clinical practiceThe newengl andjournalo f medicineThis Journal feature begins with a case vignette highlighting a common clinical problem.Evidence supporting various strategies is then presented, followed by a review of formal guidelines,when they exist. The article ends with the authors clinical recommendations. n engl j med 362;7nejm.orgfebruary 18, 2010624Small Renal MassInderbir S. Gill, M.D., Monish Aron, M.D., Debra A. Gervais, M.D.,and Michael A.S. Jewett, M.D.From the Center for Robotic Surgery and Advanced Laparoscopy, USC Institute of Urology, Keck School of Medicine, Univer-sityofSouthernCalifornia,LosAngeles, (I.S.G., M.A.); the Department of Radiol-ogy,MassachusettsGeneralHospital, Boston (D.A.G.); and the Division of Urol-ogy,DepartmentofSurgicalOncology, Princess Margaret Hospital, University of Toronto,Toronto(M.A.S.J.).Addressre-print requests to Dr. Gill at USC Institute ofUrology,KeckSchoolofMedicine, UniversityofSouthernCalifornia,1441 EastlakeAve.,Suite7416,LosAngeles, CA 90089, or at gillindy@gmail.com.N Engl J Med 2010;362:624-34.Copyright 2010 Massachusetts Medical Society.A 65-year-old man with a history of well-controlled hypertension presents for a follow-up visit after an incidental finding of a small mass in the right kidney on an abdominal computed tomographic (CT) scan. (The scan had been ordered to evaluate pain in the lower quadrant, which resolved.) The mass is 3.2 cm in its largest dimension, anterior, heterogeneous, and solid, and it is in the right renal hilum near the main renal artery, vein,andureter;theleftkidneyappearsnormal.Thepatientfeelswell,andhis physical examination is unremarkable. His serum creatinine level is 1.2 mg per deci-liter (106 mol per liter). How should this patient be further evaluated and treated?TheClinicalProblemOne result of the widespread use of advanced cross-sectional imaging is that small, incidental renal masses have become common radiologic findings. Approximately 13 to 27% of abdominal imaging studies incidentally identify a renal lesion.1,2 The majority of these lesions are small, simple cysts that do not show enhancement after the administration of contrast material, are benign, and require no treatment. A minority of small renal masses are solid masses or complex cystic masses, show contrast enhancement on CT images, and are suggestive of cancer. An enhancing mass is a mass that is seen on CT to have an increase in density of more than 15 Hounsfield units after the administration of contrast material.3For the purposes of this article, a small renal mass is defined as a contrast-enhancing mass with a largest dimension of 4 cm or less on abdominal imaging.4 From1988to2003,theincidenceofsmallrenalmassesincreasedrelativeto other renal tumors, and they now make up 48 to 66% of all renal tumors that are diagnosed and 38% of all renal tumors that are excised5,6; often the patient has had no symptoms. Of small renal masses, approximately 80% are malignant and 20% are benign.7 When a small renal mass is identified incidentally on imaging, theclinical-managementchallengeinvolvesdistinguishingbenignmassesfrom those likely to be malignant and determining the appropriate treatment of malig-nant masses.StrategiesandEvidenceRadiologic Assessment and Characterization of Renal MassesSimple renal cysts can be reliably diagnosed noninvasively on the basis of well-defined radiologic criteria. However, the term cystic mass is ambiguous, since it spansthespectrumfromdefinitivelybenigntoalmostcertainlymalignant. The Bosniak classification system8 can be used to assign cystic masses to one of four categories that represent the range of diagnostic possibilities (Fig. 1). Macro-An audio version of this article is available at NEJM.org The New England Journal of Medicine Downloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. clinicalpracticen engl j med 362;7nejm.orgfebruary 18, 201062533p9AUTHORFIGUREJOB:ISSUE:4-CH/TRETAKE 1st2ndSIZEICMCASEEMailLineH/TComboRevisedAUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.Please check carefully.REG FFILLTITLE3rdEnonARTIST:Gill1a-f2-18-10mst36207A BD CF EFigure 1. Benign Renal Masses.Unenhanced (Panel A) and enhanced (Panel B) CT scans show no enhancement in a simple cyst (arrows; Bosniak class I) with the density of water and imperceptible walls. An unenhanced CT scan of a minimally complex