Showing papers on "Papillary renal cell carcinomas published in 2017"

Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma

Abstract: The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma).A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival.Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.

Visual evaluation and differentiation of renal oncocytomas from renal cell carcinomas by means of 99m Tc-sestamibi SPECT/CT

Abstract: Despite the progress in the quality of multiphasic CT and MRI scans, it is still difficult to fully characterize a solid kidney lesion. Approximately 10% of all solid renal tumours turn out to be oncocytomas. In actual clinical practice, this is verified only following unnecessary surgery or a renal biopsy/ablation. The objective of our pilot study examines whether 99mTc-sestamibi SPECT/CT can play a crucial role in the characterization of solid renal neoplasms and the differentiation of oncocytomas from renal cell carcinomas. The study included 27 patients identified with 31 solid renal lesions. All patients were discussed in a multidisciplinary conference, and a decision for surgery or biopsy was taken. Prior to invasive procedures, patients underwent a SPECT/CT with 99mTc-sestamibi. Visual evaluation was performed, and any focal 99mTc-sestamibi uptake detected on SPECT in the localisation of tumour was considered as positive. Eleven out of 12 oncocytomas (91.6%) displayed positive uptake of 99mTc-sestamibi. Three hybrid tumours (mixed-type oncocytoma and chromophobe renal cancer) were positive on SPECT/CT. One papillary renal cell carcinoma had a slight uptake of 99mTc-sestamibi. The remaining 11 renal cell carcinomas were sestamibi negative. Differentiation of benign renal oncocytomas from renal cell carcinomas seems very promising on 99mTc-sestamibi SPECT/CT examination. Additional supplement to visual evaluation, i.e. quantitative tools, should be sought for an accurate estimate of biological behaviour and hence a secure diagnosis.

Reduced expression of CXCR4, a novel renal cancer stem cell marker, is associated with high-grade renal cell carcinoma

Abstract: Cancer stem cells (CSCs) represent a population with tumour-initiating, self-renewal, and differentiation potential. This study aimed to evaluate the expression patterns and clinical significance of chemokine receptor type 4 (CXCR4) as a novel CSC marker in renal cell carcinoma (RCC). The expression of CXCR4 was examined in 173 well-defined renal tumour tissues, including 106 (61.5 %) clear cell renal cell carcinomas (ccRCCs), 35 (20 %) papillary renal cell carcinomas (pRCCs), and 32 (18.5 %) chromophobe renal cell carcinomas (ChRCCs), by immunohistochemistry on a tissue microarray. The association between expression of this marker and clinicopathologic parameters was then analysed. There was a significant difference in the expression levels of CXCR4 in the ccRCC samples compared to the ChRCC and pRCC samples (P < 0.001). Increased expression of CXCR4 was significantly correlated with higher-grade tumours (P < 0.001) and worse stage (P = 0.001). A significant association was also found between expression of CXCR4 and microvascular invasion (P = 0.018). Among RCC subtypes, comparison of the differences between CXCR4 expression in low- and high-grade tumours demonstrated that pRCC tumours had a significantly higher expression of CXCR4 (P < 0.001) than ccRCC tumours (P = 0.01). Significantly higher expression levels of CXCR4 were found in pRCC and ccRCC samples. Increased CXCR4 expression was associated with more aggressive tumour behaviour in RCC patients, especially in pRCC and ccRCC subtypes due to their more metastatic behaviour. These findings suggest that CXCR4 can be considered as a novel diagnostic and therapeutic marker for targeted therapy of renal carcinoma.

PD-L1 expression in papillary renal cell carcinoma

Abstract: The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2). In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC). We found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases (p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD-L1 expression and all clinicopathological factors in pRCC. High expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis.

Characterizing the outcomes of metastatic papillary renal cell carcinoma.

Abstract: Outcomes of metastatic papillary renal cell carcinoma (pRCC) patients are poorly characterized in the era of targeted therapy. A total of 5474 patients with metastatic renal cell carcinoma (mRCC) in the International mRCC Database Consortium (IMDC) were retrospectively analyzed. Outcomes were compared between clear cell (ccRCC; n = 5008) and papillary patients (n = 466), and recorded type I and type II papillary patients (n = 30 and n = 165, respectively). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) favored ccRCC over pRCC. OS was 8 months longer in ccRCC patients and the hazard ratio of death was 0.71 for ccRCC patients. No differences in PFS or ORR were detected between type I and II PRCC in this limited dataset. The median OS for type I pRCC was 20.0 months while the median OS for type II was 12.6 months (P = 0.096). The IMDC prognostic model was able to stratify pRCC patients into favorable risk (OS = 34.1 months), intermediate risk (OS = 17.0 months), and poor-risk groups (OS = 6.0 months). pRCC patient outcomes were inferior to ccRCC, even after controlling for IMDC prognostic factors. The IMDC prognostic model was able to effectively stratify pRCC patients.

Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients.

Abstract: The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

Comparison of magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in the evaluation of unclear solid renal lesions.

Abstract: Purpose To compare the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI) in the evaluation of unclear renal lesions to the histopathological outcome. Materials and methods A total of 36 patients with a single unclear solid renal lesion with initial imaging studies between 2005 and 2015 were included. CEUS and MRI were used for determining malignancy or benignancy and initial findings were correlated with the histopathological outcome. Out of the 36 renal masses a total of 28 lesions were malignant (77.8%) and 8 were found to be benign (22.2%). Diagnostic accuracy was testes by using the histopathological diagnosis as the gold standard. Results CEUS showed a sensitivity of 96.4%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 88,9%. MRI showed a sensitivity of 96.4%, a specificity of 75.0%, a PPV of 93.1% and a NPV of 85.7%. Out of the 28 malignant lesions a total of 18 clear cell renal carcinomas, 6 papillary renal cell carcinomas and 4 other malignant lesions, e.g. metastases, were diagnosed. Out of the 8 benign lesions a total 3 angiomyolipomas, 2 oncocytomas, 1 benign renal cyst and 2 other benign lesions, e.g. renal adenomas were diagnosed. Using CEUS, 1 lesion was falsely identified as benign. Using MRI, 2 lesions were falsely identified as benign and 1 lesion was falsely identified as malignant. Conclusion CEUS is an useful method which can be additionally used to clinically differentiate between malignant and benign renal lesions. CEUS shows a comparable sensitivity, specificity, PPV and NPV to MRI. In daily clinical routine, patients with contraindications for other imaging modalities can particularly benefit using this method.

Oncocytic papillary renal cell carcinoma: A clinicopathological and genetic analysis and indolent clinical course in 14 cases.

Abstract: A sort of PRCC with distinct eosinophilic cytoplasm named Oncocytic Papillary Renal Cell Carcinoma (OPRCC) has been increasingly attracting the attention of researchers recently. However, owing to the rarity of OPRCC, the clinicopathological and genetic features of the tumor have still not been well elucidated and whether it should be regarded as an independent subtype of PRCC remains controversial. Herein, a cohort of 14 OPRCCs was studied with the aim of revealing the distinct clinicopathological features, facilitating the classification and correct diagnosis of OPRCC. Men and women each accounted for a half of the cohort with the median age of 64 years old. The majority of patients (9/14) were identified by medical examination and the remaining presented with macroscopic haematuria or lumbar pain. Grossly, tumors were well demarcated and varied from 1.5 to 9cm in diameter. Microscopically, typical OPRCC possessed fine papillary structures with delicate fibrovascular cores, lined with a single layer cell with large, deeply eosinophilic granular cytoplasm and round or polygonal-shaped nucleus exhibiting low nuclear grade in 10 cases (WHO/ISUP grade I-II). Most cases (12/14) possessed hemosiderin-laden and foam-like cells. Focal necrosis presented in 5 cases. Furthermore, solid oncocytoma-like areas appeared in 5 cases and focal sarcomatoid differentiation was identified in 1 case. Immunohistochemically, the majority of tumors presented high expression rates of alpha-methylacylCoA racemase (AMACR), CD10 and vimentin, which were similar to type 2 PRCC. The immune markers including cytokeratin-7 (CK7), KSP-cadherin and EMA exhibited variable positive immunostaining. Genetically, FISH analysis demonstrated trisomy of chromosome 7 in 7 OPRCCs and trisomy of chromosome 17 in 6 OPRCCs. Among 7 male cases, loss of chromosome Y was revealed in 2 cases. Follow-up data was available in 13 patients and only 1 patient died of bone metastasis of the tumor. The other 12 patients were all alive uneventfully at a mean follow-up time of 37 months, indicating that OPRCC is a unique subtype of PRCC with indolent clinical behavior. In conclusion, OPRCCs show a single layer tumor cell of low nuclear grade similar to type 1 PRCC, and abundant eosinophilic cytoplasm resembling type 2 PRCC. Furthermore, the tumor presents the same immunophynotype as type 2 PRCC but the same genetic features and prognosis as type 1 PRCC. OPRCC should be classified as an independent subtype of PRCC with different features from both type 1 and type 2 PRCC.

