Kidney cancer is not a single disease but comprises a number of different types of cancer that occur in the kidney, each caused by a different gene with a different histology and clinical course that ...responds differently to therapy. Each of the seven known kidney cancer genes, VHL, MET, FLCN, TSC1, TSC2, FH and SDH, is involved in pathways that respond to metabolic stress or nutrient stimulation. The VHL protein is a component of the oxygen and iron sensing pathway that regulates hypoxia-inducible factor (HIF) levels in the cell. HGF-MET signaling affects the LKB1-AMPK energy sensing cascade. The FLCN-FNIP1-FNIP2 complex binds AMPK and, therefore, might interact with the cellular energy and nutrient sensing pathways AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR. TSC1-TSC2 is downstream of AMPK and negatively regulates mTOR in response to cellular energy deficit. FH and SDH have a central role in the mitochondrial tricarboxylic acid cycle, which is coupled to energy production through oxidative phosphorylation. Mutations in each of these kidney cancer genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy or nutrient sensing, suggesting that kidney cancer is a disease of cell metabolism. Targeting the fundamental metabolic abnormalities in kidney cancer provides a unique opportunity for the development of more-effective forms of therapy for this disease.
The development of new forms of treatment of advanced renal cell carcinoma over the past two decades has been primarily focused on targeting the VHL/HIF pathway. The recent identification of ...mutations of chromatin-remodeling genes in clear-cell renal carcinoma (ccRCC), of genomic heterogeneity, and of a Warburg-like metabolic phenotype in advanced disease has had a profound effect on our understanding of the evolution of ccRCC and on potential approaches to personalized therapy. Early approaches to therapy for patients with advanced type I papillary RCC that have centered around the MET/HGF pathway will expand as more genomic information becomes available. Sporadic and familial type II papillary renal cell carcinoma are characterized by enhanced aerobic glycolysis and share an antioxidant response phenotype. In fumarate hydratase-deficient RCC, fumarate-induced succination of KEAP1 activates Nrf2 signaling. CUL3 and Nrf2 mutations as well as an Nrf2 activation phenotype are found in sporadic type II papillary RCC. Therapeutic approaches designed to target the Nrf2 pathway as well as to impair blood flow and glucose delivery in these cancers that are highly dependent on a robust tumor vasculature and on ready availability of glucose for energy production and glycolysis are in development.
Learning Objectives
After completing this course, the reader will be able to:
Describe histologic features associated with sarcomatoid renal cell carcinoma.
Outline current surgical approaches to ...treating sarcomatoid renal cell carcinoma.
This article is available for continuing medical education credit at CME.TheOncologist.com
Recent advancements in the molecular characterization of renal cell carcinoma altered the classification system and now kidney cancer is divided into several distinct histologic subtypes. Although once a separate histologic category, sarcomatoid renal cell carcinoma is no longer considered a separate tumor type because it can occur with all histologic subtypes. Limited research on tumors with sarcomatoid change has led to minimal progress in the understanding and treatment of these tumors. Because the sarcomatoid variant of renal cell carcinoma can account for approximately one in six cases of advanced kidney cancer, we hope to familiarize clinicians with these tumors by describing the historic background, histologic features, molecular characterization, diagnosis, prognosis, treatment strategies, and active clinical trials of this aggressive type of tumor.
摘要
肾细胞癌分子定性的最新进展改变了分类系统，目前肾癌可分为几个不同的组织学亚型。肉瘤样肾细胞癌一度是独立的组织学类别，但因可见于所有组织学亚型，现已不再列为独立的肿瘤类型。肉瘤样变肿瘤的研究有限，对这些肿瘤的了解和治疗进展缓慢。肾细胞癌的肉瘤样变异型约占晚期肾癌的1/6，我们因此希望通过描述此类侵袭性肿瘤的历史背景、组织学特征、分子定性、诊断、预后、治疗策略和进行中的临床试验，使医生能熟悉此类肿瘤。
The historic background, histologic features, molecular characterization, diagnosis, prognosis, treatment strategies, and active clinical trials of the sarcomatoid variant of renal cell carcinoma are described.
Approximately 5% to 8% of renal cell carcinoma (RCC) is hereditary. No guidelines exist for patient selection for RCC germline mutation testing. We evaluate how age of onset could indicate the need ...for germline mutation testing for detection of inherited forms of kidney cancer.
We analyzed the age distribution of RCC cases in the SEER-17 program and in our institutional hereditary kidney cancer population. The age distributions were compared by sex, race, histology, and hereditary cancer syndrome. Models were established to evaluate the specific age thresholds for genetic testing.
The median age of patients with RCC in SEER-17 was 64 years, with the distribution closely approaching normalcy. Statistical differences were observed by race, sex, and subtype (P < .05). The bottom decile cutoff was ≤ 46 years of age and slightly differed by sex, race, and histology. The mean and median ages at presentation of 608 patients with hereditary kidney cancer were 39.3 years and 37 years, respectively. Although age varied by specific syndrome, 70% of these cases were found to lie at or below the bottom age decile. Modeling age-based genetic testing thresholds demonstrated that the 10th percentile maximized sensitivity and specificity.
Early age of onset might be a sign of hereditary RCC. Even in the absence of clinical manifestations and personal/family history, an age of onset of 46 years or younger should trigger consideration for genetic counseling/germline mutation testing and may serve as a useful cutoff when establishing genetic testing guidelines.
Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell ...carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.
Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET 7q31 amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).
Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.
Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.
Published series of growth rates of renal tumors on active surveillance largely consist of tumors without pathologic or genetic data. Growth kinetics of genetically defined renal tumors are not well ...known. Here, we evaluate the growth of genetically defined renal tumors and their association with patient clinical and genetic characteristics.
We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of
or
with at least 1 solid renal mass managed with active surveillance at our institution. Tumor growth rates (GR) were calculated and patients were stratified by genetic alteration and other clinical and genetic factors to analyze differences in growth rates using linear regression and comparative statistics.
A total of 292 patients with 435 genetically defined tumors were identified, including 286
-deficient, 91
-deficient, 52
-activated, and 6
-deficient tumors. There were significant differences in GRs when stratified by genetic alteration.
-deficient tumors had the fastest median GR (0.6 cm/y; interquartile range IQR, 0.57-0.68 cm/y), followed by
-deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y),
-deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with
activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y;
< .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR (
= .005).
In a cohort of genetically defined tumors, tumor growth rates varied in a clinically and statistically different manner according to genetic subtype. Rapid growth of
-deficient tumors indicates that these patients should be managed with caution. The faster growth of tumors in younger patients may support more frequent imaging, whereas the slower growth of other tumors may support extended surveillance beyond annual imaging in some instances.
Purpose Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits ( SDHB / C / D ) of the Krebs cycle enzyme, succinate dehydrogenase. We report our ...experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. Materials and Methods Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB , SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. Results A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. Conclusions SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors.
Inactivation of the TCA cycle enzyme, fumarate hydratase (
FH), drives a metabolic shift to aerobic glycolysis in
FH-deficient kidney tumors and cell lines from patients with hereditary ...leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.
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► Loss of
FH drives a glycolytic shift and reduces AMPK levels in HLRCC tumor cells ► Reduced AMPK levels in
FH−/− cells activate ACC and rpS6 and decrease p53 levels ► Reduced AMPK levels in
FH−/− cells decrease DMT1 levels and increase IRP activities ► Reduced iron uptake and activation of IRPs increase levels of HIF-1α but not HIF-2α
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