cyst (Bosniak class IIF) shows discontinuous, slightly thick calcification (Panel C, arrow). An enhanced CT scan of the same cyst shows min-imally thickened internal septation (Panel D, arrow), with perceptible enhancement but no enhancing mural nodules. The Bosniak classification8 categorizes cystic masses on the basis of their radiologic characteristics. Class I lesions are be-nign, nonenhancing simple cysts with thin walls and without any septa, calcifications, or solid components. Class II le-sions are benign cysts with a few hairline-thin septa; perceived enhancement, fine calcification, or a short segment of slightly thickened calcification may be present. Uniformly high-attenuation, well-marginated, nonenhancing lesions 3 cm in diameter or less (so-called high-density cysts) are included in this group. Cysts in this category do not require further evaluation. Class IIF cysts have multiple hairline-thin septa or minimal smooth thickening of the walls or septa that may contain thick and nodular calcification; these cysts do not have measurable contrast enhancement. Totally intrarenal, nonenhancing, high-attenuation renal lesions 3 cm in diameter or less are also included in this category. These lesions require follow-up studies to prove benignity. Class III lesions are indeterminate cysts with thickened irregular or smooth walls or septa in which measurable enhancement is present; some are malignant. Class IV lesions are malignant; they have all the characteristics of class III cysts and also contain enhancing soft-tissue components adjacent to but inde-pendent of the wall or septum. Surgical removal is recommended. A small renal mass is shown in an unenhanced CT scan (Panel E, arrow) and in an enhanced scan (Panel F, arrow), with fat density diagnostic of angiomyolipoma.The New England Journal of Medicine Downloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. The newengl andjournalo f medicinen engl j med 362;7nejm.orgfebruary 18, 2010626scopicfatwithinarenalmass,identifiedby meansofCTormagneticresonanceimaging (MRI),isdiagnosticofangiomyolipoma(abe-nign mass), unless calcification is present, which would indicate a malignant condition.9In the case of a solid mass or a complex cystic renal mass, but not a simple cyst, assessment of the size, shape, contour, and tissue-enhancement characteristics is important for determining the likelihoodofcancer.Assessmentisbestper-formedbymeansofdedicatedrenalCTscans (with and without the administration of contrast material)ordedicatedMRIscans(withand without gadolinium enhancement), obtained at a slice thickness of 3 to 5 mm.Masses with measurable enhancement on CT or MRI (with the exception of angiomyolipoma) are classified as solid masses or complex cystic masses (Bosniak class III or class IV)8,9 (Fig. 2). The majority of enhancing masses are malignant; no specific findings on imaging conclusively iden-tify a mass as malignant or benign. Thus, when management decisions are being made in the case of a patient with a long life expectancy, a solid, enhancing small renal mass must be considered malignant unless proven otherwise.The smaller the mass, the greater the chance that it is benign. In a report on 2770 surgically excisedsolidrenalmassesstratifiedaccording to size, 46% of masses that were less than 1 cm in diameter were benign, as were 22% of those thatwere1to2.9cm,and20%ofthosethat were 3 to 3.9 cm.7 Among masses that are malig-nant, greater size correlates with a higher patho-logicalgrade.Thegrowthrateofsmallrenal masses is typically slow (2 to 4 mm per year)10; in studies involving relatively short-term follow-up (3 years), the growth rate has been reported to be similar for masses subsequently found to be malignant (renal-cell carcinoma) and those found tobebenign(oncocytoma).10,11Inonemeta-analysis, 30% of small renal masses showed no growthoveranobservationperiodof23to39 months.10 Masses that showed no growth were aboutaslikelytobemalignant(83%)aswere those that grew (89%).12 There are no definable clinicalorradiologiccharacteristicsthateffec-tively predict future growth; neither size at pre-sentation nor the final histologic diagnosis (even ifitisprovenrenal-cellcarcinoma)correlates withgrowthrates.10Mostexcisedsmallrenal cancers are classified as low grade. However, in three studies involving excised renal cancers that were 3 to 4 