- SIR RFS IO Service Line -

Created By: Sam McMurry D.O.

Date: 10/21/13

Understanding Renal Cell Carcinoma (RCC):

General Approach & Management

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EpidemiologyEtiology/Risk FactorsPathophysiologyRelated AnatomySigns & SymptomsWork-Up/DiagnosisPrognosis Morbidity & MortalityPre-therapy management

Role of VIRTerminology

Other TreatmentsTroubleshooting

Post-procedure management and follow-upKey Points Summary

Renal Cell Carcinoma: Objectives

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Hypernephroma or Grawitz's tumor90% of all renal malignancies~338,000 new cases worldwide in 2012

Cancer research UKIn the US, incidence has risen consistently

over timeIncreased cross sectional imaging and incidental

detection>1/2 of all RCCs diagnosed incidentally

~65,000 new cases in US ; ~14,000 deaths from RCC each year

RCC Epidemiology

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Cigarette smokingThought to be due to chronic tissue hypoxia by

COMay be associated with deletions in

chromosome 3pSeen in peripheral blood lymphocytes treated after

benzo[α]pyrene diol epoxide treatment which is a major constituent of cigarette smoke

Etiology/Risk Factors for RCC

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Obesitymay account for over 40% of RCC in the USincrease 24% for men and 34% for women for

every 5 kg/m2 increase in body mass index (BMI)

Etiology/Risk Factors for RCC

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Hypertensionmay result from chronic hypoxia and lipid

peroxidation leading to reactive oxygen species formation

Chronic Hepatitis C

Etiology/Risk Factors for RCC

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End-stage renal disease while undergoing long-term hemodialysis and after renal transplantation

Acquired renal cystic diseaseFamilial cancer syndromes,

Von Hippel-Lindau (VHL) syndrome, hereditary papillary renal carcinoma, hereditary leiomyomatosis renal cell carcinoma, Birt-Hogg-Dube, tuberous sclerosis

Occupational Exposurecadmium, asbestos, and petroleum by-products

Etiology/Risk Factors for RCC

Gross appearanceAppear encapsulatedCan be solid, cystic, or mixed, May contain fat and/or calcifications10% of tumors have some cystic

component may be more aggressive

Pathophysiology of RCC

Distinct Histologic subtypes of RCCClear cell (75 to 85 percent of tumors)

arise from proximal tubule associated with VHLpoor prognosis when higher grade or sarcomatoid

variantmore favorable prognosis when multilocular variant of

cystic clear cell RCCPapillary (chromophilic) (10 to 15 percent)

can be multifocal and bilateraloriginate from proximal tubule

Chromophobe (5 to 10 percent) lack abundant lipid and glycogen seen in most RCCsoriginate from intercalated cells of collecting system have lower risk of disease progression & death compared

to clear cell carcinomas

Pathophysiology of RCC

Distinct Histologic subtypes of RCCOncocytic (3 to 7 percent)

usually unilateral; singlemultiple and bilateral : tuberous sclerosis & Birt-

Hogg-Dube syndromegenerally well encapsulated and rarely invasive or

associated with metastasesCollecting duct (Bellini's duct) (very rare)

younger patients frequently aggressive commonly gross hematuriasarcomatoid variants notedmedullary carcinoma: highly aggressive variant

associated with the sickle cell trait; develops in young patients

Pathophysiology of RCC

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Anatomy of Renal Cell Carcinoma

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Many patients asymptomatic until disease advanced at presentation, ~25 % have either have distant

metastases or advanced locoregional diseaseMost cases diagnosed incidentally via imaging

study preformed in 1971 of 309 patients showed the most common presenting symptoms were hematuria, abdominal mass, pain, and weight lossNo longer the case due to imagingOnly present in ≤ 10% of casesWhen present strongly suggests locally advanced

disease

Signs & Symptoms of RCC

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Hematuriaobserved only with tumor invasion of the collecting system

abdominal or flank massassociated with lower pole tumors

Scrotal varicocelesmajority are left-sided11 percent of men

Symptoms related to IVC involvement lower extremity edemaasciteshepatic dysfunction (may be related to a Budd-Chiari

syndrome)pulmonary emboli

Signs & Symptoms of RCC

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“The internist's tumor” Paraneoplastic symptoms possible:

Hypertension (renin), Hypercalcemia (PTHrP), Polycythemia/erythrocytosis (erythropoietin), Cushing’s syndrome (ACTH)

Anemia ,Eosinophilia, Leukemoid reactionsFever /wasting syndromesStauffer's syndrome (reversible hepatic

dysfunction after primary tumor removal)