Recent advances in genitourinary tumors: A review focused on biology and systemic treatment

Abstract: Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3, PI3K/AKT, RTK/RAS, CDKN2A, ARIDIA, ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.

Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells.

Abstract: The aim of this study is to determine the effect of hypoxia on axitinib and sorafenib-treated renal cell carcinoma (RCC) cells. Hypoxia is a crucial factor influencing transcription process via protein modulation, which was shown i.e. in pancreatic cancer. Until now, hypoxia has been defined as associated with poorer outcome and inducing chemotherapy resistance in solid tumors. The unique phenomenon of pseudo-hypoxia connected with vhl mutation was observed in clear-cell, but not in papillary RCC, and the treatment of this subtype of cancer is still challenging. Despite the introduction of new antiangiogenic targeted therapies (inter alia tyrosine kinase inhibitors, TKIs), patients still develop both primary and acquired resistance. Overcoming resistance to TKIs, also in papillary RCC, may be possible by finding significantly modified protein expression. To do this, hypoxic 3D in vitro models must be developed to mimic both molecular pathways typical for low oxygen tension and cell–cell dynamics in tumor-like spatial structures. Clear-cell and papillary renal cell carcinoma (cc and pRCC) cell lines were used in the study to determine the impact of hypoxia on primary drug resistance phenomenon previously observed in papillary, but not in ccRCC. Resistance was confirmed in monolayer culture and in 3D models in soft agar and suspension culture. Human papillary kidney cancer stem-like cells (HKCSCs) cultured in hypoxia developed resistance to sorafenib, while when cultured in normoxia resistance to axitinib has developed. Flow cytometry revealed that hypoxia decreased proliferation rates in all investigated RCC cells. In HKCSCs, there was an increase of quiescent cells (Ki67−) and percentage of cells arrested in S phase. It also appeared that map2k1 and eif4b protein expression is altered in papillary RCC resistant to tested drugs at different oxygen tensions. Also, HKCSCs did not express vegfr-1, braf nor c-kit, TKIs target receptors, which were present in ccRCC cells sensitive to TKI treatment. The results confirm that low oxygen tension affects RCC cells. Hypoxia facilitates induction of sorafenib resistance in pRCC and induces map2k1 overexpression, while normoxic axitinib-resistant cells up-regulated eif4b. Further studies may determine if map2k1 or eif4b proteins play a role in pRCC resistance to TKIs. It is also of interest to establish if other than vegfr-1, braf, c-kit receptors can serve as potential molecular targets for more effective anti-RCC strategies.

Functional significance of CD105-positive cells in papillary renal cell carcinoma

Abstract: CD105 was postulated as a renal cell carcinoma (RCC) stem cell marker, and CD133 as a putative RCC progenitor. Hypoxia, a natural microenvironment that prevails in tumors, was also incorporated into the study, especially in terms of the promotion of hypothetical stem-like cell properties. Within this study, we verify the existence of CD105+ and CD133+ populations in selected papillary subtype RCC (pRCC) cell lines. Both populations were analyzed for correlation with stem-like cell properties, such as stemness gene expression, and sphere and colony formation. For the preliminary analysis, several RCC cell lines were chosen (786-O, SMKT-R2, Caki-2, 796-P, ACHN, RCC6) and the control was human kidney cancer stem cells (HKCSC) and renal cells of embryonic origin (ASE-5063). Four cell lines were chosen for further investigation: Caki-2 (one of the highest numbers of CD105+ cells; primary origin), ACHN (a low number of CD105+ cells; metastatic origin), HKCSC (putative positive control), and ASE-5063 (additional control). In 769-P and RCC6, we could not detect a CD105+ population. Hypoxia variously affects pRCC cell growth, and mainly diminishes the stem-like properties of cells. Furthermore, we could not observe the correlation of CD105 and/or CD133 expression with the enhancement of stem-like properties. Based on this analysis, CD105/CD133 cannot be validated as cancer stem cell markers of pRCC cell lines.

Impressive and durable response to nivolumab in a patient with metastatic type 2 papillary renal cell carcinoma: On-label but without evidence.