cm in diameter, 14 to 26% were high grade (grade 3 or 4) and 12 to 36% locally invaded perirenalfat(classifiedaspT3atumors).13-15 Patientswithsmallrenalmassesthatleadto symptoms such as flank discomfort or hematu-ria seem to have a worse prognosis than patients with similar-size masses that are detected inci-dentally.16At the time of diagnosis, metastases are pres-ent in 1 to 8% of patients with renal cancers that are 3 to 4 cm in diameter.10,13-15 An analysis of the National Cancer Institutes Surveillance, Epi-demiology,andEndResultsProgramdatabase for1998to2003showeda5.2%prevalenceof metastasis at presentation among 8792 patients Figure 2 (facing page). Small Renal Masses.Various radiologic characteristics of small renal masses (e.g., tumor size, location, depth of infiltration, relation-ship to the renal hilum, and status of contralateral kid-ney) affect management decision-making. A right hilar, midrenal, enhancing, small renal mass (Panel A, arrow) is the tumor of the patient presented in the vignette. Hilar tumors are in direct contact with the main renal artery, vein, or both on preoperative CT or MRI. Since they are so close to major renal blood vessels, hilar tu-mors present a special technical challenge during par-tial nephrectomy surgery. In this patient, laparoscopic partial nephrectomy was performed successfully. Panel B shows a cystic left renal mass (arrow) with an en-hancing solid component (Bosniak class IV [a clearly malignant cyst that has thickened irregular or smooth walls or septa in which measurable enhancement is present and that has enhancing soft-tissue components adjacent to, but independent of, the wall or septum; surgical removal is required]). Partial nephrectomy con-firmed cystic renal-cell carcinoma. (Image provided by Peter L. Choyke, M.D.). Panel C shows a completely intra-parenchymal, solid, enhancing, central right renal mass (arrow), 5.5 cm in diameter, in a functionally solitary kidney in an otherwise healthy 72-year-old patient with stage III chronic kidney disease. The atrophic left kidney had extremely poor function and an incidental renal cyst. Laparoscopic partial nephrectomy was performed successfully. Panel D shows an enhancing small renal mass (arrow), 0.9 cm in diameter, in the left kidney. Given the option of active surveillance, the young pa-tient elected laparoscopic partial nephrectomy. Despite the small tumor size, final histologic analysis revealed grade 3 clear-cell renal-cell carcinoma with capsular in-vasion. Panel E shows a left anterior enhancing small renal mass (arrow), 4 cm in diameter. After partial ne-phrectomy, histologic analysis showed an oncocytoma, a benign tumor. (Image provided by Michael Marberger, M.D.) Panel F shows bilateral enhancing small renal masses (arrows). These were treated with bilateral lap-aroscopic partial nephrectomy.The New England Journal of Medicine Downloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. clinicalpracticen engl j med 362;7nejm.orgfebruary 18, 2010627with pathologically confirmed small renal can-cers (4 cm in diameter)17; for each 1-cm increase in the size of the primary cancer, the calculated prevalence of metastases increased by 3.5%.Needle BiopsyTypically performed under CT guidance, needle biopsies appear to be safe (with a minimal risk of bleedingorofseedingoftheneedletractwith malignant cells), and they have a sensitivity for the detection of cancer of 80 to 92% and a speci-ficity of 83 to 100%.18-20 Smaller masses (3 cm) have higher false negative rates (negative predic-tive value, 60%); the false negative rate can be reducedbyrepeatbiopsiesandahighlevelof experience on the part of operators and pathol-ogists.20In most cases, benign findings on examina-tion of a biopsy specimen cannot rule out cancer in the rest of the tumor, but a definitive benign diagnosis may be made in cases of angiomyoli-poma, metanephric adenoma, or focal infection. A benign diagnosis may be strongly suggested forsomeoncocytomas,althoughchromophobe renal-cell carcinoma may have a similar appear-ance on biopsy.19 In the absence of findings that 33p9AUTHORFIGUREJOB:ISSUE:4-CH/TRETAKE 1st2ndSIZEICMCASEEMailLineH/TComboRevisedAUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.Please check carefully.REG FFILLTITLE3rdEnonARTIST:Gill2a-f2-18-10mst36207A BD CF EThe New England Journal of Medicine Downloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. The newengl andjournalo f medicinen engl j med 362;7nejm.orgfebruary 18, 2010628are diagnostic of renal-cell carcinoma or a defi-nitebenignentity,abiopsyspecimenshowing nondiagnosticornonmalignantfindingsmust beconsideredwithcaution,andsurveillance imaging,repeatbiopsy,orsurgeryshouldbe performed.Combining histologic and molecular or cyto-genetic techniques may improve the accuracy of a diagnosis that was based on needle biopsy. As compared with histologic analysis alone, the ad-ditionofmoleculardiagnosticalgorithmsthat incorporate RNA extraction and polymerase chain reactionforfourgeneproductstodistinguish subtypesofrenal-cellcarcinomaimprovedthe sensitivity(100%vs.87%)andnegativepredic-tive value (100% vs. 87.5%) of needle biopsies for the diagnosis of clear-cell renal-cell carcinoma.21 However,thesefindingsrequirevalidationat other centers, and currently, molecular diagnostic algorithms are not used routinely in practice.management OptionsOptions for the management of small renal mass-es that are worrisome because of the risk of malig-nant conditions include active surveillance, surgery, andablation.Datafromrandomized,controlled trialscomparingvarioustreatmentoptionsare lacking; thus, available data are observational or are based on case series (Table 1). Decision mak-ing should take into account a patients coexist-ing conditions, life expectancy, and preferences and the treatment providers level of experience.Active SurveillanceActive surveillance involves the monitoring of tu-mor size by means of serial ultrasonography, CT, orMRI.22Althoughcomparativedataarelack-ing, CT or MRI is generally preferred over ultra-sonography, owing to greater resolution and re-producibility. The typical recommendation is to performrepeatimagingatintervalsof6to12 months;however,thefinancialcostsofserial imaging and the risks associated with radiation from serial CT scanning in particular (30 to 90 mSv per CT study23) should be taken into consider-ation.The growth of or the metastasis from initial-ly asymptomatic, incidental small renal masses hasbeenextremelyuncommon,althoughthe availablestudiesofcaseseriesinvolvedashort follow-up, of only 23 to 39 months10; therefore, active surveillance is an attractive option most-ly for elderly or infirm patients with a short life expectancy. This strategy also seems reasonable for masses that are 1 cm in diameter or smaller, regardless of the patients age, although data are neededtohelpdeterminethefrequencyand duration of follow-up imaging in these cases. In selected patients who are undergoing active sur-veillance,interventioncanbeperformedifthe tumor grows; such delayed intervention does not seem to compromise future treatment options.24 However,giventhelimitationsoftheavailable data (including relatively short follow-up, limited samplesize,andinsufficienthistologicassess-ment)andthefactthatimagingstudiescan neither definitively rule out cancer nor predict its behavior, active surveillance is not generally rec-ommended for young, healthy patients. However, surveillancedatadoprovidereassurancethat treatment is generally not warranted urgently.Nephron-Sparing SurgeryRadical (total) nephrectomy was for many years theacceptedstandardtreatmentforallorgan-confinedkidneytumors,butnephron-sparing surgery (partial nephrectomy) has now become thepreferredtreatmentforsmallrenalmasses for which surgery is warranted. Nephron-sparing surgery, which may be performed by an open or a laparoscopic approach, involves targeted exci-sion of the tumor along with an adequate rim of normal renal parenchyma, thereby preserving the uninvolved portion of that kidney.25 Chronic kid-neydiseaseisincreasinglycommon(onestudy showed previously unrecognized chronic kidney disease in one quarter of the patients who had a smallrenalmass26);therefore,renalfunctional preservation is an important consideration in man-agement.In the only randomized trial comparing par-tialwithradicalnephrectomyfortumorsless than5cmindiameter,theauthorsconcluded thatpartialnephrectomycouldbesafelyper-formedbutwouldhaveslightlyhigherratesof complications than would radical nephrectomy. Thecomplicationsincludedseverehemorrhage (3.1% vs. 1.2%), urine leak (4.4% vs. 0%), and reoperation (4.4% vs. 2.4%). However, this report did not include oncologic outcomes.27 Data from case series