Metastatic disease sxs: Bone pain, Adenopathy,Pulmonary symptoms,

Upper GI bleed, Neurologic deficits

Signs & Symptoms of RCC

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Initial workup Detailed H and PCBCComprehensive metabolic panel

serum calcium, liver function, LAD, serum creatinine

Coagulation profileUA

Work-up & Diagnosis

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Anemia  29 to 88 percent of patients with advanced disease

Hepatic dysfunction  21 percent have a paraneoplastic elevation in serum

alkaline phosphataseHypercalcemia 

up to 15 percentErythrocytosis  

1 to 5 percentThrombocytosis  

rare poor prognosis

Hematuria up to 40 percent

Work-up & Diagnosis

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Imaging and Diagnosis

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IVU: low sensitivity for detecting renal masses <2-3 cm in size

CT and IVU for microhematuria:CT accuracy 98.3%; IVU accuracy 80.9%, withCT sensitivity: 100%; IVU: 60.5%

US in radiation sensitive groups such as pregnant women and children

distinguish simple cysts from common complex masses that require follow up

Imaging and Diagnosis

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CT urogram increasingly used for evaluation

Role of MRIDelineating superior extent of tumor in IVCnephrogenic systemic fibrosis (NSF) risks in

patients with significantly impaired renal function should be considered carefully

Imaging and Diagnosis

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Detect & stage primary tumorChest CT if primary tumor is large or locally

aggressivei.e. RCC > 3cm

Brain MRI and bone scanning if there are symptoms and signs to suggest disease in these areasBone scanning may be limited in detecting

bone metastases in RCC

Imaging and Diagnosis

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Basic Imaging Findings of RCC

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Basic Imaging Findings of RCC

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Basic Imaging Findings of RCC

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Basic Imaging Findings of RCC

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Basic Imaging Findings of RCC

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General indicationdiagnosis of primary tumorconfirmation of suspected metastasisstagingdiagnose benign processmonitor treatment

Contraindicationuncorrected bleeding diathesisinaccessible lesionunwilling or uncooperative patient

Percutaneous Biopsy

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Established indicationrenal mass and known extrarenal primarymass & surgical comorbiditymass that may have also been caused by

infectionEmerging indications

small (less than or equal to 3 cm), hyper attenuating, homogenously enhancing mass

patients with mass considered for percutaneous ablation

indeterminate cystic renal mass

Percutaneous Renal Biopsy

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Usually performed under US or CT guidanceusually outpatient and with conscious sedationlow risk of clinically significant bleeding or

seeding of needle tract with malignant cells sensitivity and specificity: 80-92 %and 83 -100

%, respectivelyhelpful in differentiating RCC from a

metastasistransjugular approach for patients at

increased risk of bleeding

Percutaneous Renal Biopsy

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posterior approach, 16-18 gauge needle in inferior pole to obtain a diagnostic 5-10 glomeruli

Complicationssmall AV fistulas and pseudoaneurysms

many resolve spontaneouslyhematomas with dropping hematocrit and

persistent gross hematuria uncommonAngiographic evaluation and transcatheter

embolization for bleeding that does not stop with conservative measures

Percutaneous Renal Biopsy

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Percutaneous Renal Biopsy

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2 systems: Robson’s and TNM

Staging and Prognosis of RCC

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Staging and Prognosis of RCC

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Low-grade, low-stage RCC, 4 cm or smaller, conservative nephron-sparing surgery recommendedeither pNx or tumor enucleationoutcome comparable to radical nephrectomydistinction between Stage I and Stage II is

important Stage II disease spread, either direct or

hematogenous, to the ipsilateral adrenal gland

Staging, Prognosis and Surgical Planning

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Venous extension in 20% of patients with RCCIVC in 5–10%: requires midline incisionrenal vein involvement: routine ligation to

prevent embolization 40%tumor thrombi intrahepatic

Tumor above the hepatic veins: Thoracic surgical approach required

5–10% of tumors with caval involvement extend into right atriumcardiopulmonary bypass necessary

Staging, Prognosis and Surgical Planning

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Nephrectomy improves survival in metastatic disease only if involves one organ, particularly bonepatients with solitary metastases that can be

excised may have a 5-year survival of 25–35%In patients with multiple metastases,

treatment usually palliative

Staging, Prognosis and Surgical Planning

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Stage I/II — five-year survival rate over 90 percent

Stage III — five-year survival rate for patients who undergo nephrectomy : 59 to 70 percent.

