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OBJECTIVE: To evaluate whether bilateral, multifocal clear cell renal cell carcinoma (ccRCC) patients can be differentiated by VHL mutation analysis into cases that represent either multiple independently arising primary tumors, or a single primary tumor which has spread ipsilaterally as well as to the contralateral kidney. The nature of kidney cancer multifocality outside of known hereditary syndromes is as yet poorly understood. MATERIALS AND METHODS: DNA from multiple tumors per patient were evaluated for somatic VHL gene mutation and hypermethylation. A subset of tumors with shared VHL mutations were analyzed with targeted, next-generation sequencing assays. RESULTS: This cohort contained 5 patients with multiple tumors that demonstrated a shared somatic VHL mutation consistent with metastatic spread including to the contralateral kidney. In several cases this was substantiated by additional shared somatic mutations in ccRCC-associated genes. In contrast, the remaining 14 patients with multiple tumors demonstrated unique, unshared VHL alterations in every analyzed tumor, consistent with independently arising kidney tumors. None of these latter patients showed any evidence of local spread or distant metastasis. CONCLUSION: The spectrum of VHL alterations within evaluated bilateral, multifocal ccRCC tumors from a single patient can distinguish between multiple independent tumor growth and metastasis. This can be performed using currently available clinical genetic tests and will improve the accuracy of patient diagnosis and prognosis, as well as informing appropriate management.

INTRODUCTION AND OBJECTIVE:Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition in which affected individuals are at risk for the development of renal cysts, renal t...

INTRODUCTION AND OBJECTIVE:Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition characterized by an increased risk for a clinically aggressive papillary renal cell c...

Up to 8% of renal cancers are thought to have a hereditary component. Several hereditary renal cancer syndromes have been identified over the last few decades. It is important for the radiologist to be aware of findings associated with hereditary renal cancer syndromes to detect tumors early, enroll patients in appropriate surveillance programs, and improve outcomes for the patient and affected family members. This review discusses from a radiologist's perspective well-known hereditary renal cancer syndromes and emerging genetic mutations associated with renal cancer that are less well characterized, focusing on imaging features and known associations.

It is estimated that up to 8% of currently diagnosed renal cancers are part of a hereditary syndrome. The radiologist may be the first person to associate a renal tumor presenting during an imaging study to other manifestations of a hereditary syndrome. This diagnosis can have broad implications for the patient but also for other family members. This update reviews the current known associations and emerging mutations of hereditary renal cancers from a radiologist’s perspective. Renal manifestations, as well as associated radiological findings and pitfalls are discussed. Additionally, screening and surveillance recommendations are also discussed to aid radiologists in the decision-making process for patient management.

PURPOSE 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. PATIENTS AND METHODS We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of VHL, MET, FLCN, or BAP1 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. RESULTS A total of 292 patients with 435 genetically defined tumors were identified, including 286 VHL-deficient, 91 FLCN-deficient, 52 MET-activated, and 6 BAP1-deficient tumors. There were significant differences in GRs when stratified by genetic alteration. BAP1-deficient tumors had the fastest median GR (0.6 cm/y; interquartile range [IQR], 0.57-0.68 cm/y), followed by VHL-deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y), FLCN-deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with MET activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y; P < .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR ( P = .005). CONCLUSION 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 BAP1-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 To retrospectively investigate the radiological presentations of HLRCC-associated renal tumors to facilitate accurate lesion characterization and compare these presentations with simple cysts and characteristics of other subtypes of renal cell carcinoma (RCC) as reported in the literature. Methods The MRI and CT imaging characteristics of 39 pathologically confirmed lesions from 30 patients (20 male, 10 female) with HLRCC syndrome were evaluated by two radiologists. Patients had an average age at diagnosis of 43.8 ± 13.1 years. Lesion characteristics including laterality, homogeneity, diameter (cm), nodularity, septations, T1 and T2 signal intensity, enhancement, and restricted diffusion were recorded. Imaging characteristics of the lesions were further compared to characteristics of benign simple cysts surgically removed at the same time point. Results The examined lesions had a mean diameter of 5.06 ± 3.80 cm, an average growth rate of 2.91 × 10−3 cm/day and an estimated annual growth rate of 1.06 cm/year. 50% of lesions demonstrated nodularity, 65% were mostly T2-hyperintense, 83% demonstrated restricted diffusion in solid portions of the lesions, and 65% had well-defined margins. 76% of patients demonstrated extra-renal manifestations, 53% lymphadenopathy, and 43% distant metastasis. Conclusions Our analysis confirmed that while HLRCC-associated renal lesions demonstrate diversity in imaging presentations, the majority are unilateral and solitary, T2-hyperintense, heterogeneous with well-defined margins, and frequently demonstrate restricted diffusion and nodularity.

