was observed both in carcinomatous and sarcomatoid components of CCRCCS that resulted in the alteration in the highly conserved calcium-binding site mediating the functions of cadherins. In the additional 90 specimens, CDH23 mutation was much frequently detected in CCRCCS than that in CCRCC samples and even the high grade CCRCC. CDH23 protein was not or weakly expressed in most CCRCCS specimens with CDH23 mutation. There was an correlation between CDH23 gene mutation and negative expression of its protein (r=0.598, P<0.01). Conclusions: The present study reveals, for the first time, that the mutation of CDH23 (p.Arg1804Gln) is a genetic risk factor for CCRCCS. It is associated with the decreased expression of CDH23 protein, resulting in the absence of cadherin function of CDH23, indicating that CDH23 mutation may be involved in the sarcomatoid transformation in CCRCCS. Thus, CDH23 might be a potential therapeutic target for CCRCCS.

Application of diffusion kurtosis tensor MR imaging in characterization of renal cell carcinomas with different pathological types and grades

BackgroundTo probe the feasibility and reproducibility of diffusion kurtosis tensor imaging (DKTI) in renal cell carcinoma (RCC) and to apply DKTI in distinguishing the subtypes of RCC and the grades of clear cell RCC (CCRCC).MethodsThirty-eight patients with pathologically confirmed RCCs [CCRCC for 30 tumors, papillary RCC (PRCC) for 5 tumors and chromophobic RCC (CRCC) for 3 tumors] were involved in the study. Diffusion kurtosis tensor MR imaging were performed with 3 b-values (0, 500, 1000s/mm2) and 30 diffusion directions. The mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr) values and mean diffusity (MD) for RCC and contralateral normal parenchyma were acquired. The inter-observer agreements of all DKTI metrics of contralateral renal cortex and medulla were evaluated using Bland-Altman plots. Statistical comparisons with DKTI metrics of 3 RCC subtypes and between low-grade (Furman grade I ~ II, 22 cases) and high-grade (Furman grade III ~ IV, 8 cases) CCRCC were performed with ANOVA test and Student t test separately. Receiver operating characteristic (ROC) curve analyses were used to compare the diagnostic efficacy of DKTI metrics for predicting nuclear grades of CCRCC. Correlations between DKTI metrics and nuclear grades were also evaluated with Spearman correlation analysis.ResultsInter-observer measurements for each metric showed great reproducibility with excellent ICCs ranging from 0.81 to 0.87. There were significant differences between the DKTI metrics of RCCs and contralateral renal parenchyma, also among the subtypes of RCC. MK and Ka values of CRCC were significantly higher than those of CCRCC and PRCC. Statistical difference of the MK, Ka, Kr and MD values were also obtained between CCRCC with high- and low-grades. MK values were more effective for distinguishing between low- and high- grade CCRCC (area under the ROC curve: 0.949). A threshold value of 0.851 permitted distinction with high sensitivity (90.9%) and specificity (87.5%).ConclusionOur preliminary results suggest a possible role of DKTI in differentiating CRCC from CCRCC and PRCC. MK, the principle DKTI metric might be a surrogate biomarker to predict nuclear grades of CCRCC.Trial registrationChiCTC, ChiCTR-DOD-17010833, Registered 10 March, 2017, retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=17559.

Evaluation of Human Kidney Injury Molecule 1 (hKIM-1) Expression in Tumors From Various Organs by Messenger RNA In Situ Hybridization.