Abstract: Nivolumab is a treatment option for patients with metastatic renal cell carcinoma (RCC) previously treated with targeted antiangiogenic therapy. Papillary renal cell carcinoma (PRCC) comprises 10–15% of RCC cases but non-clear cell subtypes were excluded from the immunotherapy trials. We report the case of a woman with recurrent metastatic PRCC who had an impressive therapeutic response to nivolumab with no significant adverse events. She had previously been treated with sunitinib and pazopanib with no response. She showed a remarkable clinical improvement after only the first 2 immunotherapy cycles and subsequent radiographic studies demonstrated a marked decrease in tumor burden. At present, she continues to show a durable benefit after 8 months of treatment. Her tumor had <1% positivity for PD-L1 staining and a low tumor mutational burden with no actionable mutations on genomic sequencing. Considering its high genetic variation, checkpoint blockade immunotherapies (CBIs) are attractive treatment options in PRCC. This is the third case that reports objective responses of nivolumab in PRCC. We believe our patient’s experience supports the inclusion of non-clear cell RCC on clinical trials using CBIs. PD-L1 status and TMB may not serve as predictive biomarkers for response.

Histologic subtype needs to be considered after partial nephrectomy in patients with pathologic T1a renal cell carcinoma: papillary vs. clear cell renal cell carcinoma

Abstract: We compared the oncological outcomes of papillary renal cell carcinoma (pRCC) with clear cell renal cell carcinoma (ccRCC) after partial nephrectomy (PN) in patients with pathologic T1a RCC. After excluding patients with synchronous multiple renal tumors, familial RCC, and pathologic stage T1b or above, 759 patients with ccRCC and 84 patients with pRCC were included. We assessed the impact of histologic subtypes on oncologic outcomes after PN in patients with pathologic T1a RCC (median follow-up duration, 67 months). There was no difference in patient and tumor characteristics between the 2 groups, except Fuhrman grade (p = 0.006). Kaplan–Meier analysis identified 5-year recurrence-free survival of 98.7 and 95.6% in patients with ccRCC and pRCC, respectively. However, 10-year recurrence-free survival in patients with ccRCC and pRCC was 96.1 and 73.0%, respectively (p < 0.001). Recurrence ≥5 years post surgery was more common in patients with pRCC compared with those with ccRCC (0.3 vs. 4.8%; p < 0.001). In multivariate analysis, pRCC [hazard ratio (HR) 5.309; p = 0.001] was a significant risk factor for recurrence after PN in patients with pathologic T1a RCC, in addition to larger tumor size (HR 1.861; p = 0.038) and Fuhrman grade ≥3 (HR 5.176; p = 0.003). In patients with pathologic T1a RCC, recurrence after PN occurred more commonly in pRCC compared with ccRCC. As over half of the recurrence cases in patients with pRCC occurred ≥5 years post surgery, a longer follow-up time is required, even for those with pathologic stage T1a disease.

Ethnic disparities in renal cell carcinoma: An analysis of Hispanic patients in a single-payer healthcare system.

Abstract: Objective To investigate differences between Hispanics and non-Hispanic whites diagnosed with and treated for renal cell carcinoma in an equal access healthcare system. Methods We carried out a retrospective cohort study within the Kaiser Permanente healthcare system using records from renal cell carcinoma cases. Ethnicity was identified as Hispanic or non-Hispanic whites. Patient characteristics, comorbidities, tumor characteristics and treatment were compared. Overall and disease-specific survival was calculated, and a Cox proportion hazard model estimated the association of ethnicity and survival. Results A total of 2577 patients (2152 non-Hispanic whites, 425 Hispanic) were evaluated. Hispanics were diagnosed at a younger age (59.6 years vs 65.3 years). Clear cell renal cell carcinoma was more prevalent, whereas papillary renal cell carcinoma was less common among Hispanics. Hispanics had a lower American Joint Committee on Cancer stage (I/II vs III/IV) than non-Hispanic whites (67.4% vs 62.2%). Hispanics were found to have a greater frequency of comorbidities, such as chronic kidney disease and diabetes, but were more likely to receive surgery. The presence of metastases, nodal involvement, increased tumor size, non-surgical management, increasing age and Hispanic ethnicity were independent predictors of worse cancer-specific outcome. Conclusions Within an equal access healthcare system, Hispanics seem to be diagnosed at younger ages, to have greater comorbidities and to present more frequently with clear cell renal cell carcinoma compared with non-Hispanic white patients. Despite lower stage and greater receipt of surgery, Hispanic ethnicity seems to be an independent predictor of mortality. Further work is necessary to confirm these findings.