INTRODUCTION AND OBJECTIVES:Genetically-defined renal cell carcinomas (RCC), including those associated with von Hippel-Lindau (VHL; clear cell RCC, VHL gene), Hereditary Papillary Renal Carcinoma ...

PURPOSE: To determine whether objective volumetric whole-lesion apparent diffusion coefficient (ADC) distribution analysis improves upon the capabilities of conventional subjective small region-of-interest (ROI) ADC measurements for prediction of renal cell carcinoma (RCC) subtype. METHODS: This IRB-approved study retrospectively enrolled 55 patients (152 tumors). Diffusion-weighted imaging DWI was acquired at b values of 0, 250, and 800 s/mm(2) on a 1.5T system (Aera, Siemens Healthcare). Whole-lesion measurements were performed by a research fellow and reviewed by a fellowship-trained radiologist. Mean, median, skewness, kurtosis, and every 5th percentile ADCs were determined from the whole-lesion histogram. Linear mixed models that accounted for within-subject correlation of lesions were used to compare ADCs among RCC subtypes. Receiver-operating characteristic (ROC) curve analysis with optimal cutoff points from the Youden index was used to test the ability of ADCs to differentiate clear cell RCC (ccRCC), papillary RCC (pRCC), and oncocytoma subtypes. RESULTS: Whole-lesion ADC values were significantly different between pRCC and ccRCC, and between pRCC and oncocytoma, demonstrating strong ability to differentiate subtypes across the quantiles (both P < 0.001). Best percentile ROC analysis demonstrated AUC values of 95.2 for ccRCC vs. pRCC; 67.6 for oncocytoma vs. ccRCC; and 95.8 for oncocytoma vs. pRCC. Best percentile ROC analysis further indicated model sensitivities/specificities of 84.5%/93.1% for ccRCC vs. pRCC; 100.0%/10.3% for oncocytoma vs. ccRCC; and 88.5%/ 93.1% for oncocytoma vs. pRCC. CONCLUSION: The objective methodology of whole-lesion volumetric ADC measurements maintains the sensitivity/ specificity of conventional expert-based ROI analysis, provides information on lesion heterogeneity, and reduces observer bias.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant inherited syndrome involving multiple organs. In young patients, renal neoplasms that are multiple, bilateral, or both, such as oncocytomas, chromophobe renal cell carcinoma (RCC), hybrid chromophobe RCC-oncocytomas, clear cell RCC, and papillary RCC, can suggest BHD syndrome. Extrarenal findings, including dermal lesions, pulmonary cysts, and spontaneous pneumothoraces, also aid in diagnosis.Radiologists may be one of the first medical specialists to suggest the diagnosis of BHD syndrome. Knowledge of pathogenesis and management, including the importance of the types of renal neoplasms in a given patient, is needed to properly recognize this rare condition.