Human kidney injury molecule 1 (hKIM-1) is a sensitive and specific marker for detection of clear cell renal cell carcinoma (CRCC), papillary renal cell carcinoma (PRCC), and ovarian clear cell carcinoma (OCCC). Its use was limited to a few surgical pathology laboratories because this specific antibody to hKIM-1 was not commercially available. We investigated the diagnostic utility of RNA in situ hybridization/RNAscope in the detection of hKIM-1 in tumors from various organs. RNAscope for hKIM-1 was performed on 1,252 cases on tissue microarray sections, including CRCC (n = 185), PRCC (n = 59), chromophobe renal cell carcinoma (n = 18), oncocytoma (n = 12), OCCC (n = 27), and metastatic CRCC (n = 46). Fifty-nine (100%) of 59 PRCCs, 94 (95%) of 99 low-grade CRCCs, 83 (96%) of 86 high-grade CRCCs, and 24 (89%) of 27 OCCCs, and 44 (96%) of 46 metastatic CRCCs were positive for hKIM-1. In contrast, hKIM-1 expression was not seen in normal renal tubules or in most nonrenal tumors. Low-level expression could be seen in a small percentage of urothelial, hepatocellular, and colon carcinomas. hKIM-1 is a sensitive and relatively specific marker (1) for diagnosing PRCC, CRCC, and OCCC when working on a tumor of unknown origin and (2) for differentiating CRCC from chromophobe renal cell carcinoma and oncocytoma.

Diffusion weighted imaging in differentiation of the clear cell RCC from the major non-clear cell RCC subtypes

Introduction. Renal cell carcinoma (RCC) is the most common malignant renal tumor in adults accounting for 80-90% of primary malignant adult renal neoplasms. RCC represents a very heterogenous groups of tumors with a number of distinct histological varieties, of which the major 3 subtypes are clear cell RCC (70-80%), papillary RCC (13-20%), and chromophobe RCC (5%). Imaging features are varied from solid and relatively homogenous appearance to markedly heterogenous appearance with cystic changes, hemorrhage and necrosis. The use of diffusion weighted imaging (DWI) for RCC subtyping and also for differentiation of high grade and low grade tumors has been showed to be useful in many studies in the literature. Aim. In this study, we aimed to determine the comparative contribution of DWI in differentiation of the clear cell RCC from the major non-clear cell RCC subtypes at standard high b-value (1000 s/mm2) versus low b-value (500 s/mm2). In addition, we also aimed to assess the diagnostic performance of DWI for differentiating high grade clear cell RCC from low grade clear cell RCC based on Fuhrman grades in our patients. Material and methods. 62 cases with a prediagnosis of RCC according to MRI findings including DWI sequence with histological verification and subtyping of renal cortical tumor following a total or partial nephrectomy were included in the study. Results. Among 62 cases, 46 were male and 16 were female, with mean age of 59.5 ± 15.7. Pathological diagnoses of 62 cases were as follows, clear cell RCC, (44) papillary cell RCC (14) and chromophobe cell RCC (4). They were divided into two groups as clear cell RCC group (44 cases) and non-clear cell RCC group (18 cases). There was no statistically significant difference between the mean ADC values of clear cell and non-clear cell groups at b-value of 1000 s/mm2 (p&gt;0.05). However, the mean ADC level for clear cell RCC group at b-value of 500 s/mm2 were significantly higher than for non-clear cell RCC group (p&lt;0.05). When a value of 0.99x10-3 mm2/s was set as cut-off for ADC at b-factor of 500 s/mm2, differentiation was achieved with a high sensitivity (91%) and specificity (56%). Regarding the diagnostic performance of DWI for differentiating high from low Fuhrman grades clear cell RCCs, there was no statistically significant difference between the ADC values of Grade I-II clear cell RCC cases and Grade III-IV clear cell RCC cases at b-factor of 1000 s/mm2 (p&gt;0.05). However, ADC values for grade III-IV group was statistically significantly lower than ADC values for Grade I-II group at b-factor of 500 s/mm2 level. Conclusion. ADC measurements at moderate b-value of 500 s/mm2 were more sensitive in subtyping and grading of RCC cases. This technique can be used in clinical practice as a fast and additional sequence in abdominal MRI.

A novel highly frequent single‑nucleotide polymorphism site of cadherin 23 in clear cell renal cell carcinoma with sarcomatoid differentiation based on whole exome sequencing.

