ABSTRACT
Chromophobe renal cell carcinoma (ChRCC) accounts for 5% of all sporadic renal cancers and can also occur in genetic syndromes including Birt-Hogg-Dube (BHD) and tuberous sclerosis complex (TSC). ChRCC has a distinct accumulation of abnormal mitochondria, accompanied by characteristic chromosomal imbalances and relatively few "driver" mutations. Metabolomic profiling of ChRCC and oncocytomas (benign renal tumors that share pathological features with ChRCC) revealed both similarities and differences between these tumor types, with principal component analysis (PCA) showing a distinct separation. ChRCC have a striking decrease in intermediates of the glutathione salvage pathway (also known as the gamma-glutamyl cycle) compared with adjacent normal kidney, as well as significant changes in glycolytic and pentose phosphate pathway intermediates. We also found that gamma glutamyl transferase 1 (GGT1), the key enzyme of the gamma-glutamyl cycle, is expressed at â¼100-fold lower levels in ChRCC compared with normal kidney, while no change in GGT1 expression was found in clear cell RCC (ccRCC). Significant differences in specific metabolite abundance were found in ChRCC vs. ccRCC, including the oxidative stress marker ophthalmate. Down-regulation of GGT1 enhanced the sensitivity to oxidative stress and treatment with buthionine sulfoximine (BSO), which was associated with changes in glutathione-pathway metabolites. These data indicate that impairment of the glutathione salvage pathway, associated with enhanced oxidative stress, may have key therapeutic implications for this rare tumor type for which there are currently no specific targeted therapies.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/enzymology , Kidney Neoplasms/enzymology , Neoplasm Proteins/metabolism , Oligopeptides/metabolism , gamma-Glutamyltransferase/metabolism , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Male , Neoplasm Proteins/genetics , Oligopeptides/genetics , Oxidative Stress/genetics , Signal Transduction/genetics , gamma-Glutamyltransferase/geneticsABSTRACT
Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.
Subject(s)
Biomarkers, Tumor , Carcinoma, Renal Cell , Kidney Neoplasms , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met , TOR Serine-Threonine Kinases , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolismABSTRACT
A significantly increased level of the reactive oxygen species (ROS) scavenger glutathione (GSH) has been identified as a hallmark of renal cell carcinoma (RCC). The proposed mechanism for increased GSH levels is to counteract damaging ROS to sustain the viability and growth of the malignancy. Here, we review the current knowledge about the three main RCC subtypes, namely clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC), at the genetic, transcript, protein, and metabolite level and highlight their mutual influence on GSH metabolism. A further discussion addresses the question of how the manipulation of GSH levels can be exploited as a potential treatment strategy for RCC.
Subject(s)
Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Glutathione/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Animals , Biomarkers, Tumor , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/therapy , Disease Models, Animal , Disease Progression , Humans , Kidney Neoplasms/etiology , Kidney Neoplasms/therapy , Metabolic Networks and Pathways , Molecular Targeted Therapy , Oxidative Stress , Reactive Oxygen Species , Tumor Microenvironment/immunologyABSTRACT
Renal cell carcinoma (RCC) occasionally has sarcomatoid differentiation and rarely contains heterologous components. We report a case of chromophobe RCC with sarcomatoid differentiation that had various heterologous components including a unique lipomatous area. The patient was an 83-year-old woman with a palpable mass in the left lower abdomen. Grossly, the tumor was 14 cm in diameter and had yellowish-to-whitish color with focal necrosis and hemorrhage. Histologically, the tumor was composed of an eosinophilic subtype of chromophobe RCC with sarcomatoid differentiation including mainly chondrosarcoma, some osteosarcoma and a lipomatous area. The heterologous components of sarcomatoid RCC are usually osteosarcoma or chondrosarcoma, and sarcomatoid RCC with multiple heterologous components is extremely rare.