Renal cell carcinoma histological subtype distribution differs by age, gender, and tumor size in coastal Chinese patients.

Abstract: The distribution pattern of renal cell carcinoma (RCC) histological subtypes according to age, gender and tumor size has not been well illustrated in RCC patients living in fast-developing regions of China We recruited 2941 patients with clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PCC) or chromophobe from two hospitals in coastal China (2004-2012) consecutively and draw 538 American Chinese RCC patients' data with time matched from the Surveillance, Epidemiology, and End Results database We found that compared with ccRCC patients, chromophobe patients were more likely to be female (OR: 2538, 95% CI: 1923-3350), younger (OR for 51-60 years old: 0686; OR for over 60 years old: 0478; reference: age 7 cm: 1883; reference: Dmax ≤ 4 cm) Besides, in comparison with coastal Chinese patients, American Chinese individuals had lower Fuhrman grades (P < 0001) and had an onset age 10 years delay In conclusion, we were the first to observe marked gender, age and tumor size differences in the proportional subtype distribution of RCCs in coastal Chinese patients, and also the first to compare coastal Chinese with American Chinese data

Chromosomal abnormalities of high-grade mucinous tubular and spindle cell carcinoma of the kidney.

Abstract: Introduction Mucinous tubular and spindle cell carcinoma (MTSC) of the kidney is a distinct entity characterized by bland tightly packed elongated tubules and spindle cells with low nucleolar grade in a basophilic mucinous stroma. Several case studies have reported MTSC with high grade features and have brought into question whether they represented MTSC or a variant of papillary renal cell carcinoma. Materials and methods We searched our pathology database and identified seven cases: six MTSC with high International Society of Urological Pathology (ISUP) nucleolar grade, and one MTSC with overall low nucleolar grade but extensive necrosis. DNA samples were extracted from paraffin blocks and analyzed using a SNP array platform. Results Six out of seven patients were female, with ages between 46 to 82 years. Tumour sizes range from 3 to 7.5 cm. One case showed involvement of renal sinus fat and a second case showed involvement of the perinephric fat. All cases shared common chromosomal abnormalities observed with the more typical MTSC, with monosomy of chromosomes 1,4,6,8,9,13,14,15 and 22. Trisomy of chromosomes 7, 17 and loss of Y chromosome were not observed in any of the cases. None of the patients showed evidence of recurrence or metastasis. Discussion The molecular analysis performed in this study support that MTSC of the kidney can have high nucleolar grade or extensive necrosis, and that they are not papillary renal cell carcinoma. We support modifying the definition of MTSC to include those with higher nucleolar grade. This article is protected by copyright. All rights reserved.

SETDB2 and RIOX2 are differentially expressed among renal cell tumor subtypes, associating with prognosis and metastization

Abstract: Increasing detection of small renal masses by imaging techniques entails the need for accurate discrimination between benign and malignant renal cell tumors (RCTs) as well as among malignant RCTs, owing to differential risk of progression through metastization. Although histone methylation has been implicated in renal tumorigenesis, its potential as biomarker for renal cell carcinoma (RCC) progression remains largely unexplored. Thus, we aimed to characterize the differential expression of histone methyltransferases (HMTs) and histone demethylases (HDMs) in RCTs to assess their potential as metastasis biomarkers. We found that SETDB2 and RIOX2 (encoding for an HMT and an HDM, respectively) expression levels was significantly altered in RCTs; these genes were further selected for validation by quantitative RT-PCR in 160 RCTs. Moreover, SETDB2, RIOX2, and three genes encoding for enzymes involved in histone methylation (NO66, SETD3, and SMYD2), previously reported by our group, were quantified (RT-PCR) in an independent series of 62 clear cell renal cell carcinoma (ccRCC) to assess its potential role in ccRCC metastasis development. Additional validation was performed using TCGA dataset. SETDB2 and RIOX2 transcripts were overexpressed in RCTs compared to renal normal tissues (RNTs) and in oncocytomas vs. RCCs, with ccRCC and papillary renal cell carcinoma (pRCC) displaying the lowest levels. Low SETDB2 expression levels and higher stage independently predicted shorter disease-free survival. In our 62 ccRCC cohort, significantly higher RIOX2, but not SETDB2, expression levels were depicted in cases that developed metastasis during follow-up. These findings were not apparent in TCGA dataset. We concluded that SETDB2 and RIOX2 might be involved in renal tumorigenesis and RCC progression, especially in metastatic spread. Moreover, SETDB2 expression levels might independently discriminate among RCC subgroups with distinct outcome, whereas higher RIOX2 transcript levels might identify ccRCC cases with more propensity to endure metastatic dissemination.

