RENAL CELL CARCINOMA CLINICAL PROGRESS AND CURRENT MANAGEMENT DR KALYAN K SARKAR MS FRCSEd

RCC : SURGICAL OR MEDICAL DISEASE ? Early initial diagnosis and advent of laparoscopic surgery has provided different treatment options. Molecular pathology of these lesions is better understood Advanced lesions remain difficult to treat by conventional cytoreductive surgery or biological response modifier therapy

INCIDENCE Incidence –There are approximately 30,000 new cases per year and 12,000 cancer related deaths –Incidence is rising 6.1 to 9.3 per 100,000 over 20 years –Mortality rate has not decreased even with greater detection of small tumors Lead time bias Short follow up Less aggressive? –25% of tumors present with advanced disease

PREVALENCE IN INDIA casesprev1yrprev5yrmort M F

EPIDEMIOLOGY Equal racial distribution 2:1 male to female distribution Occurs in 5th to 7th decade of life Tobacco greatest risk factor Obesity may be a risk factor Most cases sporadic, yet also occurs with Von Hippel-Lindau disease (VHL) [45%], and less commonly with tuberous sclerosis, and in rare familial distributions

PATHOLOGY RENAL CELL CARCINOMA –Clear cell renal cell carcinoma –Papillary renal cell carcinoma –Oncocytoma –Chromophobe renal cell carcinoma –Collecting duct renal cell carcinoma Other parenchymal renal tumours

PATHOLOGY Clear cell carcinoma: comprises >70% of renal lesions –VHL gene mutation principAL event. Recent association between VHL protein and hypoxia inducing factor [HIF] protein ties pathology into angiogenesis cascade pathway. Papillary renal cell carcinoma: comprises % of renal lesions –Sporadic and hereditary forms –Associated with alterations in chromosomes 7, 17, and Y –Generally better survival

PATHOLOGY Chromophobe tumors: 5 % of cases –Loss on chromosome 1 Collecting duct carcinoma: one percent or less of cases –Can mimic transitional cell Ca –Generally poor outcome Oncocytoma: 5 % of renal tumors –Generally localized and encapsulated. 5% bilaterality –Mahogany brown color, acidophilic cells secondary to dense mitochondrial hyperplasia –Distinction from renal cell cancer difficult on imaging or needle biopsy. Best treated with surgical removal

PATHOLOGY Angiomyolipoma: Renal Hamartomas comprised of fat, muscle and blood vessels. Tissue signature on CT by demonstration of negative Hounsfield units. –Sporadic, isolated lesions present age with a 4:1 female ratio –Tuberous Sclerosis patients demonstrate multiple and bilateral lesions. 80% of patients will develop AML. –Tumours 4cm undergo selective angioembolization or partial nephrectomy

PATHOLOGY Renal Sarcoma –Pure sarcoma is rare and usually lieomyosarcoma –All tumor types can degenerate towards sarcoma –Generally poorer outcome Rare Renal lesions –Adult Wilms tumor –Lymphoma –Xanthogranulomatous Pyelonephritis [XPG] –Haemangiopericytoma

GRADING Fuhrman grading system –Grade is an important variable –Fuhrman system has issues with interobserver variability

STAGING UICC-AJCC system is generally accepted –Currently T1 lesion is 7 cm or less in size, yet 4.0 cm associated with very low recurrence rate –T1a category of <4.0 cm suggested

PROGNOSIS STAGE 5 YR 10 YR I90%80% II80%70% III50%35% IV10%3% RECURRENCE PULMONARY, HEPATIC OR BONE FEW ARE LOCAL MSKCC NOMOGRAM PARTIAL NEPH IN TUMOURS < 4 CM HAS SURVIVAL OF 100% AT 5 YRS

FOLLOW-UP –Traditionally, most patients with sporadic RCC are followed every 6 months or yearly with a history and physical examination (H&P), liver function studies, serum chemistry (including alkaline phosphatase), CXR, and abdominal cross-sectional imaging. T1: H&P, serum chemistry, and CXR yearly for 5 years T2: H&P, serum chemistry, and CXR every 6 months; abdominal CT scan at 2 and 5 years for 5 years T3: H&P, serum chemistry, and CXR at 3 months, then every 6 months; abdominal CT scan at 2 and 5 years

CLINICAL PRESENTATION A QUARTER PRESENT WITH ADVANCED DISEASE, LOCALLY ADVANCED OR METASTATIC A THIRD OF PATIENTS POST SURGERY FOR LOCALISED DISEASE WILL RELAPSE WITH METASTATIC DISEASE THE MEDIAN SURVIVAL IS 13 MONTHS

CLINICAL PRESENTATION THE CLASSIC TRIAD <10 % INCIDENTAL DETECTION ALMOST 50% SYSTEMIC SYNDROMES –ANAEMIA, FATIGUE, CACHEXIA, WEIGHT LOSS, HYPERCALCEMIA, HEPATIC DYSFUNCTION RARE SYNDROMES –ERYTHROCYTOSIS, ENtEROPATHY, NEUROPATHY, AMYLOIDOSIS

Imaging Increased use of imaging has increased the detection of renal lesions most of which are simple cysts. Also a greater percentage of small renal lesions have been noted which has changed the therapeutic strategy towards renal lesions. CT and MRI findings are fairly classical for renal tumors. Initial diagnosis with IV urography or ultrasound may require further confirmatory testing.

