Understanding Renal Cell Carcinoma (RCC): General Approach & Management

1. Understanding Renal Cell Carcinoma (RCC): General Approach & Management - SIR RFS IO Service Line - Created By: Sam McMurry D.O. Date: 10/21/13

2. Renal Cell Carcinoma: Objectives • Epidemiology • Etiology/Risk Factors • Pathophysiology • Related Anatomy • Signs & Symptoms • Work-Up/Diagnosis • Prognosis Morbidity & Mortality • Pre-therapy management • Role of VIR • Terminology • Other Treatments • Troubleshooting • Post-procedure management and follow-up • Key Points Summary

3. RCC Epidemiology • Hypernephromaor Grawitz's tumor • 90% of all renal malignancies • ~338,000 new cases worldwide in 2012 • Cancer research UK • In the US, incidence has risen consistently over time • Increased cross sectional imaging and incidental detection • >1/2 of all RCCs diagnosed incidentally • ~65,000 new cases in US ; ~14,000 deaths from RCC each year

4. Etiology/Risk Factors for RCC • Cigarette smoking • Thought to be due to chronic tissue hypoxia by CO • May be associated with deletions in chromosome 3p • Seen in peripheral blood lymphocytes treated after benzo[α]pyrenediolepoxide treatment which is a major constituent of cigarette smoke

5. Etiology/Risk Factors for RCC • Obesity • may account for over 40% of RCC in the US • increase 24% for men and 34% for women for every 5 kg/m2 increase in body mass index (BMI)

6. Etiology/Risk Factors for RCC • Hypertension • may result from chronic hypoxia and lipid peroxidation leading to reactive oxygen species formation • Chronic Hepatitis C

7. Etiology/Risk Factors for RCC • End-stage renal disease while undergoing long-term hemodialysis and after renal transplantation • Acquired renal cystic disease • Familial cancer syndromes, • Von Hippel-Lindau (VHL) syndrome, hereditary papillary renal carcinoma, hereditary leiomyomatosis renal cell carcinoma, Birt-Hogg-Dube, tuberous sclerosis • Occupational Exposure • cadmium, asbestos, and petroleum by-products

8. Pathophysiology of RCC Gross appearance • Appear encapsulated • Can be solid, cystic, or mixed, • May contain fat and/or calcifications • 10% of tumors have some cystic component • may be more aggressive

9. Pathophysiology of RCC Distinct Histologic subtypes of RCC • Clear cell (75 to 85 percent of tumors) • arise from proximal tubule • associated with VHL • poor prognosis when higher grade or sarcomatoid variant • more favorable prognosis when multilocularvariant of cystic clear cell RCC • Papillary (chromophilic) (10 to 15 percent) • can be multifocal and bilateral • originate from proximal tubule • Chromophobe(5 to 10 percent) • lack abundant lipid and glycogen seen in most RCCs • originate from intercalated cells of collecting system • have lower risk of disease progression & death compared to clear cell carcinomas

10. Pathophysiology of RCC Distinct Histologic subtypes of RCC • Oncocytic(3 to 7 percent) • usually unilateral; single • multiple and bilateral : tuberous sclerosis & Birt-Hogg-Dube syndrome • generally well encapsulated and rarely invasive or associated with metastases • Collecting duct (Bellini's duct) (very rare) • younger patients • frequently aggressive • commonly gross hematuria • sarcomatoidvariants noted • medullary carcinoma: highly aggressive variant associated with the sickle cell trait; develops in young patients

12. Anatomy of Renal Cell Carcinoma

13. Signs & Symptoms of RCC • Many patients asymptomatic until disease advanced • at presentation, ~25 % have either have distant metastases or advanced locoregionaldisease • Most cases diagnosed incidentally via imaging • study preformed in 1971 of 309 patients showed the most common presenting symptoms were hematuria, abdominal mass, pain, and weight loss • No longer the case due to imaging • Only present in ≤ 10% of cases • When present strongly suggests locally advanced disease

14. Signs & Symptoms of RCC • Hematuria • observed only with tumor invasion of the collecting system • abdominal or flank mass • associated with lower pole tumors • Scrotal varicoceles • majority are left-sided • 11 percent of men • Symptoms related to IVC involvement • lower extremity edema • ascites • hepatic dysfunction (may be related to a Budd-Chiarisyndrome) • pulmonary emboli

15. Signs & Symptoms of RCC “The internist's tumor” • Paraneoplastic symptoms possible: • Hypertension (renin), Hypercalcemia(PTHrP), Polycythemia/erythrocytosis(erythropoietin), Cushing’s syndrome (ACTH) • Anemia ,Eosinophilia, Leukemoid reactions • Fever /wasting syndromes • Stauffer's syndrome (reversible hepatic dysfunction after primary tumor removal) Metastatic disease sxs: • Bone pain, Adenopathy,Pulmonarysymptoms, Upper GI bleed, Neurologic deficits

