Renal cell carcinoma with unusual morphological features: the clinical utility of next-generation sequencing in distinguishing renal cell tumors.

327 Background: This phase 2 randomized discontinuation trial evaluated tivozanib, a potent and selective vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 kinase inhibitor. Median progression-free survival (PFS) in all pts was 11.8 mo, and the objective response rate (ORR) was 27%. Methods: Pts received 1.5 mg/d tivozanib (3 wk on, 1 wk off = 1 cycle). A retrospective analysis evaluated efficacy and safety by histologic subtype. Response was evaluated by independent radiology review using standard RECIST criteria. Results: 272 pts were enrolled: 70% were male; median age was 56 y (range, 26–79). 226 (83%) pts had clear cell (CC) RCC; 46 had non–clear cell (NCC) RCC, including 11 with papillary RCC. Of pts with CC RCC, 176 (78%) had undergone nephrectomy; of pts with NCC RCC, 23 (50%) had undergone nephrectomy. Median treatment duration was 8.5 mo (range, 0.03– 23.8) as of the data cutoff. Median PFS was 12.5 mo (range, 9.9–17.7) for pts with CC RCC, not yet reached for pts with papillary RCC, and 5.4 mo (range, 3.7–12.0) for pts with other NCC subtypes. ORR and disease control rate (DCR; ORR + stable disease), respectively, were 29% and 85% for pts with CC RCC, 18% and 100% for pts with papillary RCC, and 17% and 74% for pts with other NCC subtypes. For pts with CC RCC, median PFS, ORR, and DCR, respectively, were 14.8 mo, 32%, and 88% for those who had undergone nephrectomy and 8.9 mo, 18%, and 76% for those who had not. Among pts with NCC RCC, median PFS was 6.6 mo for pts who had undergone nephrectomy and 7.2 mo for pts without nephrectomy; ORR was 17% for both NCC subgroups, with a DCR of 78% for pts who had undergone nephrectomy and 83% for pts who had not. Common drug- related adverse events (AEs) for pts with CC and NCC RCC, respectively, included hypertension (49% and 48%), dysphonia (22% and 22%), asthenia (12% and 13%), and diarrhea (13% and 9%). The most common grade ≥3 drug-related AE was hypertension (CC, 8%; NCC, 4%). Conclusions: Disease control was observed for pts with all RCC histologic subtypes. The rate of AEs was similar among patients with CC and NCC RCC and consistent with that of a selective VEGFR inhibitor with minimal off-target toxicities. Tivozanib is currently being tested in a phase 3 trial in pts with CC RCC. [Table: see text]

To retrospectively evaluate whether the enhancement patterns of pathologically proved clear cell, papillary, and chromophobe renal cell carcinomas (RCCs) measured on clinical dynamic contrast agent-enhanced magnetic resonance (MR) images permit accurate diagnosis of RCC subtype. This study was Institutional Review Board approved and HIPAA compliant; informed consent was waived. One hundred twelve patients (76 men, 36 women; age range, 25-88 years; mean age, 58.1 years) underwent MR imaging of 113 renal masses (mean diameter, 5.4 cm) with pathologic diagnoses of clear cell (n = 75), papillary (n = 28), or chromophobe (n = 10) RCC. A 1.5-T clinical MR protocol was used before and after (corticomedullary and nephrographic phases) intravenous administration of contrast agent. Region-of-interest measurements within tumor and uninvolved renal cortex were used to calculate percentage signal intensity change and tumor-to-cortex enhancement index. Subtype groups were compared by using linear mixed-effects models. Receiver operating characteristic (ROC) curve analysis was performed for the comparison of clear cell and papillary RCCs. On both the corticomedullary and nephrographic phase images, clear cell RCCs showed greater signal intensity change (205.6% and 247.1%, respectively) than did papillary RCCs (32.1% and 96.6%, respectively) (P < .001). Chromophobe RCCs showed intermediate change (109.9% and 192.5%, respectively). The tumor-to-cortex enhancement indexes at corticomedullary and nephrographic phases were largest for clear cell RCCs (1.4 and 1.2, respectively), smallest for papillary RCCs (0.2 and 0.4, respectively), and intermediate for chromophobe RCCs (0.6 and 0.8, respectively). Signal intensity changes on corticomedullary phase images were the most effective parameter for distinguishing clear cell and papillary RCC (area under ROC curve, 0.99); a threshold value of 84% permitted distinction with 93% sensitivity and 96% specificity. Clear cell, papillary, and chromophobe RCCs demonstrate different patterns of enhancement on two-time point clinical dynamic contrast-enhanced MR images, allowing their differentiation with high sensitivity and specificity.