Clear cell renal cell carcinoma (CCRCC) with sarcomatoid differentiation (CCRCCS) displays invasive behavior, poor prognosis, and poor therapeutic response. The present study was aimed to gain new insights into the molecular mechanisms of sarcomatoid transformation, and identify new prognostic and therapeutic targets for CCRCCS. Whole exome sequencing was performed on matched carcinomatous and sarcomatoid elements from five specimens with CCRCCS. A non‑synonymous single‑nucleotide polymorphism (SNP) of cadherin23 (CDH23) was further studied through Sanger sequencing in expanded 40specimens with CCRCCS and 50specimens with CCRCC. Carcinomatous and sarcomatoid elements shared most somatic single‑nucleotide variants (SSNVs) as revealed through whole exome sequencing. Sarcomatoid element had higher overall SSNVs than carcinomatous element. A highly frequent mutation of CDH23 (rs3802711) was observed in CCRCCS that resulted in an alteration in the highly conserved calcium‑binding site in the three‑dimensional (3D) structure mediating the functions of cadherins. In the expanded 90 specimens, CDH23 SNP (rs3802711) was a highly frequent mutation in CCRCCS than that in all CCRCC samples and even high grade CCRCC. Cox multivariate analysis indicated that CDH23 (rs3802711) genotype was an independent prognostic factor affecting the overall survival of the cohort. CDH23 gene and protein were negatively or weakly expressed in most CCRCCS specimens with CDH23 mutation. The present study revealed, for the first time, that the CDH23 (rs3802711) was a highly genetic risk factor for CCRCCS. It was associated with the decreased expression of CDH23 protein, resulting in the absence of cadherin function of CDH23, indicating that the CDH23 mutation may be involved in the sarcomatoid transformation in CCRCCS. Collectively, a novel and specific SNP of CDH23 was identified in CCRCCS and a new candidate cadherin involved in EMT was revealed. Furthermore, a new prognostic evaluation factor and potential therapeutic target for CCRCCS was identified.

Reactivity of CK7 across the spectrum of renal cell carcinomas with clear cells.

Current available data on cytokeratin 7 (CK7) immunostaining pattern in the clear cell renal cell carcinoma (RCC) spectrum is conflicting. The aim of this study was to assess CK7 immunoreactivity within the spectrum of clear cell renal neoplasms, including clear cell RCC, multicystic renal neoplasm of low malignant potential and clear cell papillary RCC-like tumours. We analysed two clones of CK7 and two tumour blocks for a total of 75 cases divided into five distinct groups: (i) low-grade clear cell RCC, (ii) high-grade clear cell RCC, (iii) multicystic renal neoplasm of low malignant potential, (iv) clear cell RCC with cystic changes and (v) clear cell papillary RCC-like tumours. We found the highest CK7 reactivity in low-grade clear cell RCC, multicystic renal neoplasm of low malignant potential and clear cell papillary RCC-like groups, ranging from 60% to 93%. Our findings show that CK7 immunoreactivity in clear cell RCC is variable, and the extent of staining depends on the grade and architectural growth patterns of the tumours.

Clear cell renal cell carcinoma: CT-based radiomics features for the prediction of Fuhrman grade

ObjectivesTo discriminate low grade (Fuhrman I/II) and high grade (Fuhrman III/IV) clear cell renal cell carcinoma (CCRCC) by using CT-based radiomic features. Methods161 and 99 patients diagnosed with low and high grade CCRCCs from January 2011 to May 2018 were enrolled in this study. 1029 radiomic features were extracted from corticomedullary (CMP), and nephrographic phase (NP) CT images of all patients. We used interclass correlation coefficient (ICC) and the least absolute shrinkage and selection operator (LASSO) regression method to select features, then the selected features were constructed three classification models (CMP, NP and with their combination) to discriminate high and low grades CCRCC. These three models were built by logistic regression method using 5-fold cross validation strategy, evaluated with receiver operating characteristics curve (ROC) and compared using DeLong test. ResultsWe found 11 and 24 CMP and NP features were independently significantly associated with the Fuhrman grades. The model of CMP, NP and Combined model using radiomic feature set showed diagnostic accuracy of 0.719 (AUC [area under the curve], 0.766; 95% CI [confidence interval]: 0.709-0.816; sensitivity, 0.602; specificity, 0.838), 0.738 (AUC, 0.818; 95% CI:0.765-0.838; sensitivity, 0.693; specificity, 0.838), 0.777(AUC, 0.822; 95% CI: 0.769-0.866; sensitivity, 0.677; specificity, 0.839). There were significant differences in AUC between CMP model and Combined model (P = 0.0208), meanwhile, the differences between CMP model and NP model, NP model and Combined model reached no significant (P = 0.0844, 0.7915). ConclusionsRadiomic features could be used as biomarker for the preoperative evaluation of the CCRCC Fuhrman grades.

