Renal TumorsRenal Tumors

Part IIPart II

Scott Wilkinson, DO, MSScott Wilkinson, DO, MS

Treatment PearlsTreatment Pearls

Obstacles Towards Obstacles Towards Treatment Treatment

RCC is historically resistant to many RCC is historically resistant to many types of treatmenttypes of treatment Chemotherapy (MDR-1)Chemotherapy (MDR-1) RadiationRadiation

Very aggressive in nature (TGF alpha Very aggressive in nature (TGF alpha and EGFR)and EGFR)

Highly vascular (VEGF secondary to Highly vascular (VEGF secondary to loss of vHL)loss of vHL)

Expresses tumor-associated antigens Expresses tumor-associated antigens (PRAME, RAGE-1, gp75, and MN-9) (PRAME, RAGE-1, gp75, and MN-9) which contributes to its which contributes to its immunogenicityimmunogenicity

Tx of Localized RCCTx of Localized RCC

Radical nephrectomyRadical nephrectomy Nephron-sparing surgery (NSS)Nephron-sparing surgery (NSS) NSS with normal opposite kidneyNSS with normal opposite kidney NSS with vHL diseaseNSS with vHL disease Thermal ablative therapiesThermal ablative therapies ObservationObservation

Radical nephrectomyRadical nephrectomy Robson and colleagues “gold Robson and colleagues “gold

standard” 1969standard” 1969 Prototype – A then B, Gerota’s Prototype – A then B, Gerota’s

intact, ipsi adrenal, LND (crus to intact, ipsi adrenal, LND (crus to aortic bifurcation)aortic bifurcation)

Now – no adrenal if: no rad Now – no adrenal if: no rad evidence unless extensive renal evidence unless extensive renal involvement, locally advanced, involvement, locally advanced, located upper pole, immediately located upper pole, immediately adjacent to adrenaladjacent to adrenal

Today – LND = controversialToday – LND = controversial Heme & Lymph spreadHeme & Lymph spread Lymphatic drainage variableLymphatic drainage variable

<2-3% benefit<2-3% benefit However, more accurate stagingHowever, more accurate staging

Risk factors indicating LNDRisk factors indicating LND High tumor gradeHigh tumor grade Sarcomatoid componentSarcomatoid component Histologic tumor necrosisHistologic tumor necrosis Large size (> 10 cm)Large size (> 10 cm) pT3 or pT4pT3 or pT4

*incidence 10% with 2 or >, 0.6% if <*incidence 10% with 2 or >, 0.6% if <

Surgical approach determined by Surgical approach determined by size, location of tumor and body size, location of tumor and body habitushabitus

TransperitonealTransperitoneal SubcostalSubcostal thoracoabdominalthoracoabdominal

Extraperitoneal Extraperitoneal FlankFlank

Laparoscopic (trans, retro, hand-Laparoscopic (trans, retro, hand-assist)assist)

LaparoscopicLaparoscopic Cancer specific survival comparable Cancer specific survival comparable

to opento open Usually < 8-10cm; localized with no Usually < 8-10cm; localized with no

local invasion, renal vein local invasion, renal vein involvement, or lymphadenopathy involvement, or lymphadenopathy

RN SurveillanceRN Surveillance

StageStage H/E/labsH/E/labs CXRCXR CTa/pCTa/p T1NOMOT1NOMO yearly yearly ---- ---- ---- ----

T2NOMOT2NOMO yearly yearly yearly yearly q 2 yrs q 2 yrs

T3a-cNOMOT3a-cNOMO q 6m x 3 yr - yrq 6m x 3 yr - yr same same 1yr 1yr then q 2 yrthen q 2 yr

Bone scans, plain xr, and head CT if clinically Bone scans, plain xr, and head CT if clinically indicatedindicated

Nephron-Sparing SurgeryNephron-Sparing Surgery Czerny 1890Czerny 1890 Vermooten 1950 – NSSVermooten 1950 – NSS Indications include situations Indications include situations

where pt would be anephric or where pt would be anephric or high risk of needing HDhigh risk of needing HD Solitary kidney RCCSolitary kidney RCC Bilateral RCCBilateral RCC Contralateral dz (RAS, Hydro, Contralateral dz (RAS, Hydro,

chronic pyelo, reflux, stones, DM, chronic pyelo, reflux, stones, DM, nephrosclerosis)nephrosclerosis)