16. Work-up & Diagnosis Initial workup • Detailed H and P • CBC • Comprehensive metabolic panel • serum calcium, liver function, LAD, serum creatinine • Coagulation profile • UA

17. Work-up & Diagnosis • Anemia • 29 to 88 percent of patients with advanced disease • Hepatic dysfunction  • 21 percent have a paraneoplastic elevation in serum alkaline phosphatase • Hypercalcemia • up to 15 percent • Erythrocytosis • 1 to 5 percent • Thrombocytosis • rare • poor prognosis • Hematuria • up to 40 percent

18. Imaging and Diagnosis

19. Imaging and Diagnosis • IVU: low sensitivity for detecting renal masses <2-3 cm in size • CT and IVU for microhematuria: • CT accuracy 98.3%; IVU accuracy 80.9%, with • CT sensitivity: 100%; IVU: 60.5% • US in radiation sensitive groups such as pregnant women and children • distinguish simple cysts from common complex masses that require follow up

20. Imaging and Diagnosis • CT urogram increasingly used for evaluation • Role of MRI • Delineating superior extent of tumor in IVC • nephrogenicsystemic fibrosis (NSF) risks in patients with significantly impaired renal function should be considered carefully

21. Imaging and Diagnosis • Detect & stage primary tumor • Chest CT if primary tumor is large or locally aggressive • i.e. RCC > 3cm • Brain MRI and bone scanning if there are symptoms and signs to suggest disease in these areas • Bone scanning may be limited in detecting bone metastases in RCC

22. Basic Imaging Findings of RCC

23. Basic Imaging Findings of RCC

24. Basic Imaging Findings of RCC

25. Basic Imaging Findings of RCC

26. Basic Imaging Findings of RCC

27. Percutaneous Biopsy • General indication • diagnosis of primary tumor • confirmation of suspected metastasis • staging • diagnose benign process • monitor treatment • Contraindication • uncorrected bleeding diathesis • inaccessible lesion • unwilling or uncooperative patient

28. Percutaneous Renal Biopsy • Established indication • renal mass and known extrarenal primary • mass & surgical comorbidity • mass that may have also been caused by infection • Emerging indications • small (less than or equal to 3 cm), hyper attenuating, homogenously enhancing mass • patients with mass considered for percutaneous ablation • indeterminate cystic renal mass

29. Percutaneous Renal Biopsy • Usually performed under US or CT guidance • usually outpatient and with conscious sedation • low risk of clinically significant bleeding or seeding of needle tract with malignant cells • sensitivity and specificity: 80-92 %and 83 -100 %, respectively • helpful in differentiating RCC from a metastasis • transjugular approach for patients at increased risk of bleeding

30. Percutaneous Renal Biopsy • posterior approach, 16-18 gauge needle in inferior pole to obtain a diagnostic 5-10 glomeruli • Complications • small AV fistulas and pseudoaneurysms • many resolve spontaneously • hematomas with dropping hematocrit and persistent gross hematuria uncommon • Angiographic evaluation and transcatheter embolization for bleeding that does not stop with conservative measures

31. Percutaneous Renal Biopsy

32. Staging and Prognosis of RCC • 2 systems: Robson’s and TNM

33. Staging and Prognosis of RCC

34. Staging, Prognosis and Surgical Planning • Low-grade, low-stage RCC, 4 cm or smaller, conservative nephron-sparing surgery recommended • either pNx or tumor enucleation • outcome comparable to radical nephrectomy • distinction between Stage I and Stage II is important • Stage II disease spread, either direct or hematogenous, to the ipsilateraladrenal gland

35. Staging, Prognosis and Surgical Planning • Venous extension in 20% of patients with RCC • IVC in 5–10%: requires midline incision • renal vein involvement: routine ligation to prevent embolization • 40%tumor thrombi intrahepatic • Tumor above the hepatic veins: Thoracic surgical approach required • 5–10% of tumors with caval involvement extend into right atrium • cardiopulmonary bypass necessary

36. Staging, Prognosis and Surgical Planning • Nephrectomy improves survival in metastatic disease only if involves one organ, particularly bone • patients with solitary metastases that can be excised may have a 5-year survival of 25–35% • In patients with multiple metastases, treatment usually palliative

37. Prognosis for RCC • Stage I/II — five-year survival rate over 90 percent • Stage III — five-year survival rate for patients who undergo nephrectomy : 59 to 70 percent. • Stage IV — The median survival is 16 to 20 months and the five-year survival rate is less than 10 percent for patients with distant metastases