Subject(s)
Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Aged, 80 and over , Cell Differentiation , Chondrosarcoma/pathology , Female , Humans , Lipoma/pathology , Neoplasms, Complex and Mixed/pathology , Osteosarcoma/pathologyABSTRACT
PURPOSE: Concern regarding coexisting malignant pathology in benign renal tumors deters renal biopsy and questions its validity. We examined the rates of coexisting malignant and high grade pathology in resected benign solid solitary renal tumors. MATERIALS AND METHODS: Using our prospectively maintained database we identified 1,829 patients with a solitary solid renal tumor who underwent surgical resection between 1994 and 2012. Lesions containing elements of renal oncocytoma, angiomyolipoma or another benign pathology formed the basis for this analysis. Patients with an oncocytic malignancy without classic oncocytoma and those with known hereditary syndromes were excluded from study. RESULTS: We identified 147 patients with pathologically proven elements of renal oncocytoma (96), angiomyolipoma (44) or another solid benign pathology (7). Median tumor size was 3.0 cm (IQR 2.2-4.5). As quantified by the R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior and location relative to polar lines) nephrometry score, tumor anatomical complexity was low in 28% of cases, moderate in 56% and high in 16%. Only 4 patients (2.7%) were documented as having hybrid malignant pathology, all involving chromophobe renal cell carcinoma in the setting of renal oncocytoma. At a median followup of 44 months (IQR 33-55) no patient with a hybrid tumor experienced regional or metastatic progression. CONCLUSIONS: In our cohort of patients with a solitary, sporadic, solid benign renal mass fewer than 3% of tumors showed coexisting hybrid malignancy. Importantly, no patient harbored coexisting high grade pathology. These data suggest that uncertainty regarding hybrid malignant pathology coexisting with benign pathological components should not deter renal biopsy, especially in the elderly and comorbid populations.
Subject(s)
Adenoma, Oxyphilic/pathology , Angiomyolipoma/pathology , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Adenoma, Oxyphilic/metabolism , Adenoma, Oxyphilic/surgery , Aged , Angiomyolipoma/metabolism , Angiomyolipoma/surgery , Female , Humans , Immunohistochemistry , Kidney Neoplasms/metabolism , Male , Middle Aged , Retrospective StudiesABSTRACT
OBJECTIVE: To evaluate the expression and prognostic value of epithelial cell adhesion/activating molecule (EpCAM) in a large set of renal cell carcinomas (RCCs) using a tissue microarray (TMA) approach. MATERIAL AND METHODS: We studied the immunohistochemical expression and overexpression of EpCAM on TMAs containing formalin-fixed, paraffin-embedded samples of 948 patients with documented renal tumours. EpCAM expression was defined as the presence of a specific membranous staining in >5% of the tumour cells. EpCAM overexpression was specified by calculating a total staining score (score range 0-12) as the product of a proportion score and an intensity score, and defined as a score >4. RESULTS: Of 948 cases, 927 (97.8%) were evaluable morphologically (haematoxylin and eosin stain). EpCAM expression was found in 233/642 (36.3%), 126/155 (81.3%), 54/68 (78.3%), 17/45 (37.8%), 13/30 (43.3%) of clear-cell RCC, papillary RCC (pRCC), chromophobe RCC (cpRCC), oncocytomas and other unclassified tumour types, respectively. Log-rank tests showed a significantly longer overall survival (OS [P = 0.047]) and a trend of EpCAM expression to be associated with a longer progression-free survival (PFS) in all RCC entities (P = 0.065). EpCAM overexpression was significantly correlated with a better PFS in all RCC subtypes, cpRCC and pRCC (P = 0.011, 0.043 and 0.025, respectively). In multivariate analysis EpCAM overexpression was an independent marker for longer PFS in all RCC entities as well as in high grade RCC (P = 0.009 and P = 0.010, respectively). CONCLUSIONS: The histological subtypes associated with a high rate of EpCAM expression were cpRCC and pRCC. This retrospective analysis demonstrated a trend towards longer OS and PFS for all major RCC subtypes. EpCAM expression had significant prognostic value in patients with cpRCC and pRCC. Furthermore, EpCAM overexpression in high grade RCC may be a helpful marker for prognostication.