A functional remnant of at least 20% A functional remnant of at least 20% of one normal kidney is necessary to of one normal kidney is necessary to avoid end-stage renal failureavoid end-stage renal failure

IF solitary kidney, > 50% reduction IF solitary kidney, > 50% reduction in renal mass = incr risk of in renal mass = incr risk of hyperfiltration renal injury hyperfiltration renal injury (proteinuria, focal segmental (proteinuria, focal segmental glomerulosclerosis, progressive glomerulosclerosis, progressive renal failure)renal failure) Prevention: Protein restriction & ACEIPrevention: Protein restriction & ACEI

Preoperative testingPreoperative testing r/o local extension, mets, r/o local extension, mets,

vascular/collecting system relationshipvascular/collecting system relationship Renal angio, veno, 3DCT or MRIRenal angio, veno, 3DCT or MRI

Cancer-specific survival rates 78-Cancer-specific survival rates 78-100%100%

Recurrence – undetected dz in Recurrence – undetected dz in remnantremnant

Complications – majority Complications – majority hemorrhagichemorrhagic

NSS SurveillanceNSS Surveillance

StageStage H/E/labsH/E/labs CXRCXR CTa/pCTa/p

T1NOMOT1NOMO yearly yearly ---- ---- ---- ----

T2NOMOT2NOMO yearly yearly yearly yearly q 2 yrsq 2 yrs

T3NOMOT3NOMO q 6m x 3 yr - yrq 6m x 3 yr - yr same same q6m q6m x3y –q2yrx3y –q2yr

NSS with normal opposite kidneyNSS with normal opposite kidney CSS 5yr 100% with small unilat T1-2CSS 5yr 100% with small unilat T1-2

Licht et al 1994 (< 4 cm)Licht et al 1994 (< 4 cm) CSS 5 yr central vs peripheral (100 CSS 5 yr central vs peripheral (100

vs 97%), tumor recurrance (5.7 vs vs 97%), tumor recurrance (5.7 vs 4.5%), renal fxn equivocal4.5%), renal fxn equivocal Hafez et al 1999Hafez et al 1999

Adv: 17-28% excised = benign Adv: 17-28% excised = benign (MSK)(MSK)

NSS in vHL diseaseNSS in vHL disease Differs via – young age @ dx, Differs via – young age @ dx,

usually multiple bilateral tumorsusually multiple bilateral tumors Solid and cystic (lining of Solid and cystic (lining of

hyperplastic clear cells)hyperplastic clear cells) Intraop US may help to get allIntraop US may help to get all Options – B/l RN, PN & RN, B/l PNOptions – B/l RN, PN & RN, B/l PN

High incidence of recurrence in High incidence of recurrence in remnant 27.4%remnant 27.4%

Duffey and colleuges 2004 – 3 cm Duffey and colleuges 2004 – 3 cm thresholdthreshold

Thermal ablativeThermal ablative Both perc or lap approachBoth perc or lap approach Lack of histo/path stagingLack of histo/path staging ? High recurrence rate? High recurrence rate Ideal – advanced age, comorbidities, local Ideal – advanced age, comorbidities, local

recurrance, hereditary renal cancerrecurrance, hereditary renal cancer

CryosurgeryCryosurgery Repetition of freeze-thaw cycle (-20C)Repetition of freeze-thaw cycle (-20C) Immediate cellular cryodestruction Immediate cellular cryodestruction

and delayed microcirculatory failure.and delayed microcirculatory failure. Radiofrequency ablationRadiofrequency ablation

45C irreversible cell damage45C irreversible cell damage 55-60C immediate cell death55-60C immediate cell death

Thermal Ablative PearlsThermal Ablative Pearls In general, enhancement within the In general, enhancement within the

tumor bed on extended follow-up tumor bed on extended follow-up has been considered diagnostic of has been considered diagnostic of local recurrence, and the clinical local recurrence, and the clinical experience thus far has supported experience thus far has supported thisthis