have indicated low 5-year and 10-year cancer-specific mortality rates after open partial nephrectomy (2.4% and 5.5%, respectively); these data are similar to the outcomes for radical ne-The New England Journal of Medicine Downloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. clinicalpracticen engl j med 362;7nejm.orgfebruary 18, 2010629Table 1. Treatment Considerations for a Patient with a Small Renal Mass.TreatmentIndicationsContraindicationsCommentNeedle biopsyKnown extrarenal or systemic cancer; lobar contour deformity suggestive of a small renal mass; coexisting conditions that confer a poor surgical risk; an unresectable mass; some hyperattenuating masses with homogeneous en-hancement or some indeterminate cystic lesions (physi-cians discretion); suspected focal infection; choice of young patient; consideration of percutaneous ablation or neoadjuvant targeted therapyUncorrected coagulopathyNeedle-biopsy specimen may be falsely negative, and some small renal masses may require ongoing imaging in the absence of a definitive diagnosis.Active surveillanceElderly, frail patient; important coexisting conditions; poor surgical risk; limited life expectancy; severely compro-mised renal function; patient choice of no interventionYoung, healthy patientDiscuss contemporary data so the patient can partici-pate in decision making; active surveillance might be more broadly applicable, but more data are needed to determine which masses can be safely followed without intervention.Partial nephrectomyEnhancing, solid or complex cystic small renal mass in a medically fit patient; hilar mass; indications for nephron-sparing surgery*Uncorrected coagulopathy, se-vere renal dysfunction, sur-gically scarred abdomen (relative contraindication)Partial nephrectomy is the standard nephron-sparing surgical option because it has the most durable follow-up data (up to 15 yr) concerning oncology and renal function and can be performed by means of a laparoscopic, open surgical, or robotic ap-proach, depending on available expertise.Image-guided tumor ablation (cryoablation or radio-frequency ablation)A small tumor (3 cm in diameter) in an elderly, high-risk patient who opts against active surveillance and wants intervention; severe renal dysfunction; surgically scarred abdomen; a small renal mass in a postoperative renal remnant; the request of an informed younger patientHealthy patient 70 yr of age (because long-term onco-logic data are lacking), tu-mors >4 cm in diameter (risk of incomplete tumor abla-tion), hilar tumors (risk of injury to renal vessels), un-corrected coagulopathyThe main limitation to probe ablation is the lack of robust long-term oncologic data.Radical nephrectomyCentrally located small renal mass enmeshed between the branches of the main renal vessels (if excision of the tu-mor would compromise the major vessels and the col-lecting-system continuity of the renal remnant); specific request of an informed patientIndications and suitability for nephron-sparing surgeryFor small renal masses, radical nephrectomy should rarely be performed; nephron-sparing surgery de-livers similar oncologic and superior functional outcomes; if nephron-sparing surgery would be too technically complex, a radical nephrectomy can be performed.* Indications for nephron-sparing surgery are absolute (bilateral tumors, a tumor in one kidney, or a poorly functioning or nonfunctioning opposite kidney), relative (renal dysfunction; hereditary renal-cell carcinoma; a genetic predisposition to metachronous renal-cell carcinoma; systemic threats to future renal function, such as diabetes, hypertension, or nephrotoxic chemotherapy; or local threats to either kidney, such as obstructive uropathy, stone disease, or renovascular disease), or elective (a small renal mass and a normal opposite kidney).The New England Journal of Medicine Downloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. The newengl andjournalo f medicinen engl j med 362;7nejm.orgfebruary 18, 2010630phrectomy.25,28Inanobservationalstudycom-paring partial with radical nephrectomy, partial nephrectomy was associated with a significantly lowerriskofrenalinsufficiency(12%vs.22%) andproteinuria(35%vs.55%)atthe10-year follow-up.29 In one report, the risk of stage 3 or higherchronickidneydiseasewas20%after partial nephrectomy and 65% after radical neph-rectomy (P