Subject(s)
Antigens, Neoplasm/metabolism , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Adhesion Molecules/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Adolescent , Adult , Aged , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Epithelial Cell Adhesion Molecule , Female , Humans , Kidney Neoplasms/mortality , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Tissue Array Analysis , Young AdultABSTRACT
INTRODUCTION: Standard treatment for renal cell carcinomas (RCCs) is radical/partial nephrectomy and unlike upper urothelial carcinoma, complete ureteral removal is not necessary nor is advised in RCCs as tumor recurrence in ureteral remnant has scarcely been reported. Here, we present a rare case of chromophobe RCC (ChRCC) metastasis in remnant ureter following radical nephrectomy and perform a literature review in this regard. CASE PRESENTATION: A 66-year-old man presented with a CT scan-as a surveillance protocol imaging- showing a mass in ipsilateral remnant ureter 9 months after radical nephrectomy due to ChRCC while being completely asymptomatic. Cystoscopy revealed a polypoid mass protruding from right ureterovesical junction and transurethral resection of tumor revealed it to be a ChRCC. Distal ureterectomy was performed confirming pathology without any lymph node involvement. 12 months after ureterectomy, he remained asymptomatic with no sign of metastasis or recurrence in his follow up CT scan. DISCUSSION: RCC metastasis to distal ureter after radical nephrectomy has been rarely reported and only 2 cases of them were ChRCC. Gross hematuria has been the main presentation of such disease. However, our case was completely asymptomatic, highlighting necessity of surveillance imaging. No specific treatment guideline exists for such presentation but tumor resection has been the most common treatment modality. CONCLUSION: Metachronous RCC metastasis may occur in remnant ureter which can be completely asymptomatic, highlighting necessity of surveillance imaging and reviewing them meticulously. Surgical resection of the metastasis by distal ureterectomy seems to be the best treatment option.
ABSTRACT
This retrospective study aims to describe the characteristics of renal cell carcinoma (RCC) in Saudi Arabia, in terms of epidemiology, clinical presentation, tumor subtype, Fuhrman grade, tumor size and stage, and overall survival. A total of 431 adult patients with a histopathological diagnosis of RCC between 2015 and 2023 were included in the analysis. Most patients (72.4%) had clear cell tumors, followed by chromophobe (15.1%) and papillary (12.5%) subtypes. In males, papillary RCC (85.2%) was more common compared to clear cell (59.8%) and chromophobe (67.7%) subtypes. Significant differences were observed in median body mass index (BMI) across tumor subtypes, and papillary tumor patients exhibited the highest incidence of hematuria (33.3%) compared to other subtypes. The Fuhrman grade also varied significantly among RCC types. Survival times were found to be lower for patients with papillary tumors. No significant difference was observed based on patients' nationality. This study can inform clinical decision-making on patient prognosis and management as well as public health efforts aimed at reducing the alarming rise of RCC incidence.
ABSTRACT
BACKGROUND: Radiomics is a type of quantitative analysis that provides a more objective approach to detecting tumor subtypes using medical imaging. The goal of this paper is to conduct a comprehensive assessment of the literature on computed tomography (CT) radiomics for distinguishing renal cell carcinomas (RCCs) from oncocytoma. METHODS: From February 15th 2012 to 2022, we conducted a broad search of the current literature using the PubMed/MEDLINE, Google scholar, Cochrane Library, Embase, and Web of Science. A meta-analysis of radiomics studies concentrating on discriminating between oncocytoma and RCCs was performed, and the risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies method. The pooled sensitivity, specificity, and diagnostic odds ratio were evaluated via a random-effects model, which was applied for the meta-analysis. This study is registered with PROSPERO (CRD42022311575). RESULTS: After screening the search results, we identified 6 studies that utilized radiomics to distinguish oncocytoma from other renal tumors; there were a total of 1064 lesions in 1049 patients (288 oncocytoma lesions vs 776 RCCs lesions). The meta-analysis found substantial heterogeneity among the included studies, with pooled sensitivity and specificity of 0.818 [0.619-0.926] and 0.808 [0.537-0.938], for detecting different subtypes of RCCs (clear cell RCC, chromophobe RCC, and papillary RCC) from oncocytoma. Also, a pooled sensitivity and specificity of 0.83 [0.498-0.960] and 0.92 [0.825-0.965], respectively, was found in detecting oncocytoma from chromophobe RCC specifically. CONCLUSIONS: According to this study, CT radiomics has a high degree of accuracy in distinguishing RCCs from RO, including chromophobe RCCs from RO. Radiomics algorithms have the potential to improve diagnosis in scenarios that have traditionally been ambiguous. However, in order for this modality to be implemented in the clinical setting, standardization of image acquisition and segmentation protocols as well as inter-institutional sharing of software is warranted.