ObservationObservation Median growth rate 0.36 cm/yrMedian growth rate 0.36 cm/yr Alternative for asymptomatic elderly Alternative for asymptomatic elderly

and poor surgical risk, consider with and poor surgical risk, consider with solid/small/enhancing/well-solid/small/enhancing/well-marginated/homogeneousmarginated/homogeneous Serial imaging 6mo or 1yr intervalsSerial imaging 6mo or 1yr intervals

Not appropriate: >3cm, poor Not appropriate: >3cm, poor margins, nonhomogeneous, young margins, nonhomogeneous, young healthy with abn imaginghealthy with abn imaging

Tx of Locally Advanced Tx of Locally Advanced RCCRCC

IVC involvementIVC involvement Locally invasive RCCLocally invasive RCC Local recurrence after RN or NSSLocal recurrence after RN or NSS Adjuvant therapy for RCCAdjuvant therapy for RCC

IVC InvolvementIVC Involvement Unique feature of RCCUnique feature of RCC 45-70% of RCC with IVC 45-70% of RCC with IVC

thrombus curedthrombus cured Local extension/invasion much Local extension/invasion much

higher risk of recurrencehigher risk of recurrence Occurs 4-10% of patientsOccurs 4-10% of patients Suspect with : LE edema, R Suspect with : LE edema, R

varicocele, distended abd veins, varicocele, distended abd veins, proteinuria, PE, R atrial mass, proteinuria, PE, R atrial mass, nonfxn kidneynonfxn kidney

IVC Thrombus stagingIVC Thrombus staging I – adjacent to ostium of renal veinI – adjacent to ostium of renal vein II – extends up to liverII – extends up to liver III – intrahepatic portion of IVC below III – intrahepatic portion of IVC below

diaphragmdiaphragm IV – above the diaphragmIV – above the diaphragm

ImagingImaging ? CT & AUS? CT & AUS Occasional TEE and TA dopplerOccasional TEE and TA doppler Contrast inferior venacavography – if Contrast inferior venacavography – if

prob with MRIprob with MRI MRI – study of choiceMRI – study of choice ? Renal arteriography? Renal arteriography

Locally Invasive RCCLocally Invasive RCC Present with pain from invasion of Present with pain from invasion of

posterior abd wall, nerve roots or posterior abd wall, nerve roots or paraspinous musclesparaspinous muscles

Duodenal & pancreas uncommonDuodenal & pancreas uncommon En bloc may be beneficialEn bloc may be beneficial Partial / debulking – only 12% alive Partial / debulking – only 12% alive

in 1 yrin 1 yr Preoperative rad – not beneficial Preoperative rad – not beneficial

(van der Werf-Messing 1973)(van der Werf-Messing 1973) Residual tumor, rad may retard Residual tumor, rad may retard

growth (Kao et al 1994)growth (Kao et al 1994)

Local Recurrence after RN or NSSLocal Recurrence after RN or NSS LR in RN – 2-4%LR in RN – 2-4% Risk factors – T stage, local adv, Risk factors – T stage, local adv,

node + diseasenode + disease

LR in NSS – 1.4-10%LR in NSS – 1.4-10% Risk factors – T stageRisk factors – T stage Most LR occur distant to tumor bedMost LR occur distant to tumor bed

*pts with isolated recurrence after PN can ? *pts with isolated recurrence after PN can ? Repeat PNRepeat PN

Adjuvant Therapy for RCCAdjuvant Therapy for RCC Include hormonal manipulation, Include hormonal manipulation,

radiotherapy, vaccines, cytokines, radiotherapy, vaccines, cytokines, etc…etc…

Most studies to date – not Most studies to date – not significantsignificant

Vaccine – irradiated tumor Vaccine – irradiated tumor cells/BCG, heat shock proteins cells/BCG, heat shock proteins (HSPPC) = no proven benefit(HSPPC) = no proven benefit

Interferon alfa – modest survival Interferon alfa – modest survival benefitbenefit