38. Prognosis for RCC • Other Prognostic factors: • Tumor grade — Fuhrman's grade is the most widely used • five-year survival rate by tumor grade : • 89, 65, and 46 % for tumors of histologic grade 1, 2, and 3 to 4, respectively • CLINICAL FACTORS  • Negative prognostic signs include ; • poor performance status • the presence of symptoms and/or paraneoplastic syndromes • obesity

39. Management of RCC • Treatment depends on whether the disease is localized or advanced at initial presentation. • Localized disease • stage IA, IB, II, and III • surgical resection can be curative • Advanced disease • tumor invading beyond Gerota’s fascia or extending into the ipsilateral adrenal gland (T4) and metastatic disease (M1) • stage IV

40. Management of RCC • Localized • Surgery is curative in the majority without metastatic • preferred for stages I, II, and III disease • radical nephrectomy • renal-sparing approaches in select patients • partial nephrectomy or ablative techniques • resectableprimary tumor with a single metastasis • surgical resection of the metastasis with radical nephrectomy may be curative • elderly and those with significant comorbidity may not be surgical candidates • cryoablation, RFA • observation with periodic reevaluation • Adjuvant therapy : immunotherapy or molecularly targeted agents

41. Management of RCC • Advanced • the majority of patients with stage IV RCC have unresectabledisease • if tumor involves the ipsilateral adrenal gland, a radical nephrectomy is potentially curative • in general ,patients with metastatic RCC should receive medical therapy

42. Management of RCC • Advanced • medical therapy  in metastatic RCC; molecularly targeted and immunotherapy • First-line treatment • high-dose interleukin-2 (IL-2) • If not a candidatesforIL-2: molecularly targeted therapy is recommended • Second-line treatment • vascular endothelial growth factor (VEGF) inhibitor

43. Management of RCC • Advanced • Chemotherapy • no established role in advanced or metastatic RCC • Radiation Therapy • RCC typically described as a radioresistanttumor • can be useful to treat metastases • Painful bone metastases • Brain metastases • Painful recurrences in the renal bed

44. Role of IR in RCC • Procedures • radiofrequency (RFA), cryoablation, microwave ablation, high intensity, focused ultrasound • RFA and Cryoablation • acceptance based upon favorable outcomes including • low incidence of serious complications • less immediate morbidity and mortality than with surgery • lower cost • the ability to treat patients in the outpatient setting • multiple treatment sessions may be required • may not be appropriate for large lesions or tumors near the renal hilum.

45. Role of IR in RCC • RFA and Cryoablation • Factors that can lead to consideration of an ablative approach rather than surgery include: • T1 renal mass less than 7 cm who: • poor surgical candidate, based upon older age or significant comorbidity • the need for nephron-sparing treatment,/conservation of renal parenchyma as a way to postpone or avoid the need for chronic dialysis. • patients with a single kidney, bilateral RCCs, or a genetic predisposition to multiple tumors

46. Role of IR in RCC • RFA and Cryoablation • Factors that can lead to consideration of an ablative approach rather than surgery include: • multiple tumors in the same kidney where surgery would make renal reconstruction difficult • complex tumors where surgery would require an extended ischemic time • the patient prefers minimally invasive • cannot have an ET tube • local tumor recurrence after nephrectomy • intractable tumor-related hematuria • tumor debulking in metastatic disease • management of symptomatic distant metastases from a primary kidney tumor

47. Role of IR in RCC Procedure • RFA and Cryoablation • goals • kill all viable malignant cells including a 5 to 10 mm margin of surrounding tissue • minimize damage to adjacent normal kidney • performed percutaneously • usually outpatient • usually conscious sedation • some will prefer general anesthesia • local anesthesia is applied • applicator is percutaneouslyplaced into the center of the tumor using CT, ultrasound, or MRI guidance • heat or cold is then applied for approximately 10 to 20 minutes • patient is monitored for several hours post procedure • discharged home with oral analgesics for post-procedural pain • patients usually able to resume normal activity in 2-3 days

48. Role of IR in RCC Radiofrequency ablation (RFA) • utilizes a high-frequency (460 to 500 kHz) alternating current • delivered into the tumor through a thin needle (usually 21 to 14 gauge) • electrically insulated except for its terminal 1 to 3 cm • Produces resistive friction in the tissue which is converted into heat causing cellular destruction and protein denaturation • usually monopolar, utilizing grounding pads placed on the patient

49. Role of IR in RCC RFA

50. Role of IR in RCC Cryoablation • uses liquid nitrogen or argon introduced into a probe • resulting in freezing of the surrounding tissues, by formation of an "iceball" that can be visualizedby imaging • leads to the formation of intracellular ice crystals which disrupt the cell membrane and other intracellular activities, leading to cell death • cells not directly killed may undergo apoptosis • usually involves freezing, thawing, and refreezing, • complete cell death is thought to occur 3 mm inside the edge of the ice ball • most operators extend the ice ball at least 5 mm beyond the tumor margin