Subject(s)
Adenoma, Oxyphilic , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/diagnosis , Adenoma, Oxyphilic/diagnostic imaging , Adenoma, Oxyphilic/pathology , Kidney Neoplasms/diagnosis , Tomography, X-Ray Computed , Sensitivity and Specificity , Diagnosis, DifferentialABSTRACT
INTRODUCTION: 123I-metaiodobenzylguanidine scanning has high sensitivity and specificity for the diagnosis of tumors derived from sympathetic nerves or the adrenal medulla. We report the rare case of a 123I-metaiodobenzylguanidine false-positive renal cell carcinoma. CASE PRESENTATION: The patient was referred to our hospital with an incidental left renal mass during evaluation for hypertension. An ovarian tumor and prominent ascites were also observed. Serum and urine catecholamine levels were high to suspect a catecholamine-producing tumor of the kidney. 123I-metaiodobenzylguanidine scintigraphy showed increased 123I-metaiodobenzylguanidine intake in the tumor. Laparoscopic radical left nephrectomy was performed. The pathologic diagnosis was an oncocytic variant of chromophobe renal cell carcinoma. No pheochromocytoma features were found. CONCLUSION: We report the first case of a 123I-metaiodobenzylguanidine false-positive renal cell carcinoma. This case was diagnosed with primary aldosteronism and Meigs' syndrome, which made the clinical course more complicated.
ABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which renal manifestations are prominent. There are three major renal lesions in TSC: angiomyolipomas, cysts, and renal cell carcinoma (RCC). Major recent advances have revolutionized our understanding of TSC-associated RCC, including two series that together include more than 100 TSC-RCC cases, demonstrating a mean age at onset of about 36 years, tumors in children as young as 7, and a striking 2:1 female predominance. These series also provide the first detailed understanding of the pathologic features of these distinctive tumors, which include chromophobe-like features and eosinophilia, with some of the tumors unclassified. This pathologic heterogeneity is distinctive and reminiscent of the pathologic heterogeneity in Birt-Hogg-Dube-associated RCC, which also includes chromophobe-like tumors. Additional advances include the identification of sporadic counterpart tumors that carry somatic TSC1/TSC2/mTOR mutations. These include unclassified eosinophilic tumors, eosinophilic solid cystic RCC (ESC-RCC), and RCC with leiomyomatous stroma (RCCLMS). A variety of epithelial renal neoplasms have been identified both in patients with tuberous sclerosis complex (TSC) and in the nonsyndromic setting associated with somatic mutations in the TSC1 and TSC2 genes. Interestingly, whether tumors are related to a germline or somatic TSC1/2 mutation, these tumors often display similar morphologic and immunophenotypic features. Finally, recent work has identified molecular links between TSC and BHD-associated tumors, involving the TFEB/TFE3 transcription factors.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Carcinoma, Renal Cell/genetics , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis/genetics , Adult , Age of Onset , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney/pathology , Male , Mutation/genetics , TOR Serine-Threonine Kinases/genetics , Tuberous Sclerosis/complications , Tuberous Sclerosis/pathologyABSTRACT
Knowledge about molecular mechanisms driving development and progression of renal cell carcinoma has been elucidated by different studies. In few years we discovered a large difference between genomic landscapes of clear cell and non-clear cell carcinoma. Moreover, tumor heterogeneity and different acquisition of gene mutations during tumor progression are issues of particular interest. In this review we focalized our attention on principal genomic alterations identified among RCC subtypes. Acquired gene mutations may be an adaptive response to several external pressure including metabolic, treatment, genomic and immune-related external pressure. Thus we correlated and discussed principal genomic alterations adopted by tumor to escape from each external pressures. The aim of the present work is to summarize current knowledge about genomic alterations in RCC with special interest of treatment strategies tailored on the basis of disease mutations assessment.