IL-2 – no benefitIL-2 – no benefit

Tx of Metastatic RCCTx of Metastatic RCC

NephrectomyNephrectomy Hormonal therapyHormonal therapy ChemotherapyChemotherapy Radiation therapyRadiation therapy Cytokines and Immunologic Cytokines and Immunologic

therapytherapy Multimodal therapyMultimodal therapy

NephrectomyNephrectomy 1/31/3rdrd of RCC have mets of RCC have mets 40-50% will develop mets after 40-50% will develop mets after

initial dxinitial dx Regression of mets after RN – 1-2% Regression of mets after RN – 1-2%

(lung)(lung) Benefit for synchronous mets with Benefit for synchronous mets with

interferon alfa after RNinterferon alfa after RN Individuals with: adv dz (PS > 2), mets Individuals with: adv dz (PS > 2), mets

(CNS, SC compression), MOD, (CNS, SC compression), MOD, significant comorbidities – not significant comorbidities – not candidatecandidate

Hormone TherapyHormone Therapy Minimal valueMinimal value

Progesterone – inhibit growth of Progesterone – inhibit growth of DES-induced renal tumors in Syrian DES-induced renal tumors in Syrian hamstershamsters No correlation with human RCCNo correlation with human RCC

Progestational agents = useful Progestational agents = useful for symptom palliationfor symptom palliation

ChemotherapyChemotherapy 1980s – chemo-resistant tumor1980s – chemo-resistant tumor Variety of agents RR 6% Variety of agents RR 6%

Yagoda and assoc 1995Yagoda and assoc 1995 In past, fluoropyrimidines & vinblastine – In past, fluoropyrimidines & vinblastine –

RR 2.5% (better with Vin and I-alfa)RR 2.5% (better with Vin and I-alfa) Uniformly discouragingUniformly discouraging

MDR-1 (P-glycoprotein) = efflux pump MDR-1 (P-glycoprotein) = efflux pump reducing intracellular [] of agentsreducing intracellular [] of agents ? Role of Ca channel blockers, ? Role of Ca channel blockers,

cyclosporinecyclosporine Metastatic Non-clear cell or sarcomatoid diff – (doxorubicin & Metastatic Non-clear cell or sarcomatoid diff – (doxorubicin &

gemcitabine) RR 39%gemcitabine) RR 39% Anecdotal responses with collecting duct cancers with cisplatin Anecdotal responses with collecting duct cancers with cisplatin

& gemcitabine& gemcitabine

Radiation TherapyRadiation Therapy Considered as the primary Considered as the primary

therapy for palliation therapy for palliation Dose of 4500 centigray (cGy) is Dose of 4500 centigray (cGy) is

delivered, with consideration of a delivered, with consideration of a boost up to 5500 cGy boost up to 5500 cGy

Preoperative radiation therapy Preoperative radiation therapy yields no survival advantage yields no survival advantage

Palliative radiation therapy often Palliative radiation therapy often is used for local or symptomatic is used for local or symptomatic metastatic disease metastatic disease

Cytokines and Immunologic TherapyCytokines and Immunologic Therapy Interferon alfa – protein with antiviral, Interferon alfa – protein with antiviral,

immunomodulatory and immunomodulatory and antiproliferative activity antiproliferative activity

IL-2 – stimulates cell mediated IL-2 – stimulates cell mediated immunity (cytotoxic T cells)immunity (cytotoxic T cells)

Single agent ORR – 13-15%Single agent ORR – 13-15% Combination > 20%, no change OSCombination > 20%, no change OS Most effective regimen for IL-2 = Most effective regimen for IL-2 =

high dosehigh dose SE – vascular leak (HypoTN, oliguria, SE – vascular leak (HypoTN, oliguria,

organ failure = tx IVF)organ failure = tx IVF) *Improved OS with combo (vin, 5-FU, IL-2)*Improved OS with combo (vin, 5-FU, IL-2)

TreatmentTreatment

Multi-kinase inhibitors (VEGF and PDGF)Multi-kinase inhibitors (VEGF and PDGF) Sorafenib (Nexavar) – OS 3 monthsSorafenib (Nexavar) – OS 3 months

Dec 2005 FDA - 769 patients randomized Dec 2005 FDA - 769 patients randomized median PFS was 6 mo sorafenib vs. 3 mo placebomedian PFS was 6 mo sorafenib vs. 3 mo placebo 7 (2%) sorafenib patients and 0 (0%) placebo 7 (2%) sorafenib patients and 0 (0%) placebo

patients had confirmed partial responses. patients had confirmed partial responses. Sunitinib (Sutent) Sunitinib (Sutent)