Focus on kidney cancer

Long-term survival of patients with unilateral sporadic multifocal renal cell carcinoma according to histologic subtype compared with patients with solitary tumors after radical nephrectomy

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.

Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC). We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC. Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.

Prognostic Factors for Renal Cell Carcinoma Subtypes Diagnosed According to the 2016 WHO Renal Tumor Classification: a Study Involving 928 Patients.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The aim of this study was to analyse clear cell and papillary renal cell carcinoma (RCC) examined with contrast-enhanced ultrasound (CEUS) and a second generation blood pool agent (SonoVue®, Bracco, Milan, Italy) before clinical intervention. A total of 41 patients with histologically proven subtypes of RCC were examined. 29 patients had a clear cell RCC and 12 patients showed a papillary RCC. Average size in the clear cell RCC group was 6.07 cm and 1.88 cm in the papillary RCC group. An experienced radiologist examined all patients with CEUS. The following parameters were analysed: maximum signal intensity (PEAK), time elapsed until PEAK is reached (MTT), local blood flow (RBF), area under the time intensity curve (AUC) and the signal intensity (SI) during the course of time. For both groups all comparisons were made based on healthy renal parenchyma. In the clear cell RCC significant differences (significance level p < 0.05) between cancerous tissue and the healthy renal parenchyma were noticed in all four parameters. The clear cell RCC showed a significant reduced blood volume. It reached the PEAK reading relatively rapidly and its signal intensity was always lower than that of the healthy renal parenchyma. In the arterial phase retarded absorption of the contrast agent was observed, followed by fast washing out of the contrast agent bubbles.In the papillary RCC group, significant findings as to PEAK and RBF as well as a slightly significant difference as to AUC were recorded. The papillary RCC had a lower blood supply and reached its PEAK reading later. Its signal intensity was also reduced. The signal intensity of papillary NCC was significantly lower compared with clear cell RCC; absorption and washing out of the contrast agent was delayed. CEUS seems to be an useful additional method to clinically differentiate between clear cell and papillary RCC. In daily clinical use, patients with contraindication for other imaging methods, especially the magnetic resonance imaging, might particularly benefit from this method.

SummaryBackgroundTo assess semiquantitative parameters of dynamic contrast-enhanced perfusion MR imaging (DCE) in differentiation of subtypes of renal cell carcinoma (RCC).Material/MethodsProspective study conducted upon 34 patients (27 M, 7 F, aged 25–72 ys: mean 45 ys) with RCC. Abdominal dynamic contrast-enhanced gradient-recalled echo MR sequence after administration of gadopentetate dimeglumine was obtained. The time signal intensity curve (TIC) of the lesion was created with calculation of enhancement ratio (ER), and washout ratio (WR).ResultsThe subtypes of RCC were as follows: clear cell carcinomas (n=23), papillary carcinomas (n=6), and chromophobe carcinomas (n=5). The mean ER of clear cell, papillary and chromophobe RCC were 188±49.7, 35±8.9, and 120±41.6 respectively. The mean WR of clear cell, papillary and chromophobe RCCs were 28.6±6.8, 47.6±5.7 and 42.7±10, respectively. There was a significant difference in ER (P=0.001) and WR (P=0.001) between clear cell RCC and other subtypes of RCC. The threshold values of ER and WR used for differentiating clear cell RCC from other subtypes of RCC were 142 and 38 with areas under the curve of 0.937 and 0.895, respectively.ConclusionsWe concluded that ER and WR are semiquantitative perfusion parameters useful in differentiation of clear cell RCC from chromophobe and papillary RCCs.