0.5 mg/dL), perioperative CRP kinetics (non-elevated before CN vs. normalized after CN vs. non-normalized after CN), lactate dehydrogenase, corrected calcium, tumor histology, pT stage, and pN stage. Skeletal muscle index (SMI) was calculated by skeletal muscle areas at the L3 vertebra level normalized for height on diagnostic CT taken preoperatively ( 1 month before CN) and postoperatively (5-6 months after CN). Patients were considered to show SM recovery when postoperative SMI surpassed preoperative SMI. We examined variables associated with overall survival (OS) using the Cox proportional hazards model. RESULTS: Of the 30 patients, 16 (53%) showed SM recovery after CN. SM recovery was not associated with other variables including preoperative CRP. During the median follow-up of 61 months for survivors, 14 patients died (5-yr OS rate 46%). On multivariate analysis, postoperative SM recovery was a significant and independent predictor for OS (HR 0.04, p < 0.001) along with elevated preoperative CRP (HR 13.6, p < 0.001). The 5-yr OS rates for patients with and without SM recovery were 76% and 10%, respectively (p < 0.001). CONCLUSIONS: Postoperative SM recovery is associated with favorable prognosis in mRCC patients who underwent CN.

Purpose: To explore the added value of the shape of renal lesions for classifying renal neoplasms. To investigate the potential of computer-aided analysis of contrast-enhanced computed-tomography (CT) to quantify and classify renal lesions. Methods: A computer-aided clinical tool based on adaptive level sets was employed to analyze 125 renal lesions from contrast-enhanced abdominal CT studies of 43 patients. There were 47 cysts and 78 neoplasms: 22 Von Hippel-Lindau (VHL), 16 Birt-Hogg-Dube (BHD), 19 hereditary papillary renal carcinomas (HPRC), and 21 hereditary leiomyomatosis and renal cell cancers (HLRCC). The technique quantified the three-dimensional size and enhancement of lesions. Intrapatient and interphase registration facilitated the study of lesion serial enhancement. The histograms of curvature-related features were used to classify the lesion types. The areas under the curve (AUC) were calculated for receiver operating characteristic curves. Results: Tumors were robustly segmented with 0.80 overlap (0.98 correlation) between manual and semi-automated quantifications. The method further identified morphological discrepancies between the types of lesions. The classification based on lesion appearance, enhancement and morphology between cysts and cancers showed AUC = 0.98; for BHD + VHL (solid cancers) vs. HPRC + HLRCC AUC = 0.99; for VHL vs. BHD AUC = 0.82; and for HPRC vs.more » HLRCC AUC = 0.84. All semi-automated classifications were statistically significant (p < 0.05) and superior to the analyses based solely on serial enhancement. Conclusions: The computer-aided clinical tool allowed the accurate quantification of cystic, solid, and mixed renal tumors. Cancer types were classified into four categories using their shape and enhancement. Comprehensive imaging biomarkers of renal neoplasms on abdominal CT may facilitate their noninvasive classification, guide clinical management, and monitor responses to drugs or interventions.« less

INTRODUCTION AND OBJECTIVES: In 1994 we described a novel hereditary cancer syndrome, Hereditary Papillary Renal Cell Carcinoma (HPRC). HPRC is an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal, type 1 papillary kidney cancer. In 1997 we identified the proto-oncogene MET as the HPRC gene. HPRC patients are characterized by germline activating missense mutation in tyrosine kinase domain of MET and have a lifelong risk for the development of bilateral multifocal kidney tumors. Here we present our near-20-year experience on management of these patients. METHODS: From May 1992 to October 2011, 12 families with known germline MET mutation were followed with careful, periodic screening for development, growth, recurrence and metastasis of their renal tumors. Surgical removal was recommended when the largest kidney tumor reached a 3-cm cutoff size, and preference was given to nephron-sparing surgery. Median follow up was 65 months (range 1 month to 20 years). RESULTS: A total of 56 patients underwent periodic surveillance. Of these patients, 34 developed renal tumors: bilateral in 17, unilateral multiple in 13 and single in 4 patients. The average age at onset was 42 years (range 19 to 66). Twenty-nine patients underwent 42 kidney surgeries, of which 23 were performed at the National Cancer Institute: 17 were partial nephrectomies, of which 1 was a simultaneous bilateral partial nephrectomy, 2 were radical nephrectomies and 4 were radiofrequency ablation of renal tumors. Up to 59 tumors were removed from each renal unit. None of the patients required renal replacement therapy, with 22/23 patients maintaining postoperative eGFR 60. Metastatic disease developed in 5 patients all of whom presented with large or very rapidly growing lesions. CONCLUSIONS: In the largest reported experience worldwide with HPRC, patients affected by hereditary papillary renal cancer can be safely managed by expectant management, with nephron-sparing surgery triggered by tumors reaching a 3 cm size threshold. This management optimizes the renal function of these patients without compromising their oncologic outcomes.