FDA in January 2006 FDA in January 2006 (40% partial responses) and a median time to (40% partial responses) and a median time to

progression of 8.7 months and an overall survival progression of 8.7 months and an overall survival of 16.4 monthsof 16.4 months

Bevacizumab (IgG1 monoclonal abBevacizumab (IgG1 monoclonal ab Time to progression 4.8 mo vs placebo 2.5 moTime to progression 4.8 mo vs placebo 2.5 mo Combo with erlotinib – ORR 26% with PFS 11 moCombo with erlotinib – ORR 26% with PFS 11 mo

Multimodal TherapyMultimodal Therapy Synchronous mets = RN then Synchronous mets = RN then

systemic therapy (IL-2, I-a, kinase systemic therapy (IL-2, I-a, kinase inhibitors)inhibitors)

Most = RN firstMost = RN first Alternative – delayed RN and only Alternative – delayed RN and only

patients showing regression or patients showing regression or stability of mets get surgerystability of mets get surgery

Solitary mets = metatectomy Solitary mets = metatectomy (pulm have more favorable (pulm have more favorable prognosis, > 12mo)prognosis, > 12mo)

Other Malignant Renal Other Malignant Renal TumorsTumors

Sarcomas of the kidneySarcomas of the kidney Renal lymphoma and leukemiaRenal lymphoma and leukemia Metastatic tumorsMetastatic tumors Other malignant tumors of the Other malignant tumors of the

kidneykidney

Sarcomas of the kidneySarcomas of the kidney 1-2% of adult malignant tumors1-2% of adult malignant tumors 55thth decade decade Rapid growth +/- lymphadenopathyRapid growth +/- lymphadenopathy Derived mesenchymal components Derived mesenchymal components

(free of barriers)(free of barriers) PseudocapsulePseudocapsule Tx RN with enblocTx RN with enbloc Chemo (doxycycline and ifosfamide) Chemo (doxycycline and ifosfamide)

have shown some activityhave shown some activity Combo rad / chemo – not well Combo rad / chemo – not well

defined for renal defined for renal

Leiomyosarcoma – most commonLeiomyosarcoma – most common 50-60%50-60% Origin – smooth muscleOrigin – smooth muscle Female / 4Female / 4thth to 6 to 6thth decade decade

Liposarcoma – confused with AMLLiposarcoma – confused with AML +/- response to rad/cisplatin+/- response to rad/cisplatin Osteogenic sarcoma –Calcium Osteogenic sarcoma –Calcium

/rock hard/rock hard*Less common – rhadomyosarcoma, *Less common – rhadomyosarcoma,

fibrosarcoma, carcinosarcoma, fibrosarcoma, carcinosarcoma, angiosarcoma, malignant angiosarcoma, malignant hemangiopericytoma (very vascular)hemangiopericytoma (very vascular)

Renal Lymphoma and LeukemiaRenal Lymphoma and Leukemia Found in autopsy of 34% pts with Found in autopsy of 34% pts with

L or LL or L Renal involvement more common Renal involvement more common

with Non-Hodginswith Non-Hodgins B symptoms – fever, wt loss, fatigueB symptoms – fever, wt loss, fatigue

Heme dissem – 90%Heme dissem – 90% Suspect with mass RPLA, Suspect with mass RPLA,

splenomegaly, LA elsewheresplenomegaly, LA elsewhere Renal leukemia more common in Renal leukemia more common in

children (ALL > AML)children (ALL > AML) Perc bx, chemo +/- rad (CHOP)Perc bx, chemo +/- rad (CHOP)

Metastatic tumorsMetastatic tumors Most common malignant tumor Most common malignant tumor

of the kidneyof the kidney Sources – lung, breast, GI, Sources – lung, breast, GI,

malignant melanomamalignant melanoma Suspect with – multiple renal Suspect with – multiple renal

lesions and widespread mets or a lesions and widespread mets or a h/o nonrenal primary ca = Bxh/o nonrenal primary ca = Bx