Stage IV — The median survival is 16 to 20 months and the five-year survival rate is less than 10 percent for patients with distant metastases

Prognosis for RCC

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Other Prognostic factors:Tumor grade — Fuhrman's grade is the most

widely usedfive-year survival rate by tumor grade :

89, 65, and 46 % for tumors of histologic grade 1, 2, and 3 to 4, respectively

CLINICAL FACTORS Negative prognostic signs include ;

poor performance statusthe presence of symptoms and/or paraneoplastic

syndromes obesity

Prognosis for RCC

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Treatment depends on whether the disease is localized or advanced at initial presentation.

Localized diseasestage IA, IB, II, and IIIsurgical resection can be curative

Advanced disease tumor invading beyond Gerota’s fascia or

extending into the ipsilateral adrenal gland (T4) and metastatic disease (M1)

stage IV

Management of RCC

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LocalizedSurgery is curative in the majority without metastatic

preferred for stages I, II, and III diseaseradical nephrectomy renal-sparing approaches in select patients

partial nephrectomy or ablative techniques resectable primary tumor with a single metastasis

surgical resection of the metastasis with radical nephrectomy may be curative

elderly and those with significant comorbidity may not be surgical candidates cryoablation, RFA observation with periodic reevaluation

Adjuvant therapy : immunotherapy or molecularly targeted agents

Management of RCC

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Advancedthe majority of patients with stage IV RCC

have unresectable disease

if tumor involves the ipsilateral adrenal gland, a radical nephrectomy is potentially curative

in general ,patients with metastatic RCC should receive medical therapy

Management of RCC

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Advancedmedical therapy  in metastatic RCC;

molecularly targeted and immunotherapyFirst-line treatment

high-dose interleukin-2 (IL-2) If not a candidatesfor IL-2: molecularly targeted

therapy is recommendedSecond-line treatment

vascular endothelial growth factor (VEGF) inhibitor

Management of RCC

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AdvancedChemotherapy

no established role in advanced or metastatic RCCRadiation Therapy

RCC typically described as a radioresistant tumorcan be useful to treat metastases

Painful bone metastases Brain metastases Painful recurrences in the renal bed

Management of RCC

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Proceduresradiofrequency (RFA), cryoablation, microwave

ablation, high intensity, focused ultrasoundRFA and Cryoablation

acceptance based upon favorable outcomes includinglow incidence of serious complicationsless immediate morbidity and mortality than with surgerylower costthe ability to treat patients in the outpatient setting

multiple treatment sessions may be required may not be appropriate for large lesions or tumors

near the renal hilum.

Role of IR in RCC

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RFA and CryoablationFactors that can lead to consideration of an

ablative approach rather than surgery include:T1 renal mass less than 7 cm who:poor surgical candidate, based upon older age or

significant comorbiditythe need for nephron-sparing

treatment,/conservation of renal parenchyma as a way to postpone or avoid the need for chronic dialysis.patients with a single kidney, bilateral RCCs, or a

genetic predisposition to multiple tumors

Role of IR in RCC

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RFA and CryoablationFactors that can lead to consideration of an

ablative approach rather than surgery include:multiple tumors in the same kidney where surgery

would make renal reconstruction difficultcomplex tumors where surgery would require an

extended ischemic timethe patient prefers minimally invasive cannot have an ET tubelocal tumor recurrence after nephrectomyintractable tumor-related hematuriatumor debulking in metastatic diseasemanagement of symptomatic distant metastases from a

primary kidney tumor

Role of IR in RCC

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Procedure RFA and Cryoablation

goals kill all viable malignant cells including a 5 to 10 mm margin of surrounding

tissue minimize damage to adjacent normal kidney

performed percutaneously usually outpatient usually conscious sedation

some will prefer general anesthesia local anesthesia is applied applicator is percutaneously placed into the center of the tumor

using CT, ultrasound, or MRI guidance heat or cold is then applied for approximately 10 to 20 minutes patient is monitored for several hours post procedure discharged home with oral analgesics for post-procedural pain patients usually able to resume normal activity in 2-3 days