Dynamic Contrast-enhanced MRI in Renal Tumors: Common Subtype Differentiation using Pharmacokinetics

Abstract: Preoperative renal tumor subtype differentiation is important for radiology and urology in clinical practice. Pharmacokinetic data (K trans & V e, etc.) derived from dynamic contrast-enhanced MRI (DCE-MRI) have been used to investigate tumor vessel permeability. In this prospective study on DCE-MRI pharmacokinetic studies, we enrolled patients with five common renal tumor subtypes: clear cell renal cell carcinoma (ccRCC; n = 65), papillary renal cell carcinoma (pRCC; n = 12), chromophobic renal cell carcinoma (cRCC; n = 9), uroepithelial carcinoma (UEC; n = 14), and fat-poor angiomyolipoma (fpAML; n = 10). The results show that K trans of ccRCC, pRCC, cRCC, UEC and fpAML (0.459 ± 0.190 min−1, 0.206 ± 0.127 min−1, 0.311 ± 0.111 min−1, 0.235 ± 0.116 min−1, 0.511 ± 0.159 min−1, respectively) were different, but V e was not. K trans could distinguish ccRCC from non-ccRCC (pRCC & cRCC) with a sensitivity of 76.9% and a specificity of 71.4%, respectively, as well as to differentiate fpAML from non-ccRCC with a sensitivity of 100% and a specificity of 76.2%, respectively. Our findings suggest that DCE-MRI pharmacokinetics are promising for differential diagnosis of renal tumors, especially for RCC subtype characterization and differentiation between fpAML and non-ccRCC, which may facilitate the treatment of renal tumors.

GLUT1, MCT1/4 and CD147 overexpression supports the metabolic reprogramming in papillary renal cell carcinoma.

Abstract: Papillary Renal Cell carcinoma (pRCC) is the second most common type of RCC, accounting for about 15% of all RCCs. Surgical excision is the main treatment option. Still, 10 - 15 % of clinically localized tumours will recur and/or develop metastasis early after surgery, and no reliable prognostic biomarkers are available to identify them. It is known that pRCC cells rely on high rates of aerobic glycolysis, characterized by the up-regulation of many proteins and enzymes related with the glycolytic pathway. However, a metabolic signature enabling the identification of advanced pRCC tumours remains to be discovered. The aim of this study was to characterize the metabolic phenotype of pRCCs (subtypes 1-pRCC1 and 2-pRCC2) by evaluating the expression pattern of the glucose transporters (GLUTs) 1 and 4 and the monocarboxylate transporters (MCTs) 1 and 4, as well as their chaperon CD147. We analysed the clinico-pathological data and the protein and mRNA expression of GLUT1, GLUT4 and MCT1, MCT4 and CD147 in tumours from Porto and TCGA series (http://cancergenome.nih.gov/), respectively. With the exception of GLUT4, plasma membrane expression of all proteins was frequently observed in pRCCs. GLUT1 and MCT1 membrane overexpression was significantly higher in pRCC2 and significantly associated with higher pN-stage and higher Fuhrman grade. Overexpression of GLUT1, MCT1/4 and CD147, supports the metabolic reprograming in pRCCs. MCT1 expression was associated with pRCC aggressiveness, regardless of the tumour histotype.

Renal tumors with low signal intensities on T2-weighted MR image: radiologic-pathologic correlation.

Abstract: Accurate characterization of renal masses is essential for ensuring appropriate management. Low T2 signal intensity is a common feature of papillary renal cell carcinoma and fat-poor angiomyolipoma. Nonetheless, other types of renal cell carcinoma, oncocytoma, hemangioma, lymphoma, leiomyoma, and urothelial cell carcinoma also can show low signal intensities on T2-weighted imaging (T2WI). Histopathologic features that can lead to low T2 signal intensities in renal tumors include smooth muscle component, papillary architecture, a high nucleus-to-cytoplasm ratio, and hemorrhage. To establish an appropriate differential diagnosis for renal tumors on MRI, it is necessary to understand the relationship between the MR signal intensities and the histopathologic and morphologic features, in addition to contrast enhancement patterns and diffusion characteristics of the tumors.