Other Malignant Tumors of the KidneyOther Malignant Tumors of the Kidney Carcinoid (neuroedocrine cells) – rareCarcinoid (neuroedocrine cells) – rare

Correlation with horseshoe kidneyCorrelation with horseshoe kidney Check urine or plasma serotonin Check urine or plasma serotonin Minority – carcinoid syndrome (episodic Minority – carcinoid syndrome (episodic

flushing, wheezing, diarrhea)flushing, wheezing, diarrhea) Surgical exision is mainstay of txSurgical exision is mainstay of tx

NSS preferredNSS preferred Colon/EGD r/o multifocalColon/EGD r/o multifocal

Wilm’sWilm’s 3% seen in adults3% seen in adults TriphasicTriphasic Staging and tx same as for childrenStaging and tx same as for children Multimodal therapy (surg, chemo, Multimodal therapy (surg, chemo,

+/- rad)+/- rad) Prognosis worse in adultsPrognosis worse in adults

PNET (primitive neuroectodermal PNET (primitive neuroectodermal tumor)tumor)

Related to Ewing’s sarcomaRelated to Ewing’s sarcoma Derived from neural crest cellsDerived from neural crest cells Hist – small round cells (Homer Hist – small round cells (Homer

Wright rosettes)Wright rosettes) Difficult to differentiate from RCCDifficult to differentiate from RCC Multimodal tx (RN or debulk, Multimodal tx (RN or debulk,

chemo, rad)chemo, rad)

Small cell carcinomaSmall cell carcinoma Locally advanced or metastatic Locally advanced or metastatic

at presentationat presentation Multimodal tx (RN or debulk with Multimodal tx (RN or debulk with

platinum based chemo)platinum based chemo)

Paraneoplastic Paraneoplastic SyndromesSyndromes

Up to 30% of RCC patientsUp to 30% of RCC patients Reversible with tumor resectionReversible with tumor resection If persist after resection, r/o metsIf persist after resection, r/o mets SyndromesSyndromes

Elevated ESRElevated ESR Wt loss, cachexiaWt loss, cachexia Fever Fever AnemiaAnemia HTN (increased renin)HTN (increased renin) Hypercalcemia (PTH like substanceHypercalcemia (PTH like substance Stauffer’s syndromeStauffer’s syndrome Elevated Alk phosElevated Alk phos Polycythemia (incr erythropoietin)Polycythemia (incr erythropoietin)

Management of Para-neoplastic Management of Para-neoplastic ProblemsProblems

HypercalcemiaHypercalcemia Pamidronate or zolendronate Pamidronate or zolendronate

These may also alter the bone These may also alter the bone microenvironment in a way that microenvironment in a way that interrupts tumor growthinterrupts tumor growth

Inhibits osteoclastic activityInhibits osteoclastic activity Hydration Hydration DiureticsDiuretics SteroidsSteroids CalcitoninCalcitonin

Resolve with nephrectomyResolve with nephrectomy

Palliative / supportive carePalliative / supportive care Pain, bleedingPain, bleeding

Analgesic medicationsAnalgesic medications XRT to sites of painful mets (esp bone mets)XRT to sites of painful mets (esp bone mets) XRT for cord compressionXRT for cord compression Arterial embolizationArterial embolization

No survival benefit but can relieve SxNo survival benefit but can relieve Sx

““Clot colic”Clot colic” Ureteral stentsUreteral stents hydrationhydration

ReferencesReferences Wein, Alan J.; et al; Wein, Alan J.; et al; Campbell-Walsh Campbell-Walsh

UrologyUrology, Saunders publishing, 9, Saunders publishing, 9thth edition, edition, chapter 47, pages 1608-37.chapter 47, pages 1608-37.

Hanno, Philip M.; et al; Hanno, Philip M.; et al; Clinical Manual of Clinical Manual of UrologyUrology, McGraw-Hill Publishing, 3, McGraw-Hill Publishing, 3rdrd edition, pages 487-502. edition, pages 487-502.

Wieder, Jeff A.; Wieder, Jeff A.; Pocket Guide To UrologyPocket Guide To Urology, , Griffith Publishing, 3Griffith Publishing, 3rdrd edition, pages 1-20. edition, pages 1-20.

QuestionsQuestions