Subject(s)
Carcinoma, Renal Cell/therapy , Kidney Neoplasms/therapy , Mutation , Precision Medicine , Animals , Carcinoma, Renal Cell/genetics , Genomics , Humans , Kidney Neoplasms/geneticsABSTRACT
We investigated the expression of irisin in renal cancers using immunocytochemistry. Irisin has been reported to exhibit anticancer properties. The study groups consisted of 22 cases each of control renal tissue, oncocytoma, chromophobe renal cell carcinoma (RCC), clear cell RCC (Fuhrman nuclear grades 1, 2, 3 and 4) and papillary RCC. We evaluated 10 slides for each of 176 cases. Slides were immunostained for irisin and histoscores were calculated for the prevalence and strength of immunostaining. Fuhrman nuclear grade 1, 2, 3 clear cell RCC and papillary RCC exhibited no irisin immunoreactivity. Irisin immunoreactivity was observed in some Fuhrman nuclear grade 4 RCCs. We found a significant decrease in irisin staining in chromophobe RCC compared to the control. Immunoreactivity in the oncocytoma tissue was comparable to the control group. Irisin immunoreactivity in chromophobe RCC decreased and no immunoreactivity was observed in Fuhrman nuclear grade 1, 2, 3 clear cell RCC and papillary RCC. Immunistochemical screening of irisin in renal oncocytomas and renal cancers may be useful for differential diagnosis.
Subject(s)
Adenoma, Oxyphilic/pathology , Carcinoma, Renal Cell/pathology , Fibronectins , Kidney Neoplasms/pathology , Adenoma, Oxyphilic/diagnosis , Algorithms , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/diagnosis , Diagnosis, Differential , Fibronectins/metabolism , Humans , Immunohistochemistry/methods , Kidney Neoplasms/diagnosisABSTRACT
INTRODUCTION: Pazopanib is a standard first-line treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Very few data on its activity in non-clear-cell renal cell carcinoma (nccRCC) are currently available. The aim of this study was to retrospectively analyze efficacy and toxicity of pazopanib in nccRCC patients. PATIENTS AND METHODS: Records from advanced nccRCC patients (consecutive sample) treated with first-line pazopanib between 2010 and 2015 at 17 Italian centers were reviewed. Response rate, progression-free survival (PFS), and overall survival (OS) were evaluated. Univariate and descriptive analyses were performed. RESULTS: Thirty-seven patients with nccRCC were treated with first-line pazopanib; 51% had papillary histology, 24% chromophobe, 22% unclassified, and 3% had Xp11.2 translocation. Dose reductions/temporary interruptions for toxicity were required in 46% of cases. Grade (G) 3/4 toxicity was seen in 32%, G1/2 in 89% of cases; 81% achieved disease control, with 10 partial responses (27%) and 20 cases of stable disease (54%); 16% of patients had disease progression as best response. Median PFS and OS were 15.9 and 17.3 months, respectively. In univariate analysis, nephrectomy (P = .020), Memorial Sloan Kettering Cancer Center (MSKCC) score (P < .001), basal neutrophil/lymphocyte ratio (NLR; P = .009) and performance status (PS) (P = .001) were associated with PFS; MSKCC score (P < .001), International Metastatic Renal Cell Carcinoma Database Consortium score (P = .003), PS (P < .0001), nephrectomy (P = .002), histology (P = .035), dose reductions/interruptions (P = .039), best response to treatment (P < .001), and NLR (P = .008) were associated with OS. CONCLUSION: In nccRCC patients, treatment with pazopanib was effective and feasible; dose reductions required for toxicity were similar as expected in ccRCC.