Purpose: To explore the added value of the shape of renal lesions for classifying renal neoplasms. To investigate the potential of computer-aided analysis of contrast-enhanced computed-tomography (CT) to quantify and classify renal lesions.Methods: A computer-aided clinical tool based on adaptive level sets was employed to analyze 125 renal lesions from contrast-enhanced abdominal CT studies of 43 patients. There were 47 cysts and 78 neoplasms: 22 Von Hippel-Lindau (VHL), 16 Birt-Hogg-Dube (BHD), 19 hereditary papillary renal carcinomas (HPRC), and 21 hereditary leiomyomatosis and renal cell cancers (HLRCC). The technique quantified the three-dimensional size and enhancement of lesions. Intrapatient and interphase registration facilitated the study of lesion serial enhancement. The histograms of curvature-related features were used to classify the lesion types. The areas under the curve (AUC) were calculated for receiver operating characteristic curves.Results: Tumors were robustly segmented with 0.80 overlap (0.98 correlation) between manual and semi-automated quantifications. The method further identified morphological discrepancies between the types of lesions. The classification based on lesion appearance, enhancement and morphology between cysts and cancers showed AUC = 0.98; for BHD + VHL (solid cancers) vs. HPRC + HLRCC AUC = 0.99; for VHL vs. BHD AUC = 0.82; and for HPRC vs. HLRCC AUC = 0.84. All semi-automated classifications were statistically significant (p

In clinical practice, renal cancer diagnosis is performed by manual quantifications of tumor size and enhancement, which are time consuming and show high variability. We propose a computer-assisted clinical tool to assess and classify renal tumors in contrast-enhanced CT for the management and classification of kidney tumors. The quantification of lesions used level-sets and a statistical refinement step to adapt to the shape of the lesions. Intra-patient and inter-phase registration facilitated the study of lesion enhancement. From the segmented lesions, the histograms of curvature-related features were used to classify the lesion types via random sampling. The clinical tool allows the accurate quantification and classification of cysts and cancer from clinical data. Cancer types are further classified into four categories. Computer-assisted image analysis shows great potential for tumor diagnosis and monitoring.

419 Background: 2-(18F) fluoro-2 deoxy-D-glucose (FDG) PET/CT is used infrequently in renal cell carcinoma (RCC) based on modest sensitivity in patients with clear cell kidney cancer. We evaluated the ability of FDG PET/CT to identify metastatic kidney cancer in patients with the second most common variant, papillary RCC. Materials and Methods: Patients with papillary RCC who underwent FDG PET/CT in conjunction with anatomic imaging were identified in a review of our clinical database. The ability of FDG PET/CT to detect malignant lesions (categorized by radiographic criteria) was evaluated. Results: Imaging studies from 42 patients with metastatic papillary RCC were reviewed. A total of 215 lesions were characterized as metastatic based on radiologic features. The median lesion size and lesions per patient were 2.0 cm and 5, respectively. Of these, 200 lesions were correctly classified as malignant by PET/CT (sensitivity, 93.0%, 95% confidence interval (CI) 88.8-95.7%). Of histologically confirmed lesions, 35 of 39 were PET positive (sensitivity, 89.7%, CI-76.4-95.9%). FDG PET/CT sensitivity did not appear to differ by lesion size, site, or papillary subtype. In a patient based analysis, all 42 patients had evidence of at least one FDG PET/CT avid lesion (sensitivity 100%, (95% CI 91.6-100%). Conclusions: FDG PET/CT is a highly sensitive modality for identifying extra-renal disease associated with papillary RCC. These data suggest that FDG PET/CT might be a clinically useful modality in the staging and surveillance of this patient population.