Role of IR in RCC

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Radiofrequency ablation ( RFA)utilizes a high-frequency (460 to 500 kHz)

alternating currentdelivered into the tumor through a thin

needle (usually 21 to 14 gauge) electrically insulated except for its terminal 1

to 3 cmProduces resistive friction in the tissue which

is converted into heat causing cellular destruction and protein denaturation

usually monopolar, utilizing grounding pads placed on the patient

Role of IR in RCC

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 RFA

Role of IR in RCC

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Cryoablation  uses liquid nitrogen or argon introduced into a probe resulting in freezing of the surrounding tissues, by

formation of an "iceball" that can be visualized by imaging

leads to the formation of intracellular ice crystals which disrupt the cell membrane and other intracellular activities, leading to cell death

cells not directly killed may undergo apoptosisusually involves freezing, thawing, and refreezing,complete cell death is thought to occur 3 mm inside the

edge of the ice ballmost operators extend the ice ball at least 5 mm beyond

the tumor margin

Role of IR in RCC

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Cryoablation 

Role of IR in RCC

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RFA and CryoablationContraindications

uncorrectable coaulopathyunsafe routehip prosthesis in RFApace maker is a relative contraindication for RFA

can use cryoablation or wear a magnet and reactivate after

Role of IR in RCC

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RFA and CryoablationPatient selection

evaluated by IR and Urologypretreatment imaging with ultrasound, MR, or CT

guidance pretreatment biopsy is not mandatory but strongly

encouraged imaging cannot always differentiate benign from

malignant

Role of IR in RCC

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RFA and CryoablationTumor size and location are the most important

factors

0.5 to 1.0 cm "ablation margin" surrounding the tumor is needed to ensure that the entire tumor is treated

tumors <4 cm in diameter are idealmost tumors <3 cm can be treated in a single sessionbetween 3.0 and 4.0 cm may require multiple

abalationsexophytic tumors are most amenable to ablation,

avoids the heat sync effect (as opposed to more central tumors where heat sink may occur) – This is not an issue with cryoablation hence perihilar mass can also be treated with cryoablation

70 percent or more require only a single session

Role of IR in RCC

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Post ablation  surveillancePatients are seen in clinic initially at 1 week to 1

month after the procedure patients are assessed for pain, discomfort, ability to

urinate, hematuria, fever, or chills the skin entry site and abdomen are examined

 CT is typically usedSurveillance should begin about one month after

treatmentviable tumor is usually nodular and enhancessuccessfully ablated tumor show no enhancesusually performed at three to six months, 12 months, 18

months, and 24 months after ablation, and then yearly

Post-Procedure Follow-up for RCC

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Post ablation  survellance

 both RFA and cryoablation have a low incidence of serious complications

A self-limited syndrome consisting of fever and flu-like symptoms has been reported in up to one-third of patients following RFA and cryoablation

Post-Procedure Follow-up for RCC

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Complications of Percutaneous ablation Few reported Self limiting hematuria resolves within 24 hours of treatment Bowel necrosis Adrenal release of catecholamines when ablating in close proximity

to the adrenal gland No reports of clinically significant injury to the liver, spleen, or renal

bleeding There is little renal damage associated with radiofrequency ablation Track seeding - less than 0.01% Pneumothorax Ureteral stricture or hydrnephrosis Damage to genitofemoral nerve Overall, the rate of serious complications is estimated to be

approximately 1% for radiofrequency ablation of renal tumors

Post-Procedure Follow-up for RCC

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Management of post ablative complicationHemorrhage

RareEmbolization rarely required

PneumothoraxUsually smallChest tube placement if large

Ureteral injury or HydronephrosisNephrostomy placement

Post-Procedure Follow-up for RCC

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Approximately 65,000 new cases in the US and almost 14,000 deaths from RCC each year 2.3% of all cancer deaths in the US

There are many treatable associated risk factorsIncreasing incidence and early identification due to

imagingSurgery continues to play a significant role in treatmentInterventional radiology also plays an effective role in

management of RCC including biopsy and ablative therapy among many other s in providing minimally invasive techniques allowing for outpatient procedures, less pain, and early recovery without significant associated complication

Renal Cell Carcinoma Key Points

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The Epidemiology of Renal Cell Carcinoma Bo¨rje Ljungberg a,*, Steven C. Campbell b, Han Yong Cho c, Didier Jacqmin d, Jung Eun Lee e, Steffen Weikert f, Lambertus A. Kiemeney g

The Epidemiology of Renal Cell Carcinoma, Loren Lipwortha, c, Robert E. Taronea, b, Joseph K. McLaughlina, b,

Renal cell carcinoma, Rini BI, Campbell SC, Escudier B.Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

Renal Cell Carcinoma: Diagnosis, Staging, and Surveillance, Chaan S. Ng1, Christopher G. Wood2, Paul M. Silverman1, Nizar M. Tannir3, Pheroze Tamboli4 and Carl M. Sandler1

Epidemiology and risk factors for kidney cancer, Wong-Ho Chow, Senior Investigator,* Linda M. Dong, postdoctoral fellow, and Susan S. Devesa, contractor and former Senior Investigator

Epidemiology, pathology, and pathogenesis of renal cell carcinoma, Michael B Atkins, MDToni K Choueiri, MD, Section Editor Jerome P Richie, MD, FACS, Deputy EditorDon S Dizon, MD, FACP

Gordon SC, Moonka D, Brown KA, et al. Risk for renal cell carcinoma in chronic hepatitis C infection. Cancer Epidemiol Biomarkers Prev 2010; 19:1066.