Subject(s)
Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Indazoles , Italy , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyrimidines/adverse effects , Retrospective Studies , Sulfonamides/adverse effects , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Treatment of non-clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC. METHODS: We performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan-Meier method. RESULTS: 91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0-13.9). Median OS was 37.9 months (95% confidence interval [CI]: 21.4-46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2-10.9) and 22.9 months (95% CI: 17.8-49.2) versus 1.9 months (95% CI: 1.0-6.0) and 3.2 months (95% CI: 2.3-not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55). CONCLUSION: We report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/drug therapy , Kidney Neoplasms/secondary , Molecular Targeted Therapy/methods , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/mortality , Enzyme Inhibitors/therapeutic use , Female , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Male , Middle Aged , Retrospective Studies , Survival Analysis , TOR Serine-Threonine Kinases/antagonists & inhibitors , Time Factors , Treatment FailureABSTRACT
BACKGROUND: Clinical data from patients with non-clear cell renal cell carcinoma (nccRCC) receiving targeted therapy are limited, and many clinical trials have excluded these patients from study entry. We sought to investigate the outcomes of patients with nccRCC treated in clinical trials in the modern era compared with the outcomes of patients with clear cell RCC (ccRCC). PATIENTS AND METHODS: We conducted a retrospective study of patients with metastatic RCC who had received targeted therapy in Pfizer-sponsored phase II and III clinical trials from 2003 to 2013. Associations between the histologic type and treatment outcome (overall survival [OS] and progression-free survival [PFS]) were assessed using the log-rank test on univariate analysis or the Wald χ2 test from Cox regression on multivariable analysis, adjusted for baseline characteristics, including age, sex, Eastern Cooperative Oncology Group performance status, body mass index, International Metastatic RCC Database Consortium risk factors, previous nephrectomy, previous therapy, metastatic sites, angiotensin system inhibitor use, and statin use. RESULTS: We identified 4527 patients with metastatic RCC: 4235 with ccRCC and 337 with nccRCC. Overall, the median OS was shorter for those with nccRCC than for those with ccRCC (15.7 vs. 20.2 months; hazard ratio [HR], 1.41; 95% confidence interval 1.22-1.63; P < .001). When stratified by the International Metastatic RCC Database Consortium risk group, the median OS was inferior for the intermediate- and poor-risk patients with nccRCC than for those with ccRCC. However, no differences were found in the favorable risk group for nccRCC versus ccRCC. The patients with nccRCC who had received vascular endothelial growth factor-targeted therapy had shorter PFS compared with that of ccRCC patients (median, 6.1 vs. 8.5 months; HR, 1.49; P < .001) but similar PFS when treated with mammalian target of rapamycin inhibitors (median, 4.3 vs. 4.4 months; HR, 0.92; P = .63). CONCLUSION: Our findings have confirmed that patients with nccRCC are underrepresented in clinical trials and highlight the need for further prospective studies exploring current and novel agents for this patient population.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Nephrectomy/methods , Adult , Aged , Aged, 80 and over , Angiotensin Receptor Antagonists/therapeutic use , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Disease-Free Survival , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Middle Aged , Regression Analysis , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The randomized phase III trial of sunitinib versus interferon Alfa provided level-A evidence for the use of sunitinib in advanced clear cell renal cell carcinoma (RCC). This systematic literature review aims at the evaluation of the level of evidence for the use of sunitinib monotherapy for advanced non clear cell RCC in terms of efficacy and toxicity parameters. METHODS: Eligible studies were identified using MEDLINE, Google scholar, ASCO, ESMO and the Cochrane databases. Searches were last updated on 1 June 2014. Eligible studies reported survival and/or response data for patients with non clear cell RCC receiving sunitinib monotherapy. RESULTS: four hundred and five results were obtained from the searches in MEDLINE (n=319 studies) and other databases (n=86). Twelve studies (involving 980 patients) were considered eligible and were included in the final analysis: six phase II clinical trials, one expanded access prospective trial and