ObjectiveThe Wnt/ß-catenin pathway plays an important role in pathogenesis of variety cancers. Most studies on changes in WNT/β-catenin pathway in renal cell carcinoma (RCC) apply only to clear cell RCC, while there are no comparative assessments of this signaling pathway in various histological types of renal tumors in the available literature. Additionally, considering the close relationship between WNT/β-catenin signaling, CacyBP/SIP and proteasomal activity, it seemed worth comparing WNT/β-catenin pathway, CacyBP/SIP and LMP7 immunoproteasome subunit in human samples of clear cell, papillary, and chromophobe RCC.MethodsTests were performed on sections of three types of kidney tumors together with surrounding unchanged tissue fragments collected from 50 patients. Samples were divided into three groups depending on the histological type of cancer: clear cell, papillary and chromophobe RCC. Immunohistochemistry and PCR methods were used to identify WNT10A, Fzd5, β-catenin, GSK-3ß, CacyBP/SIP, LMP7, and gene expression.ResultsImmunoreactivity and expression of WNT10A, Fzd5, β-catenin, GSK-3ß, CacyBP/SIP, LMP7 in clear cell RCC was markedly increased compared to non-cancerous kidney tissue. In papillary RCC, immunoreactivity and expression of WNT/β-catenin pathway, CacyBP/SIP, LMP7 was also increased compared to non-malignant kidneys, but it was less pronounced than in clear cell RCC. The least substantial increase in immunoreactivity and expression of WNT/β-catenin pathway, CacyBP/SIP, LMP7 was found in chromophobe RCC, compared to other RCC histological subtypes studied.ConclusionsStudy results suggest an important role of WNT/β-catenin pathway, CacyBP/SIP and LMP7 in RCC carcinogenesis, and may indicate new aspects of pathomechanisms leading to differences in the biology of clear cell, papillary and chromophobe RCC.

Kidney-specific cadherin, a specific marker for the distal portion of the nephron and related renal neoplasms

Clear cell papillary renal cell carcinoma as part of histologically discordant multifocal renal cell carcinoma: A case report and review of literature

4613 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a rare tumor with unpredictable clinical course and prognosis in adults. Recognition of these tumors depends on the identification of a RCC with unique histology, particularly clear cell and papillary (CCP) features. Our objectives were to determine the incidence of Xp11.2 translocations in adult RCCs with clear cell and papillary features, and to characterize the clinicopathological features and prognosis of adult Xp11.2 RCCs. Methods: Slides for 1047 RCCs in adults (1999-2009) were retrieved from multiple institutions. Cases were reviewed histologically in order to detect any degree of clear cell and papillary change. Tissue microarrays were constructed from the clear cell and papillary RCCs as well as 40 non-papillary clear cell, 5 papillary, 3 chromophobe and 2 unclassified RCCs. Immunohistochemistry using TFE3, a marker highly sensitive (97.5%) and specific (99.6%) for Xp11.2 translocations was performed. Four pathologists independently reviewed the TFE3 results. Clinical and pathologic data were also retrieved. Results: Out of 1047 RCCs, 140 (13%) exhibited clear cell and papillary features. Four out of these 140 (3%) were positive for TFE3. All of the non-papillary clear cell, papillary, chromophobe and unclassified RCCs were negative for TFE3. Mean follow up for TFE3+ RCCs was 55 months. Conclusions: Xp11.2 translocation RCCs diagnosed by TFE3 immunohistochemistry were identified in 3% of adult RCCs that had clear cell and papillary changes. These tumors appear to present with smaller tumour size, lower stage and better prognosis in comparison to non-Xp11.2 CCPRCC and clear cell RCCs. In addition to Xp11.2 translocation carcinoma, coexistence of clear cell and papillary features may be present in other subsets of tumors that have yet to be characterized. [Table: see text]

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.