Imaging Ultrasonagraphy –Excellent in distinguishing cystic from solid masses. –30-50% of patients >50 years will have renal cysts –Bosniak classification provides guidelines. I [Simple cyst] 0% cancer risk II [Minimally complicated] 2-10% cancer risk III [Indeterminate cyst] up to 50% cancer risk IV [Cystic renal cell] up to 90% cancer risk

Imaging Intravenous Urography –Starting point for hematuria evaluations –Abnormal findings require other imaging for conformation –Calcification pattern suggestive Speckled or mottled, 90% cancer Rim calcification 10-20% cancer

Imaging Computed tomography –Provides an excellent assessment of the parenchyma and nodal status. Thin slice images provide superior definition of smaller lesions. Good assessment of nodal status is provided. Tissue signature of fat allows diagnosis of AML. 3-D reconstruction now available

Imaging Magnetic Resonance Imaging –Non ionizing radiation modality provides excellent demonstration of solid renal masses and is image test of choice to demonstrate extent of vena caval involvement with tumor. Useful in patients with renal insufficiency

Imaging Angiography –Generally supplanted by MRI angiography –Used for embolization of large lesions preoperatively Radionuclide Imaging –Most useful in detecting pseudo-masses –Tumors and cysts are photo-deficient areas Percutaneous biopsy –Generally not useful due to the high [30-50 percent] false positive rate –Some value in ruling out metastatic disease or lymphoma

CLINICAL STAGING Chest X-ray or Chest CT CT/MRI scan of abdomen or pelvis Bone scan with plan films (for elevated alkaline phosphatase or bone pain). Laboratory: CBC, LFT's, alkaline phosphotase, BUN, creatinine.

SURGICAL TREATMENT OPTIONS IN RCC CLASSICAL RADICAL NEPHRECTOMY OPEN PARTIAL NEPHRECTOMY LAPAROSCOPIC PARTIAL NEPHRECTOMY ENERGY APPLICATIONS PERCUTANEOUS, EXTRACORPOREAL, LAPAROSCOPIC EXPECTANT TREATMENT

TREATMENT Classic Radical Nephrectomy –Gold standard of comparison. Performed through several different flank or subcostal approaches. Well tolerated. –Minimal role for aggressive lymphadenectomy. Nodes generally removed from ipsilateral great vessel. –Adrenalectomy not required if preoperative imaging is normal or if the renal tumor is in the mid or lower pole of the kidney.

TREATMENT Inferior vena cava extension –Sub classification based on cranial extent of lesion figure 1 –Patient prognoses based on stage of lesion and not extent of thrombus –Complexity of surgery ranges from partial clamping of the vena cava to cardiopulmonary bypass with hypothermia and circulatory arrest. Mortality 2-14 %.

TREATMENT Expectant management –Small lesions [<3.0 cm] have a minimal risk of metastasis and increase in size approximately 6 mm per year. In elderly and very ill patients minimal intervention may be warranted

TREATMENT Percutaneous or laparoscopic ablation –CT guided radiofrequency ablation - potential minimally invasive therapy requiring further follow-up –Laparoscopic cryosurgical ablation - less invasive ablation technique will require further follow-up –These and similar technologies promising and suited to the higher incidence of smaller lesions detected incidentally.

TREATMENT Nephron-sparing surgery –Local recurrence rate 1-2% –15% of small lesions may not be renal cell Ca –Preservation of renal function is laudable –Indicated in small lesions [<4cm], patients with poor renal function, bilateral disease, and solitary kidney –Renal cooling and intraoperative ultrasound required in more difficult cases. –Open vs. laparoscopic approach based on tumor location, size, and operator experience.

TREATMENT Laparoscopic nephrectomy –Pure laparoscopic and "hand-assisted" techniques available. Hand- assisted approach has promulgated the technique, feasible for most tumors <8-10 cm depending on location. –Operative time longer, hospital stay and pain requirement less, time to normal function shorter than flank incision. –Learning curve associated with this approach.

TREATMENT Metastatic disease - Surgery –Outcome with metastatic disease depends on performance status –Low volume metastasis, especially pulmonary involvement tend to respond best. –Recent data to suggest a slight but statistically significant survival benefit if nephrectomy performed in conjunction with immunotherapy. Patients with significant disease burden and poor performance status less likely to benefit

TREATMENT Metastatic disease - Medical therapy –Few cytoreductive agents have any significant impact on renal cell carcinoma –Radiation therapy has little proven effect on renal cell carcinoma –Cytokine therapy [IL-2] demonstrates a complete response in 4% of patients and a partial response in 12-20% of patients –Antiangiogenesis agents have theoretical promise for this disease

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