five retrospective analyses. Median PFS was reported in 11 studies ranging from 1.6 to 8.9 months. Median OS was reported in 9 studies ranging from 12 months to 22 months. The disease control rate (DCR) was reported in 10 studies, and it ranged from 35% to 91%. The overall response rate (ORR) was reported in 10 studies and it ranged from 0% to 36%. Frequently reported Grade 3/4 toxicities were gastrointestinal toxicities, mucocutaneous toxicities and hematologic toxicities. CONCLUSION: There is insufficient evidence (level C) to recommend sunitinib monotherapy in advanced non clear cell RCC and the available data suggests it appears less efficacious than that in advanced clear cell RCC. Further prospective and randomized studies are needed to explore alternative therapies in this setting.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Pyrroles/therapeutic use , Angiogenesis Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/mortality , Combined Modality Therapy , Humans , Indoles/adverse effects , Kidney Neoplasms/diagnosis , Kidney Neoplasms/mortality , Neoplasm Staging , Pyrroles/adverse effects , Randomized Controlled Trials as Topic , Sunitinib , Survival Analysis , Treatment OutcomeABSTRACT
Chromophobe renal cell carcinoma (RCC), a subtype of RCC, accounts for 4-6% of all RCC and has better prognosis then conventional RCC. Sarcomatoid dedifferentiation is thought to represent the high-grade end of all subtypes. This makes chromophobe RCC with sarcomatoid changes a rare entity associated with poor prognosis in most studies. We present a case of a 40-year old female with this rare histology, with the tumour localised to the renal capsule, managed with nephrectomy and with close follow-up thereafter. The patient is free of disease after one year of treatment.
ABSTRACT
The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequently displays nuclear and nucleolar pleomorphism. The present study reevaluates this grading system in a series of patients with nonsarcomatoid chRCC. We identified 176 patients (3.6%) with nonsarcomatoid chRCC in a total of 4897 patients who underwent surgery for renal cell carcinoma at 5 centers in Germany between 1990 and 2010. The mean follow-up was 51.1 months. The 3 groups (G1 versus G2 versus G3/4) were comparable in terms of age, sex, tumor diameter, and lymph node metastasis. They only differed significantly in tumor stage (P = .01) and the incidence of synchronous visceral metastasis (P = .04). The 5-year cancer-specific survival rates were 84.4% for G1 (n = 32), 84.3% for G2 (n = 108), and 74.1% for G3/4 tumors (n = 33) (P = .58). Accordingly, multivariate analysis including age, sex, tumor stage, and metastatic disease did not identify Fuhrman grading as an independent predictor of cancer-specific survival in patients with chRCC (P = .4). We were able to demonstrate in a large multicenter cohort that the Fuhrman grading system does not qualify as a prognostic tool in patients with chRCC.
Subject(s)
Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Lymphatic Metastasis/pathology , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/surgery , Female , Humans , Kidney Neoplasms/mortality , Kidney Neoplasms/surgery , Male , Middle Aged , Neoplasm Grading , Prognosis , Retrospective Studies , Survival RateABSTRACT
To evaluate the clinicopathologic features of renal cell carcinoma in younger adults (=40 years), we retrospectively reviewed 838 consecutive cases of renal cell carcinoma (RCC) occurred in a single tertiary hospital. Forty-four 44 (5.2%) cases occurred in the young adult group (24 to 40 years of age). Clinicopathologic features including tumor size, stage, histologic subtype, lymph node and distant metastasis, and overall survival were compared with that of cases occurred in older age group (>40 years). The tumor size of the young adult group were smaller (5.3 vs 5.9 cm) and presented at less advanced stages (T3/T4 tumors, 18% vs 31%) than those occurring in the older age group (>40 years of age). The incidences of chromophobe RCC (12% vs. 6%) and of collecting duct carcinoma (5% vs 0.5%) were higher in the young adult group. The rate of nodal or distant metastasis was lower in young adult group (5% vs. 8.3%). More patients underwent partial nephrectomy in younger than older age group (30% vs 19%). There was no overall survival difference at 5 years (77% vs 70%), but there was a trend for a favorable survival in young adults at 10 years (77% vs 52%). In conclusion, RCC are relatively infrequent in patients who are younger than 40 years. The tumors in this group appear to be smaller and less advanced at presentation. Chromophobe RCC and collecting duct carcinoma are more frequently seen. More patients undergo partial nephrectomy and overall long term survival appears to be more favorable.