Complete and Prolonged Response of Renal Cell Carcinoma With Rhabdoid Features to Checkpoint Inhibitor Therapy.

Checkpoint inhibitor immunotherapy has recently been proven to be an attractive treatment option for a wide variety of malignancies. Nivolumab, an anti-programmed cell death protein-1 antibody, has been proven effective and safe in treating metastatic renal cell carcinoma (RCC) with a clear cell component. We report the case of a patient with high-grade clear cell RCC with rhabdoid features who has achieved a durable complete response with nivolumab therapy after multiple surgical interventions and progression on pazopanib. Genomic evaluation in this case was characterized in part by a PBRM1 variant, similar to the only other described case of RCC with rhabdoid features obtaining a complete response to nivolumab. This case supports the potential utility of checkpoint inhibitors in aggressive, rare subtypes of RCC where there are limited options for therapy.

The Probability of Aggressive Versus Indolent Histology Based on Renal Tumor Size: Implications for Surveillance and Treatment

BackgroundWhile the probability of malignant versus benign histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent malignant tumors can be managed with active surveillance. ObjectiveTo characterize the probability of aggressive versus indolent histology based on radiographic tumor size. Design, setting, and participantsWe evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990 and 2010. Pathology was reviewed by one genitourinary pathologist. High-grade clear-cell renal cell carcinoma (RCC), high-grade papillary RCC, collecting duct RCC, translocation-associated RCC, hereditary leiomyomatosis RCC, unclassified RCC, and malignant non-RCC tumors were all considered aggressive, as well as any tumors demonstrating coagulative necrosis (except low-grade papillary RCC) or sarcomatoid differentiation. The remaining benign and malignant tumors were considered indolent. Outcome measurements and statistical analysisCancer-specific survival (CSS) was estimated using the Kaplan-Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed. Results and limitationsOf the 2650 patients included, there were 1860 patients with indolent tumors (300 benign; 1560 malignant) and 790 with aggressive tumors. The 10-yr CSS was 96% for indolent malignant tumors and 81% for aggressive malignant tumors. The predicted percentages of any malignant histology as well as aggressive histology increased with tumor size. Specifically, 2cm, 3cm, and 4cm tumors have an estimated 84%, 87%, and 88% likelihood of malignancy, respectively, and an 18%, 24%, and 29% likelihood of aggressive histology, respectively. For any given tumor size, men had a greater chance of aggressive histology than women. Potential limitations of this observational surgical cohort include selection bias. ConclusionsWe present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for initial patient counseling and management. Patient summaryActive surveillance is an option for kidney masses, even if they are malignant. Beyond knowing whether the mass is benign or cancer, it is important to know whether or not it is an aggressive tumor. This study presents tumor size-specific and sex-specific estimates of the probability of cancer overall and aggressive cancer among patients with a kidney mass in order to aid with initial decision-making.

The additional utility of apparent diffusion coefficient values of clear-cell renal cell carcinoma for predicting metastasis during clinical staging.

