Renal Cell Carcinoma

Overview

Renal malignancy arising from the renal parenchyma / cortex

Accounts for > 80% of all renal malignanciesSixth to eighth most common malignancy in

malesOften asymptomatic and diagnosed

incidentallyIn early/local disease Sx can be curative >90%

Etiology

SmokingObesityHypertensionRenal transplantationLong term dialysisPositive family historyExposure to asbestos,cadmium and solvents

Familial forms

Von Hippel Lindau disease

• AD• 1 per 36000• RCC,Pheochromocytoma,Retinal

angiomas,Hemagioblastomas of CNS• VHL gene (chromosome 3p25-26)

Hereditary Papillary RCC

• AD

• Multiple bilateral renal tumors

• C-met oncogen on ch 7

Hereditary Leiomyomatosis

• AD• Cutaneous and uterine leiomyomas +type 2

RCC• Fumarate hydratase (chromosome 1q42-43)

• Brit-Hogg-Dube• AD• Cutaneous fibrofolliculomas,lung

cysts,spontaneous pneumothoraces and RCC• Mutations in BHD 1 gene on ch 17p11.2

Pathology

Adenocarcinomas derived from tubular epithelial cells

Most are round and ovoid with a pseudo capsule

Predilection for venous envolvementUnilateral and unifocal

Histologic classification

Conventional

Chromophilic

Chromobhobic

Collecting duct

Unclassified

Conventional(70-80)%

• Proximal tubule• Clear,granular,mixed• Deletions of chromosome 3p,mutation of VHL

gene• Hypervascular and aggressive • May respond to immunotherapy

Chromophillic (10-15 %)

• Proximal tubule• Type 1 seen in HPRCC• Type 2 seen in HLRCC• Trisomy of 7 and 17 and loss of chromosome Y• Multicentricity is common

Chromophobic (3 %-5 %)

• Arises from intercalated cells of collecting duct• Classic and eosinophilic varients• Commonly seen in Brit-Hogg –Dube syndrome• Better prognosis

Collecting duct < 1 %

• From collecting duct• Infiltrative• Renal medullary carcinoma is a varient • Deletions in chromosome 1q and monosomyof

6,8,11,18,21• Poor prognosis• May respond to chemotherapy

Unclassified (1%)

• Poorly defined• Poor prognosis

Clinical presentation

>50 % are detected incidentallyHematuria 40%Classic triad of hematuria,palpable abdominal

mass and flank pain occurs in 9%45% present with localised disease,25% with locally advanced 30% with metastatic disease

Paraneoplastic syndromes

Anemia 29-88%Hepatic dysfunction 21%Hypercalcemia 15 %Cachexia and fever 20%Polycythemia 3.5%Amyloidosis 2%Elevated ESR 55%

Diagnosis

Laboratory findings : Non specificUltrasonography : Solid vs cystic lesionsCECT : Test of choice to evaluate tummor

size,location ,lymph node involvementMRI: To evaluate collecting system and IVC

involvement

TNM ClassificationTx Primary tumor cannot be assessedT0 No evidence of primary tumorT1 7 cm or less limited to the kidneyT1a < 4cm limited to the kidneyT1b 4 – 7 cm limited to the kidneyT2 >7cm limited to the kidneyT3 Extends into major veins or invades adre nal glands or perinephric tissues but not beyond Gerota’s fasciaT3a Tumor invades adrenal gland or perinephric tissues but not beyond Gerota’s fasciaT3b Extends into renal vein or venecavaT3c Extends into venecava above diaphragmT4 Extends beyond Gerota’s fascia

N Regional lymph nodesNx Cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single regional node 2cm <N2 Metastasis in > than a single regional nodeM Distant metastasesMx Cannot be assessedM0 No distant metastasisM1 Distant metastasis

Staging

Stage 1 T1 N0 M0Stage2 T2 N0 M0Stage3 T1-T2 N1 M0 Any T3 N0 M0Stage 4 T4 N0-N1 M0 Any T N2 M0 Any T Any N M1

Localized RCC Treatment

Surgery is the only curative therapy for stage 1-3

Radical nephrectomy is gold standeredPartial nephrectomy in selected patientsNo role for adjuvant therapy except under

investigational protocol20- 30 % relapse within 2-3 years

Advanced RCC Treatment

Primary treatments are systemic therapy with immunotherapy or molecularly targeted therapy.

Cytoreductive nephrectomy before systemic therapy can be considered in carefully selected patients.

Targeted therapy

Based on advances in the understanding of the molecular biology of RCC

• Highly vascularized tumor with increased VEGF and PDGFR expression

• Tumor growth mediated via VEGF pathway and mammalian target of rapamyin(mTOR) pathway

VEGF Pathway

Tyrosine kinase inhibitors block the intracellular domain of the VGEF receptor

• Sunitinib • Sorafenib

Monoclonal antibody that binds circulating VEGF preventing the activation of the VEGF receptor

• Bevacizumab

mTOR Pathways

Temsirolimus is a rapamycin analog that inhibits the mTOR kinase

Used alone or with Interferon a

Immunotherapy

Imunnotherapy with IL 2 activates immune response against RCC resulting in tumor remision 10 – 20%

Used for patients that can tolerate side effects

Severe toxicity including hypotension,MI,renal insuffency ,pulmonary edema, hepatic and CNS dysfunction

Prognosis

5 year survival for stage 1 and 2 disease is 80-100 %

Stage 3 disease 50-60%

Metastatic disease 16-30 %