Renal Cell Carcinoma: Diagnosis, Staging, and Surveillance, Chaan S. Ng1, Christopher G. Wood2, Paul M. Silverman1, Nizar M. Tannir3, Pheroze Tamboli4 and Carl M. Sandler1

References

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Renal cell carcinoma, Dr Brian I Rini, MDa, Prof Steven C Campbell, MDb, Bernard Escudier, MDc,

Histopathological, cytogenetic, and molecular characterization of renal cortical tumors, Presti JC Jr, Rao PH, Chen Q, et al. Cancer Res 1991; 51:1544.

Adult renal epithelial neoplasms, Weiss LM, Gelb AB, Medeiros LJ. Am J Clin Pathol 1995; 103:624

Renal oncocytoma: prognosis and treatment. , Lieber MM. Eur Urol 1990; 18 Suppl 2:17 Primary neoplasms of the kidney. In: Therapy in Nephrology and Hypertension: A Companion

to Brenner and Rector's the Kidney, Garnick MB , Brady HR, Wilcox CS (Eds), WB Saunders, Philadelphia 1998.

Renal Cell Carcinoma, Namita Chittoria, MD, Brian I. Rini, MD Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309

cases, Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF, Cancer. 1971;28(5):1165.

Medical aspects of renal carcinoma, PINALS RS, KRANE SM, Postgrad Med J. 1962;38:507. Clinical manifestations, evaluation, and staging of renal cell carcinoma, Michael B Atkins, MD,

Section Editor Jerome P Richie, MD, FACS, Deputy Editor Don S Dizon, MD, FACP Paraneoplastic manifestations of renal cell carcinoma, Gold PJ, Fefer A, Thompson JA, Semin

Urol Oncol. 1996;14(4):216 Handbook of Interentional Radiology Procedures 4th edition, Krishna Kandarpa, Lindsay

Machan Vascular and Interventional Radiolgy, Valji ,Saunders 2006

References

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Diagnostic approach, differential diagnosis, and treatment of a small renal mass, Susanna I Lee, MD, PhD, Shauna Duigenan, MD, FRCPC, Section Editors Jerome P Richie, MD, FACS, Michael B Atkins, MD, Deputy Editor Don S Dizon, MD, FACP

CT/MRI in staging renal cell carcinoma, Rodney H Reznek, Cancer Imaging. 2004; 4(Spec No A): S25–S32.

Overview of the treatment of renal cell carcinoma, Michael B Atkins, MD, Section EditorJerome P Richie, MD, FACS, Deputy Editor Don S Dizon, MD, FACP

Radiofrequency ablation and cryoablation for renal cell carcinoma, Andrew Hines-Peralta, MDS Nahum Goldberg, MD, Section EditorMichael B Atkins, MD, Deputy EditorDon S Dizon, MD, FACP

Imaging-Guided Percutaneous Ablation of Renal Cell Carcinoma: A Primer of How We Do It, Raul N. Uppot1, Stuart G. Silverman2, Ronald J. Zagoria3, Kemal Tuncali2, David D. Childs3 and Debra A. Gervais1

Imaging-guided Radiofrequency Ablation of Renal Masses, Ronald J. Zagoria, MD, Radiographics 

Imaging-Guided Percutaneous Renal Biopsy: Rationale and Approach, Raul N. Uppot1, Mukesh G. Harisinghani and Debra A. Gervais

Imaging-Guided Percutaneous Ablation of Renal Cell Carcinoma: A Primer of How We Do It, Raul N. Uppot1, Stuart G. Silverman2, Ronald J. Zagoria3, Kemal Tuncali2, David D. Childs3 and Debra A. Gervais

References

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Thank you!

This presentation was adapted from a template created by Don J. Perry, MD

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M/F in 2:1 ratioMost present in the 5th-7th decade of life

median age at diagnosis, 66 median age at death, 70

2%-3% of all malignant disease in adultsEstimated 209,000 new cases and 102,000 deaths

annually worldwideEstimated 51,190 new cases and 12,890 deaths

from RCC in 2007 in the US2.3% of all cancer deaths in the US

RCC Epidemiology