Brian Shuch

Magnetic Resonance Imaging/Ultrasound–Fusion Biopsy Significantly Upgrades Prostate Cancer Versus Systematic 12-core Transrectal Ultrasound Biopsy

BACKGROUNDnGleason scores from standard, 12-core prostate biopsies are upgraded historically in 25-33% of patients. Multiparametric prostate magnetic resonance imaging (MP-MRI) with ultrasound (US)-targeted fusion biopsy may better sample the true gland pathology.nnnOBJECTIVEnThe rate of Gleason score upgrading from an MRI/US-fusion-guided prostate-biopsy platform is compared with a standard 12-core biopsy regimen alone.nnnDESIGN, SETTING, AND PARTICIPANTSnThere were 582 subjects enrolled from August 2007 through August 2012 in a prospective trial comparing systematic, extended 12-core transrectal ultrasound biopsies to targeted MRI/US-fusion-guided prostate biopsies performed during the same biopsy session.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe highest Gleason score from each biopsy method was compared.nnnINTERVENTIONSnAn MRI/US-fusion-guided platform with electromagnetic tracking was used for the performance of the fusion-guided biopsies.nnnRESULTS AND LIMITATIONSnA diagnosis of prostate cancer (PCa) was made in 315 (54%) of the patients. Addition of targeted biopsy led to Gleason upgrading in 81 (32%) cases. Targeted biopsy detected 67% more Gleason ≥4+3 tumors than 12-core biopsy alone and missed 36% of Gleason ≤3+4 tumors, thus mitigating the detection of lower-grade disease. Conversely, 12-core biopsy led to upgrading in 67 (26%) cases over targeted biopsy alone but only detected 8% more Gleason ≥4+3 tumors. On multivariate analysis, MP-MRI suspicion was associated with Gleason score upgrading in the targeted lesions (p<0.001). The main limitation of this study was that definitive pathology from radical prostatectomy was not available.nnnCONCLUSIONSnMRI/US-fusion-guided biopsy upgrades and detects PCa of higher Gleason score in 32% of patients compared with traditional 12-core biopsy alone. Targeted biopsy technique preferentially detects higher-grade PCa while missing lower-grade tumors.

Accuracy of multiparametric magnetic resonance imaging in confirming eligibility for active surveillance for men with prostate cancer.

Active surveillance (AS) is an attempt to avoid overtreatment of clinically insignificant prostate cancer (PCa); however, patient selection remains controversial. Multiparametric prostate magnetic resonance imaging (MP‐MRI) may help better select AS candidates.

Succinate Dehydrogenase Kidney Cancer: An Aggressive Example of the Warburg Effect in Cancer

PURPOSEnRecently, 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.nnnMATERIALS AND METHODSnPatients 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.nnnRESULTSnA 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.nnnCONCLUSIONSnSDH 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.

Sarcomatoid Renal Cell Carcinoma: A Comprehensive Review of the Biology and Current Treatment Strategies

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.

Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics

Patients with renal cell carcinoma (RCC) who are black tend to have poorer prognosis than similar patients who are white. This study examined whether the racial disparity in RCC patient survival varies by demographic and clinical characteristics.

An investigation of risk factors for renal cell carcinoma by histologic subtype in two case-control studies

To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary and chromophobe) in two case‐control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was abstracted from the original diagnostic pathology report. Case‐only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex and race. Case‐control analyses were performed to compute subtype‐specific ORs for other risk factors using polytomous regression. In case‐only analyses, papillary cases (N = 237) were older (OR = 1.2, 95% CI = 1.1–1.4 per 10‐year increase), less likely to be female (OR = 0.5, 95% CI = 0.4–0.8) and more likely to be black (OR = 2.6, 95% CI = 1.8–3.9) as compared to clear cell cases (N = 1,524). In case‐control analyses, BMI was associated with clear cell (OR = 1.2, 95% CI = 1.1–1.3 per 5 kg/m2 increase) and chromophobe RCC (N = 80; OR = 1.2, 95% CI = 1.1–1.4), but not papillary RCC (OR = 1.1, 95% CI = 1.0–1.2; test versus clear cell, p = 0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity‐RCC association differs by histology.

