RENAL CELL CARCINOMA CLINICAL PROGRESS AND CURRENT MANAGEMENT

1. RENAL CELL CARCINOMACLINICAL PROGRESS AND CURRENT MANAGEMENT DR KALYAN K SARKAR MS FRCSEd

2. 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

3. 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

4. PREVALENCE IN INDIA cases prev1yr prev5yr mort M 4738 2685 9783 3425 F 2129 1247 4685 1459

5. 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

6. 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

7. 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 10-15% of renal lesions • Sporadic and hereditary forms • Associated with alterations in chromosomes 7, 17, and Y • Generally better survival

8. 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

9. 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 35-50 with a 4:1 female ratio • Tuberous Sclerosis patients demonstrate multiple and bilateral lesions. 80% of patients will develop AML. • Tumours <4 cm are observed, those >4cm undergo selective angioembolization or partial nephrectomy

10. 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

11. GRADING • Fuhrman grading system • Grade is an important variable • Fuhrman system has issues with interobserver variability

12. 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

14. PROGNOSIS RECURRENCE PULMONARY, HEPATIC OR BONE FEW ARE LOCAL MSKCC NOMOGRAM PARTIAL NEPH IN TUMOURS < 4 CM HAS SURVIVAL OF 100% AT 5 YRS

15. 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

16. 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

17. 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

18. 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.

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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.

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

27. 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.

30. 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 %.

31. 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

32. 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.

34. 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.

35. 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.

36. 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

37. 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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