BackgroundThe apparent diffusion coefficient (ADC) value is known to be an indicator of tumor activity. The ADC value of high-grade clear-cell renal cell carcinoma (RCC) is significantly lower than that of low-grade clear-cell RCC.PurposeTo investigate the utility of ADC values of clear-cell RCC by comparing ADC values between groups with T1a RCC (tumor size ≤ 4 cm) without metastasis and the group with metastasis.Material and MethodsA retrospective review was performed on 51 patients with 51 RCCs who underwent 1.5 T magnetic resonance imaging (MRI) for evaluating a renal mass confirmed pathologically to be clear-cell RCC between January 2010 and August 2014. We compared ADC values between group A (T1a RCC without metastasis, T1aN0M0) and group B (RCC with metastasis) using the Mann–Whitney U test.ResultsThe patients were divided into group A (n = 30; tumor size: median, 24.5 mm; range, 8–40 mm; ADC value [×10−3 mm2/s]: median, 1.71; range, 1.23–2.24) and group B (n = 21; tumor size: median, 87.5 mm; range, 18–150 mm; ADC value [×10−3 mm2/s]: median, 1.35; range, 0.91–1.94). The ADC value differed significantly between the two groups. The area under the receiver operating characteristic curve was 0.869. Using the optimum cutoff value (1.552 × 10−3 mm2/s), ADC had a sensitivity of 80.0% and specificity of 81.0%.ConclusionThere was a statistically significant difference in the ADC between group A (T1a clear-cell RCC without distant metastasis) and group B (advanced clear-cell RCC with lymph node metastasis or distant metastasis).

Significance of amyloid A immunoexpression in the prognosis of renal cell carcinoma.

The study investigated immunoexpression of amyloid A (AA) in clear cell renal cell carcinoma (CCRCC) and evaluated its clinicopathologic correlation, particularly in disease progression. Expression of AA protein was evaluated in patients with CCRCC by immunohistochemistry. 146 cancerous tissue samples from 86 male and 60 female patients were studied. The relationship between AA protein expression and TNM stage, nuclear grade, renal capsule invasion, perirenal invasion, and survival of the patients were assessed. Thirty four percent of CCRCC cases were AA positive. The positive AA immunoexpression was related to higher Fuhrman nuclear grade, presence of perirenal invasion of the tumor, and poor survival of patients with CCRCC. There was not any statistically significant difference between patients' gender, status of capsule invasion, and stages of the tumor in terms of AA immunoexpression. Tumor stage (Hazard ratio (HR) = 7.76 (95% CI: 2.43-24.8) for stage 3 and HR = 29.9 (95% CI: 6.97-128.32) for stage 4) and AA immunoexpression (HR = 2.16 (95% CI: 1.01-4.64) were found to be associated with survival of the patients with CCRCC in Cox regression analysis. Immunoexpression of AA was increased in high grade CCRCCs. Immunoexpression of AA was associated with poor survival in patients with CCRCC. Thus, AA staining might be used as a useful immunohistological marker for the prediction of poor prognosis in renal cell cancer.

Preoperative evaluation of renal cell carcinoma by using 18F-FDG PET/CT.

PurposeThis study aimed to characterize the FDG uptake of renal cell carcinoma (RCC) by the pathological subtype and nuclear grade.Patients and MethodsWe retrospectively identified patients who underwent 18F-FDG PET and subsequent partial or radical nephrectomy for renal tumors. The relationships of the SUV of renal tumor with subtypes, nuclear grade, and clinicopathological variables were investigated.ResultsNinety-two tumors were analyzed, including 52 low-grade (G1 and G2) and 18 high-grade (G3 and G4) clear cell RCC; 7 chromophobe, 5 papillary, and 1 unclassified RCC; and 9 benign tumors (7 angiomyolipoma and 2 oncocytoma). The SUVs of high-grade clear cell RCC (mean ± SD, 6.8 ± 5.1) and papillary RCC (6.6 ± 3.7) were significantly higher than that of the controls (2.2 ± 0.3). The SUV of high-grade clear cell RCC was higher than that of low-grade tumors (median, 4.0 vs. 2.2; P < 0.001). The optimal SUV cutoff value of 3.0 helped to differentiate high-grade from low-grade clear cell RCC, with 89% sensitivity and 87% specificity. On multiple regression analysis, a high grade was the most significant predictor of SUV for clear cell RCC.ConclusionsFDG uptake higher than that observed in normal kidney tissues suggests a high-grade clear cell RCC or papillary RCC subtype. FDG-PET using SUV may have a role in prediction of pathological grade of renal tumor.