Germline PTEN Mutation Cowden Syndrome: An Underappreciated Form of Hereditary Kidney Cancer

PURPOSEnCowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma.nnnMATERIALS AND METHODSnPatients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity.nnnRESULTSnAmong 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies.nnnCONCLUSIONSnRenal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Metabolic Reprogramming for Producing Energy and Reducing Power in Fumarate Hydratase Null Cells from Hereditary Leiomyomatosis Renal Cell Carcinoma

Fumarate hydratase (FH)-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism. These changes represent multiple biochemical adaptations in glucose and fatty acid metabolism that supports malignant proliferation. However, the metabolic linkages between altered mitochondrial function, nucleotide biosynthesis and NADPH production required for proliferation and survival have not been elucidated. To characterize the alterations in glycolysis, the Krebs cycle and the pentose phosphate pathways (PPP) that either generate NADPH (oxidative) or do not (non-oxidative), we utilized [U-13C]-glucose, [U-13C,15N]-glutamine, and [1,2- 13C2]-glucose tracers with mass spectrometry and NMR detection to track these pathways, and measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of growing cell lines. This metabolic reprogramming in the FH null cells was compared to cells in which FH has been restored. The FH null cells showed a substantial metabolic reorganization of their intracellular metabolic fluxes to fulfill their high ATP demand, as observed by a high rate of glucose uptake, increased glucose turnover via glycolysis, high production of glucose-derived lactate, and low entry of glucose carbon into the Krebs cycle. Despite the truncation of the Krebs cycle associated with inactivation of fumarate hydratase, there was a small but persistent level of mitochondrial respiration, which was coupled to ATP production from oxidation of glutamine-derived α–ketoglutarate through to fumarate. [1,2- 13C2]-glucose tracer experiments demonstrated that the oxidative branch of PPP initiated by glucose-6-phosphate dehydrogenase activity is preferentially utilized for ribose production (56-66%) that produces increased amounts of ribose necessary for growth and NADPH. Increased NADPH is required to drive reductive carboxylation of α-ketoglutarate and fatty acid synthesis for rapid proliferation and is essential for defense against increased oxidative stress. This increased NADPH producing PPP activity was shown to be a strong consistent feature in both fumarate hydratase deficient tumors and cell line models.

The Surgical Approach to Multifocal Renal Cancers: Hereditary Syndromes, Ipsilateral Multifocality, and Bilateral Tumors

Although the management of sporadic renal tumors is challenging enough, dealing with those with bilateral, multifocal, and hereditary kidney cancer adds an additional level of complexity. A clinician managing this patient population must understand the hereditary syndromes and the genetic testing available. Treating physicians must be familiar with enucleative surgery, complex or multiple tumor partial nephrectomy, complex renal reconstruction, re-operative renal surgery, and active surveillance strategies. With proper management, most patients affected with bilateral, multifocal, or hereditary RCC can have a long life expectancy while maintaining adequate renal function.

Adrenal Nodular Hyperplasia in Hereditary Leiomyomatosis and Renal Cell Cancer

PURPOSEnThe condition hereditary leiomyomatosis and renal cell carcinoma is characterized by cutaneous leiomyomas, uterine fibroids and aggressive papillary renal cell carcinoma. A number of our patients with hereditary leiomyomatosis and renal cell carcinoma had atypical adrenal nodules, which were further evaluated to determine whether these nodules were associated with hereditary leiomyomatosis and renal cell carcinoma.nnnMATERIALS AND METHODSnPatients with hereditary leiomyomatosis and renal cell carcinoma underwent a comprehensive clinical and genetic evaluation. We reviewed the clinical presentation, anatomical and functional imaging, endocrine evaluation, pathological examination and germline mutation testing results.nnnRESULTSnOf 255 patients with hereditary leiomyomatosis and renal cell carcinoma 20 (7.8%) had primary adrenal lesions, including 4 with bilateral adrenal lesions and 4 with multiple nodules. Two patients had adrenocorticotropic hormone independent hypercortisolism. A total of 27 adrenal lesions were evaluated. The imaging characteristics of 5 of these lesions (18.5%) were not consistent with adenoma by noncontrast computerized tomography criteria. Positron emission tomography was positive in 7 of 10 cases (70%). A total of 12 nodules were surgically resected from 10 adrenal glands. Pathological examination revealed macronodular adrenal hyperplasia in all specimens.nnnCONCLUSIONSnUnilateral and bilateral adrenal nodular hyperplasia was detected in a subset of patients with hereditary leiomyomatosis and renal cell carcinoma. A functional endocrine evaluation is recommended when an adrenal lesion is discovered. Imaging frequently reveals lesions that are not typical of adenomas and positron emission tomography may be positive. To date no patient has had adrenal malignancy, and active surveillance of hereditary leiomyomatosis and renal cell carcinoma adrenal nodules appears justified.