Low-grade metastases in high-grade clear cell renal cell carcinomas: A clinicopathologic study of 4 cases with an insight into the role of mesenchymal-to-epithelial transition process.

Clear cell renal cell carcinoma (CCRCC) frequently develops distant metastases. However, high-grade primary CCRCC rarely leads to low-grade metastases. Cellular changes occurring during neoplastic progression known as epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions explain this apparent contradiction. Four high-grade CCRCCs, which lead to low-grade metastases, are analyzed in this study, with the focus on epithelial-to-mesenchymal and mesenchymal-to-epithelial processes. Clinicopathologic data have been collected retrospectively and immunohistochemistry has been performed with E-cadherin, N-cadherin, vimentin, and WT-1. Three cases had organ-confined disease (2 pT2 and 1 pT1b). Three cases were G3 and 1 case was G4. Lung (3 cases), bone (2 cases), and pancreas (1 case) were the metastatic organs (2 patients developed multiple metastases). Metastases were G1 in all the cases. Average elapsed time between the primary tumor and the metastasis was 35.5 months. Three patients died of disease after 36, 120, and 180 months of follow-up, respectively. One patient is alive without disease after 75 months of follow-up. E-cadherin and N-cadherin showed concordant immunostaining patterns between primaries and metastases but inverse when correlated with Fuhrman grade. Hence, E-cadherin was positive in G3 cases and negative in G4, whereas N-cadherin was negative in G3 and positive in G4. Vimentin was positive in primaries and metastases only in 2 cases. WT-1 was consistently negative in all cases. In conclusion, pathologists must remember that high-grade CCRCC may develop low-grade metastases. Cadherin switching seems to be related to Fuhrman grade in this group of cases. This preliminary observation must be confirmed in longer studies.

Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy

Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear-cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid clear-cell renal cell carcinoma. We assessed cancer-related mutations from eight cases using a clinical next-generation exome-sequencing platform. The transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid clear-cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear-cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear-cell renal cell carcinoma are often discordant across different morphologic regions, whereas the gene expression program is relatively stable. Molecular profiling of clear-cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions.

Comparison of utility of tumor size and apparent diffusion coefficient for differentiation of low- and high-grade clear-cell renal cell carcinoma

There is a significant correlation between tumor size and tumor grade for clear-cell renal cell carcinoma (RCC) in pathology. Thus, apparent diffusion coefficient (ADC) of clear-cell RCC might be influenced by tumor size. To compare the utility of tumor size and ADC for distinguishing low-grade from high-grade clear-cell RCC. Forty-nine patients undergoing preoperative magnetic resonance imaging were retrospectively assessed. ADC values were calculated using b-value combinations of 0 and 800 s/mm(2) at 1.5 T. Two radiologists in consensus measured ADC values via small region of interest (ROI) (mean ROI area, 88.8 mm(2); range, 80-108 mm(2)) placement on an area of solid tumor on a single slice. Maximum tumor diameter was measured at the maximum tumor area. A single pathologist reviewed all pathological slides to determine the nuclear grade according to the Fuhrman classification. The utility of ADC, tumor size, and ADC/size ratio for distinguishing low-grade from high-grade tumors was assessed. Receiver-operating characteristic (ROC) analysis and regression analysis of the each index were performed. The correlation between ADC and tumor size was also investigated. The 49 clear-cell RCC included 34 low-grade and 15 high-grade tumors. The differences of ADC, tumor size, and ADC/size ratio between high-grade and low-grade tumors were statistically significant (P <0.05). The area under the ROC curve of ADC, tumor size, and ADC/size ratio were 0.802, 0.763, and 0.804 respectively. However, using regression analysis, only ADC (P <0.05) was statistically significant index as independent risk factors for high-grade clear-cell RCC. Moreover, weak significant correlation was observed between tumor size and ADC (R(2) = 0.3865, P <0.01). There was a weak significant correlation between tumor size and ADC value of clear-cell RCC. Using ROC and regression analysis, ADC was statistically significant index for distinguishing low-grade from high-grade clear-cell RCC more than tumor size and ADC/size ratio.

Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke.

Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.